Clinical trial NCT02510014
Conditions: Opioid Use Disorder Opioid-related Disorders
Sponsor: Indivior Inc.
Start date: 2015-07-27; Completion date: 2017-01-31
Enrollment: 775 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
A multi-center, open-label, long-term safety study in which approximately 600 subjects diagnosed with opioid use disorder will be enrolled. Following a screening period, all subjects will receive run in SUBOXONE sublingual film followed by an initial injection of open-label high dose (300 mg) RBP-6000. The RBP-6000 monthly injection dose can be adjusted to low dose (100 mg), and back to high dose, based on the medical judgment of the Investigator. Subjects will participate in the study for either 6 or 12 months.

Detailed description:
Approximately 600 subjects diagnosed with opioid use disorder will be enrolled; approximately 300 subjects who completed the randomized,double-blind, placebo-controlled study NCT02357901 (RB-US-13-0001) ('roll-over' participants), and approximately 300 subjects who did not participate in study RB-US-13-0001 ('de novo' participants). Following informed consent and completion of screening procedures, all subjects will receive SUBOXONE sublingual film, titrated to response.

After 4-14 days of SUBOXONE sublingual film treatment, subjects will be evaluated for enrollment into the study. Eligible subjects will receive 300 mg RBP-6000 as an initial dose, followed by monthly injections of 100 mg or 300 mg RBP-6000, based on the medical judgment of the investigator.

Subjects who participated in study RB-US-13-0001 ('roll-over' participants) will receive monthly injections for up to 6 months. Subjects who did not participate in study RB-US-13-0001 ('de novo' participants) will receive monthly injections for up to12 months.

At all injection visits continuous electrocardiogram recordings and pulse oximetry will be collected prior to injection and at least 4 hours after injection. Subjects will return to the clinic every 1-4 weeks for laboratory tests, complete study questionnaires, adverse event and injection site assessments.

Arms: arm 1: Subjects who completed RB-US-13-0001 received SUBOXONE sublingual film during the Run-In period, followed by an initial open-label injection of 300 mg RBP-6000. Participants continued with monthly injections of either 300 mg or 100 mg (based on judgement of the Investigator) for a total of 6 months in the Treatment period. arm 2: Subjects who did not participate in RB-US-13-0001 received SUBOXONE sublingual film during the Run-In period, followed by an initial open-label injection of 300 mg RBP-6000. Participants continued with monthly injections of either 300 mg or 100 mg (based on judgement of the Investigator) for a total of 12 months in the Treatment period.
Interventions: intervention 1: SUBOXONE sublingual film intervention 2: RBP-6000
Intervention descriptions: intervention 1: SUBOXONE (buprenorphine sublingual film) is used for induction therapy on Days -14 to -12. Participants then complete a 4-to-11 day sublingual film dose adjustment at doses ranging from 8 mg to 24 mg sublingual film prior to starting the Treatment Period. intervention 2: Injections administered subcutaneously every 28 days on alternate sides of participant's abdomen starting at 300 mg. Subsequent doses of RBP-6000 could be adjusted down to 100 mg with the possibility of adjusting back up to 300 mg based on the medical judgment of the investigator. De novo subjects receive up to 12 injections and roll-over subjects receive up to 6 injections.

Protocol documents:
SAP_004.pdf: 
 
 
 
 
 
 
 
 
 
 
 
Study Title 
An Open-Label, Long-Term Safety and Tolerability Study of Depot 
Buprenorphine (RBP-6000) in Treatment-Seeking Subjects With 
Opioid Use Disorder 
NCT Number 
NCT02510014 
Date 
April 10, 2017 
 


                 
                             
 
     
          
                    
               
            
                                          
             
 
 
               
 
     
  
        
         
           
       
     
                   
   
                                 
                         
   
             
              
                  
         
 
     
         
    
           
               
          
 
     
        
    
        
       
            
        
   
 
    
   
                                
           
 
    
 
   
   
                    
           
 
    
 
   
                         
           
 
    
          
 
   
      
     
           
 
 
   
 
      
   
           
           
 
 


                 
                             
 
     
          
                    
               
            
                                          
             
              
         
   
              
   
            
   
                      
   
                
   
                 
   
                     
   
                  
   
              
   
                         
   
        
  
    
   
               
   
                             
   
                  
   
                     
   
                  
   
     
     
   
              
    
   
                  
    
                       
    
                  
    
                
    
                           
  
    
             
    
                          
    
                
    
                
    
             
    
   
                  
    
                                     
    
                
    
                  
             
    
                         
    
   
             
    
                             
            
    
    
          
                            
    
                 
                            
    
                              
    
                       
    
                            
    
                 
    
    
        
    
                      
    
                       
    
           
    
              
    


                 
                             
 
     
          
                    
               
            
                                          
             
                          
     
    
                                                                                
      
    
                                                                        
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


                 
                             
 
     
          
                    
               
            
                                          
             
    
    
   
                                                            
             
   
                                                       
                                
                            
       
           
                                                                                
                    
                                                                   
                       
                                                     
  
                               
                           
                        
      
                                
                    
                                                         
   
      
                         
                                             
      
    
   
  
                                  
    
             
              
                                   
                               
   
 
         
        
                                    
                
     
   
     
        
    
                                                      
                               
                                      
      
                             
                                
   
    
                                                                      
   
             
                     
              
            
    
   
                                    
         
                           
                        
 
           
     
           
      
                                                    
     
                                                                               
         
 
               
                                   
         
                           
           
    
  
                    
                        
                               
                
 
    
            
             
   
                          
   
                                                   
   
          
                                 


                 
                             
 
     
          
                    
               
            
                                          
             
      
         
                                               
       
           
                   
  
              
             
    
              
                                                    
         
                  
                                           
       
     
                 
    
                                                    
                              
    
                   
          
      
                            
                  
                                  
    
                                               
                           
     
                              
                                         
           
                            
                             
                  
   
                                                          
              
                                                                                    
    
                                       
                                 
 
                                                          
   
                   
 
           
         
         
                             
                            
                                                              
              
                                     
                     
             
                                          
                                      
                  
                                               
    
       
                            
      
          
  
                   
                     
           
                           
                                                                                 
                                                     
   
                  
       
          
                                          
              
        
                  
                                             
                         
                      
    
     
                 
     
          
        
  
       
                                                                   
  
                                                                            
     
                                             
                    
  
   
     
            
                          
               
             
      
                                   
               
              
   
         
             
                              
              
             
                     
       
                   
              
             
                     
      
                             
       
             
 
       
                                                      
              
 
                                       
      
                 
       
                                                             
           
    
          
                              
                     
      
                      
                                                      
                            
                     
              
    
                                       
   
                     
       
   
                 
 
 


                 
                             
 
     
          
                    
               
            
                                          
             
                  
                                 
                        
      
            
            
                
                       
     
                
   
                                 
           
      
                 
                                     
   
  
   
                      
                    
 
                                  
 
   
                          
   
 
                                       
                                             
     
                 
            
                                                     
      
  
                                                      
    
       
                      
  
                                                                              
      
                                                     
           
 
                                               
            
                
                               
    
               
                     
        
            
            
          
                           
                                
                                    
     
                                   
                                 
                                 
                                              
                 
                        
                                              
                        
       
                 
                
                                       
                                                         
                
   
                                                                             
                    
     
                                             
                         
                                              
  
            
   
    
              
                                                  
              
                            
                                                 
                  
             
                                                
                       
          
                 
     
                
 
                                                         
                    
             
                            
                                              
                               
                                             
                     
          
                 
     
             
          
                                                
                     
    
         
                                                                             
                        
                       
                                
            
     
               
                                                                       
       
   
              
               
 


                 
                             
 
     
          
                    
               
            
                                          
             
         
             
     
    
      
     
           
      
                                     
             
   
               
                        
  
   
                            
   
                  
   
     
                  
   
            
   
           
   
    
                  
   
            
             
   
                 
    
               
  
   
                         
   
       
   
                     
             
      
                    
      
                                    
   
             
   
             
   
                       
   
     
   
          
   
                                       
    
     
      
   
             
   
                                                       
 
   
                     
   
              
   
              
   
  
      
                
   
                       
   
   
                
      
   
       
                  
  
   
          
           


                 
                             
 
     
          
                    
               
            
                                          
             
    
 
     
  
     
                                                                               
          
    
                                          
       
   
                     
    
                           
           
                                     
                 
                                              
  
 
             
        
                                                                
      
                                             
 
           
                    
                                                                                 
      
           
           
                                  
  
       
                                        
                     
                  
                                                                        
         
                                       
                                
     
           
                                        
    
                 
 
              
        
    
            
                                    
                    
     
  
       
              
     
             
                                    
              
           
     
         
                
     
                                                                
      
     
                        
                                  
 
   
    
              
  
  
     
           
              
     
        
      
         
                                           
     
               
                        
          
           
       
         
                           
          
            
 
                           
                  
                                                    
    
               
                              
                    
        
    
                              
          
                               
                 
                                         
                     
                                                                            
                   
                             


                 
                             
 
     
          
                    
               
            
                                          
             
 
                  
                 
                              
        
    
                
  
      
        
                   
    
     
                 
       
       
                  
              
       
                                               
    
          
                    
                                                                                
                                                 
                            
   
                                                                          
                            
          
                                        
                
                                                                   
                       
                                                      
     
            
        
          
                                                                             
 
                                                                      
     
                        
                                          
             
        
                                   
                 
        
      
                         
      
                                  
              
                                               
  
                     
 
  
                                                                     
                
                                         
   
  
  
                                                
                    
            
                   
                                                                              
 
                                                                      
     
                   
        
    
   
       
      
   
           
   
           
                
       
                                                      
                                
       
                                   
               
          
          
             
             
                         
        
            
                                                    


                 
                             
 
     
          
                    
               
             
                                          
             
                
               
    
     
   
            
   
                                        
                 
                           
  
   
                                               
      
            
    
                                   
  
   
                                                   
      
           
                          
                   
   
                                     
                 
       
                  
   
      
 
    
   
 
          
   
 
   
 
   
  
          
          
          
          
       
          
       
          
          
       
       
       
 
                
                                         
                          
        
  
       
 
 
  
                    
     
  
     
  
      
      
                                   
          


                 
                             
 
     
          
                    
               
             
                                          
             
 
                   
                 
      
  
      
            
 
        
     
            
              
  
  
              
  
  
              
  
   
               
   
   
               
   
   
               
   
   
               
   
   
               
   
   
                
   
   
                
   
   
                
   
    
                 
    
    
                 
    
    
                 
    
    
                 
    
    
                 
    
    
                 
    
    
                 
    
    
                 
    
    
                 
    
    
 
        
                                           
                 
          
                                                                                 
     
                                                                   
      
       
                                               
                         
                   
                                                    
          
    
      
                        
      
          
                                       
                      
                
              
    
                
                                                             
 


                 
                             
 
     
          
                    
               
             
                                          
             
                       
                        
                                                     
   
      
   
                
    
             
                      
                                                 
           
           
                             
                           
                
                   
                                                                     
                                                           
     
                      
 
    
                                                           
                     
                 
                        
             
                        
           
                                                                 
                
      
                                          
                  
                                  
              
                 
                          
   
           
   
  
    
              
   
                                                                 
                                          
   
                
               
                       
                                                     
                                  
                                   
         
              
                   
                                              
                
  
                                        
                
                    
           
              
                                    
                   
          
       
                        
                                       
                                 
     
 
          
                
      
             
               
  
    
     
      
         
                                        
             
                          
             
                                   
       
                                                                              
   
     
        
                         


                 
                             
 
     
          
                    
               
             
                                          
             
          
      
         
                               
                     
  
            
          
                                                  
                                                                            
     
                             
                                               
 
     
      
    
                                       
                    
                      
                                                            
            
                                 
                               
 
   
      
  
      
  
                                    
                                          
   
    
                     
     
                     
                  
     
                                        
                           
         
                  
               
                
 
                                            
                                    
                                                                             
               
                    
               
                       
             
    
                         
                                  
         
             
 
         
  
                                                              
        
   
   
          
                                                              
                                                                        
          
                                         
             
                    
        
                                                                               
              
                                      
                        
                
                     
                                 
         
                                         
    
                                       
                                  
    
        
                                            
            
                 
                                    
     
                       
            
     
                      
   
                             
    
                     
 
            
                             
     
                          
                                     
        
   
                                 
     
  
     
                      
  
  
                
    
   
  
   
            
    
   
  
               
 
   
   
  
  
         
                          
                       
                                  
     
      
                      
    
                 
                   
         
                      
   
      
             
         
    
 
      
         
                 
          
           
                            
                        
       


                 
                             
 
     
          
                    
               
             
                                          
             
  
                       
                                                  
             
                        
             
                            
                      
    
               
                                                         
       
            
                                
                                    
                                                                             
                 
               
           
                                         
                    
        
                                                                    
   
                                       
  
                                          
                 
            
    
            
        
     
                 
                             
          
                     
                
                                                        
 
       
                                                                          
                                                                                     
  
                           
     
        
         
                          
               
  
            
             
                                               
                      
                                  
             
    
         
               
   
                  
   
     
                                 
             
 
                                 
             
            
        
      
                                                              
  
         
                       
                                                                                 
                                                                                  
         
           
                                                      
     
           
                                                                          
       
                             
                                      
              
                 
    
                                                             
       
         
   
             
  
              
         
                       
  


                 
                             
 
     
          
                    
               
             
                                          
             
     
    
        
          
 
  
        
                  
  
        
                        
                             
                 
                    
                                            
   
     
       
  
        
    
      
          
   
        
   
             
   
              
   
         
 
   
           
   
       
    
           
    
            
    
         
    
       
    
     
    
          
    
           
    
           
   
            
                                          
                
        
        
               
                
                                                       
                             
     
                                                    
                                                   
                                
                                                       
     
 
     
       
  
         
    
      
                
 
    
        
   
             
   
           
    
       
   
      
   
         
    
      
    
    
   
                                                                          
         
                                                           
      
                     
                           
                                  
           
      
     
                                                         
                       
 
            
   
                                               
         
    
                                                                 
     
    
     
 
   
     
     
     
     
                                                       
                     
                                                
   
  
                   
                         
                                
 
            
                                                                  


                 
                             
 
     
          
                    
               
             
                                          
             
                                           
                  
                    
             
       
                        
                   
  
                                        
                         
            
                                                                                   
                                  
 
                                             
                                                    
                         
      
                                                                      
                                                  
         
                   
                 
     
                            
                   
      
               
                                                                
                                       
     
      
                       
  
  
   
                                                    
                        
           
   
                          
            
                  
   
   
      
                                                                                  
    
       
                                   
     
                           
                                                          
         
             
                                                                            
                           
                       
             
     
      
          
                    
                     
                                   
 
              
                          
              
         
                                                     
             
           
                                          
          
                                    
                           
                                                                           
    
                           
 
                             
                                        
     
  
                  
                                                  
  
                                  
            
        
         
                          
              
         
                                          
     
     
                                                     
                 
             
     
                                                        
                                              
                               
 
                             
                                        
     
  
                  
                                                  
  
                                  
            
         
                   
                        
         
                                     
    
           
                                             
    
     
                                                                              
 
                              
 


                 
                             
 
     
          
                    
               
             
                                          
             
                                       
                                      
 
        
                  
                                                 
                                     
           
    
                 
                           
                  
    
              
  
                        
        
     
              
 
                   
                                                    
  
                  
                                                          
      
                                          
                          
        
                    
                            
                   
            
                                    
                     
       
                       
                       
                        
                     
               
                                     
             
                                                                          
                    
                                                   
   
                             
                                            
  
    
                                             
                          
       
                                          
                          
                          
  
                           
                                                 
        
                            
                                     
     
                                           
           
   
          
   
     
     
          
   
    
                    
   
            
   
                       
                                               
                
                   
                                           
                     
   
           
                                                     
                       
                  
                                                   
             
                                          
               
       
 
  
                      
                                     
                  
               
                   
        
           
   
                       
    
         
       
              
                              
                 
           
         
                          
                           
  
                          
         
                  
    
           
    
                                                        
            
                
                        
        


                 
                             
 
     
          
                    
               
             
                                          
             
      
                  
                         
         
                                   
       
                                
                        
                            
                                      
                                                                                
     
                   
                
                                      
                                         
      
         
            
                                          
                                      
                     
                                
                         
 
  
  
                                
                             
          
                                                       
             
        
   
                    
   
                                                      
 
                     
              
                               
      
       
            
                
                             
                                                    
     
    
                                     
  
             
             
   
                         
             
                         
         
    
                                
  
             
                     
                             
                                                     
     
    
                                     
  
             
              
           
                          
                                                    
    
    
                                     
  
             
           
                       
                         
          
                                           
         
                                     
  
              
          
                         
                         
          
                                           
   
         
                                     
 
              
        
                 
                         
        
                                        
    
    
                                     
  
 


                 
                             
 
     
          
                    
               
             
                                          
             
                
            
       
             
                                  
           
                
                          
         
                       
                                                                                              
                                                                          
  
    
                          
                                                 
           
                         
             
             
                
             
       
           
                                  
     
            
                  
       
                                    
                                                           
       
          
         
                   
                                                 
                                                                        
       
                                                                                       
 
                                                                                 
     
              
                   
                                                        
     
                                 
                                       
 
                          
                                                          
                                                                                        
                                                                                      
                                                                      
              
   
                                                 
          
            
   
                         
                                               
     
                        
    
    
                                     
                                        
                  
      
     
    
    
                              
                                           
                                                                                     
                                                                                      
                                                                                       
                  
     
                               
              
                           
                                                               
                  
 
                                                                                   
                                                                                       
                                                                                         
                   
                
                           
                   
                                                        
                                 
      
                                                            
                  
                                                                                 
                   
                                    
                       
      
                                                        
     
           
     
                                                   
             
           
                                                                             
    
                  
           
                                                  
                                                                                        
       


                 
                             
 
     
          
                    
               
             
                                          
             
            
                         
       
                               
            
           
              
        
                   
                                                                           
                                           
                   
              
 
       
    
        
                                                                           
        
      
     
   
          
      
         
                       
                                                                                 
         
                            
                             
     
                                                             
       
   
        
   
   
        
   
          
      
              
      
              
          
                                    
        
         
                     
    
         
           
                         
                      
            
             
      
                              
             
                                            
         
                   
                                                         
          
    
      
             
               
             
             
 
               
     
                  
  
       
     
                  
                  
                                          
         
          
                                       
                                
           
         
   
                                            
         
                   
                            
   
              
                         
       
                                                                     
          
            
   
                                             
         
                                                                             
          
            
        
                              
                
                             
                                         
          
                         
                              
                          
                 
              
                
       
   
                 
                           
   
           
         
       
                          
                     
          
                
                                              


                 
                             
 
     
          
                    
               
             
                                          
             
                                    
                             
   
              
      
                
        
         
            
      
       
                 
         
                                   
  
                           
     
           
         
            
     
                                       
                    
         
       
                  
   
                                      
  
 
                             
                      
                    
                        
               
               
      
                  
         
                      
                                                                               
    
        
  
                                                       
         
    
   
           
     
  
    
                                          
                       
        
     
  
         
                                    
     
     
        
             
             
                                      
        
               
    
                                                        
                    
  
                       


                 
                             
 
     
          
                    
               
             
                                          
             
                        
     
                   
    
           
   
            
    
                 
    
         
         
    
   
       
         
 
  
               
    
         
             
    
        
      
     
          
            
     
     
                    
       
  
                     
             
    
  
          
     
           
   
 
           
  
  
         
   
                    
       
                         
    
    
             
   
            
   
  
        
    
   
                         
    
                 
    
 
                 
   
            
   
              
     
                      
   
   
                                     
  
              
    
      
          
     
             
            
     
                         
     
               


                 
                             
 
     
          
                    
               
             
                                          
             
     
                      
    
              
    
      
         
    
                
        
 
        
                    
 


                 
                             
 
     
          
                    
               
             
                                          
             
                 
                            
    
                            
 
                
 
    
             
   
 
                
 
    
           
 
                  
    
  
            
 
    
           
                     
   
       
      
    
        
          
   
              
       
          
      
     
   
                   
       
      
             
   
      
     
              
              
   
         
   
         
          
              
   
            
       
     
         
     
     
   
                 
          
         
               
             
    
        
                  
         
      
    
        
       
     
   
       
      
     
         
          
       
     
          
  
  
            
      
   
     
    
                
        
         
 
 
  
             
 
    
             
   
              
    
         
            
      
                     
          
   
         
               
               
              
  
                
                      
             
                  
     
              
              
                         
                   
      
            
     
   
          
               
    
     
        
              
                
     
       
      
    
           
     
   
                    
    
     
           
            
   
                        
     
          
              
                         
                   


                 
                             
 
     
          
                    
               
             
                                          
             
                
 
    
          
                         
 
                
 
    
        
    
             
 
  
            
 
    
          
                         
          
          
                 
        
                     
      
          
         
                 
              
     
                            
            
       
      
  
                            
      
        
                 
           
          
        
 
          
  
                   
       
         
             
     
          
                          
 
          
      
    
                  
                   
 
        
    
                 
          
           
        
                  
              
         
           
       
                 
     
            
               
                    
                 
            
       
         
          
            
   
                 
  
            
    
           
   
          
    
                  
             
                         
                
                
              
             
              
                 
      
       
              
                   
                    
                   
        
       
              
          
     
          
           
   
   
     
   
     
         
              
                 
            
            
                
     
        
          
         
        
 
 
 
  
             
 
    
        
    
             
                  
      
    
        
          
     
              
        
          
                
          


                 
                             
 
     
          
                    
               
             
                                          
             
                
 
    
             
               
  
            
 
    
             
               
      
   
       
        
      
           
 
    
      
               
                   
         
       
       
 
   
  
  
   
                
            
   
            
           
         
                
  
   
 
      
      
   
      
        
             
        
               
      
      
          
       
      
     
  
             
  
     
  
    
          
       
       
    
                
 
 
 
                
 
    
           
         
  
            
 
    
           
        
                   
            
    
    
      
                     
            
        
 
          
     
     
    
        
       
         
 
        
     
    
        
        
               
 
      
       
                
         
    
 
      
                 
                
                  
 
      
         
        
                  
   
           
 
               
         
      
                
    
         
 
             
               
                   
 
             
        
                    
        
                    
                      
                
 
        
           
                     
                   
              
                   
            
                
               
          
       
     
         
      
        
            
          
       
         
       
           
                     
       
   
          
         
                  
           
     
               
 
                
                    
        


                 
                             
 
     
          
                    
               
             
                                          
             
                      
 
                         
     
                
             
       
        
     
           
      
        
         
       
                
  
    
 
         
               
    
              
          
 
                 
    
         
    
      
 
        
         
    
      
      
 
                
   
              
         
    
                
     
          
               
            
                    
                
              
           
           
                       
           
         
      
           
       
 
                     
                
                
      
     
             
                  
      
                    
   
      
      
   
   
                 
         
     
        
   
                   
                      
         
     
            
   
                          
  
    
            
       
                  
     
 
           
 
  
  
    
           
         
   
 
        
          
  
    
     
 
                         
                    
  
    
         
       
   
   
                   
          
   
        
                    
      
      
   
           
                  
        
      
   
              
    
             
      
      
   
                 
          
          
                    
   
         
                   
                  
         
   
       
                     
       
          
            
  
                     
        
           
         
   
                       
               
   
              
    
                         
      
           
    
          
   
                    
           
       
   
                   
        
             
                      
    
            
          
     
             
               
       
             
 
              
               
        
   
         
         
        
       
              
     
           
         
        
        
                  
        
                 
        
              
                      
              
               
                     


                 
                             
 
     
          
                    
               
             
                                          
             
                      
      
            
    
       
             
   
       
        
       
            
    
        
                  
   
       
        
        
                  
                   
          
          
                  
                    
        
    
               
 
  
          
        
         
      
                 
 
                     
                 
       
          
 
             
         
          
                      
 
                      
          
                       
      
   
        
     
          
 
                   
           
                
 
                      
           
     
            
               
         
            
       
     
             
  
       
             
                         
     
               
        
  
       
            
            
                        
                 
              
         
          
       
       
             
   
       
       
          
       
        
 
             
   
              
    
     
                
          
     
   
      
  
   
       
             
   
          
                           
                     
          
             
 


                 
                             
 
     
          
                    
               
             
                                          
             
                
 
    
          
    
      
     
  
      
     
     
                        
          
      
      
         
    
                 
       
                  
              
                       
                 
                
               
            
  
                      
                      
               
                
             
               
             
                 
                   
   
                    
             
                    
             
  
               
          
     
           
   
             
               
             
              
             
               
                
             
  
                 
          
      
               
             
                
                
          
  
  
                
           
         
                
               
              
            
  
              
  
                  
                 
                
                   
                 
                    
              
      
                    
               
                
     
                 
   
      
                     
             
      
            
   
                     
                
              
 
 
             
      
                  
            
     
 


                 
                             
 
     
          
                    
               
             
                                          
             
                  
                
             
   
                   
 
                                                                          
         
                         
 
 
 

Prot_003.pdf: 
 
 
 
 
 
 
 
 
 
 
 
Study Title 
An Open-Label, Long-Term Safety and Tolerability Study of Depot 
Buprenorphine (RBP-6000) in Treatment-Seeking Subjects With 
Opioid Use Disorder 
NCT Number 
NCT02510014 
Date 
March 25, 2016 
 


Clinical Study Protocol: RB-US-13-0003 
Study Title: 
An Open-Label, Long-Term Safety and Tolerability Study of Depot 
Buprenorphine (RBP-6000) in Treatment-Seeking Subjects With 
Opioid Use Disorder 
Study Number: 
RB-US-13-0003 
Study Phase: 
3 
Product Name: 
RBP-6000 
IND Number: 
107,607 
Indication: 
Treatment of Opioid Use Disorder 
Investigators: 
Multicenter 
Sponsor: 
Indivior Inc. 
 
10710 Midlothian Turnpike, Suite 430 
Richmond, VA 23235 
 
Sponsor Contact: 
 
Head Late Stage Development, Global Clinical Development 
 
 
Medical Monitor: 
 
 
 
Date 
Original Protocol: 
14 April 2015 
Amendment 1: 
19 August 2015 
Amendment 2: 
11 September 2015 
Amendment 3: 
25 March 2016 
 
 
 
 
Confidentiality Statement 
The information contained in this document is privileged and confidential. Do not copy, 
circulate, or otherwise distribute without written authorization from  
Indivior Inc. 


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SYNOPSIS 
Sponsor:  
Indivior Inc., formerly Reckitt Benckiser Pharmaceuticals Inc. (RBP) 
Name of Finished Product: 
RBP-6000, 18% buprenorphine sterile solution for subcutaneous (SC) injection 
Name of Active Ingredient: 
Buprenorphine 
Name of Inactive Ingredient:  
ATRIGEL® Delivery System 
Study Title: 
An Open-Label, Long-Term Safety and Tolerability Study of Depot Buprenorphine (RBP-6000) 
in Treatment-Seeking Subjects With Opioid Use Disorder 
Study Number: 
RB-US-13-0003 
Study Phase: Phase 3 
Primary Objective: 
To assess the long-term safety and tolerability of RBP-6000 subcutaneous (SC) injections in 
subjects with opioid use disorder. 
Secondary Objective: 
To collect clinical outcome data with RBP-6000 SC injections in subjects with opioid use 
disorder. 
Tertiary Objectives:  
To evaluate the: 
• Pharmacokinetics (PK) of RBP-6000,  
• Relationships between RBP-6000 PK and clinical outcome data, and 
• Impact of RBP-6000 on health and economic outcomes. 
Study Design: 
This is a multicenter, open-label, long-term safety study in which approximately 600 subjects 
diagnosed with opioid use disorder will be enrolled (approximately 300 subjects who did not 
participate in Study RB-US-13-0001, the double-blind, placebo-controlled efficacy study of 
RBP-6000 [hereafter referred to as “de novo” subjects], and 300 subjects who completed the RB-
US-13-0001 study [hereafter referred to as “roll-over” subjects]).  Subject participation will be 
based on the Investigator’s determination that initiation or continuation of study treatment is 
appropriate; and, for subjects who participated in RB-US-13-0001, that there have been no 
significant protocol deviations or clinically relevant adverse events (AEs) that would preclude 
inclusion of the subject in this study. All subjects will provide written informed consent before 
any protocol-related procedures commence. At the Screening Visit (which is up to 3 days after 
the End of Study [EOS] Visit [Day 169 + 3] for roll-over subjects), potential subjects will be 


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reviewed for eligibility against inclusion and exclusion criteria, and eligible subjects will be 
enrolled into the trial.  
SUBOXONE Sublingual Film Run-In:  Induction 
De novo Subjects: 
De novo subjects will initially be inducted onto SUBOXONE® (buprenorphine/naloxone) 
sublingual film for 3 days according to the SUBOXONE sublingual film prescribing 
information.  They will receive their first dose of SUBOXONE sublingual film on Induction 
Day 1 after it is confirmed that the subject meets eligibility criteria and has a Clinical Opiate 
Withdrawal Scale (COWS) score > 12.  Subjects will be started with an initial dose of 2 mg/0.5 
mg (buprenorphine/naloxone) or 4 mg/1 mg and may titrate upwards in 2 or 4 mg increments of 
buprenorphine, at approximately 2-hour intervals, under clinical supervision, to 8 mg/2 mg based 
on therapeutic response.  
On Induction Day 2, subjects with a COWS score > 12 or subjects reporting withdrawal 
signs/symptoms overnight will receive a dose of SUBOXONE sublingual film equal to the total 
dose given on Induction Day 1 plus 4 mg.  (For example, if a subject received a total dose of 8 
mg of buprenorphine on Induction Day 1, the starting dose for Induction Day 2 would be 12 mg).  
If the COWS score is still > 12 one hour later, another 4 mg dose can be given. The subject 
should not exceed a maximum dose of 16 mg buprenorphine for Induction Day 2. Subsequent 
SUBOXONE sublingual film doses must be separated by at least 1 hour from the preceding dose. 
SUBOXONE sublingual film doses may also be adjusted downward if necessary.  
On Induction Day 3, subjects will be titrated to therapeutic response based on COWS scores as 
well as physician judgment. Most subjects will only require a single dose on Induction Day 3, 
which will equal the Induction Day 2 dose or the Induction Day 2 dose plus 4 mg buprenorphine. 
Additional doses may also be administered on Induction Day 3 (up to 24 mg/6 mg). Subsequent 
SUBOXONE sublingual film doses must be separated by at least 1 hour from the preceding dose.  
Subjects should reach a daily dose of between 8 mg and 24 mg buprenorphine by Induction Day 
3 and continue on that dose through the remainder of the SUBOXONE sublingual film Run-In 
period, with additional dose adjustments if necessary.  
Roll-over Subjects: 
Following screening, roll-over subjects will be inducted onto SUBOXONE sublingual film to 
achieve daily doses between 8 mg to 24 mg buprenorphine according to the SUBOXONE 
sublingual film prescribing information.  
Subjects will receive their first induction dose on Induction Day 1. Subjects should be started 
with an initial dose of 2 mg/0.5 mg (buprenorphine/naloxone) or 4 mg/1 mg and may titrate 
upwards in 2 or 4 mg increments of buprenorphine, at approximately 2-hour intervals, under 
supervision, to a total dose of up to 8 mg/2 mg based on the control of acute withdrawal 
symptoms.  
On Induction Day 2, subjects with a score for COWS of >12, or subjects reporting opioid 
withdrawal signs/symptoms overnight, should receive a dose of study drug equal to the total dose 
given on Induction Day 1 plus 4 mg.  If the COWS score is still >12 one hour later, another 4 mg 
dose can be given.  The subject should not exceed a maximum dose of 16 mg/4 mg for Induction 
Day 2.  Subsequent SUBOXONE sublingual film doses must be separated by at least 1 hour 
from the preceding dose.  SUBOXONE sublingual film doses may also be adjusted downward if 


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necessary.   
On Induction Day 3, subjects will be titrated to therapeutic response until a therapeutic dosage is 
reached, based on COWS scores as well as physician judgment. Most subjects will only require a 
single dose on Induction Day 3 which will equal the Induction Day 2 dose or the Induction Day 2 
dose plus 4 mg. Additional doses may also be administered on Induction Day 3 (up to 24 mg).  
Subsequent SUBOXONE sublingual film doses must be separated by at least 1 hour from the 
preceding dose.  Although subjects should reach a daily dose of between 8 mg and 24 mg by 
Induction Day 3 and continue on that dose through the remainder of the SUBOXONE sublingual 
film Run-In period, dose adjustments may be necessary during the Run-In period.  
Roll-over subjects must be titrated to a minimum dose of 8 mg SUBOXONE by the end of the 
3-day Induction period regardless of their COWS scores and/or the presence or absence of 
withdrawal symptoms.   
The SUBOXONE sublingual film(s) will be administered under the tongue, close to the base on 
the left or right side, until they are dissolved.  If an additional sublingual film is required, it 
should be placed on the opposite side from the first film.  Subjects should be instructed to hold 
the films under the tongue until they dissolve.  If a third film is required, it should be placed 
under the tongue after the first 2 films have dissolved.   
SUBOXONE Sublingual Film Run-In:  Dose Adjustment (All Subjects) 
After the daily induction visits, all subjects will begin a 1-to 11-day SUBOXONE sublingual 
film dose adjustment period.  Subjects will return to the clinic at 3- to 4-day intervals for Opioid 
Craving Visual Analog Scale (VAS), COWS, and Subjective Opiate Withdrawal Scale (SOWS) 
assessments.  SUBOXONE sublingual film will be dispensed at each visit for at home dosing.  
Beginning on the 4th day of SUBOXONE sublingual film dosing, subjects will be evaluated for 
Day -1 criteria, which are identical to the criteria required for enrollment on Day 1.  These 
criteria include the following: no allergic reaction to SUBOXONE sublingual film, a daily dose 
of SUBOXONE sublingual film between 8 mg and 24 mg (inclusive) buprenorphine, a COWS 
score of ≤ 12, and an Opioid Craving VAS score of ≤ 20 mm. 
Open-Label Treatment with RBP-6000: 
On Day 1 of the study (first dose of RBP-6000), all subjects who meet enrollment criteria will 
receive a SC injection of 300 mg of buprenorphine in RBP-6000. Subsequent doses of RBP-6000 
may be adjusted down to 100 mg and back up to 300 mg based on the medical judgment of the 
Investigator. After injection of RBP-6000, subjects will not be permitted to receive supplemental 
SUBOXONE sublingual film during the RBP-6000 treatment period. Subjects who require 
supplemental SUBOXONE sublingual film or other sublingual buprenorphine pharmacotherapy 
during the RBP-6000 treatment period will be withdrawn from the study and referred for 
appropriate treatment. 
Subjects will return to the clinic for monthly injection visits (every 28 ±2 days) for a total of up 
to 12 injections for de novo subjects or for a total of 6 injections for roll-over subjects. 
Electrocardiogram (ECG) recordings and vital signs will be collected pre and post each SC 
injection. Subject-reported injection site pain Visual Analog Scale scores (VAS) will be 
collected at various times for 1 hour after each injection. Local injection site grading will be 
collected at various time points starting immediately after injection; the injection site will 
evaluated for pain, tenderness, warmth, itching, erythema, inflammation or swelling, and 


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bruising using a 4-point severity scale. At each visit after injections begin, the injection site will 
be assessed by site staff for potential reaction and will also be evaluated for evidence of attempts 
to remove the depot. 
Subjects will return to the clinic weekly for the first 5 weeks and then biweekly (i.e., every 2 
weeks) through to injection 6. After injection 6, visits will be monthly for the rest of the study 
period for urine drug screens (UDS), Timeline Followback (TLFB) interviews, opioid craving 
VAS evaluation, COWS and subject reported outcomes (Subjective Opiate Withdrawal Scale 
[SOWS]). Subjects will continue to receive counseling (manual-guided behavioral therapy) 
during the study.  
Safety assessments will be collected at each injection visit and/or at injection follow-up visits 
and will include the following: vital signs, electronic Columbia Suicide Severity Rating Scale 
(eC-SSRS) responses, ECGs, laboratory tests (hematology, chemistry, urinalysis, and pregnancy 
test), use of concomitant medications, and the frequency of AEs.  
Sparse PK blood samples will be collected for population PK analysis from the roll-over subjects 
only. Once 100 roll-over subjects have completed Injection 6 (Week 25, Day 169) the sites will 
be notified that no more PK samples will be required to be collected from the roll-over subjects 
for the duration of the study. PK samples for population PK analysis are not required from the de 
novo subjects. ECGs will be performed before PK sample collection. The following health 
economic and outcome assessments will also be collected: Beck Depression Inventory (BDI-II), 
brief pain inventory (BPI), EuroQol EQ-5D-5L (EQ-5D-5L), 36-Item Short Form Health Survey, 
Version 2 (SF-36v2), Medication Satisfaction Questionnaire (MSQ), healthcare resource 
utilization (HCRU), Treatment Effectiveness Assessment (TEA), and Addiction Severity Index 
Lite (ASI). 
 
For all subjects (de novo and roll-over), a PK sample will be taken as soon as possible after any 
SAE is reported. If possible, an additional sample should be collected when the SAE has been 
resolved. 
Approximately 2 months prior to the scheduled End Of Study (EOS) visit, the subject’s ongoing 
treatment options will be reviewed with the investigator. At the EOS, 2 transition treatment 
options may be offered if the subject is eligible: 
• Subjects who complete the RBP-6000 treatment period may be offered entry into an open 
label extension study of RBP-6000 (Study INDV-6000-301).  Eligibility will be based on 
meeting the inclusion and exclusion criteria and the medical judgment of the Investigator.  
• Subjects who do not meet the eligibility criteria of the extension study, or subjects who 
do not wish to enroll may alternatively enter a 4-week SUBOXONE transition period if 
deemed suitable by the investigator.  Subjects should be dosed using the Investigators 
medical judgement. Any additional unscheduled visits required by the subject for the 
SUBOXONE transition will not be compensated by the Sponsor.   
Subjects that have not enrolled onto the INDV-6000-301 should be contacted by telephone 
approximately 4 weeks after EOS for a safety follow-up assessment of AEs and use of 
concomitant medications.   


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Study Population:  
Approximately 300 de novo subjects will be enrolled into this study, as well as approximately 
300 roll-over subjects. The study population will consist of individuals diagnosed with opioid 
use disorder who are seeking treatment.  
Test Product, Dose, and Mode of Administration:  
300 mg buprenorphine in RBP-6000, subcutaneous injection 
100 mg buprenorphine in RBP-6000, subcutaneous injection 
Duration of Study Treatment:  
This will be a multiple-dose study, with the first investigational product administration 
(RBP-6000 containing 300 mg buprenorphine) on Day 1. The expected maximum duration of 
participation for de novo subjects is up to approximately 55 weeks, consisting of up to 7 days of 
screening, up to 14 days SUBOXONE sublingual film Run-In, up to a 48-week open-label 
treatment period, and a 4-week safety follow-up telephone call. The expected maximum duration 
of participation for roll-over subjects is up to approximately 31 weeks, consisting of up to a 7-
day screening period, up to 14 days SUBOXONE sublingual film Run-In, a 24-week open-label 
treatment period, and a 4-week safety follow-up telephone call. 
Subjects who enroll in the INDV-6000-301 study are not required to complete the safety follow-
up telephone call.  
Safety Assessments: 
Safety objectives for this study are to evaluate the safety and tolerability of RBP-6000 (100 mg 
and 300 mg) SC injection treatment in subjects with opioid use disorder. Safety assessments will 
include the following: frequency of all AEs, serious AEs (SAEs), discontinuations from study 
due to AEs; local injection site tolerability (e.g., injection site grading); injection site pain using a 
subject-reported VAS; suicidality using the eC-SSRS, use of concomitant medications; changes 
in clinical laboratory results; vital sign measurements; 12-lead ECGs, which will be interpreted 
by a central facility; physical examination results; body weight, height, and body mass index 
(BMI), and abdominal fat measurement (waist-to-hip ratio). 
Clinical Outcome Assessments: 
Clinical outcome assessments will include the UDS for opioids and other drugs; self-reported use 
of illicit opioids, other drugs, and alcohol on the TLFB; COWS, SOWS, and Opioid Craving 
VAS. 
PK Assessments: 
Sparse plasma samples will be collected for population PK analysis from the roll-over subjects 
only. Once 100 roll-over subjects have completed Injection 6 (Week 25 Day 169), the sites will 
be notified that no more PK samples will be required to be collected from the roll-over subjects 
for the duration of the study. 
No PK samples will be collected from the de novo subjects. 
However, for all subjects (de novo and roll-over) throughout the study, a PK sample will be 
taken as soon as possible after any SAE is reported. If possible, an additional sample should be 


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collected when the SAE has been resolved. 
Health Economics and Outcomes Assessments:  
Health economics and outcomes assessments will include: BDI-II, BPI, EQ-5D-5L, SF-36v2, 
MSQ, HCRU, TEA, and ASI-Lite. 


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Statistical Methods:  
A Statistical Analysis Plan (SAP) will be prepared after the protocol is approved and before 
database lock occurs.  The SAP will provide further details regarding the definition of analysis 
endpoints, data handling rules, and the statistical methodology to be used to address all study 
objectives.  The SAP will also include formats for the summary and analysis tables, listings, and 
graphical displays. 
Determination of Sample Size: 
Approximately 300 de novo subjects as well as approximately 300 subjects who completed the 
RB-US-13-0001 study will be enrolled into this long-term safety study to ensure 100 subjects 
reach 1 year of treatment with RBP-6000. No power analysis will be done corresponding to the 
sample sizes, but the large numbers proposed are clinically acceptable to provide adequate and 
relevant clinical conclusions from this study. 
Safety Analyses: 
Safety variables will include AEs, local injection site tolerability (e.g., injection site grading); 
injection site pain using a subject-reported VAS; suicidality using the eC-SSRS, concomitant 
medications; changes in clinical laboratory results (hematology, chemistry and urinalysis); vital 
sign measurements; 12-lead ECGs, physical examination results; body weight, height, BMI, and 
abdominal fat measurement (waist-to-hip ratio).  Safety variables will be analyzed on the safety 
population using descriptive statistics for continuous endpoints (e.g., mean, median, SD, 
minimum and maximum) and frequency counts with percentages for discrete endpoints. 
Baseline is defined as the last non-missing value prior to SC injection on Day 1.  No imputation 
of missing values will be performed. 
Clinical Outcomes Assessments: 
COWS, SOWS and Opioid Craving VAS total scores will be summarized using descriptive 
statistics (mean, median, SD, minimum, maximum), including change from baseline.  Subjects’ 
self-reported illicit drug use from the TLFB will be summarized as descriptive statistics. 
The cumulative distribution function (CDF) of the percentage of urine samples negative for 
opioids, the CDF of the percentage of self-reports from the TLFB negative for illicit opioid use, 
and other outcome measures will be calculated. 
Population PK/PD Analysis: 
The population PK model established using the data collected in the double-blind, placebo-
controlled, efficacy study (Study RB-US-13-0001) will be refined using the PK samples 
collected in the present study to characterize the disposition of buprenorphine and 
norbuprenorphine following SC injections of RBP-6000, with the assessment of potential 
covariates affecting the PK of both compounds. Subsequently, the relationships between 
buprenorphine plasma concentrations and clinical outcomes assessments will be investigated. 
These relationships will be initially assessed in a descriptive manner, and, if applicable, 
appropriate PK/PD models will be developed to describe these relationships. A stand-alone 
modeling analysis plan will be generated, and the results will be reported in a standalone 
modeling report. 


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Health Economic and Outcomes Research Analyses: 
The health economic and outcomes research endpoints for this study are: BDI-II, BPI, EQ-5D-
5L, SF-36v2, MSQ, Health Insurance, HCRU, TEA, and ASI-Lite.  
Summary scores for these measures will be calculated, as appropriate. Categorical variables will 
be summarized using frequencies and percentages. Continuous measures will be summarized 
using descriptive statistics (mean, standard deviation, median, minimum, maximum) as 
appropriate. An analysis of change will be conducted. Supplementary analyses using general 
linear, mixed, or non-parametric methods will be performed as appropriate.  
A stand-alone SAP will be developed prior to database lock with full detail regarding health 
economics and outcomes analyses. 
Date of Original Approved Protocol: 14 April 2015 
Date of Amendment 1: 19 August 2015 
Date of Amendment 2: 11 September 2015 
Date of Amendment 3: 25 March 2016 
 


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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................2 
LIST OF IN-TEXT TABLES ..................................................................................................14 
LIST OF IN-TEXT FIGURES.................................................................................................14 
LIST OF APPENDICES ..........................................................................................................14 
LIST OF ABBREVIATIONS ..................................................................................................16 
1 
INTRODUCTION ...........................................................................................................19 
1.1 
Opioid Use Disorder ..............................................................................................19 
1.2 
Buprenorphine........................................................................................................20 
1.3 
ATRIGEL Delivery System ...................................................................................20 
1.4 
Buprenorphine in the ATRIGEL Delivery System (RBP-6000) ...........................21 
1.4.1 
Summary of Nonclinical Data .....................................................................21 
1.4.2 
Summary of Previous Clinical Data ............................................................22 
1.4.3 
Pharmacokinetic/Pharmacodynamic Modeling of RBP-6000 .....................23 
1.5 
Rationale for Dose Selection .................................................................................24 
1.6 
Known and Potential Risks and Benefits ...............................................................27 
2 
STUDY OBJECTIVES ....................................................................................................28 
2.1 
Primary Objective ..................................................................................................28 
2.2 
Secondary Objectives.............................................................................................28 
2.3 
Tertiary Objectives.................................................................................................28 
3 
INVESTIGATIONAL PLAN ..........................................................................................29 
3.1 
Overall Study Design and Plan ..............................................................................29 
3.2 
Rationale for Study Design ....................................................................................34 
3.3 
Study Duration and Dates ......................................................................................34 
4 
STUDY POPULATION SELECTION ...........................................................................35 
4.1 
Study Population ....................................................................................................35 
4.2 
Inclusion Criteria ...................................................................................................35 
4.3 
Exclusion Criteria ..................................................................................................36 
4.4 
Day -1/Enrollment Criteria ....................................................................................38 
5 
STUDY TREATMENTS .................................................................................................39 
5.1 
Description of Treatments......................................................................................39 
5.1.1 
SUBOXONE Sublingual Film .....................................................................39 
5.1.2 
Investigational Medicinal Products..............................................................39 
5.2 
Treatments Administered .......................................................................................39 
5.2.1 
Run-In Treatment Period .............................................................................39 
5.2.1.1 
SUBOXONE Sublingual Film Induction (De novo Subjects) ...........39 
5.2.1.2 
SUBOXONE Sublingual Film Induction (Roll-over Subjects) .........40 


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5.2.2 
Dose Adjustment Period (All Subjects) .......................................................41 
5.2.3 
Active Study Treatment ...............................................................................41 
5.3 
Selection and Timing of Dose for Each Subject ....................................................42 
5.4 
Method of Assigning Subjects to Treatment Groups .............................................42 
5.5 
Blinding..................................................................................................................42 
5.6 
Concomitant Therapy.............................................................................................42 
5.6.1 
Permitted Concomitant Medications ............................................................43 
5.6.2 
Prohibited Concomitant Medications ..........................................................43 
5.7 
Restrictions ............................................................................................................44 
5.7.1 
Prior Therapy ...............................................................................................44 
5.7.2 
Subject Activity Restrictions .......................................................................44 
5.8 
Protocol Compliance ..............................................................................................44 
5.9 
Packaging and Labeling .........................................................................................44 
5.10 
Storage and Accountability ....................................................................................45 
5.11 
Investigational Product Retention at Study Site ....................................................45 
6 
STUDY PROCEDURES .................................................................................................47 
6.1 
Informed Consent...................................................................................................47 
6.1.1 
General Information .....................................................................................47 
6.2 
Medical History .....................................................................................................47 
6.3 
Physical Examination.............................................................................................47 
6.4 
Vital Signs ..............................................................................................................48 
6.5 
Electrocardiograms ................................................................................................48 
6.5.1 
12-Lead Electrocardiograms ........................................................................48 
6.6 
Clinical Laboratory Tests .......................................................................................49 
6.6.1 
Laboratory Parameters .................................................................................49 
6.6.2 
Sample Collection, Storage, and Shipping ..................................................51 
6.6.3 
Reference Ranges.........................................................................................51 
6.6.4 
Laboratory Results Review ..........................................................................51 
6.6.5 
Good Laboratory Practice Compliance ........................................................51 
6.7 
Pharmacokinetic Assessments ...............................................................................51 
6.8 
Administration of Study Drug ...............................................................................52 
6.9 
Safety and Suicidality Assessments .......................................................................52 
6.9.1 
Local Injection Site Tolerability ..................................................................52 
6.9.1.1 
Injection Site Grading ........................................................................52 
6.9.1.2 
Injection Site Pain Visual Analogue Scale (VAS) .............................53 
6.9.2 
Suicidality ....................................................................................................53 
6.9.2.1 
Columbia Suicide Severity Rating Scale ...........................................53 
6.10 
Adverse Events Assessments .................................................................................53 


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6.10.1 
Definition .....................................................................................................53 
6.10.2 
Performing Adverse Events Assessments ....................................................54 
6.10.3 
Timing ..........................................................................................................54 
6.10.4 
Severity ........................................................................................................54 
6.10.5 
Relationship .................................................................................................55 
6.10.6 
Expectedness ................................................................................................55 
6.10.7 
Clinical Significance ....................................................................................55 
6.10.8 
Clinical Laboratory Adverse Events ............................................................56 
6.10.9 
Serious Adverse Events ...............................................................................56 
6.10.9.1 
Definition ...........................................................................................56 
6.10.9.2 
Reporting Serious Adverse Events ....................................................56 
6.10.10 Treatment-Emergent Adverse Events ..........................................................57 
6.10.11 Procedures and Follow-Up of Subjects with Ongoing SAEs or Experiencing 
SAEs after Completion of or Withdrawal from the Study ...........................57 
6.10.12 Pregnancy .....................................................................................................57 
6.11 
Clinical Outcome Assessments ..............................................................................58 
6.11.1 
Timeline Followback Interview ...................................................................58 
6.11.2 
Opioid Craving Visual Analog Scale ...........................................................58 
6.11.3 
Clinical Opiate Withdrawal Scale ................................................................58 
6.11.4 
Subjective Opiate Withdrawal Scale ...........................................................59 
6.12 
Health Economics and Outcomes Assessments .....................................................59 
6.12.1 
EuroQoL-5 Dimensions-5 Levels (EQ-5D-5L) and EQ-VAS.....................59 
6.12.2 
Medical Outcomes Study Short Form-36 (SF-36v2) ...................................59 
6.12.5 
Treatment Effectiveness Assessment (TEA) ...............................................60 
6.12.6 
Addiction Severity Index (ASI) Lite............................................................60 
6.12.7 
Beck Depression Inventory II (BDI-II)........................................................61 
6.12.8 
Brief Pain Inventory (BPI) Short Form .......................................................61 
6.13 
Concomitant Medication Assessments ..................................................................62 
6.14 
Removal of Subjects from the Study .....................................................................62 
6.14.1 
Early Removal of RBP-6000 .......................................................................63 
6.14.2 
Stopping Rules .............................................................................................63 
6.14.3 
Screen Failures .............................................................................................63 
6.15 
Other Study Procedures .........................................................................................63 
6.15.1 
Counseling/Behavioral Therapy ..................................................................63 
6.15.2 
Unscheduled Visits ......................................................................................64 
6.15.3 
Additional Care of Study Subjects Following Completion of the Study .....64 
6.15.4 
Treating Toxicity .........................................................................................64 
6.15.5 
Ancillary Medications ..................................................................................64 


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6.16 
Appropriateness of Measurements .........................................................................65 
7 
STUDY ACTIVITIES .....................................................................................................66 
8 
QUALITY CONTROL AND ASSURANCE .................................................................67 
8.1 
Quality Control ......................................................................................................67 
8.2 
Quality Assurance ..................................................................................................67 
9 
PLANNED STATISTICAL METHODS ........................................................................68 
9.1 
General Considerations ..........................................................................................68 
9.2 
Determination of Sample Size ...............................................................................68 
9.3 
Analysis Populations ..............................................................................................68 
9.3.1 
Safety Population .........................................................................................68 
9.3.2 
Clinical Outcome Assessment and PK Populations.....................................68 
9.4 
Demographics and Baseline Characteristics ..........................................................69 
9.5 
Primary Analysis ....................................................................................................69 
9.5.1 
Safety Endpoints ..........................................................................................69 
9.5.1.1 
Adverse Events ..................................................................................69 
9.5.1.2 
Laboratory Data .................................................................................69 
9.5.1.3 
Vital Signs ..........................................................................................69 
9.5.1.4 
Other Variables Related to Safety ......................................................69 
9.6 
Secondary Analysis ................................................................................................70 
9.6.1 
Clinical Outcomes Assessments ..................................................................70 
9.7 
Other Analyses .......................................................................................................70 
9.7.1 
PK/PD Modeling ..........................................................................................70 
9.7.2 
Health Economic and Outcomes Assessment ..............................................71 
9.8 
Handling of Missing Data ......................................................................................71 
9.9 
Subjects Who Withdraw from the Study ...............................................................72 
9.10 
Interim Analyses ....................................................................................................72 
10 ADMINISTRATIVE CONSIDERATIONS ....................................................................73 
10.1 
Investigators and Study Administrative Structure .................................................73 
10.1.1 
Indivior Inc...................................................................................................73 
10.1.2 
Investigational Site(s) ..................................................................................73 
10.1.3 
Laboratories .................................................................................................73 
10.2 
Institutional Review Board or Independent Ethics Committee Approval .............73 
10.3 
Ethical Conduct of the Study .................................................................................73 
10.4 
Subject Information and Consent...........................................................................74 
10.5 
Subject Confidentiality ..........................................................................................74 
10.6 
Study Monitoring ...................................................................................................75 
10.6.1 
Study and Site Closure .................................................................................75 
10.7 
Case Report Forms and Study Records .................................................................75 


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10.8 
Data Monitoring Committee ..................................................................................76 
10.9 
Protocol Deviations ................................................................................................76 
10.10 Access to Source Documentation ..........................................................................77 
10.11 Data Generation and Analysis ...............................................................................77 
10.11.1 Data Collection and Data Management .......................................................77 
10.11.2 Database Quality Assurance ........................................................................77 
10.12 Retention of Data ...................................................................................................78 
10.13 Financial Disclosure...............................................................................................78 
10.14 Publication and Disclosure Policy .........................................................................78 
11 REFERENCE LIST .........................................................................................................79 
 
LIST OF IN-TEXT TABLES 
Table 1 
PK Parameters of the Simulated Typical PK Profile of Buprenorphine after 
Repeated RBP-6000 Injections for the Phase 3 Efficacy Study (RB-US-13-0001) ....26 
Table 2 
List of Laboratory Tests ...............................................................................50 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Model-Predicted Buprenorphine Plasma Concentrations and Mu-Opioid 
Receptor Occupancy in Each Treatment Group on RBP-6000 Following the Proposed 
Design of the Current Study ........................................................................................25 
Figure 2 
Study Overview:  De novo Subjects ............................................................32 
Figure 3 
Study Overview:  Roll-over Subjects from RB-US-13-0001 ......................33 
Figure 4 
Injection Locations.....................................................................................128 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events – Screening and SUBOXONE Film Induction ..83 
Appendix 2 
Schedule of Events – RBP-6000 Injection 1 – 3 Visits .....................86 
Appendix 3 
Schedule of Events – RBP-6000 Injection 4 – 6 Visits for all Subjects 
and End of Study/Early Termination and Follow-Up Visits for Roll-over Subjects ...89 
Appendix 4 
Schedule of Events – RBP-6000 Injection 7 – 9 Visits for de novo 
Subjects 
92 
Appendix 5 
Schedule of Events – RBP-6000 Injection 10 – 12 Visits and End of 
Study/Early Termination Visit and Follow-Up for de novo Subjects ..........................95 
Appendix 6 
Pharmacokinetic Sampling Schedule .................................................98 
Appendix 7 
SUBOXONE® (Buprenorphine/Naloxone) Sublingual Film Full 
Prescribing Information ...............................................................................................99 
Appendix 8 
Study Drug Preparation, Administration, and Depot Removal 
Instructions 
127 


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Appendix 9 
Prohibited Cytochrome P450 Inhibitors and Inducers .....................130 
Appendix 10 
Columbia Suicide Severity Rating Scale (eC-SSRS) -- 
Baseline/Screening Version .......................................................................................131 
Appendix 11 
Columbia Suicide Severity Rating Scale (eC-SSRS) -- Since Last 
Visit Version 
133 
Appendix 12 
Clinical Opiate Withdrawal Scale (COWS) ....................................135 
Appendix 13 
Subjective Opiate Withdrawal Scale (SOWS) .................................137 
Appendix 14 
Opioid Craving Visual Analog Scale (Opioid Craving VAS) .........138 
Appendix 15 
Injection Site Grading Scale ............................................................139 
Appendix 16 
Injection Site Pain Visual Analog Scale (Injection Site Pain VAS) 140 
Appendix 17 
Timeline Followback (TLFB) Interview .........................................141 
Appendix 18 
Euro QoL EQ-5D-5L Health Questionnaire ....................................142 
Appendix 19 
Short Form (36) Health Survey v2...................................................144 
Appendix 20 
Medication Satisfaction Questionnaire ............................................148 
Appendix 21 
Health Care Resource Utilization Questionnaire .............................149 
Appendix 22 
Treatment Effectiveness Assessment (TEA) ...................................151 
Appendix 23 
Addiction Severity Index (ASI) Lite................................................152 
Appendix 24 
Beck Depression Inventory II (BDI-II)............................................168 
Appendix 25 
Brief Pain Inventory (BPI) Short Form ...........................................169 
Appendix 26 
Sponsor Signatures...........................................................................170 
Appendix 27 
Investigator’s Signature ...................................................................171 
 


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LIST OF ABBREVIATIONS 
AE 
adverse event 
AIDS 
acquired immunodeficiency syndrome 
ANOVA 
analysis of variance 
ASI-Lite 
Addiction Severity Index - Lite 
AUC 
area under the plasma concentration-time curve 
BDI-II 
Beck Depression Inventory - II 
BMI 
body mass index 
BP 
blood pressure 
BPI 
Brief Pain Inventory Short Form 
Cavg 
average plasma concentration 
Cmax 
maximum plasma concentration 
Ctrough 
plasma concentration at trough, i.e. before the next injection  
CDF 
cumulative distribution function 
CNS 
central nervous system 
COWS 
Clinical Opiate Withdrawal Scale 
CRA 
clinical research associate 
DAWN 
Drug Abuse Warning Network 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
EC50 
concentration yielding 50% of the maximal effect 
eCRF 
electronic case report form 
e C-SSRS 
Electronic Columbia Suicide Severity Rating Scale 
Emax 
maximum effect 
ECG 
electrocardiogram 
ED 
emergency department 
EOS 
end of study 
ET 
early termination 
EQ-5D 
EuroQol EQ-5D (standard instrument) 
EQ-5D-5L 
EuroQol EQ-5D-5L (self-complete version) 


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EQ-VAS 
EQ-5D using visual analog scale 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B surface antigen  
hCG 
urine human chorionic gonadotropin 
HCl 
hydrochloride 
HCRU 
healthcare resource utilization  
HEOR 
health economics and outcomes research 
HIV 
human immunodeficiency virus 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation  
IEC 
independent ethics committee 
IM 
intramuscular 
IMP 
investigational medicinal product 
IND 
investigational new drug application (i.e., Notice of Claimed 
Investigational Exemption for a New Drug) 
INDV 
Indivior Inc. 
INR 
international normalized ratio 
IRB 
institutional review board 
IV 
intravenous 
IWRS 
interactive web response system 
MAR 
missing at random  
MCAR 
missing completely at random  
MMRM 
mixed model repeated measures 
MSQ 
Medication Satisfaction Questionnaire 
NMP 
N-methyl pyrrolidone 
NOAEL 
no observable adverse effect level 


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OTC 
over-the-counter 
PD 
pharmacodynamic or pharmacodynamics 
PE 
physical examination 
PK 
pharmacokinetic or pharmacokinetics 
PLG or PLGH 
poly (DL-lactide-co-glycolide)  
PET 
positron emission tomography  
PI 
Principal Investigator 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
RBP 
Reckitt Benckiser Pharmaceuticals Inc. 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SD 
standard deviation 
SF-36v2 
36-Item Short Form Health Survey, Version 2 
SL 
sublingual 
SOE 
schedule of events 
SOP 
standard operating procedure 
SOWS 
Subjective Opiate Withdrawal Scale 
tmax 
time to maximum plasma concentration 
TEA 
Treatment Effectiveness Assessment  
TEAE 
treatment-emergent adverse event 
TLFB 
timeline followback 
UDS 
urine drug screen 
ULN 
upper limit of normal 
US/USA 
United States/United States of America 
VAS 
visual analog scale 


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1 
INTRODUCTION 
1.1 
Opioid Use Disorder 
Opioid use disorder, as defined in the Diagnostic and Statistical Manual of Mental Disorders, 
Fifth Edition (DSM-5; American Psychiatric Association 2013), is a neurobehavioral syndrome 
characterized by the repeated, compulsive seeking or use of an opioid despite adverse social, 
psychological, and/or physical consequences.  Opioid use disorder is a medical illness with high 
costs to individuals, families, and society.  Direct and indirect costs attributable to illicit drug use 
are estimated in 3 principal areas: crime, productivity, and health (US Department of Justice, 
Economic Impact of Illicit Drug Use on American Society, 2011).  Approximately one-third of 
all acquired immunodeficiency syndrome (AIDS) cases diagnosed in the United States (US) 
through 2009 (Centers for Disease Control and Prevention: HIV/AIDS Surveillance Report, 
2009) and many cases of hepatitis C (National Institute on Drug Abuse 2000; Thomas 2001) 
were associated with injection drug use.   
The increasing abuse of and addiction to prescription opioids is another major concern.  
According to the Substance Abuse and Mental Health Services Administration’s Office of 
Applied Studies, the incidence of abuse of prescription opioid pain medications (narcotic 
analgesics) such as hydrocodone, oxycodone, meperidine, and propoxyphene has risen markedly 
in recent years (Crane 2003).  The incidence of emergency department (ED) visits related to 
these medications has been increasing since the 1990s and has more than doubled between 1994 
and 2001 (Crane 2003).  The most recently published data from the Drug Abuse Warning 
Network (Drug Abuse Warning Network, 2009: National Estimates of Drug-Related Emergency 
Department Visits, 2011) estimated that about 2.1 million ED visits resulted from drug misuse or 
abuse, which was the equivalent of 674.4 ED visits per year per 100,000 population.  Although 
the overall number of ED visits attributable to drug misuse or abuse was stable from 2004 to 
2009, increases were seen in ED visits involving nonmedical use of pharmaceuticals with no 
other drug involvement (117% increase).  An estimated 1,079,683 ED visits in 2009 involved the 
nonmedical use of prescription drugs, over-the-counter (OTC) medicines, or other types of 
pharmaceuticals, representing about a quarter of all drug-related ED visits and over half of ED 
visits for drug abuse or misuse.  Pain relievers were the most common type of drugs reported in 
the nonmedical use category of ED visits (47.8%).  Among specific types of pain relievers, 
narcotic pain relievers such as oxycodone, hydrocodone, and methadone (13.7%, 8.0%, and 
5.8%, respectively) were most prevalent (Drug Abuse Warning Network, 2009: National 
Estimates of Drug-Related Emergency Department Visits, 2011). 
The economic burden of prescription opioid abuse is very high.  Total US societal costs of 
prescription opioid abuse were estimated at $55.7 billion in 2007 (US dollars in 2009).  
Workplace costs accounted for $25.6 billion (46%), health care costs accounted for $25.0 billion 
(45%), and criminal justice costs accounted for $5.1 billion (9%) (Birnbaum 2011).  Mean 
annual direct health care costs for opioid abusers were more than 8 times higher than for 
nonabusers.  Hospital inpatient and physician outpatient costs accounted for 46% and 31% 
respectively, of opioid abusers' health care costs.  The high costs of opioid abuse are driven 
primarily by high comorbidity rates and high utilization rates of medical services and 
prescription drugs (White 2005).  It was also found that opioid use results in lower quality of life, 


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including significantly worse physical and psychological health, compared with the general 
population (Ryan 1996). 
Given the high costs of opioid addiction to individuals, families, and society, treatments for this 
disease therefore aim to reduce the use of prescription or illicit opioids as well as the risks 
associated with injection, including transmission of human immunodeficiency virus (HIV) and 
hepatitis C virus.  Implantable formulations of opioid receptor partial agonists and antagonists 
represent an innovative alternative to daily dosing regimens, and several delivery systems are 
currently in clinical trials (Ling 2010, Rosenthal 2013).  The goal of this study is to determine 
whether RBP-6000, which is a sustained release formulation of buprenorphine in the ATRIGEL® 
delivery system, is a safe and effective treatment for opioid use disorder. 
1.2 
Buprenorphine 
In the central nervous system (CNS), opioid receptors are found in high concentrations in the 
limbic system and the spinal cord. The natural ligands for these receptors are a group of 
neuropeptides known as endorphins. Opioid analgesics mimic the action of endorphins but have 
a more prolonged action because the analgesics are not subject to rapid local metabolism. 
Three major opioid receptor subclasses have been identified: mu, kappa, and delta.  These 
subclasses mediate distinct actions with natural endorphins and opioid analgesics.  Different 
endorphin and opioid analgesic ligands demonstrate different binding affinities for the various 
subclasses of receptors.   
Buprenorphine is a member of the large family of opioid analgesics used in the treatment of 
moderate and severe acute and chronic pain. Opioid receptors are found in both the CNS and the 
periphery. Buprenorphine is a partial agonist at the mu receptor, producing a sub-maximal 
response compared to that of a full agonist. Hence, buprenorphine provides a greater margin of 
safety regarding respiratory depression in comparison to full agonist opioids. Buprenorphine is 
also an antagonist at the kappa receptor (Cowan 1977, Jasinski 1978). 
Buprenorphine has been reported to have a lower physical dependence liability than pure agonist 
analgesics such as morphine, and at a sufficient dose, it can suppress opioid withdrawal signs 
and symptoms for at least 24 hours.  Limited euphoric and respiratory depressant effects have led 
to its therapeutic use as a pharmacotherapy for opioid use disorder. 
Selected pharmacokinetic (PK) parameters for buprenorphine when administered sublingually as 
buprenorphine/naloxone films are in the SUBOXONE sublingual film prescribing information 
(Appendix 7).  Further details on the PK of buprenorphine in the ATRIGEL delivery system are 
described in Section 1.4.2. 
1.3 
ATRIGEL Delivery System 
The ATRIGEL Delivery System is a sterile, polymeric solution of a biodegradable 
poly DL-lactide-co-glycolide (PLGH) copolymer, dissolved in the water-miscible, biocompatible 
solvent N-methyl pyrrolidone (NMP).  The polymers belong to a family of poly α-hydroxy acids 
that are used in medical devices such as resorbable sutures and degradable drug delivery 


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systems.  Polymerization, which is initiated with glycolic acid, leads to a linear polymer 
containing a carboxylic acid end group.  The ATRIGEL Delivery System can be formulated to 
deliver different active ingredients for various lengths of time. 
The ATRIGEL Delivery System is well characterized.  It is currently used in 7 approved 
products worldwide, including 4 ELIGARD® products (subcutaneous [SC] depot formulations of 
leuprolide acetate), ATRIDOX® (doxycycline hyclate applied to the periodontal pocket), the 
ATRISORB® Bioabsorbable Guided Tissue Regeneration Barrier for periodontal application, and 
the ATRISORB-D Barrier (ATRISORB with doxycycline) for periodontal guided tissue 
regeneration. 
Clinical studies with these products demonstrated that the ATRIGEL Delivery System was well 
tolerated and provided consistent sustained release of the incorporated drug over the designated 
dosing interval.  Injection site reactions are expected to be mild and appear early in treatment, as 
observed in previous local irritation ATRIGEL studies (RBP-6000 Investigator’s Brochure [IB], 
Edition 4, 24 February 2014). 
1.4 
Buprenorphine in the ATRIGEL Delivery System (RBP-6000) 
RBP-6000 is a subcutaneously injected depot product under development for the treatment of 
opioid addiction. It contains buprenorphine in the ATRIGEL Delivery System and provides 
sustained plasma levels of buprenorphine over a minimum of 28 days. There is no currently 
approved, parenterally administered, sustained-release buprenorphine formulation for the 
treatment of opioid use disorder. Such a formulation could offer advantages over existing 
buprenorphine products by improving subject compliance and reducing diversion, abuse, and 
unintended exposure (e.g., in pediatric exposure), and reduce chances of swallowing drug. 
The safety profile and clinical efficacy of RBP-6000 are expected to be similar to and 
comparable with that of buprenorphine or SUBOXONE sublingual treatment.  
1.4.1 
Summary of Nonclinical Data 
Nonclinical data suggest that toxicity from RBP-6000 is unlikely at the doses planned for this 
clinical study.  The no observable adverse effect levels (NOAELs) were determined to be 250 
mg/kg (rat) and 40 mg/kg (dog) following single SC injections of RBP-6000 in 4-week toxicity 
studies.  These levels are equivalent to human buprenorphine doses of 2419 mg and 1333 mg, 
respectively (based on 60 kg body weight and calculated according US Food and Drug 
Administration guidance [FDA 2005]).  These levels provide approximately 8.1x (rat) and 4.4x 
(dog) safety margins when compared to the 300-mg buprenorphine dose in humans (based on 
60 kg body weight and calculated according US Food and Drug Administration guidance 
[FDA 2005]).  Systemic effects seen in the rat and dog 4-week toxicity studies were related to 
the pharmacology of buprenorphine or local tolerance effects of the formulation as a result of 
high dose and volume, so the safety margins are considered acceptable. 
Chronic repeated-dose studies were conducted in rats and dogs dosed with RBP-6000 once every 
4 weeks for 6 or 9 months, respectively.  These studies demonstrated systemic effects consistent 
with buprenorphine administration, such as stained fur, aggressive behavior, decreased activity, 


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reduced food consumption and body weight gain, and abnormal feces.  Minimal to mild lung 
alveolar macrophage infiltration and pancreatic acinar cell apoptosis were seen with increased 
incidence in rats, but not dogs, treated with RBP-6000.  Injection site findings were seen in both 
species, characterized microscopically by minimal to moderate granuloma formation.  Injection 
volumes were high, being 2.73 mL/m2 in rats and 3.64 mL/ m2 in dogs, compared with a volume 
of 0.62 mL/ m2 at the highest proposed clinical dose, contributing to these local findings.  
Systemic chronic NOAELs were considered to be 10 mg/kg in rats and 40 mg/kg in dogs.   
Overall, the extensive preclinical data on both the buprenorphine and SUBOXONE products and 
nonclinical PK and toxicity studies in rats and dogs support the clinical development of 
RBP-6000.  Systemic exposure to buprenorphine is not considered to pose any significant safety 
concerns following SC administration of RBP-6000.  Additionally, this clinical study will be 
conducted in subjects who have a current diagnosis of opioid use disorder and who would thus 
be expected to have a certain degree of cross-tolerance to the opioid agonist effects of 
buprenorphine.  Minimal to moderate irritation at the injection site, seen in both rats and dogs, 
may warrant attention to ensure local tolerability (RBP-6000 IB, Edition 4, 24 February 2014). 
1.4.2 
Summary of Previous Clinical Data 
In the first-in-human trial to evaluate the safety, tolerability, and PK of RBP-6000, 12 subjects 
received a single SC injection of RBP-6000 containing 20 mg of buprenorphine.  Of these 
12 subjects, 6 subjects completed the study through Day 85.  The majority (94%) of 
treatment-emergent adverse events (TEAEs) were mild, 5.4% were moderate, and 1 was severe 
in intensity.  TEAEs considered related to the study drug included injection site pain, injection 
site warmth, and injection site bruising, erythema, and edema.  All subjects experienced mild to 
moderate symptoms of withdrawal at study entry, prior to study drug injection, and after study 
drug injection.  One serious adverse event (SAE) was reported.  The SAE was notably identified 
psychosocial stressors and intermittent withdrawal, for which the subject had prolonged 
hospitalization for treatment.  This SAE was not considered to be related to the study drug.  No 
respiratory depression, temperature elevations, clinically significant lowering of oxygen 
saturation, or electrocardiogram (ECG) abnormalities were observed.  There was 1 clinically 
significant laboratory adverse event (AE; elevated hepatic enzymes), which resolved.  No 
unexpected side effects occurred in the RBP-6000 depot formulation of buprenorphine 
(RBP-6000 IB, Edition 4, 24 February 2014).  Buprenorphine was rapidly absorbed over the first 
day and peaked on the second day, with a slow decrease in plasma concentrations thereafter that 
is consistent with the slow release of buprenorphine from the ATRIGEL Delivery System.   
The PK of 50, 100, and 200 mg buprenorphine (as RBP-6000) was also evaluated in a single-
ascending-dose study in 51 subjects (RB-US-11-0020).  In this study, median buprenorphine 
time to peak concentration (tmax) in the initial burst period was observed at 24 hours for all 3 
dosages.  Buprenorphine mean plasma terminal half-life increased slightly with the increase in 
dose from 50 mg to 200 mg (1078 hours [44.9 days] at 50 mg, 1376 hours at 100 mg, and 1573 
hours at 200 mg).  Buprenorphine exhibited overall geometric mean average concentration 
values of 0.356, 0.624, and 1.108 ng/mL, respectively with 50, 100 and 200 mg buprenorphine 
while overall geometric mean Cmax values of 0.999, 1.518, and 2.381 ng/mL were observed for 
buprenorphine doses of 50, 100, and 200 mg, respectively.  With an increase in dose of RBP-


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6000 from 50 to 200 mg, mean buprenorphine exposure parameters increased less than 
proportionally to dose (RBP-6000 IB, Edition 4, 24 February 2014).  A single SC injection of 
RBP-6000 was generally safe and well tolerated.  A total of 46 of 51 subjects (90.2%) had at 
least 1 TEAE.  A total of 30 of 51 subjects (58.8%) had TEAEs that were related to treatment 
with RBP-6000.  The majority of AEs were qualified as moderate in severity (68.6%).  
Two subjects reported TEAEs that were considered to be severe but unrelated to RBP-6000.  No 
subjects withdrew from the study because of an AE. 
The safety profile of multiple-dose SC injections of RBP-6000 containing 50 mg, 100 mg, 
200 mg, and 300 mg of buprenorphine in treatment-seeking, opioid-dependent subjects in an 
open-label, multiple-dose study has recently been examined.  The results suggest that all doses 
were safe and well-tolerated following a 13-day induction and stabilization on SUBUTEX.  In 
addition, a study investigating the blockade of subjective opioid effects demonstrated that RBP-
6000 was safe and well tolerated after the SC administration of 2 monthly 300-mg doses of 
buprenorphine in RBP-6000, following a 14-day induction and stabilization period on 
SUBOXONE Film. 
1.4.3 
Pharmacokinetic/Pharmacodynamic Modeling of RBP-6000 
A population PK model was developed to characterize the disposition of buprenorphine and 
norbuprenorphine following SC injection of RBP-6000 (Nasser 2014).  This model was built 
using plasma concentration data collected in 36 opioid-dependent subjects who received single 
doses (50 mg, 100 mg, and 200 mg) of RBP-6000 in the single-ascending-dose study (RB-US-
11-0020).  Analysis of the PK profiles of RBP-6000 revealed a complex and multi-phase 
absorption profile, presenting double peaks and a prolonged plasma terminal half-life.  These 
distinguishing features of the PK of RBP-6000 required the development of a complex structural 
PK model accounting for this dual absorption process: a first absorption process that was 
associated with an initial, rapid delivery from the SC injection site, and a second absorption 
process that was associated with the slow release of buprenorphine from the ATRIGEL Delivery 
System into the systemic circulation.  The population PK model accurately predicted the PK data 
after repeated doses of RBP-6000 in the multiple ascending dose study (RB-US-12-0005) and in 
the opioid blockade study (RB-US-13-0002).  
Another population PK/PD model was developed to characterize the link between buprenorphine 
plasma concentration and mu opioid receptor occupancy (Nasser 2014).  Individual data from 15 
heroin-dependent subjects were taken from two published clinical trials (Greenwald 2003; 
Greenwald 2007).  A saturable maximum effect (Emax) model with 0.67 ng/mL effective 
concentration at 50% of maximum (EC50) and 91% Emax best described mu opioid receptor 
occupancy versus buprenorphine plasma concentrations.  At buprenorphine concentrations 
greater than 2 ng/mL, saturation occurred on mu opioid receptor occupancy where a 4.5-fold 
increase in observed buprenorphine concentrations resulted in observed mu opioid receptor 
occupancy between 70% and 90%. 
Positron emission tomography (PET) scan data were obtained in 2 subjects participating in the 
multiple-ascending dose study RB-US-12-0005 (PET scan sub-study) and receiving either 200 or 
300 mg of RBP-6000.  The PET scans were conducted at 7 days and 28 days post-dose following 


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the 12th SC injection for the first subject receiving 200 mg, and following the 6th SC injection for 
the second subject receiving 300 mg.  Both subjects were considered to be at steady-state for 
buprenorphine at the time of the PET scan measurements.  The mu opioid receptor availabilities 
of four different regions in the brain were measured, and the mu opioid receptor occupancy in 
the whole brain was calculated as described in Greenwald et al. (2003). 
The subject receiving 200 mg of RBP-6000 in the PET scan sub-study showed 79% and 75% mu 
opioid receptor occupancy on Day 7 and Day 28, respectively, following the 12th SC injection of 
RBP-6000.  The subject receiving 300 mg of RBP-6000 in the PET scan sub-study showed 92% 
and 81% mu opioid receptor occupancy on Day 7 and Day 28, respectively, following the 6th SC 
injection of RBP-6000.  These values and the corresponding PK concentrations were in 
agreement with the model predictions and the previous individual observations used to build the 
population PK/PD model. 
Linear relationships were found between mu opioid receptor occupancy and opioid withdrawal 
symptoms, and between mu opioid receptor occupancy and hydromorphone agonist blockade, 
based on the data from 15 heroin-dependent subjects (Nasser 2014).  These data suggest that a 
mean buprenorphine plasma concentration of 2 ng/mL is able to provide 70 % mu opioid 
receptor occupancy associated with low reported agonist drug effects and withdrawal symptoms 
(scores ≤2). 
Model simulations indicated that the desired 70% mu opioid receptor occupancy may be 
achieved after multiple doses of 200 mg of RBP-6000 (Nasser 2014).  The 300 mg dose was 
considered to be a full opioid blockade dose. 
1.5 
Rationale for Dose Selection 
The results of the opioid blockade study (RB-US-13-0002) showed that 300 mg was a full opioid 
blocking dose (i.e., for the “drug liking” VAS scores the upper bound of the 95% confidence 
interval ≤11), which is consistent with PK/PD modeling and simulation results. The least means 
“drug liking” VAS scores in the opioid blockade study showed that the blockade was achieved 
from the first SC injection and was maintained after the second SC injection until week 12 (i.e., 2 
months after the second injection). 
The population PK and PK/PD models presented in Section 1.4.3 were used to simulate the 
double-blind efficacy study (RB-US-13-0001).  The results of these simulations are displayed in 
Figure 1 for the two treatment arms on RBP-6000 receiving either 6 SC injections of 300 mg 
(300 mg × 2 + 300  mg × 4), or 2 SC injections of 300 mg followed by 4 SC injections of 100 mg 
(300  mg ×2  + 100  mg × 4).  
 


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Figure 1 
Model-Predicted Buprenorphine Plasma Concentrations and Mu-
Opioid Receptor Occupancy in Each Treatment Group on RBP-
6000 Following the Proposed Design of the Current Study 
 
The blue line represents the median model prediction; the yellow areas represent the 5th and the 95th 
percentiles of the predictions; µ-ORO: mu opioid receptor occupancy; wks: weeks. 
The PK parameters calculated from the simulated typical PK profile of buprenorphine are listed 
in Table 1.  Average buprenorphine plasma concentration (Cavg) over the monthly dosing interval 
was 1.9 ng/mL after the first SC injection at 300 mg, and 3.1 ng/mL after the second SC 
injection at 300 mg.  
For the subjects receiving 6 monthly SC injections of RBP-6000 at 300 mg, the predicted Cavg 
value after the 4th SC injection was 5.1 ng/mL, which is close to mean value of 4.8 ng/mL 
observed in the multiple-ascending dose study.  The predicted Cavg value after the 6th SC 
injection was 6.0 ng/mL.  For the patients receiving 2 monthly SC injections at 300 mg followed 
by 4 monthly SC injections at 100 mg, the predicted Cavg after the 6th SC injection was 
2.6 ng/mL.  All these values were above the 2 ng/mL threshold for achieving the desired 
efficacy. 
Overall, the modeling and simulation work and the opioid blockade study have shown that the 
300 mg SC dose is an appropriate dose to assess for efficacy. The current study will therefore 
evaluate the long-term safety and tolerability of this dose. It is recognized, however, that some 
individuals may need lower doses based on genetic variations, abuse behavior, etc. Accordingly, 
subsequent doses of RBP-6000 may be adjusted down to 100 mg and back up to 300 mg based 
on the medical judgment of the Investigator. 
 


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Table 1 
PK Parameters of the Simulated Typical PK Profile of Buprenorphine after Repeated RBP-6000 
Injections for the Phase 3 Efficacy Study (RB-US-13-0001) 
Buprenorphine 
(ng/mL) 
SC Injection Number 
1 
2 
3 
4 
5 
6 
 
Cmax 
Cavg 
Cmax Ctrough Cavg 
Cmax 
Ctrough 
Cavg 
Cmax 
Ctrough 
Cavg 
Cmax 
Ctrough 
Cavg 
Cmax 
Ctrough 
Cavg 
300mgx2 + 
100mgx4 
2.9 
1.9 
4.2 
1.3 
3.1 
3.5 
2.5 
3.0 
3.6 
2.6 
3.0 
3.5 
2.5 
2.8 
3.2 
2.3 
2.6 
300mgx2 + 
300mgx4 
2.9 
1.9 
4.2 
1.3 
3.1 
5.4 
2.5 
4.3 
6.4 
3.5 
5.1 
7.1 
4.2 
5.7 
7.5 
4.6 
6.0 
Cmax: maximum plasma concentration; Cavg : average plasma concentration; Ctrough: plasma concentration at trough (ie, before the next injection). 
 
 


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1.6 
Known and Potential Risks and Benefits 
The AE profile of buprenorphine is well-characterized; commonly reported effects include 
constipation, nausea, vomiting, and headache.  Buprenorphine is approved for use by various 
routes of administration (e.g., SL, intramuscular [IM], intravenous [IV], transdermal, and rectal). 
Studies of buprenorphine receptor binding in human subjects have consistently and reproducibly 
established that buprenorphine is a highly lipophilic, mu-opioid receptor partial agonist with 
slow receptor association and dissociation kinetics.  Buprenorphine has an improved safety 
profile relative to mu-opioid receptor full agonists due to its partial agonist properties.  These 
attributes of buprenorphine allow it to perform well as substitution therapy for opioid-dependent 
individuals over short-term and long-term durations.  The experiments used to establish the 
binding profile of buprenorphine were consistent across differing parenteral routes of 
administration (IV, IM, and SL); therefore, RBP-6000 is expected to perform similarly when 
administered as a SC depot in the ATRIGEL Delivery System. 
The efficacy of buprenorphine in the treatment of opioid dependence has been well established 
(see for example, New Drug Applications 20-732; 20-733; 22-410).  Buprenorphine has been 
used for medically-supervised taper (i.e., detoxification) medication and as a long-term 
medication assisted therapy (i.e., maintenance).  A recent Cochrane Review meta-analysis 
revealed that buprenorphine is statistically significantly superior to placebo in the retention of 
subjects and reduction of opioid-positive urine tests, and that buprenorphine and methadone may 
be equally efficacious at adequate dose levels of both medications (Mattick 2008). 
A sustained-release formulation of buprenorphine using the ATRIGEL Delivery System offers a 
number of potential benefits relative to shorter-acting formulations, including improved subject 
compliance, reduced diversion and misuse, as well as a reduced risk to subjects, their families, 
and the community.  


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2 
STUDY OBJECTIVES 
Indivior Inc., formerly Reckitt Benckiser Pharmaceuticals Inc. (RBP), is developing RBP-6000, 
a long-acting formulation of buprenorphine for monthly SC administration, for the treatment of 
opioid use disorder.   
2.1 
Primary Objective 
To assess the long-term safety and tolerability of RBP-6000 subcutaneous (SC) injections in 
subjects with opioid use disorder. 
2.2 
Secondary Objectives 
To collect clinical outcome data with RBP-6000 SC injections in subjects with opioid use 
disorder. 
2.3 
Tertiary Objectives 
To evaluate the: 
• PK of RBP-6000,  
• Relationship between RBP-6000 PK and clinical outcome data, and 
• Impact of RBP-6000 on health and economic outcomes. 


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a multicenter, open-label, long-term safety study in which approximately 600 subjects 
diagnosed with opioid use disorder will be enrolled (approximately 300 subjects who did not 
participate in the RB-US-13-0001 study [hereafter referred to as “de novo” subjects] and 
approximately 300 subjects that completed the RB-US-13-0001 study [hereafter referred to as 
“roll-over” subjects]).  Subject participation will be based on the Investigator’s determination 
that initiation or continuation of study treatment is appropriate; and, that among subjects who are 
continuing from the RB-US-13-0001 study, there have been no significant protocol deviations or 
clinically relevant AEs that would preclude inclusion of the subject in this study. All subjects 
will need to provide written informed consent before any protocol-related procedures commence. 
At the Screening Visit (which is up to 3 days after the End of Study [EOS] Visit (Day 169 + 3]), 
for roll-over subjects), potential subjects will be reviewed for eligibility against inclusion and 
exclusion criteria, and eligible subjects will be enrolled into the trial.  
Before receiving the first injection of RBP-6000 in this safety study, all subjects will undergo a 
Run-In period with SUBOXONE® (buprenorphine/naloxone) sublingual film to avoid 
precipitating a withdrawal syndrome and to preserve the blind in subjects treated with placebo in 
the RB-US-13-0001 study. Subjects will be inducted onto SUBOXONE sublingual film 
consistent with the SUBOXONE sublingual film label; they will then complete a 1 to 11 day 
SUBOXONE sublingual film Dose Adjustment period (Section 5.2.1). SUBOXONE dose 
adjustments will be made based on COWS scores as well as physician judgment (Section 5.2.2).   
Once subjects meet the criteria (on Day -11 to Day -1) of no significant opioid craving (≤20 mm 
on the Opioid Craving Visual Analog Scale [VAS] and no significant withdrawal (≤ 12 on the 
Clinical Opiate Withdrawal Scale [COWS]) they may receive the first SC injection of RBP-6000 
(containing 300 mg buprenorphine). Subjects with significant withdrawal signs/symptoms 
(defined as >12 on the COWS) or significant cravings for opioids (defined as >20 mm on the 
Opioid Craving VAS) after the end of the 2-week SUBOXONE sublingual film Run-In period 
will not be eligible to continue in the study and will be referred for treatment.   
On Day 1 of the study (initiation of study drug injections), all subjects will receive a SC injection 
of 300 mg of buprenorphine in RBP-6000. Subsequent doses of RBP-6000 may be adjusted 
down to 100 mg and back up to 300 mg based on the medical judgment of the Investigator. After 
injection of RBP-6000, subjects will not be permitted to receive supplemental SUBOXONE 
sublingual film during the RBP-6000 treatment period. Subjects who require supplemental 
SUBOXONE sublingual film or other sublingual buprenorphine pharmacotherapy during the 
RBP-6000 treatment period will be withdrawn from the study and referred for appropriate 
treatment. 
Subjects will return to the clinic for monthly injection visits (every 28 ±2 days) for a total of up 
to 12 injections for de novo subjects or for a total of 6 injections for roll-over subjects. ECG 
recordings and vital signs will be collected pre and post each SC injection. All ECGs will be 
interpreted by a central monitoring facility.  Subject-reported injection site pain Visual Analog 


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Scale scores (VAS) will be collected at various times up to 1 hour after each injection. Local 
injection site grading will be collected at various time points starting immediately after injection 
and will be evaluated for pain, tenderness, warmth, itching, erythema, inflammation or swelling, 
and bruising using a 4-point severity scale. At each visit after injections begin, the injection site 
will be assessed by site staff and will also be evaluated for evidence of attempts to remove the 
depot.  
Subjects will need to return to the clinic weekly for the first 5 weeks and biweekly (i.e., every 2 
weeks) until injection 6, and monthly for the rest of the study period for urine drug screens 
(UDS), Timeline Followback (TLFB) interviews, opioid craving VAS evaluation, COWS and 
subject reported outcomes (Subjective Opiate Withdrawal Scale [SOWS]). Subjects will 
continue to receive counseling (manual-guided behavioral therapy) during the study.  
Safety assessments will be collected at each visit and will include the following:  vital signs, 
electronic Columbia Suicide Severity Rating Scale (eC-SSRS) responses, ECGs, laboratory tests 
(hematology, chemistry, urinalysis, and pregnancy test), concomitant medications, and AEs.   
Sparse PK blood samples will be collected for population PK analysis for the roll-over subjects 
only. Once 100 roll-over subjects have completed Injection 6 (Week 25, Day 169) the sites will 
be notified that no more PK samples will be required to be collected from the roll-over subjects 
for the duration of the study. PK samples will not be collected for the de novo subjects. However, 
for all subjects (de novo and roll-over) throughout the study, a PK sample will be taken as soon 
as possible after any SAE is reported. If possible, an additional sample should be collected when 
the SAE has been resolved. ECGs will be performed before PK sample collection. The following 
depression, pain, and health economic outcome assessments will also be collected: Beck 
Depression Inventory (BDI-II), brief pain inventory (BPI), EuroQol EQ-5D-5L (EQ-5D-5L), 
36-Item Short Form Health Survey, Version 2 (SF-36v2), Medication Satisfaction Questionnaire 
(MSQ), healthcare resource utilization (HCRU), Treatment Effectiveness Assessment (TEA) and 
Addiction Severity Index Lite (ASI-Lite). 
Approximately 2 months prior to the scheduled EOS visit, the subject’s ongoing treatment 
options will be reviewed with the investigator. At the EOS, 2 transition treatment options may be 
offered if the subject is eligible: 
• Subjects who complete the RBP-6000 treatment period may be offered entry into an open 
label extension study of RBP-6000 (Study INDV-6000-301).  Eligibility will be based on 
meeting the inclusion and exclusion criteria and the medical judgment of the Investigator. 
• Subjects who do not meet the eligibility criteria of the extension study, or subjects who 
do not wish to enroll may alternatively enter a 4-week SUBOXONE transition period if 
deemed suitable by the investigator.  Subjects should be dosed using the Investigators 
medical judgement. Any additional unscheduled visits required by the subject for the 
SUBOXONE transition will not be compensated by the Sponsor.   


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Subjects that have not enrolled onto the INDV-6000-301 should be contacted by telephone 
approximately 4 weeks after EOS for a safety follow-up assessment of AEs and use of 
concomitant medications.   
A schematic depicting the study design for de novo subjects is in Figure 2 and a schematic for 
roll-over subjects is in Figure 3.  A complete list of procedures and assessments for subjects is in 
the Schedule of Events (SOE) in Appendix 1, Appendix 2, Appendix 3, Appendix 4, and 
Appendix 5. 


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Figure 2 
Study Overview:  De novo Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Injection No. 7 (Week 25/Day 169) 
Injection No. 8 (Week 29/Day 197)  
Injection No. 9 (Week 33/Day 225)  
 
Injection No. 10 (Week 37/Day 253)  
Injection No. 11 (Week 41/Day 281)  
Injection No. 12 (Week 45/Day 309)  
End of Study Visit (Week 49 / Day 337) 
Safety Follow up Telephone Call (Week 53 / Day 365) 
Injection No. 1 (Week 1/Day 1)  
 Followed by weekly assessment visits 
Injection No. 2 (Week 5/Day 29)  
Followed by biweekly assessment visits 
Injection No. 3 (Week 9/Day 57)  
Followed by biweekly assessment visits 
Injection No. 4 (Week 13/Day 85)  
Followed by biweekly assessment visits
Injection No. 5 (Week 17/Day 113)  
Followed by biweekly assessment visits 
Injection No. 6 (Week 21/Day 141)  
SUBOXONE Sublingual Film Run-In 
• 
Induction (3 days) 
Subjects complete daily visits on Day -14 to Day -12  
• 
Dose Adjustment (1-11 days) 
Subjects complete visits on Day -11, Day -8, Day -4, and Day -1 (all visits not required) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Early 
Termin
ation 
Subjects 
return 
to clinic 
for this 
visit 
Screening  
(Day -21 to Day -15)  
 


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Figure 3 
Study Overview:  Roll-over Subjects from RB-US-13-0001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Injection No. 1 (Week 1/Day 1) 
 Followed by weekly assessment visits 
Injection No. 2 (Week 5/Day 29)  
Followed by biweekly assessment visits 
Injection No. 3 (Week 9/Day 57)  
Followed by biweekly assessment visits 
Injection No. 4 (Week 13/Day 85)  
Followed by biweekly assessment visits 
Injection No. 5 (Week 17/Day 113)  
Followed by biweekly assessment visits 
Injection No. 6 (Week 21/Day 141)  
SUBOXONE Sublingual Film Run-In 
• 
Induction (3 days) 
Subjects complete daily visits on Day -14 to Day -12  
• 
Dose Adjustment (1-11 days) 
Subjects complete visits on Day -11, Day -8, Day -4, and Day -1 (all visits not required) 
End of Study Visit (Week 25 / Day 169) 
Safety Follow Up Telephone Call (Week 29 / Day 197) 
 
 
 
 
 
 
 
Early 
Termin
ation 
Subjects 
return to 
clinic 
for this 
visit 
Screening  
(Days -21 to -15 [Up to 3 days after EOS Visit/Day169 + 3 for Subject’s Completing  
Study RB-US-13-0001])  
Note: RB-US-13-0001 assessments completed at EOS/Day 169 will serve as screening 
assessments  


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3.2 
Rationale for Study Design 
This study is designed to assess the long-term safety, tolerability, and clinical outcomes of  
RBP-6000 SC injections in subjects with opioid use disorder.  The planned number of subjects 
was designed to ensure at least 100 subjects reach 1 year of treatment with RBP-6000 (as advised 
in the ICH-E1A Guideline - The Extent of Population Exposure to Assess Clinical Safety: For 
Drugs Intended for Long-term Treatment of Non-Life-Threatening Conditions).  The safety 
assessments used include evaluations of AEs, serious AEs (SAEs), discontinuations from study 
due to AEs; local injection site tolerability (e.g., injection site grading); injection site pain using a 
subject-reported VAS; suicidality using the eC-SSRS, concomitant medications; changes in 
clinical laboratory results; vital sign measurements; 12-lead ECGs, and physical examination 
results.  The instruments used to measure clinical outcomes (e.g., COWS, SOWS, Opioid 
Craving VAS, and eC-SSRS) were developed to measure the specific symptoms exhibited by 
and the challenges facing opioid-dependent individuals.   
3.3 
Study Duration and Dates 
The expected maximum duration of participation for de novo subjects is up to approximately 55 
weeks consisting of up to a 7-day screening period, up to a 14-day SUBOXONE sublingual film 
Run-In, up to a 48-week open-label treatment period, and a 4-week safety follow-up telephone 
call. 
The expected maximum duration of participation for roll-over subjects is up to approximately 31 
weeks, consisting of up to a 7-day screening period, up to a 14-day SUBOXONE sublingual film 
Run-In, a 24-week open-label treatment period, and a 4-week safety follow-up telephone call.  
Subjects who enroll in the INDV-6000-301 study at the EOS visit are not required to be 
contacted with a safety follow-up telephone call. 
Subjects who receive at least 1 dose of RBP-6000 and discontinue the trial for any reason will be 
required to complete the Early Termination (ET) visit. 
If a sufficient number of subjects reach 1 year of exposure to RBP-6000, the study may be 
stopped early, and all remaining subjects will complete EOS procedures. 
 


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4 
STUDY POPULATION SELECTION 
4.1 
Study Population 
Approximately 300 de novo subjects will be enrolled into this study as well as approximately 
300 roll-over subjects. The study population will consist of individuals diagnosed with opioid 
use disorder who are seeking treatment.  
4.2 
Inclusion Criteria 
A. De novo Subjects: Subjects who have not participated in Study RB-US-13-0001 must meet 
the following criteria to be enrolled in this study: 
1. Subjects seeking treatment for opioid use disorder who currently, and by medical history 
over the previous 3 months, meet the DSM-5 criteria for moderate or severe opioid use 
disorder.  
2. Subjects who provide written informed consent to participate in this study. 
3. Subjects who are an appropriate candidate for opioid partial-agonist treatment in the 
opinion of the Investigator or medically responsible physician. 
4. Either male or female. 
5. Age ≥ 18 to ≤ 65 years. 
6. Have a body mass index (BMI) of ≥ 18.0 to ≤ 35.0 kg/m2. 
7. Females: Women of childbearing potential (defined as all women who are not surgically 
sterile or postmenopausal for at least 1 year prior to informed consent), must have a 
negative pregnancy test prior to enrollment and must agree to use a medically acceptable 
means of contraception from screening through at least 6 months after the last dose of 
investigational medicinal product (IMP). 
Males: Subjects with female partners of child-bearing potential must agree to use 
medically acceptable contraception after signing the informed consent form (ICF) 
through at least 6 months after the last dose of IMP. Male subjects must also agree not to 
donate sperm during the study and for 6 months after receiving the last dose of IMP. 
The following methods of contraception are considered to be medically acceptable: 
established use of oral, injected or implanted hormonal contraception; placement of an 
intrauterine device or intrauterine system; use of a double-barrier method of 
contraception (condom or occlusive cap with use of a spermicide) or male sterilization.   
8. Subjects must agree not to take any buprenorphine products other than those administered 
during the current study throughout participation in the study. 
9. Subjects must be willing to adhere to study procedures. 
 
B. Roll-Over Subjects: Subjects who have successfully completed Study RB-US-13-0001 in its 
entirety must complete EOS/Day 169 assessments, which will serve as screening for this 
study. In addition, only the following criteria must be met to be enrolled in this study: 
1. Provide written consent to participate in this study. 
2. Be considered eligible in the medical judgment of the Investigator. 


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3. Females: Women of childbearing potential (defined as all women who are not surgically 
sterile or postmenopausal for at least 1 year prior to informed consent) must have a negative 
pregnancy test prior to enrollment and must agree to use a medically acceptable means of 
contraception from screening through at least 6 months after the last dose of IMP. 
Males: Subjects with female partners of child-bearing potential must agree to use medically 
acceptable contraception after signing the ICF through at least 6 months after the last dose of 
IMP. Male subjects must also agree not to donate sperm during the study and for 6 months 
after receiving the last dose of IMP. 
The following methods of contraception are considered to be medically acceptable:  
established use of oral, injected or implanted hormonal contraception; placement of an 
intrauterine device or intrauterine system; use of a double-barrier method of contraception 
(condom or occlusive cap with use of a spermicide) or male sterilization.   
4. Subjects must agree not to take any buprenorphine products other than those administered 
during the current study throughout participation in the study. 
5. Subjects must be willing to adhere to study procedures. 
 
4.3 
Exclusion Criteria 
A. De novo Subjects who meet any of the following criteria will be excluded from the study: 
1. Current diagnosis, other than opioid use disorder, requiring chronic opioid treatment. 
2. Current substance use disorder, as defined by DSM-5 criteria, with regard to any 
substances other than opioids, cocaine, cannabis, tobacco, or alcohol. 
3. Positive UDS result at screening for cocaine or cannabis AND meets DSM-5 criteria for 
either moderate or severe cocaine or cannabis use disorder, respectively. 
4. Meets DSM-5 criteria for moderate or severe alcohol use disorder. 
5. Treatment for opioid use disorder required by court order.   
6. Current incarceration or pending incarceration/legal action that could interfere with a 
subject’s ability to participate in the study. 
7. Pregnant or lactating females. 
8. Current use of prescription or OTC medications that are clinically relevant cytochrome 
P450 3A4 or cytochrome P450 2C8 inducers or inhibitors (e.g., rifampicin, azole 
antifungals [e.g., ketoconazole], macrolide antibiotics [e.g., erythromycin]) with the 
exception of marijuana.  More examples are provided in the excluded medications list 
(Appendix 9). 
9. History of suicidal ideation within 30 days prior to providing written informed consent as 
evidenced by answering “yes’ to questions 4 or 5 on the suicidal ideation portion of the 
eC-SSRS completed at the screening visit or history of a suicide attempt (per the eC-
SSRS) in the 6 months prior to informed consent. 
10. Current or history (within the 6 months prior to providing written informed consent) of 
chest pain or palpitation with either exertion or drug use, peripheral or generalized 
edema, clinically significant cardiovascular disease, including myocardial infarction, 
heart failure, uncontrolled hypertension, clinically significant orthostatic hypotension, 
endocarditis, or myocarditis.  
11. Clinically significant abnormal systolic blood pressure (BP) or diastolic BP, in the 
opinion of the Investigator. 


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12. Uncontrolled medical or psychiatric illness that, in the opinion of the Investigator or 
Sponsor, may place the subject at risk or interfere with outcome measures or a subject’s 
ability to participate in the study. 
13. Clinically significant abnormality (e.g., severe respiratory insufficiency) in past medical 
history or at the screening physical examination that, in the opinion of the Investigator or 
Sponsor, may place the subject at risk or interfere with outcome variables.   
14. History or presence of allergic or adverse response (including rash or anaphylaxis) to 
buprenorphine, naloxone, or the ATRIGEL Delivery System. 
15. Total bilirubin ≥ 1.5x the upper limit of normal (ULN), alanine aminotransferase (ALT) 
≥3xULN, aspartate aminotransferase (AST) ≥ 3xULN, serum creatinine > 2xULN, 
international normalized ratio (INR) >1.5xULN, lipase >3xULN, amylase >3xULN, or 
any abnormal pancreatic enzyme value above ULN that is associated with clinically 
significant, active pancreatic disorder. 
16. Congenital long QT syndrome, history of prolonged QT in the 3 months prior to 
screening, or a corrected QT interval (Fridericia’s – QTcF) >450 msec (male) or >470 
msec (female) or history of risk factors for Torsades de Pointes. 
17. Diagnosis of acquired immunodeficiency syndrome (AIDS). 
18. Affiliated with, or a family member of, site staff directly involved in the study. 
19. Unable, in the opinion of the Investigator or the medically responsible physician, to 
comply fully with the study requirements.   
20. Clinically significant anemia or low hemoglobin (levels < 9 g/dL) at Screening.  
21. Donation of > 250 mL of blood or plasma within the 30 days prior to providing written 
informed consent  
22. Participation in any other clinical trial within 30 days prior to informed consent  
23. Received medication-assisted treatment for opioid use disorder (e.g., methadone, 
buprenorphine) in the 90 days prior to providing written informed consent  
24. Previously received RBP-6000. 
25. Use of (within the past 30 days prior to providing written informed consent) or positive 
UDS result at screening for barbiturates, benzodiazepines, or methadone.  
 
B. Roll-Over Subjects who meet any of the following criteria will be excluded from the study: 
1. Discontinued early from Study RB-US-13-0001 
2. Experienced any major protocol deviations or adverse events during the RB-US-13-0001 
study which, in the opinion of the Investigator, could potentially compromise subject 
safety. 
3. Women of childbearing potential who have a positive pregnancy test at EOS/Day 169, 
who are pregnant or breastfeeding, seeking pregnancy, or failing to use adequate 
contraceptive methods during the study. 
 


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4.4 
Day -1/Enrollment Criteria 
Beginning on the 4th day of SUBOXONE sublingual film dosing (Study Day -11) through the 
14th day of dosing, subjects will be evaluated for Day -1 criteria.  Subjects must meet the 
following criteria in order to be enrolled: 
1. No allergic reaction to SUBOXONE sublingual film. 
2. Daily dose of SUBOXONE sublingual film between 8 mg/2 mg - 24 mg/6 mg (inclusive) 
buprenorphine/naloxone. 
3. COWS score of ≤ 12. 
4. Opioid Craving VAS score of ≤ 20 mm. 
 


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5 
STUDY TREATMENTS 
5.1 
Description of Treatments 
5.1.1 
SUBOXONE Sublingual Film 
SUBOXONE sublingual film is supplied as an orange rectangular sublingual film with a white 
printed logo.  Each SUBOXONE sublingual film contains buprenorphine HCl and naloxone HCl 
dihydrate at a 4:1 ratio expressed as the free bases.  Films are intended for SL administration and 
are available in 4 dosage strengths (2 mg/0.5 mg; 4 mg/1 mg; 8 mg/2 mg; and 12 mg/3 mg).   
5.1.2 
Investigational Medicinal Products 
RBP-6000 uses buprenorphine base in the ATRIGEL Delivery System, which is currently used 
in a number of approved commercial products.  RBP-6000 will be supplied as a single-syringe 
system, which is prefilled with RBP-6000.  The entire contents of the prefilled syringe will be 
administered.  (See Appendix 8: Study Drug Preparation and Dispensing Procedures for detailed 
dosage instructions).   
RBP-6000 is manufactured by Indivior Inc. according to Good Manufacturing Practice 
standards. 
All used syringes components will be disposed of in accordance with the site’s standard 
operating procedures (SOP) or pharmacy destruction policy. The site’s clinical research associate 
(CRA) will review the site’s SOP and/or pharmacy destruction policy.  All IMP packaging will 
be retained for CRA verification. 
5.2 
Treatments Administered 
5.2.1 
Run-In Treatment Period 
5.2.1.1 
SUBOXONE Sublingual Film Induction (De novo Subjects) 
De novo subjects will receive their first dose of SUBOXONE sublingual film on Induction 
Day 1.  Subjects will be started with an initial dose of 2 mg/0.5 mg or 4 mg/1 mg and may titrate 
upwards in 2 or 4 mg increments of buprenorphine, at approximately 2-hour intervals, under 
clinical supervision, to 8 mg/2 mg based on therapeutic response.  
On Induction Day 2, subjects with a COWS score > 12, or subjects reporting withdrawal 
signs/symptoms overnight, will receive a dose of SUBOXONE sublingual film equal to the total 
dose given on Induction Day 1 plus 4 mg. (For example, if a subject received a total dose of 8 
mg on Induction Day 1, the starting dose of buprenorphine for Induction Day 2 would be 12 mg).  
If the COWS score is still > 12 one hour later, another 4 mg dose can be given. The subject 
should not exceed a maximum dose of 16 mg/4 mg for Induction Day 2. Subsequent 
SUBOXONE sublingual film doses must be separated by at least 1 hour from the preceding dose. 
SUBOXONE sublingual film doses may also be adjusted downward if necessary.  


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On Induction Day 3, subjects will be titrated to therapeutic response based on COWS scores as 
well as physician judgment. Most subjects will only require a single dose on Induction Day 3 
which will equal the Induction Day 2 dose or the Induction Day 2 dose plus 4 mg buprenorphine. 
Additional doses may also be administered on Induction Day 3 (up to 24 mg). Subsequent 
SUBOXONE sublingual film doses must be separated by at least 1 hour from the preceding dose.  
Subjects should reach a daily dose of between 8 mg/2 mg and 24 mg/6 mg by Induction Day 3 
and continue on that dose through the remainder of the SUBOXONE sublingual film Run-In 
period, with additional dose adjustments if necessary.  
The SUBOXONE sublingual film(s) will be administered under the tongue, close to the base on 
the left or right side, until they are dissolved.  If an additional sublingual film is required, it 
should be placed on the opposite side from the first film.  Subjects should be instructed to hold 
the films under the tongue until they dissolve.  If a third film is required, it should be placed 
under the tongue after the first 2 films have dissolved.   
For more information about SUBOXONE sublingual film administration, please refer to the 
SUBOXONE Full Prescribing Information (See Appendix 7). 
5.2.1.2 
SUBOXONE Sublingual Film Induction (Roll-over Subjects) 
Following screening, roll-over subjects will be inducted on SUBOXONE sublingual film to 
achieve daily doses between 8 mg to 24 mg buprenorphine according to the SUBOXONE 
sublingual film prescribing instructions. Roll-over subjects may start their SUBOXONE run in 
on the same day that they complete the RB-US-13-0001 EOS visit (and up to 7 days after this 
date) provided they meet the appropriate inclusion criteria and do not meet any exclusion 
criteria. Subjects must be titrated to a minimum dose of 8 mg SUBOXONE by the end of the 3-
day Induction period regardless of their COWS scores and/or the presence or absence of 
withdrawal symptoms.   
Subjects will receive their first induction dose on Induction Day 1. Subjects should be started 
with an initial dose of 2 mg/0.5 mg or 4 mg/1 mg buprenorphine/naloxone and may titrate 
upwards in 2 or 4 mg increments of buprenorphine, at approximately 2-hour intervals, under 
supervision, to a total dose of up to 8 mg/2 mg buprenorphine/naloxone based on the control of 
acute withdrawal symptoms.  
On Induction Day 2, subjects with a score for COWS of > 12, or subjects reporting opioid 
withdrawal signs/symptoms overnight, should receive a dose of study drug equal to the total dose 
given on Induction Day 1 plus 4 mg.  If the COWS score is still > 12 one hour later, another 4 
mg dose can be given.  The subject should not exceed a maximum dose of 16 mg/4 mg 
buprenorphine/naloxone for Induction Day 2.  Subsequent SUBOXONE sublingual film doses 
must be separated by at least 1 hour from the preceding dose.  SUBOXONE sublingual film 
doses may also be adjusted downward if necessary.   
 
On Induction Day 3, subjects will be titrated to therapeutic response until a therapeutic dosage is 
reached, based on COWS scores as well as physician judgment. Most subjects will only require a 
single dose on Induction Day 3 which will equal the Induction Day 2 dose or the Induction Day 2 
dose plus 4 mg. Additional doses may also be administered on Induction Day 3 (up to 24 mg).  


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Subsequent SUBOXONE sublingual film doses must be separated by at least 1 hour from the 
preceding dose.  Although subjects should reach a daily dose of between 8 mg and 24 mg by 
Induction Day 3 and continue on that dose through the remainder of the SUBOXONE sublingual 
film Run-In period, dose adjustments may be necessary during the Run-In period.  
The SUBOXONE sublingual film(s) will be administered under the tongue, close to the base on 
the left or right side, until they are dissolved.  If an additional sublingual film is required, it 
should be placed on the opposite side from the first film.  Subjects should be instructed to hold 
the films under the tongue until they dissolve.  If a third film is required, it should be placed 
under the tongue after the first 2 films have dissolved.   
For more information about SUBOXONE sublingual film administration, please refer to the 
SUBOXONE Full Prescribing Information (See Appendix 7). 
5.2.2 
Dose Adjustment Period (All Subjects) 
Beginning at Day -11, subjects will be assessed to determine whether they meet Day -1 
/enrollment criteria as defined in Section 4.4.  Once subjects meet the enrollment criteria (no 
significant opioid craving (≤20 mm on the Opioid Craving Visual Analog Scale [VAS] and no 
significant withdrawal (≤ 12 on the Clinical Opiate Withdrawal Scale [COWS]), they are eligible 
to receive the first SC injection of RBP-6000 (containing 300 mg buprenorphine). Subjects with 
significant withdrawal signs/symptoms (defined as >12 on the COWS) or significant cravings for 
opioids (defined as >20 mm on the Opioid Craving VAS) after the end of the 2-week 
SUBOXONE sublingual film Run-In period will not be eligible to continue in the study and will 
be referred for treatment.   
5.2.3 Active Study Treatment 
On Day 1 of the study (initiation of study drug injections), all subjects will receive a SC injection 
of 300 mg of buprenorphine in RBP-6000. Subsequent doses of RBP-6000 may be adjusted 
down to 100 mg and back up to 300 mg based on the medical judgment of the Investigator.   All 
subjects will receive injections of RBP-6000 separated by 28 (± 2) days.   
After injection of RBP-6000, subjects will not be permitted to receive supplemental 
SUBOXONE sublingual film during the RBP-6000 treatment period. Subjects who require 
supplemental SUBOXONE sublingual film or other sublingual buprenorphine pharmacotherapy 
during the RBP-6000 treatment period will be withdrawn from the study and referred for 
appropriate treatment. 
A single SC dose will be injected by an individual who is medically qualified to perform the 
procedure and delegated by the Principal Investigator to perform the task.  Injections of 
RBP-6000 will be administered in the abdominal area below the waist but above the hip bone; 
more specifically, injection should occur in the region where the body curves at the side to about 
2 inches from the middle of the abdomen with adequate amounts of subcutaneous tissue that 
does not have excessive pigment, nodules, lesions, or hair.  RBP-6000 will form a solid polymer 
depot that contains the buprenorphine.  As the depot degrades, buprenorphine will be released 


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into the systemic circulation at a consistent rate over an approximately 28-day period.  For 
detailed instructions on use, see Appendix 8. 
Approximately 2 months prior to the scheduled EOS visit, the subject’s ongoing treatment 
options will be reviewed with the investigator. At the EOS, 2 transition treatment options may be 
offered if the subject is eligible: 
• Subjects who complete the RBP-6000 treatment period may be offered entry into an open 
label extension study of RBP-6000 (Study INDV-6000-301).  Eligibility will be based on 
meeting the inclusion and exclusion criteria and the medical judgment of the Investigator. 
• Subjects who do not meet the eligibility criteria of the extension study, or subjects who 
do not wish to enroll may alternatively enter a 4-week SUBOXONE transition period if 
deemed suitable by the investigator.  Subjects should be dosed using the Investigators 
medical judgement. Any additional unscheduled visits required by the subject for the 
SUBOXONE transition will not be compensated by the Sponsor.   
5.3 
Selection and Timing of Dose for Each Subject 
The study schedule is designed so that each of the injections will be separated by a maximum of 
30 days (28 days ± 2 days) and will be given on alternate sides of the subject’s abdomen (see 
Appendix 8 and the Pharmacy Manual for detailed information on administration).   
5.4 
Method of Assigning Subjects to Treatment Groups 
When a de novo or roll-over subject signs the ICF, she/he will be assigned a unique subject 
number in numerical sequence, which will be used for the duration of the study. Roll-over 
subjects will retain the subject number assigned to them in the RB-US-13-0001 study. De novo 
subjects will be assigned a unique subject number, consisting of the site number followed by 9 
and a 3 digit number in numerical sequence (e.g., the first de novo subject screened at site # 001 
will be assigned the number 0019001).  The subject number will be recorded in the source 
document and electronic case report form (eCRF). 
All subjects will be assigned to receive the 300 mg RBP-6000 dose. Subsequent doses of 
RBP-6000 may be adjusted down to 100 mg and back up to 300 mg based on the medical 
judgment of the Investigator 
5.5 
Blinding 
Not applicable; this is an open-label study  
 
5.6 
Concomitant Therapy 
Concomitant therapies are defined as prescribed medications and OTC preparations, including 
herbal preparations and vitamins, other than study medication and supplementary medication that 
the subject receives within 30 days of screening and for the during the course of the study.  Any 
medication taken by the subject is to be reported by the subject and noted on the subject’s source 


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document and concomitant medication page.  Any changes in concomitant therapy during the 
study will be documented, including cessation of therapy, initiation of therapy, and dose 
changes. 
Roll-over subjects who started on a benzodiazepine during the RB-US-13-0001 study will be 
evaluated on a case-by-case basis for inclusion in the RB-US-13-0003 study.  The investigator 
will discuss these subjects with the medical monitor before enrolling into the RB-US-13-0003 
study. 
The Investigator or designee will also record any medications given for the treatment of AEs on 
the concomitant medication page.   
5.6.1 
Permitted Concomitant Medications 
Following screening and enrollment, ancillary medications (ibuprofen, acetaminophen, 
methocarbamol, hydroxyzine, and loperamide) may be administered to subjects to help alleviate 
signs and symptoms of opioid withdrawal as deemed necessary by the Investigator or medically 
qualified sub-investigator.  Details on acceptable administration of these medications and 
preparations are provided below: 
• Ibuprofen (400 mg orally) may be given every 4 to 6 hours as needed for pain up to a 
maximum of 2400 mg per day.  Subjects for whom ibuprofen is contraindicated or not 
tolerated may be given acetaminophen (325 to 1000 mg every 4 to 6 hours) as needed up 
to a maximum of 3000 mg per day.  Caution should be exercised when using 
acetaminophen concomitantly with other medications that have potential hepatotoxic 
effects.  Methocarbamol may also be given as needed for relief of muscle pain in 
clinically appropriate doses based on physician assessment. 
• Hydroxyzine (50 to 100 mg orally) may be given every 6 hours as needed for anxiety, 
nausea, or vomiting.  Additionally, hydroxyzine (50 to 100 mg orally) may be given at 
bedtime as needed for sleep.  The hydroxyzine daily dose should not exceed a maximum 
of 600 mg per day. 
• Loperamide (2 to 4 mg orally) may be given as needed for diarrhea up to a maximum of 
16 mg per day. 
5.6.2 
Prohibited Concomitant Medications 
Concomitant therapies subject to the restrictions indicated under Prohibited Concomitant 
Medications may be used only following approval by the Sponsor unless an immediate medical 
need necessitates their use.  These are listed below:   
• Use of buprenorphine. 
• Ongoing prescription that are clinically relevant P450 3A4 inducers or inhibitors, such as 
azole antifungals (e.g., ketoconazole) and macrolide antibiotics (e.g., erythromycin). 
• Herbal supplements that have the potential to cause prolongation of the QTc interval.   


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• Over-the-counter medications that have the potential to cause prolongation of the QTc 
interval.  This does not apply to over-the-counter medications listed under Concomitant 
Therapies above that are prescribed by the Investigator, or over-the counter medications 
that may be used by the Investigator for an immediate medical need that necessitates their 
use. The medical monitor should be consulted for any questions. 
• Medications, in the addition to those listed above, which may be expected to significantly 
interfere with the metabolism or excretion of buprenorphine that may be associated with 
a significant drug interaction with buprenorphine, or may pose a significant risk to 
subjects’ participation in the study. 
Other concomitant medications, OTC preparations, or therapies that are not allowed during study 
participation are listed in Appendix 9. 
5.7 
Restrictions 
5.7.1 
Prior Therapy 
All prior medications including OTC, dietary supplements, and herbal preparations taken by the 
subject within the 30 days prior to screening will be recorded. 
5.7.2 
Subject Activity Restrictions 
Subjects should be advised to avoid strenuous exercise. 
5.8 
Protocol Compliance 
This study involves the SC injection of multiple doses of RBP-6000 containing 100 or 300 mg of 
buprenorphine (see the Schedule of Events [SOE], Appendix 2).  The Investigator may terminate 
a subject based on the subject’s inability or willingness to comply with the protocol 
requirements. 
IMP will be administered by designated and qualified study personnel at the site.  The time and 
duration, the dose delivered, and any dosing observations will be recorded in source 
documentation.  The Investigator or designated individual will maintain a log of all study drugs 
dispensed and returned (if applicable).  Drug supplies will be inventoried and accounted 
throughout the study. 
5.9 
Packaging and Labeling 
RBP-6000 will be packaged and labeled in a manner consistent with the study design and 
applicable regulations.  The study medication will be provided to the investigator(s) by the 
Sponsor or contractor.   
The SUBOXONE sublingual film will be supplied as bulk films in the following buprenorphine 
dosage strengths: 2mg /0.5 mg; 4 mg/1 mg; 8 mg/2 mg; and 12 mg/3 mg.  Containers will be 
labeled with a single panel disclosing the product name, lot number, contents, Sponsor name and 
address, route of administration, and appropriate precautionary statements. 


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The study drug, RBP-6000, will be identified as an investigational compound. 
The following components will be used in the preparation of RBP-6000: 
• One sealed foil pouch containing a syringe prefilled with RBP-6000 and an oxygen 
absorber pack. 
• One sterile 19-gauge, 1 inch hypodermic safety needle. 
5.10 Storage and Accountability 
RBP-6000 should be stored under refrigerated conditions between 2-8ºC (36-46°F). Temperature 
excursions between 8 and 25°C (46 and 77°F) are permitted for a maximum duration of 48 
hours; Temperature excursions between 2 and -20°C (-4 and 36°F) are permitted for a maximum 
duration of 7 days. Temperature excursions outside of these ranges or timeframes should be 
reported to the Sponsor immediately and approval for use should be obtained. 
 
SUBOXONE sublingual films should be stored at 25°C (77°F) with excursions permitted 
between 15-30°C (59-86°F).  Temperature excursions outside of these ranges should be reported 
to the Sponsor immediately and approval for use should be obtained. 
 
The PI or designee is responsible for ensuring that all study drug received at the site is 
inventoried and accounted for throughout the study. Drug accountability is the responsibility of 
the PI or designee, with verification by the CRA. Study drug must be handled strictly in 
accordance with the protocol, handling guidelines and the label, and must be stored in a locked, 
limited access area under appropriate environmental conditions. The PI must ensure that proper 
conditions exist for storage of study treatments. The dispensing of study drug to the subject must 
be documented on the drug dispensing form. 
 
Unused study drug must be available for verification by the Sponsor’s site monitor during on-site 
monitoring visits. The return to the Sponsor of unused study drug will be documented on the 
Study Drug Return Form. 
 
The Investigator agrees not to supply RBP-6000 to any person except study personnel for SC 
injection of subjects in this study.   
5.11 Investigational Product Retention at Study Site 
The PI or medically-qualified designee agrees to conduct a study drug supply inventory for  
RBP-6000, to record results of this inventory, and to return all unused study drug to the Sponsor 
at times specified by Indivior. Indivior will arrange for the appropriate and timely destruction of 
all returned, unused RBP-6000. All used needles and syringes from RBP-6000 will be disposed 
of into an appropriate secure biohazard container per the standard operating procedures (SOPs) 
at the study site.  


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All used IMP packaging (e.g. carton, foil pouch) will be retained at the study site until 
reconciliation is performed by the CRA. After reconciliation is completed, the used IMP 
packaging may be disposed of per the SOPs at the study site. 


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6 
STUDY PROCEDURES 
The SOE for this study is provided in Appendix 1, Appendix 2, Appendix 3, Appendix 4, and 
Appendix 5. 
For roll-over subjects, study procedures completed at EOS/Day 169 for study RB-US-13-0001 
will serve as screening assessments for the open-label study.   
6.1 
Informed Consent 
6.1.1 
General Information 
Prior to entering the study, the Investigator or designated individual must explain to each subject 
the nature of the study, its purpose, procedures, expected duration, alternative therapies 
available, and the benefits and risks involved in study participation. Subjects must be given the 
Institutional Review Board (IRB)-approved ICF version to review and the opportunity to ask 
questions. Subjects must be informed of their right to withdraw from the study at any time 
without prejudice. The potential subjects should be able to answer simple questions about the 
study after the ICF has been reviewed and explained. After this explanation and before any 
study-specific procedures have been performed, the subject must voluntarily sign and date the 
ICF to indicate the desire to participate in the study. Prior to participation in the study, the 
subject must receive a copy of the signed and dated ICF.  
Roll-over subjects will complete all Day 169/EOS procedures for study RB-US-13-0001 prior to 
signing the ICF for this study.  
6.2 
Medical History 
For de novo subjects, a detailed medical history will be obtained by the PI or medically qualified 
designee during the screening visit (Visit 1). This will include information regarding the 
subject’s full history of medical and psychiatric conditions, diagnoses, procedures, treatments, 
concomitant medications, demographic information, and use of tobacco, drugs of abuse, alcohol, 
and caffeine, and any other noteworthy medical information, including suicidality measured 
using the eC-SSRS. Any updates to medical history information that the PI or medically 
qualified designee becomes aware of will be captured throughout the study.  All prior 
medications, OTC health, and dietary supplements taken by the subject within 30 days will be 
recorded.  In addition, hospitalizations in the past 3 months and the reason for admission 
(medical/surgical/psychiatric/other) will be recorded.   
For roll-over subjects medical history will not be re-obtained, except for new information. 
6.3 
Physical Examination 
A complete physical examination (PE) will be performed by the Investigator or medically 
qualified designee.  The physical examination will consist of an examination of the following:  
general appearance, skin, head, eyes, ears, nose, throat, neck (including thyroid), lymph nodes, 
chest and lungs, heart, abdomen, extremities, body weight, and a brief neurological assessment.  


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The examination will not include a pelvic, breast, or rectal examination.  If any clinically 
significant abnormal findings started before the date that informed consent was given, these 
findings should be recorded on the Medical History case report form (eCRF).   
If any clinically significant change from screening (Visit 1 for de novo subjects; Study RB-US-
13-0001 EOS visit (Day 169) for roll-over subjects) is noted, it will be reported as an AE and 
followed up to resolution or until reaching a stable end point. 
Weight (kg) will be assessed (in ordinary indoor clothing with shoes off) and will be recorded at 
screening as well as periodically throughout the study.  Height (cm) will be recorded at screening 
only.  BMI will be calculated at screening as well as periodically throughout the study.  BMI is 
defined as the subject’s weight in kg divided by the square of the subject’s height in meters 
(kg/m2).  The amount of abdominal fat will be measured using the waist-to-hip ratio and will be 
recorded at screening as well as periodically throughout the study.   
Procedures performed at Day 169/EOS in the RB-US-13-0001 study will not be repeated at the 
screening visit for roll-over subjects. 
Assessments are performed at the time points detailed in the SOEs (Appendix 1, Appendix 2, 
Appendix 3, Appendix 4, and Appendix 5). 
6.4 
Vital Signs 
Evaluation of vital signs will be performed after the subject has been supine for ≥ 3 minutes and 
will include a measurement of systolic and diastolic BP, pulse rate, pulse oximetry, respiratory 
rate, and oral temperature.   
If clinically significant findings, as determined by the Investigator or medically qualified sub-
investigator, occur in any vital sign measurement, that measurement will be captured as an AE 
and repeated at medically appropriate intervals until the value returns to an acceptable range, a 
specific diagnosis is established, or the condition is otherwise explained. 
Assessments will be recorded in the source documents and eCRF and will be performed at the 
time points detailed in the SOE (Appendix 1, Appendix 2, Appendix 3, Appendix 4, and 
Appendix 5). 
6.5 
Electrocardiograms 
6.5.1 
12-Lead Electrocardiograms 
Resting 12-lead ECGs will be recorded with the subject in supine position following a 10-minute 
rest period. For roll-over subjects, ECGs will be recorded prior to the PK blood sampling. 
(Appendix 6). 
Resting 12-lead ECGs will be recorded as indicated in the SOEs (Appendix 1, Appendix 2, 
Appendix 3, Appendix 4, and Appendix 5). ECGs recorded at screening will be recorded in 
triplicate, at approximately 2 - 5 minute intervals.  


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ECG intervals including HR, QT, QTcF, QTcB, RR, PR, QRS and T wave changes will be 
recorded.  ECGs will be reviewed by the Investigator during the visits for any immediate 
abnormalities. ECGs will also be reviewed by a central facility.   
The findings of the ECGs as determined by the central facility will be assessed by the 
Investigator and marked as normal, abnormal-not clinically significant, or abnormal-clinically 
significant.  All clinically significant abnormalities will be captured as AEs.  In the event that a 
clinically significant AE related to an ECG assessment occurs during the study, the Investigator 
should contact the Indivior Medical Monitor. 
6.6 
Clinical Laboratory Tests 
6.6.1 
Laboratory Parameters 
All clinical laboratory assessments will be performed by a clinical laboratory accredited by the 
College of American Pathologists or with a certificate of compliance (or certificate of waiver for 
CLIA-waived tests) issued by the Center for Medicare & Medicaid Services or Clinical 
Laboratory Improvement Amendments.  The laboratory assessments will include routine and 
screening laboratory tests.   
See the SOEs in Appendix 1, Appendix 2, Appendix 3, Appendix 4, and Appendix 5 for the 
timing of the specific required laboratory tests which are listed in Table 2.  
Any abnormal hematology, chemistry, or urinalysis test result deemed clinically significant by 
the Investigator will be repeated, including test results obtained on the final study day.  For any 
test abnormality deemed clinically significant, an AE will be recorded (unless the result was 
considered erroneous) and repeat analysis will be performed until resolution or until the 
Investigator determines that resolution of the laboratory abnormality is not expected.   
Subjects will be in a seated or supine position during blood collection.  Clinical laboratory panels 
are listed in Table 2. 


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Table 2 
List of Laboratory Tests 
Hematology: 
Hematocrit 
Hemoglobin  
Mean corpuscular hemoglobin  
Mean corpuscular hemoglobin concentration  
Mean corpuscular volume  
Platelet count 
Pancreatic enzymes 
Red blood cell count 
White blood cell count with differential 
 
Urinalysis: 
Appearance 
Bilirubin 
Color 
Glucose 
Ketones 
Leucocyte esterase 
Microscopic examination of sedimenta 
Nitrite 
Occult blood 
pH 
Protein 
Specific gravity 
Urobilinogen 
 
Hormone Panel: 
Adrenocorticotropic hormone (ACTH) Follicle Stimulating 
Hormone 
Testosterone (total and free) 
 
Pregnancy: 
Urine Pregnancy (only for females not postmenopausal or 
surgically sterile for at least 1 year) 
Serum Pregnancy 
 
Screening:    
Hemoglobin A1c  
HIV-1 and -2 antibodies 
PTT 
PT with INR 
Serum pregnancy 
 
Serum Chemistry: 
Albumin 
Alkaline phosphatase 
Alanine aminotransferase (ALT) 
Amylase 
Aspartate aminotransferase (AST) 
Blood urea nitrogen 
Calcium 
Calculated creatinine clearance 
Carbon dioxide 
Chloride 
Creatinine 
Creatine kinase and subtypes 
Gamma-glutamyl transferase 
Globulin 
Glucose (non-fasting) 
High-density lipoprotein (HDL) 
Immunoreactive trypsinogen 
Lactate dehydrogenase 
Lipase 
Low-density lipoprotein (LDL) 
Magnesium 
Phosphorus 
Potassium 
Sodium 
Total bilirubin 
Direct bilirubin 
Total cholesterol 
Total protein 
Triglycerides 
Uric acid 
 
Urine Drug Screen (UDS): 
Opioidsb 
Cocaine 
Amphetamines 
Methadone 
Cannabinoids 
Barbiturates 
Benzodiazepines 
Methamphetamine 
Phencyclidine 
Anti-HIV = human immunodeficiency virus antibodies; hCG = human chorionic gonadotropin; INR = 
international normalized ratio; IRT = immunoreactive trypsinogen; PT = prothrombin time; and PTT = 
partial thromboplastin time. 
a 
Microscopic examination of sediment will be performed only if the results of the urinalysis evaluation are 
positive (microscopic examination may include but is not limited to WBC count, RBC count, casts, and crystals). 
b 
Oxycodone may not show up in all opiate assays and should be assessed separately. 
   
 


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6.6.2 
Sample Collection, Storage, and Shipping 
All blood sampling will be by individual venipuncture or with the use of a saline lock.  Blood 
and urine sample collection and processing procedures will be outlined in a separate reference 
manual to be provided to the site. 
6.6.3 
Reference Ranges 
Up-to-date reference ranges for the above investigations must be obtained for the laboratory 
performing analyses prior to the start of the study and be updated as appropriate during the 
course of the study. 
6.6.4 
Laboratory Results Review 
The Investigator will review the results and comment on the laboratory results sheet for all 
abnormal values, identifying those that are abnormal but not clinically significant as well as 
those that are significantly abnormal.  The Investigator will sign and date the laboratory results 
sheet to indicate that the review has taken place. 
Clinical Laboratory Changes:  It is the Investigator’s responsibility to review the results of all 
laboratory tests as they become available.  This review will be documented by the Investigator 
on the laboratory report.  For each abnormal laboratory test result, the Investigator needs to 
ascertain if this is a clinically significant abnormal change from baseline for that individual 
subject.  
6.6.5 
Good Laboratory Practice Compliance 
Confirmation of compliance with Good Laboratory Practice (GLP) will be obtained from the 
designated Bioanalytical Laboratory prior to the start of the study. 
6.7 
Pharmacokinetic Assessments 
Blood samples for population PK analysis will be collected from roll-over subjects only at the 
time points indicated in the PK sampling schedule (Appendix 6). Once 100 roll-over subjects 
have completed Injection 6 (Week 25, Day 169) the sites will be notified that no more PK 
samples will be required to be collected from the roll-over subjects for the duration of the study. 
The plasma concentrations of buprenorphine and norbuprenorphine will be quantified using 
specific and validated liquid chromatography tandem mass spectrometry methods. A laboratory 
manual for PK sample collection, processing, storage, and shipping will be supplied. 
However, for all subjects (de novo and roll-over) throughout the study, a PK sample will be 
taken as soon as possible after any SAE is reported.  If possible, an additional sample should be 
collected when the SAE has been resolved. 
The exact times (to the minute) of PK blood sampling as well as the exact times of drug 
administration will be recorded in the source and eCRF.   


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6.8 
Administration of Study Drug 
The study drug will be assigned by an IWRS system. Injections will be administered by a 
physician or suitably-qualified designee (e.g., physician, nurse, nurse practitioner, PA) who has 
been delegated to perform the task.  Study drug will be supplied only to subjects participating in 
the study. The Investigator agrees not to allow the study drug to be administered from, nor stored 
at, any site other than the study site agreed upon with the Sponsor. 
See Appendix 7 for detailed descriptions of dosing for the SUBOXONE sublingual film. 
Detailed instructions for the preparation and administration of RBP-6000 are in Appendix 8. 
If at an injection visit there is a safety concern with administration of RBP-6000, after discussion 
with the medical monitor or sponsor, dosing can be delayed up to one week.  In the event this 
occurs, the subsequent doses will be delayed.  There must be at least 26 days between injections 
of study medication. 
All used syringe components will be disposed of into an appropriate secure biohazard container 
or per the SOPs at the study site. 
All used IMP packaging (e.g., carton, foil pouch) will be retained at the study site until the CRA 
conducts a visit to perform reconciliation.  After the reconciliation is completed, the used IMP 
packaging may then be disposed of per the SOPs at the study site. 
Unused IMP and returned SUBOXONE sublingual film must be available for verification by the 
Sponsor’s site monitor during on-site monitoring visits.  The return of unused or used returned 
IMP for destruction will be documented on the drug return form. 
6.9 
Safety and Suicidality Assessments 
Safety will be assessed by AEs, vital signs, ECGs, clinical laboratory assessments, local injection 
site grading scale, injection site pain VAS, and eC-SSRS responses. See the SOE for specific 
timing of assessments (Appendix 1, Appendix 2, Appendix 3, Appendix 4, and Appendix 5). 
6.9.1 
Local Injection Site Tolerability 
6.9.1.1 
Injection Site Grading 
Local injection site grading will be performed by the Investigator or a trained and qualified 
health care professional, according to the SOE in Appendix 2, Appendix 3, Appendix 4, and 
Appendix 5.  Injection sites will be assessed for pain, tenderness, erythema/redness, induration, 
or swelling.  Local injection site tolerability will be assigned a severity grade, including none 
(grade 0), mild (grade 1), moderate (grade 2), severe (grade 3), or potentially life threatening 
(grade 4) utilizing the Injection Site Grading Scale in Appendix 15.  The local injection site 
grading assessment will be completed electronically on injection days immediately after each 
injection (within 10 minutes) and at 1 hour (± 15 minutes). For Injection 1 only, local injection 
site grading will be completed 24 hours (±4 hours) after the injection. 


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6.9.1.2 
Injection Site Pain Visual Analogue Scale (VAS)  
Injection site pain will be assessed by the subject at each injection visit electronically with a 
100mm VAS scale, where 0 represents no pain and 10 represents maximum pain (Appendix 16).  
The injection site-pain VAS scores will be obtained (after the completion of the injection) within 
1 minute and then at 5, 10, 15, 30, and 60 minutes (±5 minutes).  The timing of the Injection Site 
Pain VAS should be measured from the end of the injection.  In addition to rating pain levels by 
marking on the line the point they feel best represents their perception of their current state, the 
subject will also answer the following question with either a Yes or No: Are you currently 
experiencing any burning or stinging at the injection site? 
6.9.2 
Suicidality 
6.9.2.1 
Columbia Suicide Severity Rating Scale 
The eC-SSRS will be administered according to the SOE in Appendix 1, Appendix 2, Appendix 
3, Appendix 4, and Appendix 5.  The eC-SSRS is a questionnaire designed for assessment of 
suicidal ideation and behavior in adolescents and adults (Posner 2011).  The questionnaire will 
be administered as an electronic, self-rated version (eC-SSRS).  Clinical trial versions of the 
questionnaire are available for trial screening and follow-up visits.  A sample section from the 
Baseline/Screening eC-SSRS and the follow-up eC-SSRS are presented in Appendix 10 and 
Appendix 11, respectively.   
If a subject becomes suicidal during the study, the investigator should provide the appropriate 
treatment to the subject.  If the suicidality is deemed to be related to IMP and it is within 14 days 
of an injection, the depot may be removed (Section 6.14.1).  
The eC-SSRS should be completed prior to SUBOXONE and RBP-6000 injection and at 
approximately the same time each day ±2 hours. 
If, there is a positive on the eC-SSRS after screening the subject will be evaluated by the 
investigator for continuation in the study.  If needed, the investigator can consult with the 
medical monitor on continuation in the study of subjects with a positive eC-SSRS. 
6.10 Adverse Events Assessments 
6.10.1 
Definition 
In accordance with ICH and US FDA guidance, any untoward medical occurrence incurred by a 
subject that occurs after the first study-related procedure to the completion of the protocol-
defined safety surveillance period and is associated with the use of the drug, regardless of the 
presence of causal relationship, is a reportable AE.   
Abnormal results of diagnostic procedures, including laboratory test abnormalities, are 
considered AEs if they: 
• Result in discontinuation from the study, 


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• Require treatment or any other therapeutic intervention, 
• Require further diagnostic evaluation (excluding a repetition of the same procedure to 
confirm the abnormality), or 
• Are associated with clinical signs or symptoms that would have a significant clinical 
impact, as determined by the Investigator. 
6.10.2 
Performing Adverse Events Assessments 
The Investigator is ultimately responsible for assessing and reporting all AEs as outlined in the 
protocol.  The assessment of AEs may be delegated to a medically qualified sub-investigator, 
trained on this study protocol, who is listed on the FDA Form 1572 or equivalent document, and 
on the delegation of authority form. 
AEs should be volunteered by the subject or solicited from the subject using a standard 
statement, obtained from examination of the subject at a clinic visit, or from observations of 
clinically significant laboratory values or special examination abnormal values.  If an event 
assessed by one of the study scales requires intervention, or if in the opinion of the Investigator, 
it is clinically significant, then it will be reported as an AE. 
All AEs are to be assessed and recorded in a timely manner and followed to resolution or until 
the Investigator determines that there is not an anticipated resolution.  Each AE is to be 
documented with reference to severity, date of occurrence, duration, treatment, and outcome.  
Furthermore, each AE is to be classified as being serious or non-serious.  In addition, the 
Investigator must assess whether the AE is drug-related or not.  Changes in severity of AEs 
should be documented as one event at the maximum severity that occurred during the study. 
6.10.3 
Timing 
AEs will be captured from the time the subject gives informed consent until the subject 
completes the study. 
Surgical procedures, planned before enrollment of the subject in the study, are not considered 
AEs if the condition was known before study inclusion.  In this case the medical condition 
should be reported in the subject’s medical history.   
If a subject experiences the onset of an SAE within 30 days following study completion and in 
the opinion of the Investigator, that SAE is associated with the study, it will be followed and 
reported as described in Section 6.10.9.2. 
If a SAE occurs a PK sample will be taken as soon as possible after the event is reported.  If 
possible, an additional sample should be collected when the SAE has been resolved. 
6.10.4 
Severity 
Adverse events with changes in severity should be documented as one event at the maximum 
severity. 


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Intensity 
Definition 
Mild 
Causes transient or mild discomfort ; no limitation of usual activities; no 
medical intervention required 
Moderate 
Causes mild to moderate limitation in activity; some limitation of usual 
activities: no or minimal medical intervention or therapy is required. 
Severe 
Causes marked limitation in activity; some assistance is usually required; 
medical intervention or therapy is required; hospitalization is probable.   
 
The term “severe” is used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe); the event itself, however, may be of relatively minor medical significance 
(such as a severe headache). This is not the same as “serious,” which is based on subject/event 
outcome or action criteria usually associated with events that pose a threat to a subject’s life or 
functioning. Seriousness (not severity) serves as a guide for defining regulatory reporting 
obligations. 
6.10.5 
Relationship 
The Investigator or a medically qualified sub-investigator, trained on this study protocol, listed 
on the 1572 form or equivalent document and on the delegation of authority form is responsible 
for determining the AE relationship to the investigational product. 
The following categories will be used to define the relationship of an AE to the administration of 
the investigational product: 
 
Not Related: 
Data are available to identify a clear alternative cause for the AE other than 
the investigational product. 
Related: 
The cause of the AE is related to the investigational product and cannot be 
reasonably explained by other factors (e.g., the subject’s clinical state, 
concomitant therapy, and/or other interventions). 
 
6.10.6 
Expectedness 
An unexpected AE is any AE, the nature and severity of which is not consistent with the 
applicable product information (e.g., Investigator’s Brochure for an investigational product or 
product label/summary of product characteristics for an approved product). 
6.10.7 
Clinical Significance 
The Investigator or medically qualified sub-investigator, trained on this study protocol, listed on 
the 1572 form or equivalent document and on the delegation of authority form is responsible for 
determining clinical significance of abnormal assessment results (e.g., laboratory or ECG results) 
for the subject. 


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6.10.8 
Clinical Laboratory Adverse Events 
Changes in laboratory values or vital signs, or other safety parameters (e.g., ECG, neurological 
and clinical symptom assessments) as noted in the protocol are a subset of AEs and are 
reportable only if considered to be clinically significant by the investigator or medically qualified 
sub-investigator except that: 
• Baseline assessments are differentiated from AE/symptoms that are incurred post 
informed consent.  These baseline lab assessments, if determined to be clinically 
significant abnormal values, reflect the status of the subject prior to study participation.  
These clinically significant pre-dose abnormal assessments without clinical symptoms 
will not be reported as AEs.  
6.10.9 
Serious Adverse Events 
6.10.9.1 
Definition 
A SAE is defined as any AE occurring at any dose that results in any of the following outcomes:  
• death,  
• life-threatening AE, 
• hospitalization or prolongation of existing hospitalization,  
• a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or 
• a congenital anomaly or birth defect. 
“Important medical events may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.”  
6.10.9.2 
Reporting Serious Adverse Events 
All SAEs must be reported to the Sponsor by the Investigator or designee by email or fax within 
24 hours of discovery, using the form provided by the Sponsor. The SAE report should also be 
emailed to the Sponsor Medical Monitor. 
In the event of an SAE, the Investigator or designee will notify Medical Monitor and the Indivior 
Pharmacovigilance: 
Medical Monitor: 
 
 
 
Indivior Pharmacovigilance: 
Email: PatientSafetyNA@indivior.com  


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Fax: (804) 423-8951 
Indivior Inc. 
10710 Midlothian Turnpike, Suite 430 
Richmond, VA 23235 
 
The Investigator or designee must inform the IRB immediately regarding any AE (does not have 
to be causally related) that is both serious and unexpected; or that represents a series of AEs that 
on analysis is unanticipated, or occurs at an unanticipated frequency, or otherwise represents an 
unanticipated safety risk to the study subject. The IRB may subsequently choose to modify the 
informed consent or request changes to the protocol or Investigator’s Brochure.  A PK sample 
will be taken as soon as possible after any SAE is reported. If possible, an additional sample 
should be collected when the SAE has been resolved. 
6.10.10 Treatment-Emergent Adverse Events 
A TEAE is an AE that either commenced following initiation of study drug or was present prior 
to the initiation of study drug, but increased in frequency or severity following initiation of 
treatment, regardless of causality. 
6.10.11 Procedures and Follow-Up of Subjects with Ongoing SAEs or Experiencing 
SAEs after Completion of or Withdrawal from the Study 
Subjects with SAEs ongoing at the end of the study or after ET will be followed by the 
Investigator until stabilization or resolution.  If a subject experiences the onset of an SAE within 
a period of 30 days following study completion or withdrawal and, in the opinion of the 
Investigator or medically qualified sub-investigator, it is associated with the study, it will be 
followed up and reported as described for other SAEs. 
6.10.12 Pregnancy 
If a female subject believes she is pregnant (e.g., missed period, self-administered pregnancy 
test) the subject will be instructed to return to the clinical unit within 48 hours to undergo a 
serum pregnancy test.  If a pregnancy in a subject is confirmed at any time during the study 
through a serum pregnancy performed by the study laboratory, the subject will be discontinued 
from the study and will undergo all final study visit procedures (with the exception of a urine 
pregnancy test).  If the partner of a study subject becomes pregnant, the pregnancy will be 
reported to the clinical unit within 48 hours of the subject’s knowledge of the pregnancy.   
All confirmed pregnancies that occur within this study will be followed until resolution (i.e., 
termination [voluntary or spontaneous] or birth).   
Pregnancy ([study subject or the partner of a study subject] [without associated unexpected or 
adverse sequelae]) is not a reportable AE but must be reported to the Sponsor within 24 hours of 
the Investigator or study staff first being aware of the subject’s condition. 


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6.11 Clinical Outcome Assessments 
Clinical outcome assessments will include the UDS for opioids and other drugs; self-reported use 
of illicit opioids, other drugs, and alcohol on the TLFB; COWS, SOWS, and Opioid Craving 
VAS. 
6.11.1 
Timeline Followback Interview 
The TLFB Interview will be administered according to the SOE in Appendix 1, Appendix 2, 
Appendix 3, Appendix 4, and Appendix 5. The TLFB Interview is a method to assess recent drug 
use and will be administered electronically.  The questionnaire should be administered by an 
interviewer.  The interview instrument asks subjects to retrospectively estimate their drug use in 
the 30 days prior to screen at the screening visit and since the last visit at all subsequent visits.  
Only occurrence of use is captured (i.e., used or did not use) (Fals-Stewart 2000). The interview 
takes approximately 10-30 minutes to complete and is appropriate for males and females 14 
years of age and older.  Drugs to be assessed in this study include opioids, methadone, 
buprenorphine, cocaine, barbiturates, benzodiazepines, amphetamines/methamphetamine, 
phencyclidine, and ethanol (Appendix 17). 
The timeline followback interview should be completed prior to SUBOXONE and RBP-6000 
injection and at approximately the same time each day ± 2 hours. 
6.11.2 
Opioid Craving Visual Analog Scale  
The Opioid Craving VAS will be administered electronically according to the SOE in Appendix 
1, Appendix 2, Appendix 3, Appendix 4, and Appendix 5.  A VAS is an instrument that 
measures a characteristic or attitude that is believed to range across a continuum of values and 
cannot easily be directly measured.  The amount of opioid craving that a subject feels for illicit 
opioids (not the buprenorphine used for treatment of opioid use disorder) can be recorded along a 
continuum from “no craving at all” to “strongest craving ever” (McMillan and Gilmore-Thomas 
1996).  Operationally, the VAS is a horizontal line, 100 millimeters (mm) in length, anchored by 
word descriptors at each end, as illustrated in Appendix 14.  The subject indicates the point on 
the line that he/she feels represents his/her perception of their current state.  The VAS score is 
the difference from the left hand end of the line to the point that the subject marks and will be 
electronically calculated. 
6.11.3 
Clinical Opiate Withdrawal Scale  
The COWS assessment will be administered electronically according to the SOE in Appendix 1, 
Appendix 2, Appendix 3, Appendix 4, and Appendix 5.  The COWS is an 11-item, validated 
instrument used to assess symptoms of opiate withdrawal (Wesson 2003, Tompkins 2009).  The 
score is the sum of the response to each of the 11 items.  The COWS is sometimes used by 
clinicians treating subjects with buprenorphine.  A score of 5 to 12 is considered mild, 13 to 24 is 
moderate, 25 to 36 is moderately severe, and a score of exceeding 36 is considered severe 
withdrawal.  COWS scores will be electronically calculated.  Each subject should be assessed by 
the same qualified and trained individuals throughout the course of the study as much as 
possible.  This scale is presented in Appendix 12. 


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6.11.4 
Subjective Opiate Withdrawal Scale 
The SOWS (Handlesman 1987) will be administered electronically according to the SOE in 
Appendix 1, Appendix 2, Appendix 3, Appendix 4, and Appendix 5.  The SOWS is a 16-item 
scale completed by the subject and used to assess the subject’s perception of opiate withdrawal 
symptoms.  SOWS scores will be electronically calculated.  This scale is presented in Appendix 
13. 
6.12 Health Economics and Outcomes Assessments 
Health economics and outcomes assessments will include: EQ 5D-5L, SF-36v2, MSQ, HCRU, 
TEA, ASI-Lite, BDI-II, and BPI.  
All questionnaires will be completed at the appropriate study visits as indicated in the following 
sections. 
6.12.1 
EuroQoL-5 Dimensions-5 Levels (EQ-5D-5L) and EQ-VAS 
The EQ-5D-5L will be used to record subjects’ health-related quality of life throughout the study 
at the time points indicated in the SOEs (Appendix 1, Appendix 2, Appendix 3, Appendix 4, and 
Appendix 5).  It will be administered electronically.  
The EQ-5D-5L is a widely-used, generic health-related quality of life instrument, which consists 
of 2 sections:  the EQ-5D-5L descriptive system and the EQ visual analogue scale (EQ VAS) 
(Appendix 18).  The EQ-5D-5L is comprised of 5 questions/dimensions (mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression) each of which can take 1 of 5 
responses.  The responses record 5 levels of severity (no problems/slight problems/moderate 
problems/severe problems/extreme problems) within a particular EQ-5D dimension.  EQ-5D -5L 
health states can be converted to a single summary index (range: 0-1) by using value sets that 
attaches values to each of the levels in each dimension.  The EQ-VAS is a standard, vertical, 20 -
cm visual analogue scale and will be used for recording a subject’s rating for their current health-
related quality of life state (Herdman 2007).   
6.12.2 
Medical Outcomes Study Short Form-36 (SF-36v2) 
The SF-36v2 is a generic, subject-reported outcome instrument used to assess quality of life, 
which will be administered electronically at the time points indicated in the SOEs (Appendix 1, 
Appendix 2, Appendix 3, Appendix 4, and Appendix 5).  
The SF-36v2 is a 36-question instrument, which assesses 8 health concepts: 1) limitations in 
physical activities because of health problems; 2) limitations in social activities because of 
physical or emotional problems; 3) limitations in usual role activities because of physical health 
problems; 4) bodily pain; 5) general mental health (psychological distress and well-being); 6) 
limitations in usual role activities because of emotional problems; 7) vitality (energy and 
fatigue); and 8) general health perceptions (Appendix 19).  The scale score of each domain is 
calculated based on the summed score across items included in the domain and is rescaled to 0 to 
100 with higher scores indicating better health states. 


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The SF-36v2 provides scores for each of the eight health domains and psychometrically-based 
physical component summary (PCS) and mental component summary (MCS) scores. The 
physical functioning, role physical, bodily pain, and general health can be used to construct a 
PCS score, while the vitality, social functioning, role emotional, and mental health scales are 
used to construct the MCS Scores (Ware 2007). 
6.12.3 
Medication Satisfaction Questionnaire (MSQ) 
The MSQ is a single-item, patient-rated questionnaire (Appendix 20) that evaluates patient 
satisfaction with opioid medication. (Vernon 2010).  Medication satisfaction will be measured 
with the MSQ at the time points indicated in the SOEs (Appendix 2, Appendix 3, Appendix 4, 
and Appendix 5) electronically. 
6.12.4 
Healthcare Resource Utilization (HCRU) Questionnaire 
The Healthcare Resource Utilization questionnaire will be completed by the Investigator or 
designee at the time points indicated in the SOEs (Appendix 1, Appendix 2, Appendix 3, 
Appendix 4, and Appendix 5).  The HCRU will be used to collect current health insurance status, 
hospitalizations; residential substance abuse treatment; general practitioner, specialist, and 
counseling visits; and ED visits (Appendix 21).  It will be administered electronically. 
The outpatient services captured on this questionnaire are ones conducted outside the study.  
Visits to the study site for scheduled study visits should not be reported here. 
6.12.5 
Treatment Effectiveness Assessment (TEA) 
The TEA is a patient-reported instrument which will be measured at the time points indicated in 
the SOEs (Appendix 1, Appendix 2, Appendix 3, Appendix 4, and Appendix 5). 
 
The TEA is a 4-item scale completed by the subject and used to assess the subject’s perception 
of treatment effectiveness (Ling 2012).  Patients respond to the TEA questions providing both 
numerical responses and brief feedback about their situation on four domains: substance use 
(drugs, alcohol, tobacco), health (e.g., physical, emotional health), lifestyle (e.g., housing or 
living situation, family, employment, relationships), and community (e.g., obeying laws and 
becoming a responsible member of society).  The TEA scale is presented in Appendix 22. 
6.12.6 
Addiction Severity Index (ASI) Lite 
The ASI Lite is a patient-reported instrument that is conducted via interview by a team member 
trained in the administration of the ASI Lite. ASI Lite will be administered at the time points 
indicated in the SOEs (Appendix 2, Appendix 3, Appendix 4, and Appendix 5). Given the nature 
of the ASI Lite, this instrument can be administered before or after injection of RBP-6000.  
The ASI Lite, in an interview used to assess the subject’s addiction severity, covers 7 potential 
problem areas: medical, employment/support status, alcohol, drug, legal, family/social, and 
psychiatric problems (Strain 1996). The ASI Lite interview text is presented in Appendix 23. The 
ASI obtains lifetime information about problem behaviors, as well as problems within the 


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previous 30 days. Of note, some items of the ASI Lite are only asked once at the initial visit; at 
subsequent time points only items indicated in the questionnaire should be administered.  
Below is a brief description of each of the scales that will be included within the trial:   
The medical status section of the ASI gathers basic information about the patient's medical 
history. It addresses information about lifetime hospitalizations, long-term medical problems and 
recent physical ailments.  The employment/support status section of the ASI gathers information 
about the resources a patient can record on a job application, as well as his or her current sources 
of income. Many items will have a 30-day recall period regarding current employment. The 
drug/alcohol section of the ASI gathers information about the patient's substance abuse history. It 
addresses information about current and lifetime substance abuse, consequences of abuse, 
periods of abstinence, treatment episodes, and financial burden of substance abuse. While 
lifetime versions of these items are also available, this would only be assessed at first interview.  
The legal status section of the ASI gathers information about the patient's legal history. It 
addresses information about probation or parole, charges, convictions, incarcerations or 
detainments, and illegal activities.  The family/social relationships section is designed to 
summarize the psychiatric, alcohol and drug abuse problems of the patient's relatives in each of 
the specified categories.  The psychiatric problem section gathers information on psychiatric 
symptoms experienced by the patient. 
6.12.7 
Beck Depression Inventory II (BDI-II) 
Depression is highly prevalent in patients with opioid use disorders.  Studies have been 
conducted using buprenorphine as a treatment for major depressive disorder.  
The Beck Depression Inventory II (BDI-II) is used to measure the severity of depression in 
adults and adolescents.  The BDI-II is scored on a 4 point Likert scale, each item ranging from 0-
3; it has a 2 week recall period, can be self-administered or administered by interview and takes 
5-10 minutes to complete.  
The strengths of the BDI-II include its ease of use; also, it is widely known and the results are 
easy to score and interpret.  The BDI-II has been successfully used to discriminate and measure 
depression in chronic pain patients on opioid therapy (Geisser 1997, Farren 2002, McCauley 
2014).   
The BDI-II assessment will be administered electronically according to the SOE in Appendix 1, 
Appendix 2, Appendix 3, Appendix 4, and Appendix 5.  This scale is presented in Appendix 24. 
Roll-over subjects who did not complete the BDI-II at EOS/Day 169 will complete this 
assessment at the screening visit. 
6.12.8 
Brief Pain Inventory (BPI) Short Form 
A substantial number of patients in the US with opioid use disorder began by using prescription 
pain medications and subsequently developed dependence. Many of these patients are concerned 
at the beginning of therapy that their pain may worsen when they are no longer taking their 
opioid medication.   
The Brief Pain Inventory Short Form (BPI-SF) is used to measure the severity of pain and the 
impact of pain on daily functions in adults. The BPI-SF has a 24-hour recall period and can be 


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self-administered or administered by an interviewer. It takes approximately 5 minutes to 
complete an instrument.  
The BPI has been widely used to measure pain severity among opioid users (Rosenblum 2003).  
BPI-SF consists of a combination of yes/no questions, an item based on human figure drawing, 
open-ended questions, and items based on a numeric rating scale.  Key strengths of the BPI-SF 
are that it is easy to administer and can provide rapid assessment of pain. BPI has been translated 
in many languages and is widely used. It captures all the components of pain: structural, intensity 
and its effect on patients.   
The BPI assessment will be administered electronically according to the SOE in Appendix 1, 
Appendix 2, Appendix 3, Appendix 4, and Appendix 5.  This scale is presented in Appendix 25.  
Roll-over subjects who did not complete the BPI at EOS/Day 169 will complete this assessment 
at the screening visit. 
6.13 Concomitant Medication Assessments 
The Investigator or designee will record any concomitant therapies given for 30 days prior to the 
start of and during the course of the study on the concomitant medication page of the subject’s 
source documentation and eCRF. Any changes in concomitant therapy during the study will also 
be documented, including cessation of therapy, initiation of therapy, and dose changes. 
6.14 Removal of Subjects from the Study 
Subjects will be free to withdraw at any time for any reason, or they may be withdrawn if 
necessary, to protect their health and safety or the integrity of the study data.   
The Investigator or medically qualified sub-investigator may choose to withdraw a subject from 
the study at any time.  Reasons for removing a subject from the study may include, but are not 
limited to the following: 
• Protocol deviation that might compromise data integrity, protocol compliance, or subject 
safety, 
• An AE is reported that compromises or potentially compromises subject safety, 
• The Sponsor or Investigator terminates the study, or 
• The subject requests to be discontinued from the study (i.e., subject declines further study 
participation). 
 
If a subject withdraws prematurely from the study after receiving IMP, the primary reason for 
withdrawal will be documented as 1 of the above, lost to follow-up, or other in the source 
documentation.  
In the event a subject is lost to follow up, the site staff must make reasonable attempts to contact 
the subject.  A minimum of 2 documented telephone calls followed by a certified mailed letter is 
considered reasonable. 


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6.14.1 
Early Removal of RBP-6000 
In the event of an emergency or if a subject withdraws or is withdrawn within the first 14 days of 
receiving an injection of RBP-6000, subjects may have the option to have the depot surgically 
removed by a physician delegated to perform surgery. The medically responsible physician 
should carefully discuss this option with subjects given the use of ATRIGEL Delivery System 
and the feasibility of extracting the depot. The surgical procedure requires a small incision in the 
abdomen where the depot was placed, removal of the depot with forceps, and suturing to close 
the incision.  The subject should have the EOS assessments performed at the time of early 
removal of RBP-6000. Subjects that have had an RBP-6000 depot removed should have follow-
up telephone contact(s) within 7 to 14 days to assess status and for resolution of related AEs. In 
the event a subject cannot be contacted for the follow-up telephone contact, a minimum of 2 
documented telephone calls followed by a certified mailed letter is considered reasonable. At this 
point, the subject may be considered lost to follow-up. 
The extracted RBP-6000 depot will be disposed of into an appropriate, secure biohazard 
container per the standard operating procedures (SOPs) at the study site.  
Detailed RBP-6000 depot removal instructions are in Appendix 8. 
6.14.2 
Stopping Rules 
The Investigator must contact the Sponsor immediately to discuss whether to suspend dosing if 
an AE or laboratory abnormalities indicates that continued dosing of subsequent subjects would 
not be tolerated or would jeopardize the subjects’ safety.  The Sponsor alone may suspend dosing 
at any time for any reason. 
Factors that must be considered for suspension of dosing include the frequency, severity, clinical 
significance, possible causality, and anticipated reversibility of all observed AEs or laboratory 
abnormalities for each specific SC injection group.  If dosing is suspended, the IRB will be 
notified in accordance with IRB requirements. 
6.14.3 
Screen Failures 
A screen failure subject is one from whom informed consent is obtained and is documented in 
writing (i.e., the subject signs the ICF) but who did not receive study medication. 
Rescreening of a de novo subject may be permitted after consultation with the study medical 
monitor. 
6.15 Other Study Procedures 
6.15.1 
Counseling/Behavioral Therapy 
After enrollment, subjects will receive manual-guided, individual behavioral therapy once a 
week for 5 weeks, then bi-weekly (every 2 weeks) up until injection 6, at which point it will 
occur monthly to accompany the pharmacotherapy as indicated in the SOEs (Appendix 2, 


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Appendix 3, Appendix 4, and Appendix 5). Behavioral therapy will continue through the end of 
the study (EOS/ET visit). It is at the Investigator’s discretion to provide additional behavioral 
counseling above this standard frequency. The reason(s) that additional counseling was provided 
should be documented in source documentation. Behavioral therapy can be conducted by any 
appropriately trained staff member at the site. 
An Individual Drug Counseling (IDC) reference manual will be provided to each site.   
6.15.2 
Unscheduled Visits 
If unscheduled visits occur, the Investigator must record the following in the subject’s source 
documentation: 
• Any AEs 
• Reason for unscheduled visit 
• Recording of any changes or additions to concomitant medications dose or regimen 
• COWS (if deemed appropriate) 
• Any clinical assessments deemed appropriate for the clinical care of the subject 
Unscheduled visits should not alter the timing of the routine study schedule. 
6.15.3 
Additional Care of Study Subjects Following Completion of the Study 
Each subject will be evaluated on his or her final study day.  Subjects who experience SAEs at 
the EOS, or experience the onset of an SAE after the final visit, will be followed up as described 
in Section 6.10.11.  No other additional care of study subjects will take place following 
completion of the study.  
6.15.4 
Treating Toxicity 
Treatment of suspected RBP-6000 toxicity should be at the judgment of the Investigator or 
medically-qualified sub-investigator and may include an attempt to remove the depot if toxicity 
is discovered within the first 14 days post injection.  Subjects who have had RBP-6000 removed 
will be followed up according to the procedures described in the SOE (EOS/ET Visit; Appendix 
3 and Appendix 5) and Section 6.14. 
6.15.5 
Ancillary Medications 
Treatment of signs and symptoms of opioid withdrawal after enrollment can be treated with 
ancillary medications allowed by the protocol, as clinically indicated by the Investigator or 
physician Sub-Investigator.  Subjects whose symptoms are not manageable will be discontinued 
from the study and will be followed up according to the procedures described in the SOE 
(EOS/ET Visit; Appendix 3 and Appendix 5) and Section 6.14. 


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6.16 Appropriateness of Measurements 
Within the study population of opioid-dependent subjects, certain common signs and symptoms 
are displayed that must be evaluated for safety and efficacy of treatment during clinical trials.  
The instruments used (e.g., COWS, SOWS, Opioid Craving VAS, and eC-SSRS) were 
developed to measure the specific symptoms exhibited by and challenges facing opioid-
dependent individuals. 


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7 
STUDY ACTIVITIES 
This study will be conducted as a fully non-residential (outpatient) study.  An overview of the 
study is shown in Figure 2 and Figure 3.  Details on procedures/activities for this study are 
provided in Section 6 and SOEs are provided in Appendix 1, Appendix 2, Appendix 3, Appendix 
4, and Appendix 5. 


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8 
QUALITY CONTROL AND ASSURANCE 
8.1 
Quality Control 
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study centers, review of protocol procedures with the investigators 
and associated personnel before the study, periodic monitoring visits by the Sponsor, and direct 
transmission of clinical laboratory data from a central laboratory into the Sponsor’s (or 
designee’s) database.  Written instructions will be provided for study drug preparation and 
dosing, collection, preparation, and shipment of blood, plasma, and urine samples.  Guidelines 
for eCRF completion will be provided and reviewed with study personnel before the start of the 
study.  The Sponsor (or designee) will review eCRFs for accuracy and completeness during on-
site monitoring visits and after transmission to the Sponsor (or designee).  Any discrepancies will 
be resolved with the Investigator or suitably qualified designee, as appropriate. 
8.2 
Quality Assurance 
This study will be organized, performed, and reported in compliance with the protocol, Standard 
Operating Procedures (SOPs), working practice documents, and applicable regulations and 
guidelines.   
In accordance with the standards defined in Sponsor SOPs and applicable regulatory 
requirements, clinical studies sponsored by Sponsor are subject to Sponsor Quality Audits at the 
study sites that will be conducted by personnel from an appropriate unit.  Site audits will be 
made periodically by the Sponsor’s (or contractor’s) qualified compliance auditing team, which 
is an independent function from the study conduct team.  Audits will include review of, but are 
not limited to, drug supply, presence of required documents, the informed consent process, and 
comparison of eCRFs with source documents.  The investigator agrees to participate with audits 
conducted at a reasonable time in a reasonable manner.  Full consultation with the Investigator 
will be made prior to and during such an audit, which will be conducted according to the Quality 
Assurance Unit SOPs.  In addition, this study is subject to inspection by regulatory authorities.  
If such a regulatory inspection occurs, the Investigator agrees to allow the regulatory inspector 
direct access to all relevant study documents.  The investigator should contact the Sponsor 
immediately if this occurs and must fully cooperate with the inspection conducted at a reasonable 
time in a reasonable manner. 


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9 
PLANNED STATISTICAL METHODS 
9.1 
General Considerations 
A Statistical Analysis Plan (SAP) will be prepared after the protocol is approved and before 
database lock occurs.  The SAP will provide further details regarding the definition of analysis 
endpoints, data handling rules, and the statistical methodology to be used to address all study 
objectives.  The SAP will also include formats for the summary and analysis tables, listings, and 
graphical displays. 
This section describes methods for sample size determination, analysis populations, and planned 
analyses for, safety, PK, and clinical outcomes endpoints.  Additional unplanned analyses may 
be required after all planned analyses have been completed.  Any unplanned analyses will be 
clearly identified in the clinical study report.  Any deviations from the analyses described below 
will be included in the SAP, which will form Appendix 16.1.9 of the clinical study report. 
Continuous variables will be summarized using descriptive statistics such as means, standard 
deviations (SD), medians, minimums, and maximums.  Categorical variables will be reported as 
frequency counts (including number missing) and the percentage of subjects in corresponding 
categories.  Individual subject data will be presented by subject in data listings.  Data listings will 
include all data collected from the initial screening visit to the end of study for all subjects 
enrolled.   
9.2 
Determination of Sample Size 
There is no formal sample size calculation. Approximately 300 de novo subjects as well as 
approximately 300 subjects who completed the RB-US-13-0001 efficacy study will be enrolled 
into this study to ensure at least 100 subjects reach 1 year of treatment with RBP-6000. 
9.3 
Analysis Populations 
The following populations will be used for data analyses: 
9.3.1 
Safety Population 
The Safety Population comprises all subjects who received at least 1 dose of RBP-6000 during 
the open-label treatment phase of the study. This population will be used for all safety analyses.   
9.3.2 
Clinical Outcome Assessment and PK Populations 
The Clinical Outcome Assessment population will include subjects who were dosed with 
RBP-6000 and have at least 1 post-dose Clinical Outcome Assessment value.  
The PK Population will include any subject who receives a dose of RBP-6000 or at least 1 dose 
of SUBOXONE sublingual film and has at least 1 sample collected post-dose.  
   


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9.4 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics (gender, race, age, weight, height) will be summarized 
by treatment group using descriptive statistics.  Qualitative variables (gender, race) will be 
summarized using frequencies while quantitative variables (age, weight, height) will be 
summarized using mean, SD, median, minimum, and maximum. 
9.5 
Primary Analysis 
9.5.1 
Safety Endpoints 
Safety variables will include AEs, local injection site tolerability (e.g., injection site grading); 
injection site pain using a subject-reported VAS; suicidality using the eC-SSRS, concomitant 
medications; changes in clinical laboratory results (hematology, chemistry and urinalysis); vital 
sign measurements; 12-lead ECGs, physical examination results; body weight, height, BMI, and 
abdominal fat measurement (waist-to-hip ratio). Safety variables will be analyzed using the 
safety population.  
Baseline is defined as the last non-missing value prior to SC injection on Day 1.  No imputation 
of missing values will be performed. 
9.5.1.1 
Adverse Events 
All AEs will be coded using the most up-to-date version of the Medical Dictionary for 
Regulatory Activities (MedDRA) and reported to the FDA. AEs that began more than 30 days 
after the last study subject assessment day will not be included in the safety analysis. Only 
TEAEs occurring post administration of RBP-6000 will be included in the safety analysis (See 
Section 6.10.10). 
The incidence of AEs (number and percent of subjects reporting the AE at least once during the 
study) will be summarized for all AEs, by the relationship to study drug and by severity. 
9.5.1.2 
Laboratory Data 
At each visit where clinical laboratory assessments are conducted, summary statistics for the 
absolute laboratory value and the changes from baseline will be presented.   
9.5.1.3 
Vital Signs 
Vital signs measurements will be assessed for clinical relevance and be performed as deemed 
medically necessary by research personnel.  Vital signs will be taken after the subject has 
completed a minimum 3-minute rest in the supine position.  Systolic and diastolic BP 
measurements will be assessed while supine throughout the trial. 
9.5.1.4 
Other Variables Related to Safety 
Results from 12-lead ECGs will be categorized as normal, abnormal clinically significant, or 
abnormal not clinically significant and will be summarized by time point using frequency counts 


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and percentages.  ECG interval measurements as well as change from baseline will also be 
summarized by time point using descriptive statistics (mean, median, SD, minimum, maximum).  
Additional analysis of ECG parameters will be outlined in the SAP. 
Medical history will be coded using MedDRA and summarized by treatment group as described 
for AEs (Section 9.5.1.1).  Body weight, height, BMI, and abdominal fat measurement (waist-to-
hip ratio) will be summarized using descriptive statistics (mean, median, SD, minimum, 
maximum), including change from baseline. 
Total eC-SSRS scores will be summarized using descriptive statistics (mean, median, SD, 
minimum, maximum), including change from baseline.  Subjects’ self-reported illicit drug use 
from the TLFB will be summarized as descriptive statistics. 
Prior and concomitant medications will be coded using the most recent version of the World 
Health Organization (WHO) Drug dictionary.  Incidence (number and percent of subjects 
reporting the medication at least once during the study) will be summarized for all concomitant 
medications. 
Local injection site tolerability as assessed by the Injection Site Grading scale will be 
summarized by category and severity using frequency counts and percentages similar to 
summaries for AEs (Section 9.5.1.1).  Injection Site Pain VAS scores will be summarized by 
dose, injection, and time point after injection.  The burning/stinging categorical variable 
(Yes/No) will be summarized by percent of responses in each treatment. 
9.6 
Secondary Analysis 
9.6.1 
Clinical Outcomes Assessments 
COWS, SOWS and Opioid Craving VAS total scores will be summarized using descriptive 
statistics (mean, median, SD, minimum, maximum), including change from baseline. Subjects’ 
self-reported illicit drug use from the TLFB will be summarized using descriptive statistics. 
The cumulative distribution function (CDF) of the percentage of urine samples negative for 
opioids and that of the percentage of self-reports from the TLFB negative for illicit opioid use 
will be calculated. Other outcome efficacy measures will be estimated using descriptive 
statistics.  
9.7 
Other Analyses 
9.7.1 
PK/PD Modeling 
The population PK model established using the data collected in the double-blind, placebo-
controlled, efficacy study (Study RB-US-13-0001) will be refined using the PK samples 
collected in the present study to characterize the disposition of buprenorphine and 
norbuprenorphine following SC injections of RBP-6000, with the assessment of potential 
covariates affecting the PK of both compounds.  Subsequently, the relationships between 
buprenorphine plasma concentrations and clinical outcomes assessments will be investigated.  


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These relationships will be initially assessed in a descriptive manner, and, if applicable, 
appropriate PK/PD models will be developed to describe these relationships.  A stand-alone 
modeling analysis plan will be generated, and the results will be reported in a standalone 
modeling report.  
9.7.2 
Health Economic and Outcomes Assessment 
The health economic and outcomes research endpoints for this study are: 
• EQ-5D-5L 
• SF-36v2  
• MSQ  
• HCRU  
• TEA 
• ASI Lite 
• BDI-II 
• BPI 
Summary scores for these measures will be calculated, as appropriate. Categorical variables will 
be summarized using frequencies and percentages. Continuous measures will be summarized 
using descriptive statistics (mean, standard deviation, median, minimum, maximum) as 
appropriate. An analysis of change will be conducted.  A stand-alone statistical analysis plan will 
be developed prior to database lock for health economics and outcomes research assessments.  
A separate stand-alone SAP will be developed prior to database lock with full detail regarding 
health economics and outcomes analyses. 
9.8 
Handling of Missing Data 
For dichotomous outcome measures such as UDS results (negative; non-negative) and self-
reports for illicit opioid use (negative; non-negative), any missing observation will be recorded 
as “non-negative.” For all continuous endpoints (e.g., COWS, SOWS, and VAS), the missing 
data mechanism will be assumed to be either missing completely at random (MCAR) or missing 
at random (MAR).  The missing data will not be imputed because the analysis method, mixed 
model for repeated measures (MMRM), does not require any imputation and no sensitivity 
analyses will be performed on these variables.  For time-to-event variables, if the event of 
interest is not observed prior to withdrawal or end of treatment, the observations will be censored 
at the time of withdrawal or at the end of treatment.  For example, if some subjects still have not 
had a urine sample negative for opioids combined with self-reports negative for illicit opioid use 
when the study ends or at the time of withdrawal from the study, then the time to first urine 
sample negative for opioids combined with self-reports negative for illicit opioid use will be 
censored at the last time they were assessed. 


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9.9 
Subjects Who Withdraw from the Study 
Subjects who withdraw after receiving RBP-6000 will not be replaced. 
9.10 Interim Analyses 
No interim analysis will be performed for this study.   


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10 ADMINISTRATIVE CONSIDERATIONS 
10.1 Investigators and Study Administrative Structure 
10.1.1 
Indivior Inc. 
Indivior Inc. 
10710 Midlothian Turnpike, Suite 430 
Richmond, VA 23235 
 
10.1.2 
Investigational Site(s) 
This study will be conducted at up to 50 sites in the US. 
10.1.3 
Laboratories 
The safety laboratory tests (serum chemistry, hematology, serology, and urinalysis), as well as 
the specialty laboratory tests (Bioanalytical and Pharmacokinetic) will be conducted at a central 
laboratory that is certified and accredited to perform the assigned assessments. 
Collection of safety laboratory samples is described in Section 6.6.2.  The Clinical Laboratory 
will provide normal ranges and collection, processing, and shipping instructions to the sites in a 
separate laboratory reference manual. 
10.2 Institutional Review Board or Independent Ethics Committee 
Approval 
The protocol will be reviewed by an independent, appropriately constituted, centralized IRB/ 
Independent Ethics Committee (IEC).  Study enrolment and protocol related procedures, which 
do not form part of the subject’s normal clinical treatment, will not be performed until the 
IRB/IEC of record has provided written approval of the protocol or a modification thereof.  The 
IRB/IEC must be constituted and operate in accordance with the principles and requirements of 
ICH GCP. 
Study drug can only be supplied to the Investigator after documentation on all ethical and legal 
requirements for starting the study has been received by the Sponsor.  This documentation must 
also include an IRB/IEC membership list that contains member’s occupations.  If the IRB/IEC 
will not disclose the names of the committee members, the IRB/IEC Federalwide Assurance 
Number may be accepted as a substitute for this list.  Formal approval by the IRB/IEC should 
mention the study title, study code, study site (or region or area of jurisdiction, as applicable), 
and any other documents reviewed.  It must mention the date on which the decision was made 
and must be officially signed by a committee member. 
10.3 Ethical Conduct of the Study 
The Investigator is responsible for ensuring that the clinical study is performed in accordance 
with the protocol, current ICH GCP guidelines, and applicable regulatory and country-specific 


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requirements.  GCP is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects.  
Compliance with this standard provides the public assurance that the rights, safety, and 
well-being of study subjects are protected and that the clinical study data are credible. 
10.4 Subject Information and Consent 
Prior to the subject incurring the first study related procedure, the Investigator or designated 
individual will explain to each subject the nature of the study, its purpose, procedures, expected 
duration, alternative therapies available, and the benefits and risks involved in study 
participation. It should also be mentioned that all informed consent documents and other 
documents used in the conduct of the study have been approved by an IRB/IEC. 
In the case of a non-medically qualified person conducting the consent process, he/she should 
have ready access to a medically qualified investigator to whom any questions from the study 
subject may be referred. Subjects will be given consent documents to review and the opportunity 
to ask questions. Subjects must be informed of their right to withdraw from the study at any time 
without prejudice.  
After this explanation and before any study-specific procedures have been performed, the subject 
must voluntarily sign and date the ICF to indicate he/she wishes to participate in study. The 
Investigator or the individual designated to conduct the consent discussion for the Investigator 
must also sign and date the ICF. The time (hour and minute) the consent is signed must also be 
recorded in the subject’s source notes, by the person obtaining consent from the subject. Verbal 
informed consent followed by a signed consent short form is not acceptable to Sponsor. 
Prior to participation in the study, the subject will receive a copy of the signed and dated ICF 
along with an emergency card with contact information for the Investigator and site staff in the 
event of a medical emergency during the study. 
10.5 Subject Confidentiality 
All subject-identifying documentation generated in this study must be considered confidential 
and must not be disclosed to any persons not directly concerned with the study without written 
permission from the subject.  However, authorized regulatory officials and Sponsor personnel (or 
their representatives) will be allowed full access to inspect and copy the records.  All subject 
bodily fluids, and/or other materials collected shall be used solely in accordance with this 
protocol and the informed consent signed by the subject, unless otherwise agreed to in writing by 
the Sponsor. 
Each subject will be identified by initials and an assigned subject number when reporting study 
information to any entity outside of the study center.  Data containing subject identification will 
not be removed from the study center without subject identifiers having been redacted. 
  


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10.6 Study Monitoring 
In accordance with applicable regulations, GCP, and Sponsor procedures, the clinical monitor(s) 
will periodically contact the site, including conducting on-site visits at intervals agreed by the 
Investigator and documented in the Clinical Monitoring Plan and the Site Initiation Visit Report.   
The clinical monitor(s) will contact the site prior to the start of the study to discuss the protocol 
and data collection procedures with site personnel.  In accordance with applicable regulations 
and GCP guidelines, the Investigator shall make available for direct access all study-related 
records upon request of the Sponsor, the Sponsor’s agents, clinical monitor(s), auditors, and/or 
IRB/IEC.  The Sponsor’s monitors will visit the site during the study in addition to maintaining 
frequent telephone and written communication.  The extent, nature, and frequency of on-site 
visits will be based on such considerations as the study objectives and/or endpoints, the purpose 
of the study, study design complexity, and enrolment rate.   
The Investigator must allow the clinical monitor(s) direct access to all relevant documents and to 
allocate his/her time and the time of his/her staff to the clinical monitor(s) to discuss findings and 
any relevant issues. 
10.6.1 
Study and Site Closure 
Upon completion of the study, study closeout activities must be conducted by the Sponsor or its 
designee in conjunction with the Investigator, as appropriate. 
In addition, the Sponsor reserves the right to temporarily suspend or prematurely discontinue this 
study at any time and for any reason.  If such action is taken, the Sponsor will discuss this with 
the Investigator (including the reason[s] for taking such action) at that time.  The Sponsor will 
also inform the regulatory authorities of the suspension or termination of the study and the 
reason(s) for the action.  If required by applicable regulations, the Investigator must inform the 
IRB/IEC promptly and provide the reason(s) for the suspension or termination.  If the study is 
prematurely discontinued, all study data and study drug remaining on site must be returned to the 
Sponsor or its designee. 
10.7 Case Report Forms and Study Records 
The Investigator is responsible for the quality of the data recorded in the electronic Case Report 
Forms (eCRFs). The data recorded should be a complete and accurate account of the subject’s 
record collected during the study. Study data are not to be gathered directly onto the eCRF but 
must be gathered onto primary source documents at the study site. Completion of source 
documents will precede the completion of the eCRF. Source data transfer into the eCRF should 
occur timely and on an ongoing basis. Source documents may be electronic, hard copy, or a 
combination of both. Source documents are defined as the results of original observations and 
activities of a clinical investigation. Source documents will include, but are not limited to, 
progress notes, electronic data, screening logs, and recorded data from automated instruments. 
All source documents pertaining to this study will be maintained by the investigators and made 
available for direct inspection by the authorized study personnel outlined in the ICF. The ePRO 


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tablet will be considered the source document for individual ePRO elements such as study-
specific scales when collected directly onto the tablet. 
Data collection will be completed according to the guidelines provided by Sponsor or its 
designee.   
For all subjects who signed an informed consent, all required data are to be recorded using 
source documents and reported on the eCRF, except for study scales that are recorded directly on 
the ePRO tablet.  Site staff will receive training on the eCRF completion guidelines and 
requirements for source documentation. 
Completed eCRFs will be reviewed by the study monitor in line with eCRF completion 
guidelines for the study to ensure completeness and consistency. The study monitor will review 
every subject’s eCRF with source data verification for at least all critical data points. The clinical 
management plan for this study will define the level of source data verification required for 
non-critical data points.  Any discrepancies found during the eCRF review will be clarified by 
the Investigator or designated individual. This includes eCRF reviews at the site by Sponsor or 
its designee, or during quality assurance review of the data.  
An explanation must be documented for any missing data.  Any changes to information in the 
study progress notes and other source documents will be initialled and dated on the day the 
change is made by a site staff member authorized to make the change.  Changes will be made by 
striking a single line through erroneous data (so as not to obliterate the original data), and clearly 
entering the correct data (e.g., wrong data right data).  If the reason for the change is not 
apparent, a brief explanation for the change will be written in the source documentation by the 
clinician. 
The Investigator must sign and date a declaration attesting to his/her responsibility for the quality 
of all data recorded, and that the data represents a complete and accurate record of each subject’s 
participation in the study.   
All eCRF entries, corrections, and alterations must be made by the Investigator or designated 
individual.  The Investigator or designated individual must adjust the eCRF (if applicable) and 
complete the query. 
10.8 Data Monitoring Committee 
Not applicable; there will be no data monitoring committee for this study. 
10.9 Protocol Deviations 
This study is intended to be conducted as described in this protocol.  At the outset of the study, a 
process for defining and handling protocol deviations will be established and defined in the 
medical management plan.  This will include determining which violations will be designated 
important and require immediate notification to the Sponsor.  In the event of a deviation from the 
protocol due to an emergency, accident, or mistake, the Investigator or designated individual 
must contact the Sponsor at the earliest possible time by telephone.  This will allow an early joint 


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decision regarding the subject’s continuation in the study.  This decision will be documented by 
the Investigator and the Sponsor, and reviewed by the monitor.  Deviations from the protocol are 
to be documented.  The Investigator or designated individual will be responsible for identifying 
and reporting all deviations, which are defined as isolated occurrences involving a procedure that 
did not follow the study protocol or study-specific procedure.  Deviations will be reported as 
required to the IRB and in the final study report. 
10.10 Access to Source Documentation 
The Investigator must agree to complete a subject identification and enrolment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
Sponsor site contact for completeness. The subject identification and enrollment log will be 
treated as confidential and will be filed by the Investigator in the investigator site file. To ensure 
subject confidentiality, no copy will be made. All reports and communications relating to the 
study will identify subjects by initials and assigned number only. The Investigator must also 
complete a subject-screening log, which reports on all subjects who were seen to determine 
eligibility for inclusion in the study. 
At a minimum, source documentation must be available for the following to confirm data 
collected in the eCRF: subject identification, eligibility, and study identification; study 
discussion and date of informed consent; dates of visits; results of safety and efficacy parameters 
as required by the protocol; record of all AEs; concomitant medications; study drug 
administered; date of study completion or early discontinuation, and reason for early 
discontinuation if applicable. 
10.11 Data Generation and Analysis 
10.11.1 Data Collection and Data Management 
Study specific data that has been outlined in the protocol will be entered into the clinical 
database by individual(s) designated by the Investigator in accordance with the CRF Completion 
Guidelines. Data is verified electronically using a series of on-line programmed edit checks that 
have been created by the Clinical Data Manager and programmed by the Clinical Data 
Programmer or Designee. Data discrepancies will be brought to the attention of the clinical team 
and investigated by the CRA and Site Study Coordinator. CRAs will review and verify all data 
collected in the eCRF against source documentation during scheduled monitoring visits. The 
CRA will work closely with the Site Study Coordinator to address any discrepancies which have 
been found so that proper resolutions can be made and documented into the clinical database. An 
audit trail within the system will track all changes made to the data. 
10.11.2 Database Quality Assurance  
The clinical database will be reviewed and checked for omissions, apparent errors, and values 
requiring further clarification using computerized and manual procedures.  Data queries 
requiring clarification will be generated and addressed by the investigational site.  Only 
authorized personnel will make corrections to the clinical database, and all corrections will be 
documented in an audit trail.   


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10.12 Retention of Data 
All documents pertaining to the study, including all versions of the approved study protocol, 
copy of the informed consent document and Health Insurance Portability and Accountability Act 
documents, completed eCRFs, source documents (subject records, subject diaries, hospital 
records, laboratory records, drug accountability records, etc.), and other study-related documents 
will be retained in the permanent archives of the study site. 
The Investigator must therefore notify and obtain approval in writing from the Sponsor prior to 
destruction of any study records or provide an opportunity for the Sponsor to collect such 
records.  If the investigator withdraws from the study (e.g., relocation, retirement) all study-
related records should be transferred, in a written agreement with the Sponsor, to a mutually 
agreed upon designee within a Sponsor-specified timeframe. 
10.13 Financial Disclosure 
Indivior requires, for each study, the disclosure of any financial interests from each investigator 
or sub-investigator, including financial interests of the spouse and each dependent child of the 
investigator who is directly involved in the treatment or evaluation of research subjects that 
could affect the reliability of data submitted to regulatory authorities. The collection of this 
financial interest information at the start of the study, as well as any updates should this 
information change, is required by the FDA when submitting a marketing application and is in 
line with the GCP requirement to consider any potential conflicts of interest. 
10.14 Publication and Disclosure Policy 
A clinical study report will be prepared following completion of the study.  The report will be a 
record of the total study conduct and will be subject to Sponsor approval and restrictions on 
distribution/disclosure.   
The study data will be owned by the Sponsor. Publication of any and all data will be at the 
discretion of the Sponsor. The Investigator will not disseminate, present, or publish any of the 
study data without the prior written Sponsor approval to do so. 


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validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry. 168 (12): 1266-77. 
Reckitt Benckiser Pharmaceuticals RBP-6000 Investigator's Brochure, Edition 4. 24 February 
2014. 
Rosenblum A, Joseph H, Fong C, Kipnis S, Cleland C, Portenoy RK (2003).  Prevalence and 
characteristics of chronic pain among chemically dependent patients in methadone maintenance 
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Satisfaction Questionnaire (MSQ) to assess satisfaction with antipsychotic medication among 
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Walsh SL, Preston KL, Stitzer ML, Cone EJ, Bigelow GE (1994).  Clinical pharmacology of 
buprenorphine: ceiling effects at high doses. Clin Pharmacol Ther. 55:569–580. 
Ware JE, Jr, Kosinski M, Bjorner JB, Turner-Bowker, DM, Gandek, B. and Maruish, ME 
(2007).  User's Manual for the SF-36v2TM Health Survey (2nd Ed). Lincoln, RI, QualityMetric 
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White AG, Birnbaum HG, Mareva MN, et al (2005).  Direct costs of opioid abuse in an insured 
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Buprenorphine in Experienced Opioid Abusers.  J Clin Psychopharmacol. 24(5):479-487. 
 


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Appendix 1 
Schedule of Events – Screening and SUBOXONE Film Induction 
Evaluation 
Screening 
Visit  
(Up to 3 days after 
EOS Visit/Day 169 
of RB-US-13-0001 
for roll-over 
subjects) 15 
SUBOXONE sublingual film 
Run-In 
Induction  
(3 days) 
Dose Adjustment  
(1 to 11 days) 
Days  
-21 to -15 
Day  
-14  
Day  
-13 
Day 
-12 
Day 
-11 
Day 
-8 
Day 
-4 
Day 
-1 
 
 
 
 
+1 day 
±1 day 
-1 day 
Informed Consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria Reviewed 
X 
 
 
 
 
 
 
 
IWRS 
X 
X 
X 
X 
X 
X 
X 
X 
Demographics 1 
X 
 
 
 
 
 
 
 
Medical History 1 
X 
 
 
 
 
 
 
 
eC-SSRS (Baseline Version) 
X 13 
 
 
 
 
 
 
 
Physical Examination 2 
X 13 
 
 
 
 
 
 
 
Vital Signs 3 
X 13 
X 
X 
X 
X 
X 
X 
X 
Body Weight 
X 13 
 
 
 
 
 
 
 
BMI Calculation 
X 13 
 
 
 
 
 
 
 
Hip-to-Waist Ratio 
X 13 
 
 
 
 
 
 
 
12-lead ECG (supine > 10 min) 4 
X 13 
 
 
 
 
 
 
 
Urine Drug Screen (UDS) 
X 13 
 
 
 
 
 
 
 
Urine Pregnancy Test 5 
 
X 
 
 
 
 
 
 
Screening Labs / Hormone Panel 
X 13 
 
 
 
 
 
 
 
Urinalysis/ Hematology/Serum Chemistry 
X 13 
 
 
 
 
 
 
 
Opioid Craving VAS 6 
X 13 
 
 
 
X 
X 
X 
X 
Clinical Opiate Withdrawal Scale (COWS) 6 
X 13 
X 
X 
X 
X 
X 
X 
X 
Subjective Opiate Withdrawal Scale (SOWS) 6 
X 13 
X 
X 
X 
X 
X 
X 
X 


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Evaluation 
Screening 
Visit  
(Up to 3 days after 
EOS Visit/Day 169 
of RB-US-13-0001 
for roll-over 
subjects) 15 
SUBOXONE sublingual film 
Run-In 
Induction  
(3 days) 
Dose Adjustment  
(1 to 11 days) 
Days  
-21 to -15 
Day  
-14  
Day  
-13 
Day 
-12 
Day 
-11 
Day 
-8 
Day 
-4 
Day 
-1 
 
 
 
 
+1 day 
±1 day 
-1 day 
BDI-II 
X 13,14 
 
 
 
 
 
 
 
BPI 
X 13, 14 
 
 
 
 
 
 
 
TLFB Interview 
X 13 
 
 
 
 
 
 
 
Concomitant Medications 
X 7, 13 
X 
X 
X 
X 
X 
X 
X 
AE Assessment 8 
X 13 
X 
X 
X 
X 
X 
X 
X 
Day -1 Criteria Reviewed 
 
 
 
 
X 9 
X 9 
X 9 
X 10 
SUBOXONE SL film administration 11 
 
X 
X 16 
X 16 
X 12 
X 12 
X 12 
X 12 
EQ-5D-5L 
X 13 
 
 
 
 
 
 
 
SF-36v2 
X 13 
 
 
 
 
 
 
 
Health Insurance 
X 13 
 
 
 
 
 
 
 
HCRU 
X 13 
 
 
 
 
 
 
 
TEA 
X 
 
 
 
 
 
 
 
AE = adverse event; BDI-II = Beck Depression Inventory II; BMI = body mass index; BPI = Brief Pain Inventory Short Form; COWS = Clinical Opiate 
Withdrawal Scale; eC-SSRS =  electronic Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; EQ-5D-5L =  EuroQol EQ-5D-5L;; 
HCRU = Healthcare resource utilization; IXRS=Interactive voice/web response system; MSQ =  Medication Satisfaction Questionnaire; SF-36v2 = 36-
Item Short Form Health Survey, Version 2; SL = sublingual; SOWS = subjective opiate withdrawal scale; TEA = Treatment Effectiveness Assessment; 
TLFB = Timeline Followback; VAS = Visual Analog Scale 
 
1. A complete medical and psychiatric history, including use of tobacco, drugs of abuse, alcohol and caffeine.  Update demographics and medical history, 
including use of tobacco, drugs of abuse, alcohol, and caffeine for roll-over subjects. 
2. Complete examination (excluding pelvic, breast, and rectal), including general appearance, skin, head, eyes, ears, nose, throat, neck, thyroid, 
chest/lungs, heart, abdomen, lymph nodes, extremities, and a brief neurological assessment.   


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3. Includes blood pressure (BP; supine ≥ 3 minutes), pulse oximetry, pulse rate, respiratory rate, oral temperature, and height (screening visit only).  Vital 
signs will be assessed within < 60 minutes before administration of SUBOXONE sublingual film. 
4. 
Must be performed prior to labs 
5. Only for female subjects who are of childbearing potential (not postmenopausal or surgically sterile for at least 1 year). 
6. Assessments should be performed prior to each SUBOXONE SL film dosing and at approximately the same time each day (±2 hours).   
7. Include a review of previous (within 30 days prior to screen) and ongoing medications. 
8. A PK sample will be taken as soon as possible after any SAE is reported.  If possible, an additional sample should be collected when the SAE has been 
resolved. 
9. This visit becomes Day -1 if the following criteria are met: 
• 
No allergic reaction to SUBOXONE sublingual film 
• 
Daily dose of SUBOXONE sublingual film between 8 mg/2 mg - 24 mg/6 mg (inclusive) buprenorphine/naloxone. 
• 
COWS score of ≤ 12 
• 
Opioid Craving VAS score of ≤ 20 mm 
If Day -1 criteria are met, the subject will be scheduled the following day (Injection Visit 1/Day 1) to receive the first injection of RBP-6000 after 
enrollment criteria are met.  
10. If Day -1 criteria are not met after 14 days of SUBOXONE sublingual film treatment, and a subject still has significant withdrawal signs/symptoms and 
opioid cravings (COWS score >12 and Opioid Craving VAS >20 mm), they will not be eligible to continue in the study.  They will be provided with 
information on the options for opioid use disorder treatment. 
11. SUBOXONE SL film dosing should take place at the same time of day (± 2 hours).   
12. Subjects should not take their dose of SUBOXONE SL film until after it has been determined if they have met Day -1 criteria (footnote #10). 
13. RB-US-13-0001 roll-over subjects study procedures completed at EOS/Day 169 will serve as the screening assessments for Protocol RB-US-13-0003 
14. Roll-over subjects who did not complete the BDI-II and the BPI at EOS/Day 169 visit will complete these assessments at Screening for Protocol RB-
US-13-0003 only after consent for the RB-US-13-0003 is obtained. 
15. For roll-over subjects only and at the Investigator’s discretion: Induction can begin on the day of screening for subjects who meet study criteria. 
16. Subjects with a score for COWS of >12, or subjects reporting opioid withdrawal signs/symptoms overnight, may receive a dose of an additional 4 mg.  
If the COWS score is still >12 one hour later, another 4 mg dose can be given.  Subjects should not exceed a maximum dose of 16 mg/4 mg for 
Induction Day 2, or 24 mg/6 mg on subsequent days.   
 


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Appendix 2 
Schedule of Events – RBP-6000 Injection 1 – 3 Visits 
Evaluation 
Inj 1 
Post Inj 1 Assessments 
 
Inj 2 
Post 
Inj 2 
24hrs 
Post 
Inj 2 
Inj 3 
Post 
Inj 3 
24hrs 
Post 
Inj 3 
Wk1 
D 
1 
Wk1 
D 
2 
Wk2 
D 
8 
Wk3 
D 
15 
Wk4 
D 
22 
Wk5 
D 
29 
Wk5 
D 
30 
Wk7 
D 
43 
Wk9 
D 
57 
Wk9 
D 
58 
W11 
D 
71 
Window  
 
+1 
±2 
±2 
±2 
±2 
+1 
±2 
±2 
+1 
±2 
IWRS 
X 
 
 
 
 
X 
 
 
X 
 
 
Enrollment 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs 1 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
Body Weight 
X 
 
 
 
 
 
 
 
 
 
 
BMI Calculation 
X 
 
 
 
 
 
 
 
 
 
 
Hip-to-Waist Ratio 
X 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 2 
(supine > 10 min) 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
Hematology/ Serum Chemistry 3 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
Hormone Panel 3 
X 
 
 
 
 
 
 
 
 
 
 
Urinalysis 3 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
Urine Pregnancy Test 4 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
Urine Drug Screen 5 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
PK Sampling (Roll-over patients only) 6  
X 
 
 
X 
 
X 
 
X 
X 
 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X13 
X 
X 
X13 
X 
AE Assessment 7 
X 
X 
X 
X 
X 
X 
X13 
X 
X 
X13 
X 
eC-SSRS (Since last-visit-version) 7 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
TLFB Interview 7 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
Opioid Craving VAS  7 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
COWS 7 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
SOWS 7 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
BDI-II 7 
X 
 
 
 
 
X 
 
 
X 
 
 
BPI  7 
X 
 
 
 
 
X 
 
 
X 
 
 
RBP-6000 Injection 
X 
 
 
 
 
X 
 
 
X 
 
 
Injection Site Grading Scale 8 
X 
X 
 
 
 
X 
 
 
X 
 
 
Injection Site Pain VAS 9 
X 
 
 
 
 
X 
 
 
X 
 
 


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Evaluation 
Inj 1 
Post Inj 1 Assessments 
 
Inj 2 
Post 
Inj 2 
24hrs 
Post 
Inj 2 
Inj 3 
Post 
Inj 3 
24hrs 
Post 
Inj 3 
Wk1 
D 
1 
Wk1 
D 
2 
Wk2 
D 
8 
Wk3 
D 
15 
Wk4 
D 
22 
Wk5 
D 
29 
Wk5 
D 
30 
Wk7 
D 
43 
Wk9 
D 
57 
Wk9 
D 
58 
W11 
D 
71 
Window  
 
+1 
±2 
±2 
±2 
±2 
+1 
±2 
±2 
+1 
±2 
Injection Site Evaluation 10 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
Behavioral Therapy 11 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
EQ-5D-5L 7 
X 
 
 
 
 
 
 
 
X 
 
 
SF-36v2 7 
X 
 
 
 
 
 
 
 
X 
 
 
MSQ 7 
 
 
 
 
 
 
 
 
X 
 
 
Health Insurance  
X 
 
 
 
 
X 
 
 
X 
 
 
HCRU  
X 
 
 
 
 
X 
 
 
X 
 
 
TEA 
X 
 
 
 
 
X 
 
 
X 
 
 
ASI Lite 
X 
 
 
 
 
 
 
 
X12 
 
 
AE = adverse event; ASI = Addiction Severity Index; BDI-II = Beck Depression Inventory II; BMI = body mass index; BPI = Brief Pain Inventory Short Form; 
COWS = Clinical Opiate Withdrawal Scale; eC-SSRS = electronic Columbia Suicide Severity Rating Scale; D = Day; ECG = electrocardiogram; EQ-5D-5L =  
EuroQol EQ-5D-5L; HCRU = Healthcare resource utilization; Inj. = injection; IXRS=Interactive voice/web response system; MSQ =  Medication Satisfaction 
Questionnaire; PK = pharmacokinetic/pharmacokinetics; SF-36v2 = 36-Item Short Form Health Survey, Version 2; SC = subcutaneous; SOWS = subjective 
opiate withdrawal scale; TEA = Treatment Effectiveness Assessment; TLFB = Timeline Followback; VAS = Visual Analog Scale 
 
1. Includes blood pressure, pulse oximetry, pulse rate, respiratory rate, and oral temperature which must be taken after subject is supine ≥ 3 minutes. On 
injection day 1, vital signs will be taken ≤ 60 minutes prior to SC injection, and then 0.5 (± 15 minutes), and 2 hours post SC injection (± 15 minutes). 
For all subsequent injection days, vital signs will be taken ≤ 60 minutes prior to SC injection, and 1 hour post SC injection (± 15 minutes). For non-
injection days, vital signs will be taken at approximately the same time of day as the Day 1 pre-injection vital signs. 
2. On Injection day 1, an ECG will be performed ≤ 60 minutes prior to SC injection, and then 0.5 (± 15 minutes),and 2 hours post SC injection (± 30 
minutes). For all subsequent injection days, an ECG will be recorded ≤ 60 minutes prior to SC injection, and 1 hour post SC injection (± 30 minutes). 
For non-injection days, an ECG will be performed at approximately the same time of day as the Day 1 pre-injection ECG. All ECGs must be performed 
prior to laboratory assessments. 
3. On injection days blood and urine samples will be taken ≤ 60 minutes prior to SC injection and after the ECG has been performed. 
4. Only for female subjects who are of childbearing potential (not postmenopausal or surgically sterile for at least 1 year). 
5. An additional urine drug screen can be done if use is suspected.  Oxycodone may not show up in all opiate assays and should be assessed separately. 
6. PK samples taken for roll-over subjects only. See PK table (Appendix 6) for exact time points. However, a PK sample should be taken as soon as 
possible after any SAE is reported regardless if the patient is de novo or roll-over. If possible, an additional sample should be collected when the SAE 
has been resolved.  
7. Assessments should be performed prior to RBP-6000 injection and at approximately the same time each day ±2 hours. 


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8. Local injection site grading will be performed at time of SC injection (within 10 minutes), 1 hour (± 15 minutes). For Injection 1 only, the local injection 
site grading will also be taken 24 hours (±4 hours) post SC injection. 
9. Injection Site Pain VAS will be completed by the subject within 1 minute after the completion of the injection and then at 5, 10, 15, 30, and 60 minutes 
(± 5 minutes) post-completion of injection. 
10. Injection site will be evaluated for evidence of attempted removal.   
11. Additional unscheduled visits for behavioral therapy may be added at the Investigator’s discretion.  
12. Collect information for the Employment/Support Status, Alcohol, Drug, Legal, Family/Social, and Psychological section only. Follow-up version of the 
questionnaire (only circled items, no lifetime recall). 
13. Subjects should be contacted by telephone at 24 hrs (± 4 hours) and will be assessed for AEs and any changes to Con Meds. Subjects are not required to 
return to the site unless the investigator deems it medically necessary. 
 
 


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      25 March 2016 
 
 
Confidential 
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Appendix 3 
Schedule of Events – RBP-6000 Injection 4 – 6 Visits for all Subjects and End of 
Study/Early Termination and Follow-Up Visits for Roll-over Subjects 
Evaluation 
Inj 4 
Post 
Inj 4 
24hrs 
Post 
Inj 4 
Inj 5 
Post 
Inj 5 
24hrs 
Post 
Inj 5 
Inj 6 
Post 
Inj 6 
24hrs 
EOS/ET 13 
Safety  
Follow-Up 20 
Wk13 
D 
85 
Wk13 
D 
86 
W15 
D 
99 
Wk17 
D 
113 
Wk17 
D 
114 
Wk19 
D 
127 
Wk21 
D 
141 
Wk21 
D 
142 
Wk25 
D 
169 
Wk29 
D 
197 
Window  
±2 
+1 
±2 
±2 
+1 
±2 
±2 
+1 
±2 
±2 
IWRS 
X 
 
 
X 
 
 
X 
 
X14 
 
Vital Signs 1 
X 
 
X 
X 
 
X 
X 
 
X 
 
Body Weight 
X 
 
 
 
 
 
X 
 
X 
 
BMI Calculation 
X 
 
 
 
 
 
X 
 
X 
 
Hip-to-Waist Ratio 
X 
 
 
 
 
 
X 
 
X 
 
12-lead ECG (supine > 10 min) 2 
X 
 
X 
X 
 
X 
X 
 
X 
 
Hematology/ Serum Chemistry 3 
X 
 
X 
X 
 
X 
X 
 
X 
 
Hormone Panel 3 
X 
 
 
 
 
 
X 
 
X 
 
Urinalysis 3 
X 
 
X 
X 
 
X 
X 
 
X 
 
Urine Pregnancy  
Test 3 
X 
 
X 
X 
 
X 
X 
 
X 
 
Serum Pregnancy Test 4 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screen 5 
X 
 
X 
X 
 
X 
X 
 
X 
 
PK Sampling (Roll-over patients only) 6 
X 
 
X 
X 
 
X 
X 
 
X 
 
Concomitant Medications 
X 
  X 19 
X 
X 
X 19 
X 
X 
X 19 
X 
X 
AE Assessment 8 
X 
  X 19 
X 
X 
X 19 
X 
X 
X 19 
X 
X 
eC-SSRS (Since last-visit-version) 8 
X 
 
X 
X 
 
X 
X 
 
X 
 
TLFB Interview 8 
X 
 
X 
X 
 
X 
X 
 
X 
 
Opioid Craving VAS  8 
X 
 
X 
X 
 
X 
X 
 
X 
 
COWS  8 
X 
 
X 
X 
 
X 
X 
 
X 
 
SOWS  8 
X 
 
X 
X 
 
X 
X 
 
X 
 


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Evaluation 
Inj 4 
Post 
Inj 4 
24hrs 
Post 
Inj 4 
Inj 5 
Post 
Inj 5 
24hrs 
Post 
Inj 5 
Inj 6 
Post 
Inj 6 
24hrs 
EOS/ET 13 
Safety  
Follow-Up 20 
Wk13 
D 
85 
Wk13 
D 
86 
W15 
D 
99 
Wk17 
D 
113 
Wk17 
D 
114 
Wk19 
D 
127 
Wk21 
D 
141 
Wk21 
D 
142 
Wk25 
D 
169 
Wk29 
D 
197 
Window  
±2 
+1 
±2 
±2 
+1 
±2 
±2 
+1 
±2 
±2 
BDI-II 8 
X 
 
 
X 
 
 
X 
 
X 
 
BPI 8 
X 
 
 
X 
 
 
X 
 
X 
 
RBP-6000 Injection 
X 
 
 
X 
 
 
X 
 
 
 
Injection Site  
Grading Scale 9 
X 
 
 
X 
 
 
X 
 
 
 
Injection Site Pain VAS 10 
X 
 
 
X 
 
 
X 
 
 
 
Injection Site Evaluation 11 
X 
 
X 
X 
 
X 
X 
 
X 
 
Behavioral Therapy 12 
X 
 
X 
X 
 
X 
X 
 
X 
 
EQ-5D-5L 8 
 
 
 
 
 
 
X 
 
X 
 
SF-36v2 8 
 
 
 
 
 
 
X 
 
X 
 
MSQ 8 
 
 
 
 
 
 
X 
 
X 
 
Health Insurance 8 
X 
 
 
X 
 
 
X 
 
X 
 
HCRU  8 
X 
 
 
X 
 
 
X 
 
X 
 
TEA 8 
X 
 
 
X 
 
 
X 
 
X 
 
ASI Lite 
 
 
 
 
 
 
X17 
 
X18 
 
Physical Examination 15 
 
 
 
 
 
 
 
 
X 
 
Review of Treatment Options 16 
 
 
 
X 
 
 
X 
 
X 
 
Alternative Treatment Agreed 16 
 
 
 
 
 
 
 
 
X 
 
AE = adverse event; ASI = Addiction Severity Index; BDI-II = Beck Depression Inventory II; BMI = body mass index; BPI = Brief Pain Inventory Short Form; 
COWS = Clinical Opiate Withdrawal Scale; eC-SSRS = electronic Columbia Suicide Severity Rating Scale; D = Day; ECG = electrocardiogram; EOS/ET = End 
of Study/Early Termination; EQ-5D-5L =  EuroQol EQ-5D-5L; HCRU = Healthcare resource utilization; Inj. = injection; IXRS=Interactive voice/web response 
system; MSQ =  Medication Satisfaction Questionnaire; PK = pharmacokinetic/pharmacokinetics; SF-36v2 = 36-Item Short Form Health Survey, Version 2; SC 
= subcutaneous; SL = sublingual; SOWS = subjective opiate withdrawal scale; TEA = Treatment Effectiveness Assessment; TLFB = Timeline Followback; 
VAS = Visual Analog Scale. 
1. Includes blood pressure, pulse oximetry, pulse rate, respiratory rate, and oral temperature which must be taken after subject is supine ≥ 3 minutes. On 
days injections 2-12 are given, vital signs will be taken ≤ 60 minutes prior to SC injection, and 1 hour post SC injection (± 15 minutes). For non-
injection days, vital signs will be taken at approximately the same time of day as the Day 1 pre-injection vital signs. 


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Clinical Study Protocol: RB-US-13-0003 
 
      25 March 2016 
 
 
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2. On days injections 2-12 are given, an ECG will be performed ≤ 60 minutes prior to SC injection, and 1 hour post SC injection (± 30 minutes). For non-
injection days, an ECG will be performed at approximately the same time of day as the Day 1 pre-injection ECG. All ECGs must be performed prior to 
labs and PK samples. 
3. On injection days, blood and urine samples will be taken ≤ 60 minutes prior to SC injection and after the ECGs has been performed. 
4. Only for female subjects who are of childbearing potential (not postmenopausal or surgically sterile for at least 1 year). 
5. An additional urine drug screen can be done if use is suspected.  Oxycodone may not show up in all opiate assays and should be assessed separately. 
6. PK samples taken for roll-over subjects only. See PK table (Appendix 6) for exact time points. However, a PK sample should be taken as soon as 
possible after any SAE is reported regardless if the patient is de novo or roll-over. If possible, an additional sample should be collected when the SAE 
has been resolved.  
7. A PK sample will be taken as soon as possible after any SAE is reported.  If possible, an additional sample should be collected when the SAE has been 
resolved. 
8. Assessments should be performed prior to RBP-6000 injection and at approximately the same time each day ±2 hours. 
9. Local injection site grading will be performed at time of SC injection (within 10 minutes) and 1 hour (± 15 minutes.) 
10. Injection Site Pain VAS will be completed by the subject within 1 minute after completion of the injection and then at 5, 10, 15, 30, and 60 (± 5 
minutes) post-completion of injection. 
11. Injection site will be evaluated for evidence of attempted removal.   
12. Additional unscheduled visits for behavioral therapy may be added at the Investigator's discretion. 
13. For roll-over subjects, the procedures at Week 25/Day 169 will serve as the EOS assessments.  For de novo subjects who discontinued participation in 
the study after receiving RBP-6000, the procedures at Week 25/Day 169 will serve as the ET assessments. 
14. IXRS contacted to confirm study completion or discontinuation status (date and reason for discontinuation). 
15. Complete examination (excluding pelvic, breast, and rectal), including general appearance, skin, head, eyes, ears, nose, throat, neck, thyroid, 
chest/lungs, heart, abdomen, lymph nodes, extremities, and a brief neurological assessment.   
16. Subject’s alternative treatment options should be assessed up to two months before EOS. At the EOS visit, if eligible, subjects may enroll in study 
INDV-6000-301. Alternatively, subjects can start an optional 4 week SUBOXONE program (based on Investigator’s discretion).  
17. Collect information for the Employment/Support Status, Alcohol, Drug, Legal, Family/Social, and Psychological section only. Follow-up version of the 
questionnaire (only circled items, no lifetime recall). 
18. Complete all ASI-Lite scales. Follow-up version of the questionnaire (only circled items, no lifetime recall). 
19. Subjects should be contacted by telephone at 24 hrs (± 4 hours) and will be assessed for AEs and any changes to Con Meds. Subjects are not required to 
return to the site unless the investigator deems it medically necessary. 
20. Subjects should be contacted by telephone in order to assess for AEs or Con Meds. Subjects are not required to return to the site unless the investigator 
deems it medically necessary. Subjects enrolled onto INDV-6000-301 are not required to be contacted. 
 
  
 
 


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Clinical Study Protocol: RB-US-13-0003 
 
      25 March 2016 
 
 
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Appendix 4 
Schedule of Events – RBP-6000 Injection 7 – 9 Visits for de novo Subjects  
Evaluation 
Inj 7 
Post Inj 7 
24hrs 
Inj 8 
Post Inj 8 
24hrs 
Inj 9 
Post Inj 9 
24hrs 
Wk25 
D169 
Wk25 
D170 
Wk29 
D197 
Wk29 
D198 
Wk33 
D225 
Wk33 
D226 
Window  
±2 
+1 
±2 
+1 
±2 
+1 
IWRS 
X 
 
X 
 
X 
 
Vital Signs 1 
X 
 
X 
 
X 
 
Body Weight 
X 
 
 
 
 
 
BMI Calculation 
X 
 
 
 
 
 
Hip-to-Waist Ratio 
X 
 
 
 
 
 
12-lead ECG 2 
(supine > 10 min)  
X 
 
X 
 
X 
 
Hematology/ Serum Chemistry 3 
X 
 
X 
 
X 
 
Hormone Panel 3 
X 
 
 
 
 
 
Urinalysis  3 
X 
 
X 
 
X 
 
Urine Pregnancy Test  4 
X 
 
X 
 
X 
 
Urine Drug Screen 5 
X 
 
X 
 
X 
 
Concomitant Medications  
X 
X 13 
X 
X 13 
X 
X 13 
AE Assessment 6 
X 
X 13 
X 
X 13 
X 
X 13 
eC-SSRS (Since last-visit-version) 7 
X 
 
X 
 
X 
 
TLFB Interview 7 
X 
 
X 
 
X 
 
Opioid Craving  
VAS 7 
X 
 
X 
 
X 
 
COWS 7 
X 
 
X 
 
X 
 
SOWS 7 
X 
 
X 
 
X 
 
BDI-II 7 
X 
 
X 
 
X 
 
BPI 7 
X 
 
X 
 
X 
 
RBP-6000 Injection 
X 
 
X 
 
X 
 


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Evaluation 
Inj 7 
Post Inj 7 
24hrs 
Inj 8 
Post Inj 8 
24hrs 
Inj 9 
Post Inj 9 
24hrs 
Wk25 
D169 
Wk25 
D170 
Wk29 
D197 
Wk29 
D198 
Wk33 
D225 
Wk33 
D226 
Window  
±2 
+1 
±2 
+1 
±2 
+1 
Injection Site Grading Scale 8 
X 
 
X 
 
X 
 
Injection Site Pain VAS 9 
X 
 
X 
 
X 
 
Injection Site Evaluation 10 
X 
 
X 
 
X 
 
Behavioral Therapy 11 
X 
 
X 
 
X 
 
EQ-5D-5L 7 
 
 
 
 
X 
 
SF-36v2 7 
 
 
 
 
X 
 
MSQ 7 
 
 
 
 
X 
 
Health Insurance 7 
X 
 
X 
 
X 
 
HCRU  7 
X 
 
X 
 
X 
 
TEA 7 
X 
 
X 
 
X 
 
ASI Lite 
 
 
 
 
X12 
 
 
AE = adverse event; ASI = Addiction Severity Index; BDI-II = Beck Depression Inventory II; BMI = body mass index; BPI = Brief Pain Inventory Short 
Form; COWS = Clinical Opiate Withdrawal Scale; eC-SSRS = electronic Columbia Suicide Severity Rating Scale; D = Day; ECG = electrocardiogram; EQ-
5D-5L =  EuroQol EQ-5D-5L; HCRU = Healthcare resource utilization; Inj. = injection; IXRS=Interactive voice/web response system; MSQ =  Medication 
Satisfaction Questionnaire; PK = pharmacokinetic/pharmacokinetics; SF-36v2 = 36-Item Short Form Health Survey, Version 2; SC = subcutaneous; SOWS 
= subjective opiate withdrawal scale; TEA = Treatment Effectiveness Assessment; TLFB = Timeline Followback; VAS = Visual Analog Scale 
 
1. Includes blood pressure, pulse oximetry, pulse rate, respiratory rate, and oral temperature which must be taken after subject is supine ≥ 3 minutes. On 
days injections 2-12 are given, vital signs will be taken ≤ 60 minutes prior to SC injection, and 1 hour post SC injection (± 15 minutes). For non-
injection days, vital signs will be taken at approximately the same time of day as the Day 1 pre-injection vital signs. 
2. On days injections 2-12 are given, an ECG will be recorded ≤ 60 minutes prior to SC injection, and 1 hour post SC injection (± 30 minutes). For non-
injection days, an ECG will be performed at approximately the same time of day as the Day 1 pre-injection ECG. All ECGs must be performed prior to 
labs and PK samples. 
3. On injection days, blood and urine samples will be taken ≤ 60 minutes prior to SC injection and after the ECGs has been performed. 
4. Only for female subjects who are of childbearing potential (not postmenopausal or surgically sterile for at least 1 year). 
5. An additional urine drug screen can be done if use is suspected.  Oxycodone may not show up in all opiate assays and should be assessed separately. 
6. A PK sample will be taken as soon as possible after any SAE is reported.  If possible, an additional sample should be collected when the SAE has been 
resolved. 
7. Assessments should be performed prior to RBP-6000 injection and at approximately the same time each day ±2 hours. 


RBP-6000 
 
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Clinical Study Protocol: RB-US-13-0003 
 
      25 March 2016 
 
 
Confidential 
Page 94 of 171 
8. Local injection site grading will be performed at time of SC injection (within 10 minutes) and 1 hour (± 15 minutes).  
9. Injection Site Pain VAS will be completed by the subject within 1 minute after the completion of the injection and then at 5, 10, 15, 30, and 60 minutes 
(± 5 minutes) post-completion of injection. 
10. Injection site will be evaluated for evidence of attempted removal.   
11. Additional unscheduled visits for behavioral therapy may be added at the Investigator’s discretion. 
12. Collect information for the Employment/Support Status, Alcohol, Drug, Legal, Family/Social, and Psychological section only. Follow-up version of the 
questionnaire (only circled items, no lifetime recall). 
13. Subjects should be contacted by telephone at 24 hrs (± 4 hours) and will be assessed for AEs and any changes to Con Meds. Subjects are not required to 
return to the site unless the investigator deems it medically necessary. 
 


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Clinical Study Protocol: RB-US-13-0003 
 
      25 March 2016 
 
 
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Appendix 5 
Schedule of Events – RBP-6000 Injection 10 – 12 Visits and End of Study/Early 
Termination Visit and Follow-Up for de novo Subjects  
Evaluation 
Inj 10 
Post Inj 
10 24hrs 
Inj 11 
Post Inj 
11 24hrs 
Inj 12 
Post Inj 
12 24hrs 
EOS/ET 12 
Safety 
Follow-Up 19 
Wk37 
D253 
Wk37 
D254 
Wk41 
D281 
Wk41 
D282 
Wk45 
D309 
Wk45 
D310 
Wk49 
D337 
Wk53 
D365 
Window  
±2 
+1 
±2 
+1 
±2 
+1 
±2 
±2 
IWRS 
X 
 
X 
 
X 
 
X13 
 
Vital Signs 1 
X 
 
X 
 
X 
 
X 
 
Body Weight 
X 
 
 
 
X 
 
X 
 
BMI Calculation 
X 
 
 
 
X 
 
X 
 
Hip-to-Waist Ratio 
X 
 
 
 
X 
 
X 
 
12-lead ECG (supine > 10 min) 2 
X 
 
X 
 
X 
 
X 
 
Hematology/ Serum Chemistry 3  
X 
 
X 
 
X 
 
X 
 
Hormone Panel 3 
X 
 
 
 
X 
 
X 
 
Urinalysis 3 
X 
 
X 
 
X 
 
X 
 
Urine Pregnancy Test 4 
X 
 
X 
 
X 
 
X 
 
Serum Pregnancy Test 4 
 
 
 
 
 
 
 
 
Urine Drug Screen 5 
X 
 
X 
 
X 
 
X 
 
Concomitant Medications 
X 
X18 
X 
X18 
X 
X18 
X 
X 
AE Assessment 6 
X 
X18 
X 
X18 
X 
X18 
X 
X 
eC-SSRS (Since last-visit-version) 7 
X 
 
X 
 
X 
 
X 
 
TLFB Interview 7 
X 
 
X 
 
X 
 
X 
 
Opioid Craving VAS 7 
X 
 
X 
 
X 
 
X 
 
COWS 7 
X 
 
X 
 
X 
 
X 
 
SOWS 7 
X 
 
X 
 
X 
 
X 
 
BDI-II 7 
X 
 
X 
 
X 
 
X 
 
BPI 7 
X 
 
X 
 
X 
 
X 
 


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      25 March 2016 
 
 
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Evaluation 
Inj 10 
Post Inj 
10 24hrs 
Inj 11 
Post Inj 
11 24hrs 
Inj 12 
Post Inj 
12 24hrs 
EOS/ET 12 
Safety 
Follow-Up 19 
Wk37 
D253 
Wk37 
D254 
Wk41 
D281 
Wk41 
D282 
Wk45 
D309 
Wk45 
D310 
Wk49 
D337 
Wk53 
D365 
Window  
±2 
+1 
±2 
+1 
±2 
+1 
±2 
±2 
RBP-6000 Injection 
X 
 
X 
 
X 
 
 
 
Injection Site Grading Scale 8 
X 
 
X 
 
X 
 
 
 
Injection Site Pain VAS 9 
X 
 
X 
 
X 
 
 
 
Injection Site Evaluation 10 
X 
 
X 
 
X 
 
X 
 
Behavioral Therapy 11 
X 
 
X 
 
X 
 
X 
 
EQ-5D-5L 7 
 
 
 
 
X 
 
X 
 
SF-36v2  7 
 
 
 
 
X 
 
X 
 
MSQ 7 
 
 
 
 
X 
 
X 
 
Health Insurance 7 
X 
 
X 
 
X 
 
X 
 
HCRU  7 
X 
 
X 
 
X 
 
X 
 
TEA 7 
X 
 
X 
 
X 
 
X 
 
ASI Lite 
 
 
 
 
X16 
 
X17 
 
Physical Examination 14 
 
 
 
 
 
 
X 
 
Review of Treatment Options 15 
 
 
X 
 
X 
 
X 
 
Alternative Treatment Agreed 15 
 
 
 
 
 
 
X 
 
 
AE = adverse event; ASI = Addiction Severity Index; BDI-II = Beck Depression Inventory II; BMI = body mass index; BPI = Brief Pain Inventory Short Form; 
COWS = Clinical Opiate Withdrawal Scale; eC-SSRS = electronic Columbia Suicide Severity Rating Scale; D = Day; ECG = electrocardiogram; EOS/ET = End 
of Study/Early Termination;EQ-5D-5L =  EuroQol EQ-5D-5L; HCRU = Healthcare resource utilization; Inj. = injection; IXRS=Interactive voice/web response 
system; MSQ =  Medication Satisfaction Questionnaire; PK = pharmacokinetic/pharmacokinetics; SF-36v2 = 36-Item Short Form Health Survey, Version 2; SC 
= subcutaneous; SL = sublingual; SOWS = subjective opiate withdrawal scale; TEA = Treatment Effectiveness Assessment; TLFB = Timeline Followback; 
VAS = Visual Analog Scale. 
 
1. Includes blood pressure, pulse oximetry, pulse rate, respiratory rate, and oral temperature which must be taken after subject is supine ≥ 3 minutes. On days 
injections 2-12 are given, vital signs will be taken ≤ 60 minutes prior to SC injection, and 1 hour post SC injection (± 15 minutes). For non-injection days, 
vital signs will be taken at approximately the same time of day as the Day 1 pre-injection vital signs. 


RBP-6000 
 
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Clinical Study Protocol: RB-US-13-0003 
 
      25 March 2016 
 
 
Confidential 
Page 97 of 171 
2. On days injections 2-12 are given, an ECG will be recorded ≤ 60 minutes prior to SC injection, and 1 hour post SC injection (± 30 minutes). For non-
injection days, an ECG will be performed at approximately the same time of day as the Day 1 pre-injection ECG. All ECGs must be performed prior to labs 
and PK samples. 
3. On injection days, blood and urine samples will be taken ≤ 60 minutes prior to SC injection and after the ECGs has been performed. 
4. Only for female subjects who are of childbearing potential (not postmenopausal or surgically sterile for at least 1 year). 
5. An additional urine drug screen can be done if use is suspected.  Oxycodone may not show up in all opiate assays and should be assessed separately. 
6. A PK sample will be taken as soon as possible after any SAE is reported.  If possible, an additional sample should be collected when the SAE has been 
resolved. 
7. Assessments should be performed prior to RBP-6000 injection and at approximately the same time each day ±2 hours. 
8. Local injection site grading will be performed at time of SC injection (within 10 minutes) and 1 hour (± 15 minutes).  
9. Injection Site Pain VAS will be completed by the subject within 1 minute after the completion of the injection and then at 5, 10, 15, 30, and 60 minutes (± 5 
minutes) post-completion of injection. 
10. Injection site will be evaluated for evidence of attempted removal. 
11. Additional unscheduled visits for behavioral therapy may be added at the Investigator’s discretion. 
12. For de novo subjects who discontinue participation in this study after receiving RBP-6000, the procedures at Week 49/Day 337 will serve as the ET 
assessments. 
13. IXRS contacted to confirm study completion or discontinuation status (date and reason for discontinuation). 
14. Complete examination (excluding pelvic, breast, and rectal), including general appearance, skin, head, eyes, ears, nose, throat, neck, thyroid, chest/lungs, 
heart, abdomen, lymph nodes, extremities, and a brief neurological assessment.   
15. Subject’s alternative treatment options should be assessed up to two months before EOS. At the EOS visit, if eligible, subjects may enroll in study INDV-
6000-301. Alternatively, subjects can start an optional 4 week SUBOXONE program (based on Investigator’s discretion).  
16. Collect information for the Employment/Support Status, Alcohol, Drug, Legal, Family/Social, and Psychological section only. Follow-up version of the 
questionnaire (only circled items, no lifetime recall). 
17. Complete all ASI-Lite scales. Follow-up version of the questionnaire (only circled items, no lifetime recall). 
18. Subjects should be contacted by telephone at 24 hrs (± 4 hours) and will be assessed for AEs and any changes to Con Meds. Subjects are not required to 
return to the site unless the investigator deems it medically necessary. 
19. Subjects should be contacted by telephone in order to assess for AEs or Con Meds. Subjects are not required to return to the site unless the investigator 
deems it medically necessary. Subjects enrolled onto INDV-6000-301 are not required to be contacted.  
 


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Clinical Study Protocol: RB-US-13-0003 
 
25 March 2016 
 
Confidential 
Page 98 of 171 
 
 
Appendix 6 
Pharmacokinetic Sampling Schedule 
Sample 
Number1 
Sample 
Class 
Time 
Study Phase 
Comments 
1 
PK 
Day 1 
Treatment phase (SC) 
Within 1 hour prior to 1st SC injection  
2 
PK 
Day 15 
Treatment phase (SC) 
Post 1st SC injection 
3 
PK 
Day 29 
Treatment phase (SC) 
Within 1 hour prior to 2nd SC injection  
4 
PK 
Day 43 
Treatment phase (SC) 
Post 2nd SC injection 
5 
PK 
Day 57 
Treatment phase (SC) 
Within 1 hour prior to 3rd SC injection  
6 
PK 
Day 71 
Treatment phase (SC) 
Post 3rd SC injection 
7 
PK 
Day 85 
Treatment phase (SC) 
Within 1 hour prior to 4th SC injection  
8 
PK 
Day 99 
Treatment phase (SC) 
Post 4th SC injection 
9 
PK 
Day 113 
Treatment phase (SC) 
Within 1 hour prior to 5th SC injection 
10 
PK 
Day 127 
Treatment phase (SC) 
Post 5th SC injection 
11 
PK 
Day 141 
Treatment phase (SC) 
Within 1 hour prior to 6th SC injection 
12 
PK 
Day 169 or 
ET Visit 
Treatment phase (SC) 
Post 6th SC injection 
PK = pharmacokinetic/pharmacokinetics; SC = subcutaneous 
1  Blood samples for PK analysis will be collected from roll-over subjects only (not de novo). Once 100 roll-over 
subjects have completed Injection 6 (Week 25, Day 169) no more PK samples will be required to be collected from 
the roll-over subjects for the duration of the study. 
However, for all subjects (de novo and roll-over), a PK sample will be taken as soon as possible after any SAE is 
reported. If possible, an additional sample should be collected when the SAE has been resolved. 
 


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Confidential 
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Appendix 7 SUBOXONE® 
(Buprenorphine/Naloxone) 
Sublingual Film Full 
Prescribing Information 
HIGHLIGHTS OF PRESCRIBING INFORMATION 
These highlights do not include all the information needed to use 
SUBOXONE safely and effectively.  See full prescribing information for 
SUBOXONE. 
 
SUBOXONE® (buprenorphine and naloxone) sublingual film, for sublingual 
or buccal use  CIII 
Initial U.S. Approval: 2002 
----------------------------------RECENT MAJOR CHANGES--------------------------------- 
Dosage and Administration, Method 
      of Administration (2.3) 
 
 
 
09/2015 
----------------------------------INDICATIONS AND USAGE--------------------------------- 
SUBOXONE sublingual film is a partial-opioid agonist indicated for treatment 
of opioid dependence.  Prescription use of this product is limited under the 
Drug Addiction Treatment Act. (1) 
------------------------------DOSAGE AND ADMINISTRATION----------------------------- 
• For patients dependent on short-acting opioid products who are in opioid 
withdrawal; on Day 1, administer up to 8 mg/2 mg SUBOXONE sublingual 
film (in divided doses).  On Day 2, administer up to 16 mg/4 mg of 
SUBOXONE sublingual film as a single dose. (2.1) 
• For patients dependent on methadone or long-acting opioid products, 
induction onto sublingual buprenorphine monotherapy is recommended 
on Days 1 and 2 of treatment. (2.1) 
• For maintenance treatment, the target dosage of SUBOXONE sublingual 
film is usually 16 mg/4 mg as a single daily dose. (2.2) 
• Sublingual Administration: Place one film under the tongue, close to the 
base on the left or right side, and allow to completely dissolve.   
Buccal Administration: Place one film on the inside of the left or right 
cheek and allow to completely dissolve. 
• SUBOXONE sublingual film must be administered whole.  Do not cut, 
chew, or swallow SUBOXONE sublingual film (2.3) 
-----------------------------DOSAGE FORMS AND STRENGTHS---------------------------- 
Sublingual film:  2 mg buprenorphine with 0.5 mg naloxone, 4 mg 
buprenorphine with 1 mg naloxone, 8 mg buprenorphine with 2 mg naloxone 
and 12 mg buprenorphine with 3 mg naloxone. (3)  
-------------------------------------CONTRAINDICATIONS------------------------------------ 
Hypersensitivity to buprenorphine or naloxone. (4) 
-------------------------------WARNINGS AND PRECAUTIONS----------------------------- 
• Buprenorphine can be abused in a similar manner to other opioids. 
Clinical monitoring appropriate to the patient’s level of stability is 
essential. Multiple refills should not be prescribed early in treatment or 
without appropriate patient follow-up visits. (5.1)  
• Significant respiratory depression and death have occurred in association 
with buprenorphine, particularly when taken by the intravenous (IV) 
route in combination with benzodiazepines or other CNS depressants 
(including alcohol). (5.2) 
• Consider dose reduction of CNS depressants, SUBOXONE sublingual film, 
or both in situations of concomitant prescription. (5.3) 
• Store SUBOXONE sublingual film safely out of the sight and reach of 
children. Buprenorphine can cause severe, possibly fatal, respiratory 
depression in children. (5.4)   
• Chronic administration produces opioid-type physical dependence.  
Abrupt discontinuation or rapid dose taper may result in opioid 
withdrawal syndrome. (5.5) 
• Monitor liver function tests prior to initiation and during treatment and 
evaluate suspected hepatic events. (5.6) 
• Do not administer SUBOXONE sublingual film to patients with known 
hypersensitivity to buprenorphine or naloxone. (5.7) 
• An opioid withdrawal syndrome is likely to occur with parenteral misuse 
of SUBOXONE sublingual film by individuals physically dependent on full 
opioid agonists, or by sublingual or buccal administration before the 
agonist effects of other opioids have subsided. (5.8) 
• Neonatal withdrawal has been reported following use of buprenorphine 
by the mother during pregnancy. (5.9)  
• SUBOXONE sublingual film is not appropriate as an analgesic. There have 
been reported deaths of opioid naïve individuals who received a 2 mg 
sublingual dose. (5.10) 
• Buprenorphine/naloxone products are not recommended in patients 
with severe hepatic impairment and may not be appropriate for patients 
with moderate hepatic impairment (5.11) 
• Caution patients about the risk of driving or operating hazardous 
machinery. (5.12) 
-------------------------------------ADVERSE REACTIONS------------------------------------- 
Adverse events commonly observed with the sublingual/buccal 
administration of the SUBOXONE sublingual film were oral hypoesthesia, 
glossodynia, oral mucosal erythema, headache, nausea, vomiting, 
hyperhidrosis, constipation, signs and symptoms of withdrawal, insomnia, 
pain, and peripheral edema. (6.1)     
To report SUSPECTED ADVERSE REACTIONS, contact Indivior Inc. at 1-877-
782-6966 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 
--------------------------------------DRUG INTERACTIONS----------------------------------- 
• Monitor patients starting or ending CYP3A4 inhibitors or inducers for 
potential over or under dosing.  (7.1)  
• Use caution in prescribing SUBOXONE sublingual film for patients 
receiving benzodiazepines or other CNS depressants and warn patients 
against concomitant self-administration/misuse. (7.3) 
---------------------------------USE IN SPECIFIC POPULATIONS---------------------------- 
• 
Pregnancy: Based on animal data, may cause fetal harm. (8.1) 
• 
Nursing mothers: Caution should be exercised when administered to a 
nursing woman. (8.3) 
• 
Safety and effectiveness of SUBOXONE sublingual film in patients below 
the age of 16 has not been established. (8.4) 
• 
Administer SUBOXONE sublingual film with caution to elderly or 
debilitated patients. (8.5) 
• 
Buprenorphine/naloxone products are not recommended in patients 
with severe hepatic impairment and may not be appropriate for 
patients with moderate hepatic impairment.  (8.6) 
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. 
Revised:  9/2015


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FFULL PRESCRIBING INFORMATION: CONTENTS* 
1 
INDICATIONS AND USAGE 
2 
DOSAGE AND ADMINISTRATION 
 
        2.1 
Induction 
 
        2.2 
Maintenance 
 
        2.3 
Method of Administration 
 
        2.4 
Clinical Supervision 
 
        2.5 
Patients With Hepatic Impairment 
 
        2.6 
Unstable Patients 
        2.7 
Stopping Treatment 
        2.8 
Switching Between Buprenorphine and Naloxone Sublingual Tablets and SUBOXONE Sublingual Film 
        2.9 
Switching Between SUBOXONE Sublingual Film Strengths 
        2.10 Switching Between Sublingual and Buccal Site Administrations 
3 
DOSAGE FORMS AND STRENGTHS 
4 
CONTRAINDICATIONS 
5 
WARNINGS AND PRECAUTIONS 
        5.1 
Abuse Potential 
        5.2 
Respiratory Depression  
        5.3 
CNS Depression  
        5.4 
Unintentional Pediatric Exposure 
        5.5 
Dependence 
        5.6 
Hepatitis, Hepatic Events 
        5.7 
Allergic Reactions  
        5.8 
Precipitation of Opioid Withdrawal Signs and Symptoms 
        5.9 
Neonatal Withdrawal 
        5.10 Use in Opioid Naïve Patients 
        5.11 Use in Patients With Impaired Hepatic Function 
        5.12 Impairment of Ability to Drive or Operate Machinery  
        5.13 Orthostatic Hypotension 
        5.14 Elevation of Cerebrospinal Fluid Pressure  
        5.15 Elevation of Intracholedochal Pressure 
        5.16 Effects in Acute Abdominal Conditions 
        5.17 General Precautions 
6 
ADVERSE REACTIONS 
        6.1 
Clinical Trials Experience 
        6.2 
Postmarketing Experience


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7 
DRUG INTERACTIONS   
        7.1 
Cytochrome P-450 3A4 (CYP3A4) Inhibitors and Inducers 
 
        7.2 
Antiretrovirals 
 
        7.3 
Benzodiazepines 
8 
USE IN SPECIFIC POPULATIONS 
 
        8.1 
Pregnancy 
 
        8.3 
Nursing Mothers 
 
        8.4 
Pediatric Use 
 
        8.5 
Geriatric Use  
        8.6 
Hepatic Impairment 
        8.7  
Renal Impairment 
9 
DRUG ABUSE AND DEPENDENCE 
 
        9.1 
Controlled Substance 
        9.2 
Abuse 
 
        9.3 
Dependence 
10 
OVERDOSAGE 
11 
DESCRIPTION 
12 
CLINICAL PHARMACOLOGY 
 
        12.1 Mechanism of Action 
 
        12.2 Pharmacodynamics 
 
        12.3 Pharmacokinetics 
13 
NONCLINICAL TOXICOLOGY 
        13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 
16 
HOW SUPPLIED / STORAGE AND HANDLING 
17 
PATIENT COUNSELING INFORMATION 
        Safe Use 
        Disposal of Unused SUBOXONE Sublingual Films 
 
 
* 
Sections and subsections omitted from the full prescribing information are not listed. 


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FULL PRESCRIBING INFORMATION 
1 
INDICATIONS AND USAGE 
SUBOXONE sublingual film is indicated for treatment of opioid dependence and should be used as part 
of a complete treatment plan to include counseling and psychosocial support.  
Under the Drug Addiction Treatment Act (DATA) codified at 21 U.S.C. 823(g), prescription use of this 
product in the treatment of opioid dependence is limited to physicians who meet certain qualifying 
requirements, and who have notified the Secretary of Health and Human Services (HHS) of their intent 
to prescribe this product for the treatment of opioid dependence and have been assigned a unique 
identification number that must be included on every prescription.   
2 
DOSAGE AND ADMINISTRATION 
2.1 
Induction  
Prior to induction, consideration should be given to the type of opioid dependence (i.e., long- or short-
acting opioid products), the time since last opioid use, and the degree or level of opioid dependence.  To 
avoid precipitating an opioid withdrawal syndrome, the first dose of buprenorphine/naloxone should be 
started only when objective signs of moderate withdrawal appear. 
On Day 1, an induction dosage of up to 8 mg/2 mg SUBOXONE sublingual film is recommended.  
Clinicians should start with an initial dose of 2 mg/0.5 mg or 4 mg/1 mg buprenorphine/naloxone and 
may titrate upwards in 2 or 4 mg increments of buprenorphine, at approximately 2-hour intervals, under 
supervision, to 8 mg/2 mg buprenorphine/naloxone based on the control of acute withdrawal 
symptoms.   
On Day 2, a single daily dose of up to 16 mg/4 mg SUBOXONE sublingual film is recommended.  
Because the exposure to naloxone is somewhat higher after buccal than after sublingual administration, 
it is recommended that the sublingual site of administration be used during induction to minimize 
exposure to naloxone, to reduce the risk of precipitated withdrawal. 
 
Medication should be prescribed in consideration of the frequency of visits. Provision of multiple refills is 
not advised early in treatment or without appropriate patient follow-up visits. 
Patients dependent on methadone or long-acting opioid products 
Patients dependent upon methadone or long-acting opioid products may be more susceptible to 
precipitated and prolonged withdrawal during induction than those on short-acting opioid products.  
Buprenorphine/naloxone combination products have not been evaluated in adequate and well-
controlled studies for induction in patients on long-acting opioid products, and contain naloxone, which 
is absorbed in small amounts by the sublingual route and could cause worse precipitated and prolonged 
withdrawal.  For this reason, buprenorphine monotherapy is recommended in patients taking long-
acting opioids when used according to approved administration instructions.  Following induction, the 
patient may then be transitioned to once-daily SUBOXONE sublingual film. 
Patients dependent on heroin or other short-acting opioid products  
Patients dependent on heroin or short-acting opioid products may be inducted with either SUBOXONE 
sublingual film or with sublingual buprenorphine monotherapy.  The first dose of SUBOXONE sublingual 
film or buprenorphine should be administered when objective signs of moderate opioid withdrawal 


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appear, and not less than 6 hours after the patient last used an opioid. 
It is recommended that an adequate maintenance dose, titrated to clinical effectiveness, be achieved as 
rapidly as possible.  In some studies, a too-gradual induction over several days led to a high rate of drop-
out of buprenorphine patients during the induction period. 
 2.2 
Maintenance  
For maintenance, SUBOXONE sublingual film may be administered buccally or sublingually. The dosage of 
SUBOXONE sublingual film from Day 3 onwards should be progressively adjusted in 
increments/decrements of 2 mg/0.5 mg or 4 mg/1 mg buprenorphine/naloxone to a level that holds the 
patient in treatment and suppresses opioid withdrawal signs and symptoms. 
 
After treatment induction and stabilization, the maintenance dose of SUBOXONE sublingual film is 
generally in the range of 4 mg/1 mg buprenorphine/naloxone to 24 mg/6 mg buprenorphine/naloxone per 
day depending on the individual patient and clinical response.  The recommended target dosage of 
SUBOXONE sublingual film during maintenance is 16 mg/4 mg buprenorphine/naloxone/day as a single 
daily dose.  Dosages higher than 24 mg/6 mg daily have not been demonstrated to provide a clinical 
advantage.  
2.3 
Method of Administration 
SUBOXONE sublingual film must be administered whole.  Do not cut, chew, or swallow SUBOXONE 
sublingual film. 
Sublingual Administration 
Place one film under the tongue, close to the base on the left or right side.  If an additional film is 
necessary to achieve the prescribed dose, place an additional film sublingually on the opposite side from 
the first film.  Place the film in a manner to minimize overlapping as much as possible.  The film must be 
kept under the tongue until the film is completely dissolved.  If a third film is necessary to achieve the 
prescribed dose, place it under the tongue on either side after the first 2 films have dissolved. 
Buccal Administration 
Place one film on the inside of the right or left cheek.  If an additional film is necessary to achieve the 
prescribed dose, place an additional film on the inside of the opposite cheek.  The film must be kept on the 
inside of the cheek until the film is completely dissolved.  If a third film is necessary to achieve the 
prescribed dose, place it on the inside of the right or left cheek after the first two films have dissolved. 
SUBOXONE sublingual film should NOT be moved after placement. Proper administration technique 
should be demonstrated to the patient.  
2.4  
Clinical Supervision  
Treatment should be initiated with supervised administration, progressing to unsupervised 
administration as the patient’s clinical stability permits.  SUBOXONE sublingual film is subject to 
diversion and abuse.  When determining the prescription quantity for unsupervised administration, 
consider the patient’s level of stability, the security of his or her home situation, and other factors likely 
to affect the ability to manage supplies of take-home medication. 
 
Ideally patients should be seen at reasonable intervals (e.g., at least weekly during the first month of 
treatment) based upon the individual circumstances of the patient. Medication should be prescribed in 


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consideration of the frequency of visits.  Provision of multiple refills is not advised early in treatment or 
without appropriate patient follow-up visits.  Periodic assessment is necessary to determine compliance 
with the dosing regimen, effectiveness of the treatment plan, and overall patient progress.   
 
Once a stable dosage has been achieved and patient assessment (e.g., urine drug screening) does not 
indicate illicit drug use, less frequent follow-up visits may be appropriate. A once-monthly visit schedule 
may be reasonable for patients on a stable dosage of medication who are making progress toward their 
treatment objectives. Continuation or modification of pharmacotherapy should be based on the 
physician’s evaluation of treatment outcomes and objectives such as: 
 
1.  Absence of medication toxicity. 
 
2.  Absence of medical or behavioral adverse effects. 
 
3.  Responsible handling of medications by the patient. 
 
4.  Patient’s compliance with all elements of the treatment plan (including recovery-oriented activities, 
psychotherapy, and/or other psychosocial modalities). 
 
5.  Abstinence from illicit drug use (including problematic alcohol and/or benzodiazepine use).  
 
If treatment goals are not being achieved, the physician should re-evaluate the appropriateness of 
continuing the current treatment.  
 
2.5  
Patients With Hepatic Impairment  
Severe hepatic impairment results in a reduced clearance of naloxone to a much greater extent than 
buprenorphine, and moderate hepatic impairment also results in a reduced clearance of naloxone to a 
greater extent than buprenorphine. Because the doses of this fixed combination product cannot be 
individually titrated, the combination product should generally be avoided in patients with severe 
hepatic impairment and may not be appropriate for patients with moderate hepatic impairment [see 
Warnings and Precautions (5.11)]. 
 
2.6 
Unstable Patients 
Physicians will need to decide when they cannot appropriately provide further management for 
particular patients.  For example, some patients may be abusing or dependent on various drugs, or 
unresponsive to psychosocial intervention such that the physician does not feel that he/she has the 
expertise to manage the patient.  In such cases, the physician may want to assess whether to refer the 
patient to a specialist or more intensive behavioral treatment environment.  Decisions should be based 
on a treatment plan established and agreed upon with the patient at the beginning of treatment. 
 
Patients who continue to misuse, abuse, or divert buprenorphine products or other opioids should be 
provided with, or referred to, more intensive and structured treatment. 


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2.7 
Stopping Treatment 
The decision to discontinue therapy with SUBOXONE sublingual film after a period of maintenance 
should be made as part of a comprehensive treatment plan.  Taper patients to avoid opioid withdrawal 
signs and symptoms. 
 
2.8 
Switching Between Buprenorphine or Buprenorphine and Naloxone Sublingual Tablets and 
SUBOXONE Sublingual Film 
Patients being switched between buprenorphine and naloxone or buprenorphine only sublingual tablets 
and SUBOXONE sublingual film should be started on the corresponding dosage of the previously 
administered product.  However, dosage adjustments may be necessary when switching between 
buprenorphine products.  Not all strengths and combinations of the SUBOXONE sublingual films are 
bioequivalent to the SUBOXONE (buprenorphine and naloxone) sublingual tablets as observed in 
pharmacokinetic studies [see Clinical Pharmacology (12.3)].  Therefore, systemic exposures of 
buprenorphine and naloxone may be different when patients are switched from tablets to film or vice-
versa. Patients should be monitored for symptoms related to over-dosing or under-dosing. 
 
2.9 
Switching Between SUBOXONE Sublingual Film Strengths 
As indicated in Table 1, the sizes and the compositions of the four units of SUBOXONE sublingual films, 
i.e.,  
2 mg/0.5 mg, 4 mg/1 mg, 8 mg/2 mg and the 12 mg/3 mg units, are different from one another. If 
patients switch between various combinations of lower and higher strength units of SUBOXONE 
sublingual films to obtain the same total dose, (e.g., from three 4 mg/1 mg units to a single 12 mg/3 mg 
unit, or vice-versa), systemic exposures of buprenorphine and naloxone may be different and patients 
should be monitored for over-dosing or under-dosing.  For this reason, pharmacist should not substitute 
one or more film strengths for another without approval of the prescriber. 
 
Table 1.  Comparison of Available SUBOXONE Sublingual Film Strengths by Dimensions and Drug 
Concentrations. 
 
SUBOXONE sublingual film unit strength 
(buprenorphine/naloxone) 
SUBOXONE sublingual 
film unit dimensions 
Buprenorphine 
Concentration 
% (w/w) 
Naloxone 
Concentration 
% (w/w) 
2 mg/0.5 mg 
22.0 mm x 12.8 mm 
5.4 
1.53 
4 mg/1 mg  
(2 times the length of the 2 mg/0.5 mg unit) 
22.0 mm x 25.6 mm 
5.4 
1.53 
8 mg/2 mg  
22.0 mm x 12.8 mm 
17.2 
4.88 
12 mg/3 mg 
(1.5 times the length of the 8 mg/2 mg unit) 
22.0 mm X 19.2 mm 
17.2 
4.88 


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2.10 Switching Between Sublingual and Buccal Sites of Administration 
The systemic exposure of buprenorphine between buccal and sublingual administration of SUBOXONE 
sublingual film is similar.  Therefore, once induction is complete, patients can switch between buccal 
and sublingual administration without significant risk of under or overdosing.  
3 
DOSAGE FORMS AND STRENGTHS 
SUBOXONE sublingual film is supplied as an orange rectangular film with a white printed logo in four 
dosage strengths: 
• 
buprenorphine/naloxone 2 mg/0.5 mg,  
• 
buprenorphine/naloxone 4 mg/1 mg, 
• 
buprenorphine/naloxone 8 mg/2 mg and 
• 
buprenorphine/naloxone 12 mg/3 mg 
4 
CONTRAINDICATIONS 
SUBOXONE sublingual film should not be administered to patients who have been shown to be 
hypersensitive to buprenorphine or naloxone as serious adverse reactions, including anaphylactic shock, 
have been reported [see Warnings and Precautions (5.7)]. 
5 
WARNINGS AND PRECAUTIONS 
5.1 
Abuse Potential  
Buprenorphine can be abused in a manner similar to other opioids, legal or illicit. Prescribe and dispense 
buprenorphine with appropriate precautions to minimize risk of misuse, abuse, or diversion, and ensure 
appropriate protection from theft, including in the home. Clinical monitoring appropriate to the 
patient’s level of stability is essential. Multiple refills should not be prescribed early in treatment or 
without appropriate patient follow-up visits [see Drug Abuse and Dependence (9.2)]. 
5.2 
Respiratory Depression  
Buprenorphine, particularly when taken by the IV route, in combination with benzodiazepines or other 
CNS depressants (including alcohol), has been associated with significant respiratory depression and 
death.  Many, but not all, post-marketing reports regarding coma and death associated with the 
concomitant use of buprenorphine and benzodiazepines involved misuse by self-injection. Deaths have 
also been reported in association with concomitant administration of buprenorphine with other 
depressants such as alcohol or other CNS depressant drugs.  Patients should be warned of the potential 
danger of self-administration of benzodiazepines or other depressants while under treatment with 
SUBOXONE sublingual film [see Drug Interactions (7.3)]. 
In the case of overdose, the primary management should be the re-establishment of adequate 
ventilation with mechanical assistance of respiration, if required.  Naloxone may be of value for the 
management of buprenorphine overdose. Higher than normal doses and repeated administration may 
be necessary. 
SUBOXONE sublingual film should be used with caution in patients with compromised respiratory 
function (e.g., chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, 
hypoxia, hypercapnia, or pre-existing respiratory depression). 


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5.3 
CNS Depression  
Patients receiving buprenorphine in the presence of opioid analgesics, general anesthetics, 
benzodiazepines, phenothiazines, other tranquilizers, sedative/hypnotics, or other CNS depressants 
(including alcohol) may exhibit increased CNS depression.  Consider dose reduction of CNS depressants, 
SUBOXONE sublingual film, or both in situations of concomitant prescription [see Drug Interactions 
(7.3)]. 
5.4 
Unintentional Pediatric Exposure 
Buprenorphine can cause severe, possibly fatal, respiratory depression in children who are accidentally 
exposed to it.  Store buprenorphine-containing medications safely out of the sight and reach of children. 
5.5 
Dependence 
Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces 
physical dependence of the opioid type, characterized by withdrawal signs and symptoms upon abrupt 
discontinuation or rapid taper.  The withdrawal syndrome is typically milder than seen with full agonists 
and may be delayed in onset.  Buprenorphine can be abused in a manner similar to other opioids.  This 
should be considered when prescribing or dispensing buprenorphine in situations when the clinician is 
concerned about an increased risk of misuse, abuse, or diversion [see Drug Abuse and Dependence 
(9.3)]. 
5.6 
Hepatitis, Hepatic Events 
Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving 
buprenorphine in clinical trials and through post-marketing adverse event reports.  The spectrum of 
abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports 
of death, hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy.  In many 
cases, the presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C 
virus, concomitant usage of other potentially hepatotoxic drugs, and ongoing injecting drug use may 
have played a causative or contributory role.  In other cases, insufficient data were available to 
determine the etiology of the abnormality.  Withdrawal of buprenorphine has resulted in amelioration 
of acute hepatitis in some cases; however, in other cases no dose reduction was necessary.  The 
possibility exists that buprenorphine had a causative or contributory role in the development of the 
hepatic abnormality in some cases.  Liver function tests, prior to initiation of treatment, are 
recommended to establish a baseline.  Periodic monitoring of liver function during treatment is also 
recommended.  A biological and etiological evaluation is recommended when a hepatic event is 
suspected.  Depending on the case, SUBOXONE sublingual film may need to be carefully discontinued to 
prevent withdrawal signs and symptoms and a return by the patient to illicit drug use, and strict 
monitoring of the patient should be initiated.  
5.7 
Allergic Reactions  
Cases of hypersensitivity to buprenorphine and naloxone containing products have been reported both 
in clinical trials and in the post-marketing experience.  Cases of bronchospasm, angioneurotic edema, 
and anaphylactic shock have been reported. The most common signs and symptoms include rashes, 
hives, and pruritus.  A history of hypersensitivity to buprenorphine or naloxone is a contraindication to 
the use of SUBOXONE sublingual film.  


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5.8 
Precipitation of Opioid Withdrawal Signs and Symptoms  
Because it contains naloxone, SUBOXONE sublingual film is likely to produce withdrawal signs and 
symptoms if misused parenterally by individuals dependent on full opioid agonists such as heroin, 
morphine, or methadone.  Because of the partial agonist properties of buprenorphine, SUBOXONE 
sublingual film may precipitate opioid withdrawal signs and symptoms in such persons if administered 
before the agonist effects of the opioid have subsided.  
5.9 
Neonatal Withdrawal 
Neonatal withdrawal has been reported in the infants of women treated with buprenorphine during 
pregnancy.  From post-marketing reports, the time to onset of neonatal withdrawal signs ranged from 
Day 1 to Day 8 of life with most cases occurring on Day 1.  Adverse events associated with the neonatal 
withdrawal syndrome included hypertonia, neonatal tremor, neonatal agitation, and myoclonus, and 
there have been reports of convulsions, apnea, respiratory depression, and bradycardia.  
5.10 
Use in Opioid Naïve Patients 
There have been reported deaths of opioid naïve individuals who received a 2 mg dose of 
buprenorphine as a sublingual tablet for analgesia. SUBOXONE sublingual film is not appropriate as an 
analgesic. 
5.11 
Use in Patients With Impaired Hepatic Function 
Buprenorphine/naloxone products are not recommended in patients with severe hepatic impairment 
and may not be appropriate for patients with moderate hepatic impairment.  Because hepatic 
impairment results in a reduced clearance of naloxone to a much greater extent than buprenorphine, 
the doses of buprenorphine and naloxone in this fixed-dose combination product cannot be individually 
titrated. Therefore, patients with severe hepatic impairment will be exposed to substantially higher 
levels of naloxone than patients with normal hepatic function. This may result in an increased risk of 
precipitated withdrawal at the beginning of treatment (induction) and may interfere with 
buprenorphine’s efficacy throughout treatment.  In patients with moderate hepatic impairment, the 
differential reduction of naloxone clearance compared to buprenorphine clearance is not as great as in 
subjects with severe hepatic impairment.  Therefore, buprenorphine/naloxone products are not 
recommended for initiation of treatment (induction) in patients with moderate hepatic impairment due 
to the increased risk of precipitated withdrawal. However, buprenorphine/naloxone products may be 
used with caution for maintenance treatment in patients with moderate hepatic impairment who have 
initiated treatment on a buprenorphine product without naloxone. However, patients should be 
carefully monitored and consideration given to the possibility of naloxone interfering with 
buprenorphine’s efficacy [see Use in Specific Populations (8.6)]. 
5.12 
Impairment of Ability to Drive or Operate Machinery  
SUBOXONE sublingual film may impair the mental or physical abilities required for the performance of 
potentially dangerous tasks such as driving a car or operating machinery, especially during treatment 
induction and dose adjustment.  Patients should be cautioned about driving or operating hazardous 
machinery until they are reasonably certain that SUBOXONE sublingual film therapy does not adversely 
affect his or her ability to engage in such activities.   
5.13 
Orthostatic Hypotension 
Like other opioids, SUBOXONE sublingual film may produce orthostatic hypotension in ambulatory 
patients. 


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5.14 
Elevation of Cerebrospinal Fluid Pressure  
Buprenorphine, like other opioids, may elevate cerebrospinal fluid pressure and should be used with 
caution in patients with head injury, intracranial lesions, and other circumstances when cerebrospinal 
pressure may be increased.  Buprenorphine can produce miosis and changes in the level of 
consciousness that may interfere with patient evaluation. 
5.15 
Elevation of Intracholedochal Pressure 
Buprenorphine has been shown to increase intracholedochal pressure, as do other opioids, and thus 
should be administered with caution to patients with dysfunction of the biliary tract. 
5.16 
Effects in Acute Abdominal Conditions 
As with other opioids, buprenorphine may obscure the diagnosis or clinical course of patients with acute 
abdominal conditions. 
5.17 
General Precautions 
SUBOXONE sublingual film should be administered with caution in debilitated patients and those with 
myxedema or hypothyroidism, adrenal cortical insufficiency (e.g., Addison's disease); CNS depression or 
coma; toxic psychoses; prostatic hypertrophy or urethral stricture; acute alcoholism; delirium tremens; 
or kyphoscoliosis. 
6 
ADVERSE REACTIONS 
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 
the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and 
may not reflect the rates observed in practice.   
6.1 
Clinical Trials Experience 
The safety of SUBOXONE sublingual film is supported by clinical trials using SUBUTEX (buprenorphine) 
sublingual tablets and SUBOXONE (buprenorphine and naloxone) sublingual tablets, and other trials 
using buprenorphine sublingual solutions, as well as an open-label study in 194 patients treated with 
SUBOXONE sublingual film administered sublingually and 188 patients treated with the film 
administered buccally.  In total, safety data from clinical studies are available from over 3000 opioid-
dependent subjects exposed to buprenorphine at doses in the range used in the treatment of opioid 
dependence.  Few differences in the adverse event profile were noted with regard to sublingually and 
bucally administered SUBOXONE sublingual film, SUBOXONE (buprenorphine and naloxone) sublingual 
tablets, SUBUTEX (buprenorphine) sublingual tablets and a buprenorphine ethanolic sublingual solution.   
The most common adverse event (>1%) associated with the sublingual administration of the SUBOXONE 
sublingual film was oral hypoesthesia. Other adverse events were constipation, glossodynia, oral 
mucosal erythema, vomiting, intoxication, disturbance in attention, palpitations, insomnia, withdrawal 
syndrome, hyperhidrosis, and blurred vision. 
The most common adverse events associated with the buccal administration were similar to those 
observed with sublingual administration of the film. 
Other adverse event data were derived from larger, controlled studies of SUBOXONE (buprenorphine 
and naloxone) sublingual tablets and SUBUTEX (buprenorphine) tablets and of buprenorphine sublingual 
solution.  In a comparative study of SUBOXONE (buprenorphine and naloxone) sublingual tablets and 
SUBUTEX (buprenorphine) sublingual tablets, adverse event profiles were similar for subjects treated 


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with 16 mg/4 mg SUBOXONE (buprenorphine and naloxone) sublingual tablets or 16 mg SUBUTEX 
(buprenorphine) sublingual tablets.  The following adverse events were reported to occur by at least 5% 
of patients in a 4 week study of SUBOXONE (buprenorphine and naloxone) sublingual tablets and 
SUBUTEX (buprenorphine) sublingual tablets. 
 
Table 2.  Adverse Events (≥ 5%) by Body System and Treatment Group in a 4 Week Study 
Body System/ Adverse Event 
(COSTART Terminology) 
SUBOXONE 
(buprenorphine and 
naloxone) sublingual 
tablets 
16 mg/4 mg/day 
N=107 
n (%) 
SUBUTEX 
(buprenorphine) 
sublingual tablets 
16 mg/day 
N=103 
n (%) 
Placebo 
N=107 
n (%) 
Body as a Whole 
Asthenia 
7 (6.5%) 
5 (4.9%) 
7 (6.5%) 
Chills 
8 (7.5%) 
8 (7.8%) 
8 (7.5%) 
Headache 
39 (36.4%) 
30 (29.1%) 
24 (22.4%) 
Infection 
6 (5.6%) 
12 (11.7%) 
7 (6.5%) 
Pain 
24 (22.4%) 
19 (18.4%) 
20 (18.7%) 
Pain abdomen 
12 (11.2%) 
12 (11.7%) 
7 (6.5%) 
Pain back 
4 (3.7%) 
8 (7.8%) 
12 (11.2%) 
Withdrawal syndrome 
27 (25.2%) 
19 (18.4%) 
40 (37.4%) 
Cardiovascular System 
Vasodilation 
10 (9.3%) 
4 (3.9%) 
7 (6.5%) 
Digestive System 
Constipation 
13 (12.1%) 
8 (7.8%) 
3 (2.8%) 
Diarrhea 
4 (3.7%) 
5 (4.9%) 
16 (15.0%) 
Nausea 
16 (15.0%) 
14 (13.6%) 
12 (11.2%) 
Vomiting 
8 (7.5%) 
8 (7.8%) 
5 (4.7%) 
Nervous System 
Insomnia 
15 (14.0%) 
22 (21.4%) 
17 (15.9%) 
Respiratory System 
Rhinitis 
5 (4.7%) 
10 (9.7%) 
14 (13.1%) 
Skin And Appendages 
Sweating 
15 (14.0%) 
13 (12.6%) 
11 (10.3%) 


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Abbreviations: COSTART = Coding Symbols for Thesaurus of Adverse Reaction Terms. 
The adverse event profile of buprenorphine was also characterized in the dose-controlled study of a 
buprenorphine ethanolic solution, over a range of doses in four months of treatment.  Table 3 shows 
adverse events reported by at least 5% of subjects in any dose group in the dose-controlled trial. 
 
Table 3.  Adverse Events (≥5%) by Body System and Treatment Group in a 16 Week Study 
Body 
System/ 
Adverse 
Event 
(COSTART 
Terminology) 
Buprenorphine Dose 
Very 
Low* 
N=184 
n (%) 
Low* 
N=180 
n (%) 
Moderate* 
N=186 
n (%) 
High* 
N=181 
n (%) 
Total* 
N=731 
n (%) 
Body as a Whole 
Abscess 
9 (5%) 
2 (1%) 
3 (2%) 
2 (1%) 
16 (2%) 
Asthenia 
26 (14%) 
28 (16%) 
26 (14%) 
24 (13%) 
104 
(14%) 
Chills 
11 (6%) 
12 (7%) 
9 (5%) 
10 (6%) 
42 (6%) 
Fever 
7 (4%) 
2 (1%) 
2 (1%) 
10 (6%) 
21 (3%) 
Flu syndrome 4 (2%) 
13 (7%) 
19 (10%) 
8 (4%) 
44 (6%) 
Headache 
51 (28%) 
62 (34%) 
54 (29%) 
53 (29%) 
220 
(30%) 
Infection 
32 (17%) 
39 (22%) 
38 (20%) 
40 (22%) 
149 
(20%) 
Injury 
accidental 
5 (3%) 
10 (6%) 
5 (3%) 
5 (3%) 
25 (3%) 
Pain 
47 (26%) 
37 (21%) 
49 (26%) 
44 (24%) 
177 
(24%) 
Pain back 
18 (10%) 
29 (16%) 
28 (15%) 
27 (15%) 
102 
(14%) 
Withdrawal 
syndrome 
45 (24%) 
40 (22%) 
41 (22%) 
36 (20%) 
162 
(22%) 
Digestive System 
Constipation 
10 (5%) 
23 (13%) 
23 (12%) 
26 (14%) 
82 (11%) 
Diarrhea 
19 (10%) 
8 (4%) 
9 (5%) 
4 (2%) 
40 (5%) 
Dyspepsia 
6 (3%) 
10 (6%) 
4 (2%) 
4 (2%) 
24 (3%) 
Nausea 
12 (7%) 
22 (12%) 
23 (12%) 
18 (10%) 
75 (10%) 
Vomiting 
8 (4%) 
6 (3%) 
10 (5%) 
14 (8%) 
38 (5%) 


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Nervous System 
Anxiety 
22 (12%) 
24 (13%) 
20 (11%) 
25 (14%) 
91 (12%) 
Depression 
24 (13%) 
16 (9%) 
25 (13%) 
18 (10%) 
83 (11%) 
Dizziness 
4 (2%) 
9 (5%) 
7 (4%) 
11 (6%) 
31 (4%) 
Insomnia 
42 (23%) 
50 (28%) 
43 (23%) 
51 (28%) 
186 
(25%) 
Nervousness 
12 (7%) 
11 (6%) 
10 (5%) 
13 (7%) 
46 (6%) 
Somnolence 
5 (3%) 
13 (7%) 
9 (5%) 
11 (6%) 
38 (5%) 
Respiratory System 
Cough 
increase 
5 (3%) 
11 (6%) 
6 (3%) 
4 (2%) 
26 (4%) 
Pharyngitis 
6 (3%) 
7 (4%) 
6 (3%) 
9 (5%) 
28 (4%) 
Rhinitis 
27 (15%) 
16 (9%) 
15 (8%) 
21 (12%) 
79 (11%) 
Skin and Appendages 
Sweat 
23 (13%) 
21 (12%) 
20 (11%) 
23 (13%) 
87 (12%) 
Special Senses 
Runny eyes 
13 (7%) 
9 (5%) 
6 (3%) 
6 (3%) 
34 (5%) 
*Sublingual solution.  Doses in this table cannot necessarily be delivered in tablet form, but for 
comparison purposes: 
1 mg solution would be less than a tablet dose of 2 mg 
4 mg solution approximates a 6 mg tablet dose 
8 mg solution approximates a 12 mg tablet dose 
16 mg solution approximates a 24 mg tablet dose 
The safety of SUBOXONE sublingual film during treatment induction is supported by a clinical trial using 16 
patients treated with SUBOXONE sublingual film and 18 treated with a buprenorphine-only sublingual film.  
Few differences in the adverse event profiles were noted between SUBOXONE sublingual film and the 
buprenorphine-only sublingual film.   
The most common adverse event occurring during treatment induction and the 3 days following induction 
using SUBOXONE sublingual film was restlessness. Other adverse events were anxiety, piloerection, 
stomach discomfort, irritability, headache, rhinorrhea, cold sweat, arthralgia, and lacrimation increased. 
Four subjects left the study early on the first day of sublingual film administration.  However, there was 
not evidence to suggest that any of the four subjects experienced precipitated withdrawal secondary to 
the administration of buprenorphine or buprenorphine/naloxone sublingual films.  


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6.2 
Postmarketing Experience 
The following adverse reactions have been identified during post-approval use of SUBOXONE sublingual 
film. Because these reactions are reported voluntarily from a population of uncertain size, it is not 
always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 
The most frequently reported postmarketing adverse events were peripheral edema, stomatitis, 
glossitis, and blistering and ulceration of the mouth or tongue.  
7 
DRUG INTERACTIONS 
7.1 
Cytochrome P-450 3A4 (CYP3A4) Inhibitors and Inducers 
Buprenorphine is metabolized to norbuprenorphine primarily by cytochrome CYP3A4; therefore, 
potential interactions may occur when SUBOXONE sublingual film is given concurrently with agents that 
affect CYP3A4 activity.  The concomitant use of SUBOXONE sublingual film with CYP3A4 inhibitors (e.g., 
azole antifungals such as ketoconazole, macrolide antibiotics such as erythromycin, and HIV protease 
inhibitors) should be monitored and may require dose-reduction of one or both agents. 
The interaction of buprenorphine with CYP3A4 inducers has not been studied; therefore, it is 
recommended that patients receiving SUBOXONE sublingual film be monitored for signs and symptoms 
of opioid withdrawal if inducers of CYP3A4 (e.g., efavirenz, phenobarbital, carbamazepine, phenytoin, 
rifampicin) are coadministered [see Clinical Pharmacology (12.3)]. 
7.2 
Antiretrovirals 
Three classes of antiretroviral agents have been evaluated for CYP3A4 interactions with buprenorphine.  
Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme 
pathway, thus no interactions with buprenorphine are expected.  Non-nucleoside reverse transcriptase 
inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine and etravirine are 
known CYP3A inducers whereas delavirdine is a CYP3A inhibitor. Significant pharmacokinetic 
interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in 
clinical studies, but these pharmacokinetic interactions did not result in any significant 
pharmacodynamic effects. It is recommended that patients who are on chronic buprenorphine 
treatment have their dose monitored if NNRTIs are added to their treatment regimen.  Studies have 
shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, 
lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant 
pharmacodynamic effects.  Other PIs with CYP3A4 inhibitory activity (atazanavir and 
atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine and patients in 
one study reported increased sedation. Symptoms of opioid excess have been found in post-marketing 
reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly.  
Monitoring of patients taking buprenorphine and atazanavir with and without ritonavir is 
recommended, and dose reduction of buprenorphine may be warranted. 
7.3 
Benzodiazepines 
There have been a number of postmarketing reports regarding coma and death associated with the 
concomitant use of buprenorphine and benzodiazepines.  In many, but not all, of these cases, 
buprenorphine was misused by self-injection.  Preclinical studies have shown that the combination of 
benzodiazepines and buprenorphine altered the usual ceiling effect on buprenorphine-induced 
respiratory depression, making the respiratory effects of buprenorphine appear similar to those of full 


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opioid agonists.  SUBOXONE sublingual film should be prescribed with caution to patients taking 
benzodiazepines or other drugs that act on the CNS, regardless of whether these drugs are taken on the 
advice of a physician or are being abused/misused.  Patients should be warned that it is extremely 
dangerous to self-administer non-prescribed benzodiazepines while taking SUBOXONE sublingual film, 
and should also be cautioned to use benzodiazepines concurrently with SUBOXONE sublingual film only 
as directed by their physician. 
8 
USE IN SPECIFIC POPULATIONS 
8.1 
Pregnancy 
Pregnancy Category C. 
Risk Summary  
There are no adequate and well-controlled studies of SUBOXONE sublingual film or 
buprenorphine/naloxone in pregnant women. Limited published data on use of buprenorphine, the 
active ingredient in SUBOXONE sublingual film, in pregnancy, have not shown an increased risk of major 
malformations. All pregnancies, regardless of drug exposure, have a background risk of 2% to 4% for 
major birth defects, and 15% to 20% for pregnancy loss. Reproductive and developmental studies in rats 
and rabbits identified adverse events at clinically relevant doses. Pre- and postnatal development 
studies in rats demonstrated dystocia, increased neonatal deaths, and developmental delays. No clear 
teratogenic effects were seen with a range of doses equivalent to or greater than the human dose. 
However, in a few studies, some events such as acephalus, omphalocele, and skeletal abnormalities 
were observed but these findings were not clearly treatment-related. Embryofetal death was also 
observed in both rats and rabbits. 
SUBOXONE sublingual film should be used during pregnancy only if the potential benefit justifies the 
potential risk to the fetus.  
Clinical Considerations 
Disease-associated maternal and embryo-fetal risk 
Opioid dependence in pregnancy is associated with adverse obstetrical outcomes such as low birth 
weight, preterm birth, and fetal death. 
Fetal/neonatal adverse reactions 
Neonatal abstinence syndrome may occur in newborn infants of mothers who were on buprenorphine 
maintenance treatment. Observe newborns for poor feeding, diarrhea, irritability, tremor, rigidity, and 
seizures, and manage accordingly [see Warnings and Precautions (5.9)]. 
Labor or Delivery 
As with all opioids, use of buprenorphine prior to delivery may result in respiratory depression in the 
newborn. Closely monitor neonates for signs of respiratory depression. An opioid antagonist such as 
naloxone should be available for reversal of opioid induced respiratory depression in the neonate. 
Data 
Human Data 
Studies have been conducted to evaluate neonatal outcomes in women exposed to buprenorphine 
during pregnancy. Limited published data on malformations from trials, observational studies, case 
series, and case reports on buprenorphine use in pregnancy have not shown an increased risk of major 
malformations. Based on these studies the incidence of neonatal abstinence syndrome is not clear and 
there does not appear to be a dose-response relationship. 


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Animal Data 
Effects on embryo-fetal development were studied in Sprague-Dawley rats and Russian white rabbits 
following oral (1:1) and intramuscular (IM) (3:2) administration of mixtures of buprenorphine and 
naloxone.  Following oral administration to rats and rabbits, no teratogenic effects were observed at 
buprenorphine doses up to 250 mg/kg/day and 40 mg/kg/day, respectively (estimated exposure 
approximately 150 times and 50 times, respectively, the recommended human daily sublingual dose of 
16 mg on a mg/m² basis).  No definitive drug-related teratogenic effects were observed in rats and 
rabbits at IM doses up to 30 mg/kg/day (estimated exposure approximately 20 times and 35 times, 
respectively, the recommended human daily dose of 16 mg on a mg/m² basis).  Acephalus was observed 
in one rabbit fetus from the low-dose group and omphalocele was observed in two rabbit fetuses from 
the same litter in the mid-dose group; no findings were observed in fetuses from the high-dose group.  
Following oral administration of buprenorphine to rats, dose-related post-implantation losses, 
evidenced by increases in the numbers of early resorptions with consequent reductions in the numbers 
of fetuses, were observed at doses of 10 mg/kg/day or greater (estimated exposure approximately 
6 times the recommended human daily sublingual dose of 16 mg on a mg/m² basis).  In the rabbit, 
increased post-implantation losses occurred at an oral dose of 40 mg/kg/day.  Following IM 
administration in the rat and the rabbit, post-implantation losses, as evidenced by decreases in live 
fetuses and increases in resorptions, occurred at 30 mg/kg/day.   
Buprenorphine was not teratogenic in rats or rabbits after IM or subcutaneous (SC) doses up to 5 
mg/kg/day (estimated exposure was approximately 3 and 6 times, respectively, the recommended 
human daily sublingual dose of 16 mg on a mg/m2 basis), after IV doses up to 0.8 mg/kg/day (estimated 
exposure was approximately 0.5 times and equal to, respectively, the recommended human daily 
sublingual dose of 16 mg on a mg/m2 basis), or after oral doses up to 160 mg/kg/day in rats (estimated 
exposure was approximately 95 times the recommended human daily sublingual dose of 16 mg on a 
mg/m2 basis) and 25 mg/kg/day in rabbits (estimated exposure was approximately 30 times the 
recommended human daily sublingual dose of 16 mg on a mg/m2 basis). Significant increases in skeletal 
abnormalities (e.g., extra thoracic vertebra or thoraco-lumbar ribs) were noted in rats after SC 
administration of 1 mg/kg/day and up (estimated exposure was approximately 0.6 times the 
recommended human daily sublingual dose of 16 mg on a mg/m2 basis), but were not observed at oral 
doses up to 160 mg/kg/day.  Increases in skeletal abnormalities in rabbits after IM administration of 5 
mg/kg/day (estimated exposure was approximately 6 times the recommended human daily sublingual 
dose of 16 mg on a mg/m2 basis) or oral administration of 1 mg/kg/day or greater (estimated exposure 
was approximately equal to the recommended human daily sublingual dose of 16 mg on a mg/m2 basis) 
were not statistically significant. 
In rabbits, buprenorphine produced statistically significant pre-implantation losses at oral doses of 1 
mg/kg/day or greater and post-implantation losses that were statistically significant at IV doses of 0.2 
mg/kg/day or greater (estimated exposure approximately 0.3 times the recommended human daily 
sublingual dose of 16 mg on a mg/m2 basis). 
Dystocia was noted in pregnant rats treated intramuscularly with buprenorphine 5 mg/kg/day 
(approximately 3 times the recommended human daily sublingual dose of 16 mg on a mg/m² basis).  
Fertility, peri-, and post-natal development studies with buprenorphine in rats indicated increases in 
neonatal mortality after oral doses of 0.8 mg/kg/day and up (approximately 0.5 times the recommended 
human daily sublingual dose of 16 mg on a mg/m² basis), after IM doses of 0.5 mg/kg/day and up 
(approximately 0.3 times the recommended human daily sublingual dose of 16 mg on a mg/m² basis), 
and after SC doses of 0.1 mg/kg/day and up (approximately 0.06 times the recommended human daily 
sublingual dose of 16 mg on a mg/m² basis).  An apparent lack of milk production during these studies 
likely contributed to the decreased pup viability and lactation indices.  Delays in the occurrence of 


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righting reflex and startle response were noted in rat pups at an oral dose of 80 mg/kg/day 
(approximately 50 times the recommended human daily sublingual dose of 16 mg on a mg/m² basis). 
8.3 
Nursing Mothers 
Risk Summary 
Based on two studies in 13 lactating women, buprenorphine and its metabolite norbuprenorphine are 
present in low levels in human milk and infant urine, and available data have not shown adverse 
reactions in breastfed infants. There are no data on the combination product buprenorphine/naloxone 
in breastfeeding, however oral absorption of naloxone is minimal. Caution should be exercised when 
SUBOXONE sublingual film is administered to a nursing woman. The developmental and health benefits 
of breastfeeding should be considered along with the mother’s clinical need for SUBOXONE sublingual 
film and any potential adverse effects on the breastfed child from the drug or from the underlying 
maternal condition. 
Clinical Considerations 
Advise the nursing mother taking SUBOXONE sublingual film to monitor the infant for increased 
drowsiness and breathing difficulties. 
Data 
Based on limited data from a study of 6 lactating women who were taking a median oral dose of 
buprenorphine of 0.29 mg/kg/day 5 to 8 days after delivery, breast milk contained a median infant dose 
of 0.42 mcg/kg/day of buprenorphine and 0.33 mcg/kg/day of norbuprenorphine, which are equal to 
0.2% and 0.12% of the maternal weight-adjusted dose. 
Based on limited data from a study of 7 lactating women who were taking a median oral dose of 
buprenorphine of 7 mg/day an average of 1.12 months after delivery, the mean milk concentrations of 
buprenorphine and norbuprenorphine were 3.65 mcg/L and 1.94 mcg/L respectively. Based on the 
limited data from this study, and assuming milk consumption of 150 mL/kg/day, an exclusively breastfed 
infant would receive an estimated mean of 0.55 mcg/kg/day of buprenorphine and 0.29 mcg/kg/day of 
norbuprenorphine, which are 0.38% and 0.18% of the maternal weight-adjusted dose. 
No adverse reactions were observed in the infants in these two studies. 
8.4 
Pediatric Use 
The safety and effectiveness of SUBOXONE sublingual film have not been established in pediatric 
patients.  This product is not appropriate for the treatment of neonatal abstinence syndrome in 
neonates, because it contains naloxone, an opioid antagonist.  
8.5 
Geriatric Use 
Clinical studies of SUBOXONE sublingual film, SUBOXONE (buprenorphine and naloxone) sublingual 
tablets, or SUBUTEX (buprenorphine) sublingual tablets did not include sufficient numbers of subjects 
aged 65 and over to determine whether they responded differently than younger subjects.  Other 
reported clinical experience has not identified differences in responses between the elderly and younger 
patients.  In general, dose selection for an elderly patient should be cautious, usually starting at the low 
end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac 
function, and of concomitant disease or other drug therapy. 


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8.6 
Hepatic Impairment 
The effect of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone has been 
evaluated in a pharmacokinetic study. Both drugs are extensively metabolized in the liver. While no 
clinically significant changes have been observed in subjects with mild hepatic impairment; the plasma 
levels have been shown to be higher and half-life values have been shown to be longer for both 
buprenorphine and naloxone in subjects with moderate and severe hepatic impairment. The magnitude 
of the effects on naloxone are greater than that on buprenorphine in both moderately and severely 
impaired subjects. The difference in magnitude of the effects on naloxone and buprenorphine are 
greater in subjects with severe hepatic impairment than in subjects with moderate hepatic impairment, 
and therefore the clinical impact of these effects is likely to be greater in patients with severe hepatic 
impairment than in patients with moderate hepatic impairment. Buprenorphine/naloxone products 
should be avoided in patients with severe hepatic impairment and may not be appropriate for patients 
with moderate hepatic impairment [see Warnings and Precautions (5.11) and Clinical Pharmacology 
(12.3)].    
8.7 
Renal Impairment  
No differences in buprenorphine pharmacokinetics were observed between 9 dialysis-dependent and 
6 normal patients following IV administration of 0.3 mg buprenorphine.  The effects of renal failure on 
naloxone pharmacokinetics are unknown. 
9 
DRUG ABUSE AND DEPENDENCE 
9.1 
Controlled Substance 
Buprenorphine is a Schedule III narcotic under the Controlled Substances Act. 
Under the Drug Addiction Treatment Act (DATA) codified at 21 U.S.C. 823(g), prescription use of this 
product in the treatment of opioid dependence is limited to physicians who meet certain qualifying 
requirements, and who have notified the Secretary of Health and Human Services (HHS) of their intent 
to prescribe this product for the treatment of opioid dependence and have been assigned a unique 
identification number that must be included on every prescription. 
9.2 
Abuse 
Buprenorphine, like morphine and other opioids, has the potential for being abused and is subject to 
criminal diversion. This should be considered when prescribing or dispensing buprenorphine in 
situations when the clinician is concerned about an increased risk of misuse, abuse, or diversion.  
Healthcare professionals should contact their state professional licensing board or state controlled 
substances authority for information on how to prevent and detect abuse or diversion of this product. 
Patients who continue to misuse, abuse, or divert buprenorphine products or other opioids should be 
provided with or referred for more intensive and structured treatment.   
Abuse of buprenorphine poses a risk of overdose and death.  This risk is increased with the abuse of 
buprenorphine and alcohol and other substances, especially benzodiazepines. 
The physician may be able to more easily detect misuse or diversion by maintaining records of 
medication prescribed including date, dose, quantity, frequency of refills, and renewal requests of 
medication prescribed. 
Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and 
proper handling and storage of the medication are appropriate measures that help to limit abuse of 
opioid drugs. 


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9.3 
Dependence  
Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces 
physical dependence of the opioid type, characterized by moderate withdrawal signs and symptoms 
upon abrupt discontinuation or rapid taper.  The withdrawal syndrome is typically milder than seen with 
full agonists and may be delayed in onset [see Warnings and Precautions (5.5)]. 
A neonatal withdrawal syndrome has been reported in the infants of women treated with 
buprenorphine during pregnancy [see Warnings and Precautions (5.9)]. 
10 
OVERDOSAGE 
The manifestations of acute overdose include pinpoint pupils, sedation, hypotension, respiratory 
depression, and death.  
In the event of overdose, the respiratory and cardiac status of the patient should be monitored 
carefully.  When respiratory or cardiac functions are depressed, primary attention should be given to the 
re-establishment of adequate respiratory exchange through provision of a patent airway and institution 
of assisted or controlled ventilation.  Oxygen, IV fluids, vasopressors, and other supportive measures 
should be employed as indicated. 
In the case of overdose, the primary management should be the re-establishment of adequate 
ventilation with mechanical assistance of respiration, if required.  Naloxone may be of value for the 
management of buprenorphine overdose.  Higher than normal doses and repeated administration may 
be necessary.  
11 
DESCRIPTION 
SUBOXONE (buprenorphine and naloxone) sublingual film is an orange film, imprinted with a logo 
identifying the product and strength in white ink.  It contains buprenorphine HCl, a mu-opioid receptor 
partial agonist and a kappa-opioid receptor antagonist, and naloxone HCl dihydrate, an opioid receptor 
antagonist, at a ratio of 4:1 (ratio of free bases).  It is intended for sublingual or buccal administration and 
is available in four dosage strengths, 2 mg buprenorphine with 0.5 mg naloxone, 4 mg buprenorphine with 
1 mg naloxone,  8 mg buprenorphine with 2 mg naloxone and 12 mg buprenorphine with 3 mg naloxone.  
Each film also contains polyethylene oxide, hydroxypropyl methylcellulose, maltitol, acesulfame 
potassium, lime flavor, citric acid, sodium citrate, FD&C yellow #6, and white ink. 
Chemically, buprenorphine HCl is (2S)-2-[17-Cyclopropylmethyl-4,5α-epoxy-3-hydroxy-6-methoxy-
6α,14-ethano-14α-morphinan-7α-yl]-3,3-dimethylbutan-2-ol hydrochloride.  It has the following 
chemical structure: 
• HCl 
Buprenorphine HCl has the molecular formula C29 H41 NO4 • HCl and the molecular weight is 504.10.  It is 
a white or off-white crystalline powder, sparingly soluble in water, freely soluble in methanol, soluble in 
alcohol, and practically insoluble in cyclohexane. 


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Chemically, naloxone HCl dihydrate is 17-Allyl-4,5 α -epoxy-3, 14-dihydroxymorphinan-6-one 
hydrochloride dihydrate.  It has the following chemical structure:  
HCl • 2H2O 
Naloxone hydrochloride dihydrate has the molecular formula C19H21NO4 • HCl • 2H2O and the molecular 
weight is 399.87.  It is a white to slightly off-white powder and is freely soluble in water, soluble in 
alcohol, and practically insoluble in toluene and ether.   
12 
CLINICAL PHARMACOLOGY 
12.1 
Mechanism of Action 
SUBOXONE sublingual film contains buprenorphine and naloxone.  Buprenorphine is a partial agonist at 
the mu-opioid receptor and an antagonist at the kappa-opioid receptor. Naloxone is a potent antagonist 
at mu-opioid receptors and produces opioid withdrawal signs and symptoms in individuals physically 
dependent on full opioid agonists when administered parenterally.  
12.2 
Pharmacodynamics 
• Subjective Effects 
Comparisons of buprenorphine to full opioid agonists such as methadone and hydromorphone suggest 
that sublingual buprenorphine produces typical opioid agonist effects which are limited by a ceiling 
effect.  
In opioid-experienced subjects who were not physically dependent, acute sublingual doses of 
buprenorphine/naloxone tablets produced opioid agonist effects which reached a maximum between 
doses of 8 mg/2 mg and 16 mg/4 mg buprenorphine/naloxone.   
Opioid agonist ceiling-effects were also observed in a double-blind, parallel group, dose-ranging 
comparison of single doses of buprenorphine sublingual solution (1, 2, 4, 8, 16, or 32 mg), placebo and a 
full agonist control at various doses.  The treatments were given in ascending dose order at intervals of 
at least one week to 16 opioid-experienced subjects who were not physically dependent.  Both active 
drugs produced typical opioid agonist effects.  For all measures for which the drugs produced an effect, 
buprenorphine produced a dose-related response.  However, in each case, there was a dose that 
produced no further effect.  In contrast, the highest dose of the full agonist control always produced the 
greatest effects.  Agonist objective rating scores remained elevated for the higher doses of 
buprenorphine (8 mg to 32 mg) longer than for the lower doses and did not return to baseline until 48 
hours after drug administration.  The onset of effects appeared more rapidly with buprenorphine than 
with the full agonist control, with most doses nearing peak effect after 100 minutes for buprenorphine 
compared to 150 minutes for the full agonist control. 
• Physiologic Effects 
HO
N
O
OH
O


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Buprenorphine in IV (2, 4, 8, 12 and 16 mg) and sublingual (12 mg) doses has been administered to 
opioid-experienced subjects who were not physically dependent to examine cardiovascular, respiratory, 
and subjective effects at doses comparable to those used for treatment of opioid dependence.  
Compared to placebo, there were no statistically significant differences among any of the treatment 
conditions for blood pressure, heart rate, respiratory rate, O2 saturation, or skin temperature across 
time.  Systolic BP was higher in the 8 mg group than placebo (3 hour AUC values).  Minimum and 
maximum effects were similar across all treatments.  Subjects remained responsive to low voice and 
responded to computer prompts. Some subjects showed irritability, but no other changes were 
observed.  
The respiratory effects of sublingual buprenorphine were compared with the effects of methadone in a 
double-blind, parallel group, dose ranging comparison of single doses of buprenorphine sublingual 
solution (1, 2, 4, 8, 16, or 32 mg) and oral methadone (15, 30, 45, or 60 mg) in non-dependent, opioid-
experienced volunteers. In this study, hypoventilation not requiring medical intervention was reported 
more frequently after buprenorphine doses of 4 mg and higher than after methadone. Both drugs 
decreased O2 saturation to the same degree. 
Effect of Naloxone 
Physiologic and subjective effects following acute sublingual administration of buprenorphine tablets 
and buprenorphine/naloxone tablets were similar at equivalent dose levels of buprenorphine.  Naloxone 
had no clinically significant effect when administered by the sublingual route, although blood levels of 
the drug were measurable.  Buprenorphine/naloxone, when administered sublingually to an opioid-
dependent cohort, was recognized as an opioid agonist, whereas when administered intramuscularly, 
combinations of buprenorphine with naloxone produced opioid antagonist actions similar to naloxone.  
This finding suggests that the naloxone in buprenorphine/naloxone tablets may deter injection of 
buprenorphine/naloxone tablets by persons with active substantial heroin or other full mu-opioid 
dependence.  However, clinicians should be aware that some opioid-dependent persons, particularly 
those with a low level of full mu-opioid physical dependence or those whose opioid physical 
dependence is predominantly to buprenorphine, abuse buprenorphine/naloxone combinations by the 
intravenous or intranasal route.  In methadone-maintained patients and heroin-dependent subjects, IV 
administration of buprenorphine/naloxone combinations precipitated opioid withdrawal signs and 
symptoms and was perceived as unpleasant and dysphoric.  In morphine-stabilized subjects, 
intravenously administered combinations of buprenorphine with naloxone produced opioid antagonist 
and withdrawal signs and symptoms that were ratio-dependent; the most intense withdrawal signs and 
symptoms were produced by 2:1 and 4:1 ratios, less intense by an 8:1 ratio.   
12.3 
Pharmacokinetics 
Absorption   
In several pharmacokinetic studies following the administration of different dosages, a dose of one or 
two of the 2 mg/0.5 mg SUBOXONE sublingual films administered  sublingually or buccally showed 
comparable relative bioavailability to the same total dose of SUBOXONE sublingual tablets. In contrast, 
one 8 mg/2 mg and one 12 mg/3 mg SUBOXONE sublingual films administered  sublingually or buccally 
showed higher relative bioavailability for both buprenorphine and naloxone compared to the same total 
dose of SUBOXONE sublingual tablets.  A combination of one 8 mg/2 mg and two 2 mg/0.5 mg  
SUBOXONE sublingual films (total dose of 12 mg/ 3 mg) administered sublingually  showed comparable 
relative bioavailability to the same total dose of SUBOXONE sublingual tablets, while buccally 
administered SUBOXONE sublingual films showed higher relative bioavailability. Table 4, below, 
illustrates the relative increase in exposure to buprenorphine and naloxone associated with SUBOXONE 


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sublingual films compared to SUBOXONE tablets, and shows the effect of route of administration  [see 
Dosage and Administration (2.8 and 2.9)]. 
Across relevant  pharmacokinetic studies, the pharmacokinetic parameters and exposures derived from 
the buccal and sublingual administrations of SUBOXONE sublingual film were comparable to one 
another. 
 
Table 4. Changes in Pharmacokinetic Parameters for SUBOXONE Sublingual Film Administered 
Sublingually or Buccally in Comparison to SUBOXONE Sublingual Tablet 
Dosage 
PK 
Parameter 
Increase in Buprenorphine 
PK 
Parameter 
Increase in Naloxone 
Film 
Sublingual 
Compared 
to Tablet 
Sublingual 
Film 
Buccal 
Compared 
to Tablet 
Sublingual 
Film 
Buccal 
Compared 
to Film 
Sublingual 
Film 
Sublingual 
Compared 
to Tablet 
Sublingual 
Film 
Buccal 
Compared 
to Tablet 
Sublingual 
Film 
Buccal 
Compared 
to Film 
Sublingual 
1 x 2 
mg/0.5 
mg 
Cmax  
22% 
25% 
- 
Cmax  
- 
- 
- 
AUC0-last  
-  
19% 
- 
AUC0-last 
- 
-  
- 
2 x 2 
mg/0.5 
mg 
Cmax 
- 
21% 
21% 
Cmax 
- 
17% 
21% 
AUC0-last 
- 
23% 
16% 
AUC0-last 
- 
22% 
24% 
1 x 8 
mg/2 
mg 
Cmax  
28% 
34% 
- 
Cmax 
41% 
54% 
- 
AUC0-last 
20% 
25% 
- 
AUC0-last 
30% 
43% 
- 
1 x 12 
mg/3 
mg 
Cmax 
37% 
47% 
- 
Cmax 
57% 
72% 
9% 
AUC0-last 
21% 
29% 
- 
AUC0-last 
45% 
57% 
- 
1 x 8 
mg/2 
mg plus 
2 x 2 
mg/0.5 
mg 
Cmax 
- 
27% 
13% 
Cmax 
17% 
38% 
19% 
AUC0-last 
- 
23% 
- 
AUC0-last 
- 
30% 
19% 
1 x 16 
mg/4 
mg film 
Cmax 
34% 
29% 
7% 
Cmax 
44% 
46% 
9% 
AUC0-last 
32% 
- 
- 
AUC0-last 
49% 
36% 
3% 
Note: 1. the 16 mg/4 mg strength film is not marketed; it is compositionally proportional to the 8 mg/2 mg 
strength film and has the same size of 2 x 8 mg/2 mg film. 2. – represents no change when the 90% confidence 
intervals for the geometric mean ratios of the Cmax and AUC0-last values are within the 80% to 125% limit. 3. 
There are no data for the 4 mg/1 mg strength film; it is compositionally proportional to 2 mg/0.5 mg strength film 
and has the same size of 2 x 2 mg/0.5 mg film strength. 
 
Distribution  
Buprenorphine is approximately 96% protein bound, primarily to alpha and beta globulin. 
Naloxone is approximately 45% protein bound, primarily to albumin. 


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Elimination 
Buprenorphine is metabolized and eliminated in urine and feces. Naloxone undergoes metabolism as 
well. When SUBOXONE sublingual film is administered sublingually or buccally, buprenorphine has a 
mean elimination half-life ranging from 24 to 42 hours and naloxone has a mean elimination half-life 
ranging from 2 to 12 hours. 
Metabolism 
Buprenorphine undergoes both N-dealkylation to norbuprenorphine and glucuronidation.  The N-
dealkylation pathway is mediated primarily by the CYP3A4.  Norbuprenorphine, the major metabolite, 
can further undergo glucuronidation. Norbuprenorphine has been found to bind opioid receptors in 
vitro; however, it has not been studied clinically for opioid-like activity. Naloxone undergoes direct 
glucuronidation to naloxone-3-glucuronide as well as N-dealkylation, and reduction of the 6-oxo group. 
Excretion 
A mass balance study of buprenorphine showed complete recovery of radiolabel in urine (30%) and 
feces (69%) collected up to 11 days after dosing.  Almost all of the dose was accounted for in terms of 
buprenorphine, norbuprenorphine, and two unidentified buprenorphine metabolites.  In urine, most of 
buprenorphine and norbuprenorphine was conjugated (buprenorphine, 1% free and 9.4% conjugated; 
norbuprenorphine, 2.7% free and 11% conjugated).  In feces, almost all of the buprenorphine and 
norbuprenorphine were free (buprenorphine, 33% free and 5% conjugated; norbuprenorphine, 21% free 
and 2% conjugated). Based on all studies performed with sublingually and buccally administered 
SUBOXONE sublingual film, buprenorphine has a mean elimination half-life from plasma ranging from 24 
to 42 hours and naloxone has a mean elimination half-life from plasma ranging from 2 to 12 hours. 
• Drug-drug Interactions 
CYP3A4 Inhibitors and Inducers:  Subjects receiving SUBOXONE sublingual film should be monitored if 
inhibitors of CYP3A4 such as azole antifungal agents (e.g., ketoconazole), macrolide antibiotics (e.g., 
erythromycin) or HIV protease inhibitors and may require dose-reduction of one or both agents.  The 
interaction of buprenorphine with all CYP3A4 inducers has not been studied, therefore it is 
recommended that patients receiving SUBOXONE sublingual film be monitored for signs and symptoms 
of opioid withdrawal if inducers of CYP3A4 (e.g., phenobarbital, carbamazepine, phenytoin, rifampicin) 
are coadministered [see Drug Interactions (7.1)].  
Buprenorphine has been found to be a CYP2D6 and CYP3A4 inhibitor and its major metabolite, 
norbuprenorphine, has been found to be a moderate CYP2D6 inhibitor in in vitro studies employing 
human liver microsomes. However, the relatively low plasma concentrations of buprenorphine and 
norbuprenorphine resulting from therapeutic doses are not expected to raise significant drug-drug 
interaction concerns.  
• Special Populations: 
Hepatic Impairment: In a pharmacokinetic study, the disposition of buprenorphine and naloxone were 
determined after administering a SUBOXONE 2.0/0.5 mg (Buprenorphine/Naloxone) sublingual tablet in 
subjects with varied degrees of hepatic impairment as indicated by Child-Pugh criteria. The disposition 
of buprenorphine and naloxone in patients with hepatic impairment were compared to disposition in 
subjects with normal hepatic function.  
 
In subjects with mild hepatic impairment, the changes in mean Cmax, AUC0-last, and half-life values of both 
buprenorphine and naloxone were not clinically significant. No dosing adjustment is needed in patients 
with mild hepatic impairment. 
 


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For subjects with moderate and severe hepatic impairment, mean Cmax, AUC0-last, and half-life values of 
both buprenorphine and naloxone were increased; the effects on naloxone are greater than that on 
buprenorphine (Table 5).  
 
Table 5.  Changes in Pharmacokinetic Parameters in Subjects With Moderate and Severe Hepatic 
Impairment 
Hepatic 
Impairment 
PK Parameters 
Increase in buprenorphine 
compared to healthy subjects 
Increase in naloxone 
compared to healthy 
subjects 
Moderate 
Cmax 
8% 
170% 
AUC0-last 
64% 
218% 
Half-life 
35% 
165% 
Severe 
Cmax 
72% 
1030% 
AUC0-last 
181% 
1302% 
Half-life 
57% 
122% 
 
The difference in magnitude of the effects on naloxone and buprenorphine are greater in subjects with 
severe hepatic impairment than subjects with moderate hepatic impairment, and therefore the clinical 
impact of these effects is likely to be greater in patients with severe hepatic impairment than in patients 
with moderate hepatic impairment. Buprenorphine/naloxone products should be avoided in patients 
with severe hepatic impairment and may not be appropriate for patients with moderate hepatic 
impairment [see Warnings and Precautions (5.11) and Use in Specific Populations (8.6)]. 
 
HCV infection: In subjects with HCV infection but no sign of hepatic impairment, the changes in the 
mean Cmax, AUC0-last, and half-life values of buprenorphine and naloxone were not clinically significant in 
comparison to healthy subjects without HCV infection.  No dosing adjustment is needed in patients with 
HCV infection. 
13 
NONCLINICAL TOXICOLOGY 
13.1 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
Carcinogenicity   
Carcinogenicity data on SUBOXONE sublingual film are not available. 
A carcinogenicity study of buprenorphine/naloxone (4:1 ratio of the free bases) was performed in 
Alderley Park rats.  Buprenorphine/naloxone was administered in the diet at doses of approximately 7, 
31, and 123 mg/kg/day for 104 weeks (estimated exposure was approximately 4, 18, and 44 times the 
recommended human sublingual dose of 16 mg/4 mg buprenorphine/naloxone based on buprenorphine 
AUC comparisons).  A statistically significant increase in Leydig cell adenomas was observed in all dose 
groups.  No other drug-related tumors were noted. 
Carcinogenicity studies of buprenorphine were conducted in Sprague-Dawley rats and CD-1 mice. 
Buprenorphine was administered in the diet to rats at doses of 0.6, 5.5, and 56 mg/kg/day (estimated 
exposure was approximately 0.4, 3, and 35 times the recommended human daily sublingual dose of 16 


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mg on a mg/m2 basis) for 27 months.  As in the buprenorphine/naloxone carcinogenicity study in rats, 
statistically significant dose-related increases in Leydig cell tumors occurred.  In an 86 week study in 
CD-1 mice, buprenorphine was not carcinogenic at dietary doses up to 100 mg/kg/day (estimated 
exposure was approximately 30 times the recommended human daily sublingual dose of 16 mg on a 
mg/m2 basis). 
Mutagenicity  
The 4:1 combination of buprenorphine and naloxone was not mutagenic in a bacterial mutation assay 
(Ames test) using four strains of S. typhimurium and two strains of E. coli.  The combination was not 
clastogenic in an in vitro cytogenetic assay in human lymphocytes or in an IV micronucleus test in the 
rat.  
Buprenorphine was studied in a series of tests utilizing gene, chromosome, and DNA interactions in both 
prokaryotic and eukaryotic systems.  Results were negative in yeast (S. cerevisiae) for recombinant, gene 
convertant, or forward mutations; negative in Bacillus subtilis “rec” assay, negative for clastogenicity in 
CHO cells, Chinese hamster bone marrow and spermatogonia cells, and negative in the mouse 
lymphoma L5178Y assay. 
Results were equivocal in the Ames test: negative in studies in two laboratories, but positive for frame 
shift mutation at a high dose (5 mg/plate) in a third study.  Results were positive in the Green-Tweets (E. 
coli) survival test, positive in a DNA synthesis inhibition (DSI) test with testicular tissue from mice, for 
both in vivo and in vitro incorporation of [3H]thymidine, and positive in unscheduled DNA synthesis 
(UDS) test using testicular cells from mice. 
Impairment of Fertility  
Dietary administration of buprenorphine in the rat at dose levels of 500 ppm or greater (equivalent to 
approximately 47 mg/kg/day or greater; estimated exposure approximately 28 times the recommended 
human daily sublingual dose of 16 mg on a mg/m2 basis) produced a reduction in fertility demonstrated 
by reduced female conception rates.  A dietary dose of 100 ppm (equivalent to approximately 10 
mg/kg/day; estimated exposure approximately 6 times the recommended human daily sublingual dose 
of 16 mg on a mg/m2 basis) had no adverse effect on fertility. 
16 
HOW SUPPLIED / STORAGE AND HANDLING 
SUBOXONE sublingual film is supplied as an orange rectangular film with a white printed logo in child-
resistant polyester/foil laminated pouches: 
• 
NDC 12496-1202-3 (buprenorphine/naloxone 2 mg/0.5 mg/film; content expressed in terms of 
free base) - 30 films per carton 
• 
NDC 12496-1204-3 (buprenorphine/naloxone 4 mg/1 mg/film; content expressed in terms of 
free base) - 30 films per carton 
• 
NDC 12496-1208-3 (buprenorphine/naloxone 8 mg/2 mg/film; content expressed in terms of 
free base) - 30 films per carton 
• 
NDC 12496-1212-3 (buprenorphine/naloxone 12 mg/3 mg/film; content expressed in terms of 
free base) - 30 films per carton 
Store at 25°C (77°F), excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room 
Temperature]. 
Patients should be advised to store buprenorphine-containing medications safely and out of sight and 
reach of children.   
Rx only 


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17 
PATIENT COUNSELING INFORMATION 
See FDA-approved patient labeling (Medication Guide). 
SUBOXONE sublingual film must be administered whole.  Advise patients not to cut, chew, or swallow 
SUBOXONE sublingual film  
Safe Use 
Before initiating treatment with SUBOXONE sublingual film, explain the points listed below to 
caregivers and patients. Instruct patients to read the Medication Guide each time SUBOXONE 
sublingual film is dispensed because new information may be available. 
• 
Patients should be warned that it is extremely dangerous to self-administer non-prescribed 
benzodiazepines or other CNS depressants (including alcohol) while taking SUBOXONE 
sublingual film.  Patients prescribed benzodiazepines or other CNS depressants should be 
cautioned to use them only as directed by their physician [see Warnings and Precautions (5.2), 
Drug Interactions (7.3)]. 
• 
Patients should be advised that SUBOXONE sublingual film contains an opioid that can be a 
target for people who abuse prescription medications or street drugs.  Patients should be 
cautioned to keep their films in a safe place, and to protect them from theft. 
• 
Patients should be instructed to keep SUBOXONE sublingual film in a secure place, out of the 
sight and reach of children.  Accidental or deliberate ingestion by a child may cause respiratory 
depression that can result in death.  Patients should be advised that if a child is exposed to 
SUBOXONE sublingual film, medical attention should be sought immediately.   
• 
Patients should be advised never to give SUBOXONE sublingual film to anyone else, even if he or 
she has the same signs and symptoms.  It may cause harm or death. 
• 
Patients should be advised that selling or giving away this medication is against the law. 
• 
Patients should be cautioned that SUBOXONE sublingual film may impair the mental or physical 
abilities required for the performance of potentially dangerous tasks such as driving or operating 
machinery.  Caution should be taken especially during drug induction and dose adjustment and 
until individuals are reasonably certain that buprenorphine therapy does not adversely affect 
their ability to engage in such activities [see Warnings and Precautions (5.11)]. 
• 
Patients should be advised not to change the dosage of SUBOXONE sublingual film without 
consulting their physician. 
• 
Patients should be advised to take SUBOXONE sublingual film once a day. 
• 
Patients should be advised that if they miss a dose of SUBOXONE they should take it as soon as 
they remember. If it is almost time for the next dose, they should skip the missed dose and take 
the next dose at the regular time. 
• 
Patients should be informed that SUBOXONE sublingual film can cause drug dependence and 
that withdrawal signs and symptoms may occur when the medication is discontinued. 
• 
Patients seeking to discontinue treatment with buprenorphine for opioid dependence should be 
advised to work closely with their physician on a tapering schedule and should be apprised of 
the potential to relapse to illicit drug use associated with discontinuation of opioid 
agonist/partial agonist medication-assisted treatment. 


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• 
Patients should be cautioned that, like other opioids, SUBOXONE sublingual film may produce 
orthostatic hypotension in ambulatory individuals [see Warnings and Precautions (5.12)]. 
• 
Patients should inform their physician if any other prescription medications, over-the-counter 
medications, or herbal preparations are prescribed or currently being used [see Drug 
Interactions (7.1, 7.2 and 7.3)]. 
• 
Women of childbearing potential who become pregnant or are planning to become pregnant, 
should be advised to consult their physician regarding the possible effects of using SUBOXONE 
sublingual film during pregnancy [see Use in Specific Populations (8.1)]. 
• 
Advise women who are breastfeeding to monitor the infant for drowsiness and difficulty 
breathing [see Use in Specific Populations (8.3)].   
• 
Patients should inform their family members that, in the event of emergency, the treating 
physician or emergency room staff should be informed that the patient is physically dependent 
on an opioid and that the patient is being treated with SUBOXONE sublingual film. 
• 
Refer to the Medication Guide for additional information regarding the counseling information. 
 
Disposal of Unused SUBOXONE Sublingual Films 
 
Unused SUBOXONE sublingual films should be disposed of as soon as they are no longer needed. 
Unused films should be flushed down the toilet.  
 
Manufactured for Indivior Inc. 
Richmond, VA 23235 by: 
MonoSol Rx, LLC, 
Warren, NJ 07059 
 
Distributed by: 
Indivior Inc. 
Richmond, VA 23235 


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Appendix 8 Study Drug Preparation, Administration, and Depot Removal 
Instructions 
RBP-6000 PREPARATION AND DOSING PROCEDURE 
• 100 MG BUPRENORPHINE 
• 300 MG BUPRENORPHINE  
 
IMPORTANT:  Only qualified study personnel can prepare the study drug.  Protective gloves 
(latex or nitrile) should be worn when preparing and dosing RBP-6000.  Remove the product 
from the refrigerator at least 15 minutes before use to allow the product to reach room 
temperature before dosing.  Product may be left at room temperature up to 8 hours prior to use.  
If product is not used that day it should be marked appropriately.   
   
FOLLOW THE INSTRUCTIONS AS DIRECTED TO ENSURE PROPER DOSING 
Preparation of the Product Prior to Administration:  
The following components will be used in the preparation of RBP-6000: 
• One sealed foil pouch containing a syringe pre-filled with RBP-6000 and an oxygen 
absorber pack.  
• One sterile 19-gauge, 1 inch hypodermic safety needle 
 
1. On a clean field, open the foil pouch and remove the contents. Discard the oxygen absorber 
pack.   The pouch must be retained for accountability. 
2. Un-cap the pre-filled RBP-6000 syringe and attach the safety needle cartridge by pushing in 
and turning the needle until it is finger tight. Do not strip the threaded fitting by over-
tightening the needle. Position the sheath at 90 degrees to the needle.  Pull off the needle 
cartridge cover.   More complete documentation on the usage of the SurGuard2 safety needle 
can be found in the included instruction sheet.  
3. While holding the syringe vertically with the tip upwards, expel air bubbles by stroking the 
plunger up and down. 
4. The product is now ready for administration.  Carefully recap the needle. 
Administration Procedure: 
IMPORTANT: Once prepared (removed from foil pouch), the product must be 
administered within a maximum of 30 minutes. 
 
Choose an injection site below the waist but above the hip bone; from where the body curves at 
the side to about 2 inches from the middle of the abdomen with adequate amounts of 
subcutaneous tissue that does not have excessive pigment, nodules, lesions, or hair.  Since you 
can vary the injection site with a subcutaneous injection, choose an area that has not recently 
been used.   
 
Possible injection site locations and an injection rotation pattern are shown in Figure 4.  
Injections should be started based on where the last injection in RB-US-13-0001 was given for 
roll-over subjects. 


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Figure 4 
Injection Locations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. Cleanse the injection-site area with an alcohol swab.   
 
2. Using the thumb and forefinger of your non-dominant hand, grab and bunch the area of skin 
around the injection site. 
 
3. Using your dominant hand, insert approximately half the needle length quickly. The 
approximate angle you use will depend on the amount and fullness of the subcutaneous tissue 
and the length of the needle. 
 
4. After the needle is inserted, release the skin with your nondominant hand. 
 
5. Pull back on the plunger to check for blood.  If blood is present in the syringe, do not inject.  
Withdraw the needle and discard all components safely in an appropriate biohazard 
container.  Repeat the “Preparation of the Product Prior to Administration” procedures and 
the “Administration Procedure” using a different abdominal injection site with another 
syringe of RBP-6000 and associated components. 
 
6. Inject the product using a slow, steady push. Press down on the plunger until the syringe is 
empty. 
 
7. Withdraw the needle at the same angle used for insertion. Do not rub the injection area.  If 
there is bleeding, apply minimal pressure with a gauze pad or bandage.  Engage the safety 
sheath on the needle as per the SurGuard2 needle instructions.   
 
8. Discard all components safely in an appropriate biohazard container. 
 
Hipbones 
Waist 
1 / 5 
2 / 6 
3 
4 


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PROCEDURE FOR REMOVAL OF THE RBP-6000 DEPOT 
 
In the event of an emergency or if a subject withdraws or is withdrawn within the first 14 days of 
receiving an injection of RBP-6000, subjects may have the option to have the depot surgically 
removed by a physician delegated to perform surgery. The medically responsible physician 
should carefully discuss this option with subjects given the use of ATRIGEL Delivery System 
and the feasibility of extracting the depot. 
 
The following surgical procedure should be followed: 
 
1. 
Palpate the depot and surrounding area to confirm its exact location. 
2. 
Cleanse the area with an antiseptic solution (e.g., Betadine).   
3. 
Infiltrate the area with a local anesthesia (e.g., Lidocaine 1% or a lidocaine/adrenaline 
[epinephrine] mixture) and wait for it to take effect. 
4. 
Cover the area with a sterile drape. 
5. 
Incise the skin up to the subcutaneous tissues using a scalpel.  
6. 
Using blunt and sharp dissection, identify the plane between the depot and surrounding 
subcutaneous tissues.  Once the plane is identified, separate the superficial 25% of the 
circumference of the depot with blunt dissection.  
7. 
Gently lift the incised ellipse of skin and depot with forceps.   
8. 
Once the depot is removed, ensure hemostasis, and close the skin with non-absorbable 
sutures.   
9. 
The extracted RBP-6000 depot will be disposed of into an appropriate, secure biohazard 
container per the SOP at the study site. 
 


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Appendix 9 
Prohibited Cytochrome P450 Inhibitors and Inducers 
The following medications are prohibited during the study: 
Cytochrome 
P450 3A4 
Inhibitors 
Cytochrome 
P450 3A4 
Inducers 
Cytochrome 
P450 2C8 
Inhibitors 
Cytochrome 
P450 2C8 
Inducers 
Amiodarone 
Ketoconazole 
Barbiturates 
Gemifibrozil 
Rifampicin 
Amprenavir 
Metronidazole 
Carbamazepine 
Trimethoprim 
 
Aprepitant 
Mibefradil 
Dexamethasone 
Glitazones 
 
Chloramphenicol Miconazole 
Efavirenz 
Montelukast 
 
Cimetidine 
Mifepristone 
Ethosuximide 
Quercetin 
 
Ciprofloxacin 
Nefazodone 
Glucocorticoids 
 
 
Clarithromycin 
Nelfinavir 
Glutethimide 
 
 
Clotrimazole 
Nicardipine 
Modafinil 
 
 
Cyclosporine 
Norfloxacin 
Nevirapine 
 
 
Delavirdine 
Norfluoxetine 
Oxcarbazepine 
 
 
Diethyl-
dithiocarbamate 
Propofol 
Phenobarbital 
 
 
Diltiazem 
Quinine 
Phenytoin 
 
 
Ethinyl estradiol 
Ritonavir 
Pioglitazone 
 
 
Erythromycin 
Saquinavir 
Primidone 
 
 
Fluconazole 
Sertraline 
Rifabutin 
 
 
Fluoxetine 
Starfruit 
Rifampin 
 
 
Fluvoxamine 
Telithromycin 
Hypericum 
perforatum 
 
 
Gestodene 
Troleandomycin 
Sulfadimidine 
 
 
Grapefruit juice 
Verapamil 
Sulfinpyrazone 
 
 
Imatinib 
Voriconazole 
Troglitazone 
 
 
Indinavir 
Zafirlukast 
Troleandomycin 
 
 
Itraconazole 
 
 
 
 
Source:  http://medicine.iupui.edu/clinpharm/ddis/clinical-table/ 


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Appendix 10 
Columbia Suicide Severity Rating Scale (eC-SSRS) -- 
Baseline/Screening Version 
 
 


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Appendix 11 
Columbia Suicide Severity Rating Scale (eC-SSRS) -- 
Since Last Visit Version 
 


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Appendix 12 
Clinical Opiate Withdrawal Scale (COWS) 
 
0 - Pulse rate 80 or below
1 - Pulse rate 81 - 100
2 - Pulse rate 101 - 120
4 - Pulse rate greater than 120
1. Resting Pulse Rate:
Measured after patient is sitting or lying for one minute.
0 - No GI symptoms
1 - Stomach cramps
2 - Nausea or loose stool
3 - Vomiting or diarrhea
5 - Multiple episodes of diarrhea or vomiting
2. GI upset: Over last 1/2 hour.
0 - No report of chills or flushing
1 - Subjective report of chills or flushing
2 - Flushed or observable moistness on face
3 - Beads of sweat on brow or face
4 - Sweat streaming off face
3. Sweating:
Over past 1/2 hour not accounted for by room temperature or patient activity.
0 - No tremor
1 - Tremor can be felt, but not observed
2 - Slight tremor observable
4 - Gross tremor or muscle twitching
4. Tremor:
Observation of outstretched hands.
0 - Able to sit still
1 - Reports difficulty sitting still, but is able to do so
3 - Frequent shifting or extraneous movements of legs/arms
5 - Unable to sit still for more than a few seconds
5. Restlessness:
For each item, mark the choice that best describes the subject's signs or symptom. Rate on just the
apparent relationship to opiate withdrawal. For example, if heart rate is increased because the patient was
jogging just prior to assessment, the increased pulse rate would not add to the score.
beats/min
Observation during assessment.
0 - No yawning
1 - Yawning once or twice during assessment
2 - Yawning three or more times during assessment
4 - Yawning several times/minute
6. Yawning: Observation durring assessment.
 
 


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0 - Not present
1 - Nasal stuffiness or unusually moist eyes
2 - Nose running or tearing
4 - Nose constantly running or tears streaming down cheeks
11. Runny nose or tearing:
0 - None
1 - Patient reports increasing irritability or anxiousness
2 - Patient obviously irritable or anxious
4 - Patient so irritable or anxious that participation in the assessment is difficult
8. Anxiety or Irritability:
0 - Not present
1 - Mild diffuse discomfort
2 - Patient reports severe diffuse aching of joints/muscle
4 - Patient is rubbing joints or muscles and is unable to sit still because of discomfort
9. Bone or Joint aches:
0 - Skin is smooth
3 - Piloerection of skin can be felt or hairs standing up on arms
5 - Prominent piloerection
10. Gooseflesh skin:
0 - Pupils pinned or normal size for room light
1 - Pupils possibly larger than normal for room light
2 - Pupils moderately dilated
5 - Pupils so dilated that only the rim of the iris is visible
7. Pupil Size:
If patient was having pain previously, only the additional component attributed to opiate
withdrawal is scored.
Not accounted for by cold symptoms or allergies.
TOTAL SCORE (sum of all 11 items):
Score Interpretation: 5 - 12= Mild, 13 - 24= Moderate, 25 - 36=Moderately Severe, More than 36= Severe Withdrawal


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Appendix 13 
Subjective Opiate Withdrawal Scale (SOWS) 
 
Modified from : Handelsman L, Cochrane KJ, Aronson MJ, Ness R, Rubenstein KJ, Kanof PD 
(1987). Two new rating scales for opiate withdrawal.  Am J Drug Alcohol Abuse 13:293-308. 


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Appendix 14 
Opioid Craving Visual Analog Scale (Opioid Craving VAS) 
 
No craving 
_________________________________________Strongest craving ever 
100 mm scale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 15 Injection Site Grading Scale 
 
Injection 
Site 
Reactions 
None 
(Grade 0) 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Pain 
None 
Does not 
interfere with 
activity 
Repeated use of non-
narcotic pain reliever 
> 24 hours or 
interferes with 
activity  
Any use of narcotic 
pain reliever or 
prevents daily 
activity 
Emergency room  
(ER) visit or  
hospitalization  
Tenderness 
None 
Mild discomfort 
to touch. 
Discomfort with 
movement. 
Significant 
discomfort at rest  
ER visit or 
hospitalization 
Erythema/ 
Redness* 
(quantitative) 
None 
2.5 – 5 cm 
5.1 – 10 cm 
> 10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration ** 
None 
2.5 – 5 cm and 
does not 
interfere  
with activity  
5.1 – 10 cm or  
interferes with  
activity  
> 10 cm or  
prevents daily  
activity  
Necrosis  
Swelling ** 
(subjective) 
None 
2.5 – 5 cm and 
does not 
interfere  
with activity  
5.1 – 10 cm or  
interferes with  
activity  
> 10 cm or  
prevents daily  
activity  
Necrosis  
 
* In addition to grading the measured local reaction at the greatest single diameter, the measurement should be  
recorded as a continuous variable.  
** Induration/Swelling should be evaluated and graded using the functional scale as well as the actual measurement.  
 
Modified from:   
U.S. Department of Health and Human Services, Food and Drug Administration, Center for 
Biologics Evaluation and Research, September 2007.  Guidance for Industry: Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials. [pdf] Available at: 
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInform
ation/Guidances/Vaccines/ucm091977.pdf.  Accessed 14 April 2015. 


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Appendix 16 
Injection Site Pain Visual Analog Scale (Injection Site Pain 
VAS) 
How would you rate your injection site pain today? 
 
                  No  _________________________________________ Pain as bad  
                  Pain                                                                                  as it could be 
 
 
 
 
 
Please answer the following question by checking the box with either a “Yes” or “No”: 
Are you currently experiencing any burning or stinging at the injection site? 
 
 
 
 
YES   
 
 
 
NO 
 


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Appendix 17 
Timeline Followback (TLFB) Interview 
 
 
Ethanol 


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Appendix 18 
Euro QoL EQ-5D-5L Health Questionnaire 
 


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Appendix 19 
Short Form (36) Health Survey v2 
 


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Appendix 20 
Medication Satisfaction Questionnaire  
Overall, how satisfied are you with your current opioid dependence medication? 
 
1 = extremely dissatisfied 
2 = very dissatisfied 
3 = somewhat dissatisfied 
4 = neither satisfied nor dissatisfied 
5 = somewhat satisfied 
6 = very satisfied 
7 = extremely satisfied 
 


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Appendix 21 
Health Care Resource Utilization Questionnaire 
HEALTH INSURANCE 
Primary Health Insurance  
(Please check all  that apply) 
 Commercial (for example, Blue Cross Blue  
Shield,  Aetna, Humana, United, Cigna) 
 Medicare 
 Medicaid 
 Veterans Affairs 
 Workers compensation 
 Other insurance 
 Self-pay / Out of pocket/No insurance 
 
 
INPATIENT ADMISSIONS 
 
• 
Please list in the table below all inpatient admissions in the past 30 days.  If patient is currently 
hospitalized, please check the box in the “Ongoing” column. 
• 
If patient has had no previous hospitalizations in the past 30 days, please check the 
appropriate box below. 
 No hospitalizations since the last study visit 
Admission Date  
(dd / mmm / yyyy) 
Discharge Date 
(dd / mmm / yyyy) 
Ongoing? 
Type of Admission 
1. 
_ _ / _ _ _ / _ _ _ _ 
_ _ / _ _ _ / _ _ _ _ 
 
Medical 
Surgical 
Psychiatric 
Other 
2. 
_ _ / _ _ _ / _ _ _ _ 
_ _ / _ _ _ / _ _ _ _ 
 
 Medical 
Surgical 
Psychiatric 
Other 
3. 
_ _ / _ _ _ / _ _ _ _ 
_ _ / _ _ _ / _ _ _ _ 
 
 Medical 
Surgical 
Psychiatric 
Other 
 


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EMERGENCY ROOM VISITS  
• 
Please list how many times the patient has been to the Emergency Room in the past 30 days. 
Type of Problem 
Number of Visits 
Substance abuse-related 
visits 
Other medical problems 
visits 
 
 
OUTPATIENT SERVICES 
• 
Please list how many times the patient has seen 1 of the following health professionals in the 
past 30 days. The outpatient services captured on this questionnaire are ones conducted 
outside the study 
Health Professional 
Number of Visits 
General practitioner / Internist 
visits 
Addiction Medicine Specialist 
visits 
Therapist / Counselor 
visits 
Other: Specialist 
visits 
Other:  Non-Specialist  
visits 
 


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Appendix 22 
Treatment Effectiveness Assessment (TEA) 
 
 


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Appendix 23 
Addiction Severity Index (ASI) Lite 
 


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Appendix 24 
Beck Depression Inventory II (BDI-II) 
To be supplied by Indivior Inc.   
http://www.pearsonclinical.com/psychology/products/100000159/beck-depression-inventoryii-
bdi-ii.html?Pid=015-8018-370&Mode=summary#tab-details 


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Appendix 25 
Brief Pain Inventory (BPI) Short Form 
To be supplied by Indivior Inc.   
http://www.mdanderson.org/education-and-research/departments-programs-and-
labs/departments-and-divisions/symptom-research/symptom-assessment-
tools/BPI_UserGuide.pdf 


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Appendix 26 
Sponsor Signatures 
Study Title: 
An Open-Label, Long-Term Safety and Tolerability Study of Depot 
Buprenorphine (RBP-6000) in Treatment-Seeking Subjects With 
Opioid Use Disorder 
Study Number: 
RB-US-13-0003 
Final Date: 
25 March 2016 
 
 
This clinical study protocol was subject to critical review and has been approved by the Sponsor 
and contracted Medical Monitor.   
 
 
Signed: 
 
 
Date:  
 
 
Head Late Stage Development, Global Clinical Development 
Indivior Inc. 
 
 
 
 
 
Signed: 
 
Date:  
 
  
Medical Monitor  
PRA Health Sciences. 


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Appendix 27 
Investigator’s Signature 
Study Title: 
An Open-Label, Long-Term Safety and Tolerability Study of Depot 
Buprenorphine (RBP-6000) in Treatment-Seeking Subjects With 
Opioid Use Disorder 
Study Number: 
RB-US-13-0003 
Final Date: 
25 March 2016 
 
I have read the protocol described above. I agree to comply with all applicable regulations and to 
conduct the study as described in the protocol.   
 
 
 
 
 
Signed: 
 
 
Date:  
 
Printed Name and Credentials: 
Title: 
Site Name: 
Address: 
Telephone: 
 
 
 
 

Prot_005.pdf: 
 
 
 
 
 
 
 
 
 
 
 
Study Title 
An Open-Label, Long-Term Safety and Tolerability Study of Depot 
Buprenorphine (RBP-6000) in Treatment-Seeking Subjects With 
Opioid Use Disorder 
NCT Number 
NCT02510014 
Date 
August 4, 2016 
 


Clinical Study Protocol: RB-US-13-0003 
Study Title: 
An Open-Label, Long-Term Safety and Tolerability Study of Depot 
Buprenorphine (RBP-6000) in Treatment-Seeking Subjects With 
Opioid Use Disorder 
Study Number: 
RB-US-13-0003 
Study Phase: 
3 
Product Name: 
RBP-6000 
IND Number: 
107,607 
Indication: 
Treatment of Opioid Use Disorder 
Investigators: 
Multicenter 
Sponsor: 
Indivior Inc. 
 
10710 Midlothian Turnpike, Suite 430 
Richmond, VA 23235 
 
Sponsor Contact: 
 
Head Late Stage Development, Global Clinical Development 
 
 
Medical Monitor: 
 
 
 
Date 
Original Protocol: 
14 April 2015 
Amendment 1: 
19 August 2015 
Amendment 2: 
11 September 2015 
Amendment 3: 
25 March 2016 
Amendment 4: 
04 August 2016 
 
 
 
 
Confidentiality Statement 
The information contained in this document is privileged and confidential. Do not copy, 
circulate, or otherwise distribute without written authorization from  
Indivior Inc. 


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SYNOPSIS 
Sponsor:  
Indivior Inc., formerly Reckitt Benckiser Pharmaceuticals Inc. (RBP) 
Name of Finished Product: 
RBP-6000, 18% buprenorphine sterile solution for subcutaneous (SC) injection 
Name of Active Ingredient: 
Buprenorphine 
Name of Inactive Ingredient:  
ATRIGEL® Delivery System 
Study Title: 
An Open-Label, Long-Term Safety and Tolerability Study of Depot Buprenorphine (RBP-6000) 
in Treatment-Seeking Subjects With Opioid Use Disorder 
Study Number: 
RB-US-13-0003 
Study Phase: Phase 3 
Primary Objective: 
To assess the long-term safety and tolerability of RBP-6000 subcutaneous (SC) injections in 
subjects with opioid use disorder. 
Secondary Objective: 
To collect clinical outcome data with RBP-6000 SC injections in subjects with opioid use 
disorder. 
Tertiary Objectives:  
To evaluate the: 
• Pharmacokinetics (PK) of RBP-6000,  
• Relationships between RBP-6000 PK and clinical outcome data, and 
• Impact of RBP-6000 on health and economic outcomes. 
Study Design: 
This is a multicenter, open-label, long-term safety study in which approximately 600 subjects 
diagnosed with opioid use disorder will be enrolled (approximately 300 subjects who did not 
participate in Study RB-US-13-0001, the double-blind, placebo-controlled efficacy study of 
RBP-6000 [hereafter referred to as “de novo” subjects], and 300 subjects who completed the RB-
US-13-0001 study [hereafter referred to as “roll-over” subjects]).  Subject participation will be 
based on the Investigator’s determination that initiation or continuation of study treatment is 
appropriate; and, for subjects who participated in RB-US-13-0001, that there have been no 
significant protocol deviations or clinically relevant adverse events (AEs) that would preclude 
inclusion of the subject in this study. All subjects will provide written informed consent before 
any protocol-related procedures commence. At the Screening Visit (which is up to 3 days after 
the End of Study [EOS] Visit [Day 169 + 3] for roll-over subjects), potential subjects will be 


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reviewed for eligibility against inclusion and exclusion criteria, and eligible subjects will be 
enrolled into the trial.  
SUBOXONE Sublingual Film Run-In:  Induction 
De novo Subjects: 
De novo subjects will initially be inducted onto SUBOXONE® (buprenorphine/naloxone) 
sublingual film for 3 days according to the SUBOXONE sublingual film prescribing 
information.  They will receive their first dose of SUBOXONE sublingual film on Induction 
Day 1 after it is confirmed that the subject meets eligibility criteria and has a Clinical Opiate 
Withdrawal Scale (COWS) score > 12.  Subjects will be started with an initial dose of 2 mg/0.5 
mg (buprenorphine/naloxone) or 4 mg/1 mg and may titrate upwards in 2 or 4 mg increments of 
buprenorphine, at approximately 2-hour intervals, under clinical supervision, to 8 mg/2 mg based 
on therapeutic response.  
On Induction Day 2, subjects with a COWS score > 12 or subjects reporting withdrawal 
signs/symptoms overnight will receive a dose of SUBOXONE sublingual film equal to the total 
dose given on Induction Day 1 plus 4 mg.  (For example, if a subject received a total dose of 8 
mg of buprenorphine on Induction Day 1, the starting dose for Induction Day 2 would be 12 mg).  
If the COWS score is still > 12 one hour later, another 4 mg dose can be given. The subject 
should not exceed a maximum dose of 16 mg buprenorphine for Induction Day 2. Subsequent 
SUBOXONE sublingual film doses must be separated by at least 1 hour from the preceding dose. 
SUBOXONE sublingual film doses may also be adjusted downward if necessary.  
On Induction Day 3, subjects will be titrated to therapeutic response based on COWS scores as 
well as physician judgment. Most subjects will only require a single dose on Induction Day 3, 
which will equal the Induction Day 2 dose or the Induction Day 2 dose plus 4 mg buprenorphine. 
Additional doses may also be administered on Induction Day 3 (up to 24 mg/6 mg). Subsequent 
SUBOXONE sublingual film doses must be separated by at least 1 hour from the preceding dose.  
Subjects should reach a daily dose of between 8 mg and 24 mg buprenorphine by Induction Day 
3 and continue on that dose through the remainder of the SUBOXONE sublingual film Run-In 
period, with additional dose adjustments if necessary.  
Roll-over Subjects: 
Following screening, roll-over subjects will be inducted onto SUBOXONE sublingual film to 
achieve daily doses between 8 mg to 24 mg buprenorphine according to the SUBOXONE 
sublingual film prescribing information.  
Subjects will receive their first induction dose on Induction Day 1. Subjects should be started 
with an initial dose of 2 mg/0.5 mg (buprenorphine/naloxone) or 4 mg/1 mg and may titrate 
upwards in 2 or 4 mg increments of buprenorphine, at approximately 2-hour intervals, under 
supervision, to a total dose of up to 8 mg/2 mg based on the control of acute withdrawal 
symptoms.  
On Induction Day 2, subjects with a score for COWS of >12, or subjects reporting opioid 
withdrawal signs/symptoms overnight, should receive a dose of study drug equal to the total dose 
given on Induction Day 1 plus 4 mg.  If the COWS score is still >12 one hour later, another 4 mg 
dose can be given.  The subject should not exceed a maximum dose of 16 mg/4 mg for Induction 
Day 2.  Subsequent SUBOXONE sublingual film doses must be separated by at least 1 hour 
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necessary.   
On Induction Day 3, subjects will be titrated to therapeutic response until a therapeutic dosage is 
reached, based on COWS scores as well as physician judgment. Most subjects will only require a 
single dose on Induction Day 3 which will equal the Induction Day 2 dose or the Induction Day 2 
dose plus 4 mg. Additional doses may also be administered on Induction Day 3 (up to 24 mg).  
Subsequent SUBOXONE sublingual film doses must be separated by at least 1 hour from the 
preceding dose.  Although subjects should reach a daily dose of between 8 mg and 24 mg by 
Induction Day 3 and continue on that dose through the remainder of the SUBOXONE sublingual 
film Run-In period, dose adjustments may be necessary during the Run-In period.  
Roll-over subjects must be titrated to a minimum dose of 8 mg SUBOXONE by the end of the 
3-day Induction period regardless of their COWS scores and/or the presence or absence of 
withdrawal symptoms.   
The SUBOXONE sublingual film(s) will be administered under the tongue, close to the base on 
the left or right side, until they are dissolved.  If an additional sublingual film is required, it 
should be placed on the opposite side from the first film.  Subjects should be instructed to hold 
the films under the tongue until they dissolve.  If a third film is required, it should be placed 
under the tongue after the first 2 films have dissolved.   
SUBOXONE Sublingual Film Run-In:  Dose Adjustment (All Subjects) 
After the daily induction visits, all subjects will begin a 1-to 11-day SUBOXONE sublingual 
film dose adjustment period.  Subjects will return to the clinic at 3- to 4-day intervals for Opioid 
Craving Visual Analog Scale (VAS), COWS, and Subjective Opiate Withdrawal Scale (SOWS) 
assessments.  SUBOXONE sublingual film will be dispensed at each visit for at home dosing.  
Beginning on the 4th day of SUBOXONE sublingual film dosing, subjects will be evaluated for 
Day -1 criteria, which are identical to the criteria required for enrollment on Day 1.  These 
criteria include the following: no allergic reaction to SUBOXONE sublingual film, a daily dose 
of SUBOXONE sublingual film between 8 mg and 24 mg (inclusive) buprenorphine, a COWS 
score of ≤ 12, and an Opioid Craving VAS score of ≤ 20 mm. 
Open-Label Treatment with RBP-6000: 
On Day 1 of the study (first dose of RBP-6000), all subjects who meet enrollment criteria will 
receive a SC injection of 300 mg of buprenorphine in RBP-6000. Subsequent doses of RBP-6000 
may be adjusted down to 100 mg and back up to 300 mg based on the medical judgment of the 
Investigator. After injection of RBP-6000, subjects will not be permitted to receive supplemental 
SUBOXONE sublingual film during the RBP-6000 treatment period. Subjects who require 
supplemental SUBOXONE sublingual film or other sublingual buprenorphine pharmacotherapy 
during the RBP-6000 treatment period will be withdrawn from the study and referred for 
appropriate treatment. 
Subjects will return to the clinic for monthly injection visits (every 28 - 2/+ 4 days) for a total of 
up to 12 injections for de novo subjects or for a total of 6 injections for roll-over subjects. 
Electrocardiogram (ECG) recordings and vital signs will be collected pre and post each SC 
injection. Subject-reported injection site pain Visual Analog Scale scores (VAS) will be 
collected at various times for 1 hour after each injection. Local injection site grading will be 
collected at various time points starting immediately after injection; the injection site will be 
evaluated for pain, tenderness, warmth, itching, erythema, inflammation or swelling, and 


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bruising using a 4-point severity scale. At each visit after injections begin, the injection site will 
be assessed by site staff for potential reaction and will also be evaluated for evidence of attempts 
to remove the depot. 
Subjects will return to the clinic weekly for the first 5 weeks and then biweekly (i.e., every 2 
weeks) through to injection 6. After injection 6, visits will be monthly for the rest of the study 
period for urine drug screens (UDS), Timeline Followback (TLFB) interviews, opioid craving 
VAS evaluation, COWS and subject reported outcomes (Subjective Opiate Withdrawal Scale 
[SOWS]). Subjects will continue to receive counseling (manual-guided behavioral therapy) 
during the study.  
Safety assessments will be collected at each injection visit and/or at injection follow-up visits 
and will include the following: vital signs, electronic Columbia Suicide Severity Rating Scale 
(eC-SSRS) responses, ECGs, laboratory tests (hematology, chemistry, urinalysis, and pregnancy 
test), use of concomitant medications, and the frequency of AEs.  
Sparse PK blood samples will be collected for population PK analysis from the roll-over subjects 
only. Once at least 75  roll-over subjects have completed Injection 6 (Week 25, Day 169) the 
sites will be notified that no more PK samples will be required to be collected from the roll-over 
subjects for the duration of the study. PK samples for population PK analysis are not required 
from the de novo subjects. ECGs will be performed before PK sample collection. The following 
health economic and outcome assessments will also be collected: Beck Depression Inventory 
(BDI-II), brief pain inventory (BPI), EuroQol EQ-5D-5L (EQ-5D-5L), 36-Item Short Form 
Health Survey, Version 2 (SF-36v2), Medication Satisfaction Questionnaire (MSQ), healthcare 
resource utilization (HCRU), Treatment Effectiveness Assessment (TEA), and Addiction 
Severity Index Lite (ASI). 
 
For all subjects (de novo and roll-over), a PK sample will be taken as soon as possible after any 
SAE is reported. If possible, an additional sample should be collected when the SAE has been 
resolved. 
Approximately 2 months prior to the scheduled End Of Study (EOS) visit, the subject’s ongoing 
treatment options will be reviewed with the investigator. At the EOS, 2 transition treatment 
options may be offered if the subject is eligible: 
• Subjects who complete the RBP-6000 treatment period may be offered entry into an open 
label extension study of RBP-6000 (Study INDV-6000-301).  Eligibility will be based on 
meeting the inclusion and exclusion criteria and the medical judgment of the Investigator.  
• Subjects who do not meet the eligibility criteria of the extension study, or subjects who 
do not wish to enroll may alternatively enter a 4-week SUBOXONE transition period if 
deemed suitable by the investigator.  Subjects should be dosed using the Investigators 
medical judgement. Any additional unscheduled visits required by the subject for the 
SUBOXONE transition will not be compensated by the Sponsor.   
Subjects that have not enrolled onto the INDV-6000-301 should be contacted by telephone 
approximately 4 weeks after EOS for a safety follow-up assessment of AEs and use of 
concomitant medications.   


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Study Population:  
Approximately 300 de novo subjects will be enrolled into this study, as well as approximately 
300 roll-over subjects. The study population will consist of individuals diagnosed with opioid 
use disorder who are seeking treatment.  
Test Product, Dose, and Mode of Administration:  
300 mg buprenorphine in RBP-6000, subcutaneous injection 
100 mg buprenorphine in RBP-6000, subcutaneous injection 
Duration of Study Treatment:  
This will be a multiple-dose study, with the first investigational product administration 
(RBP-6000 containing 300 mg buprenorphine) on Day 1. The expected maximum duration of 
participation for de novo subjects is up to approximately 55 weeks, consisting of up to 7 days of 
screening, up to 14 days SUBOXONE sublingual film Run-In, up to a 48-week open-label 
treatment period, and a 4-week safety follow-up telephone call. The expected maximum duration 
of participation for roll-over subjects is up to approximately 31 weeks, consisting of up to a 7-
day screening period, up to 14 days SUBOXONE sublingual film Run-In, a 24-week open-label 
treatment period, and a 4-week safety follow-up telephone call. 
Subjects who enroll in the INDV-6000-301 study are not required to complete the safety follow-
up telephone call.  
Safety Assessments: 
Safety objectives for this study are to evaluate the safety and tolerability of RBP-6000 (100 mg 
and 300 mg) SC injection treatment in subjects with opioid use disorder. Safety assessments will 
include the following: frequency of all AEs, serious AEs (SAEs), discontinuations from study 
due to AEs; local injection site tolerability (e.g., injection site grading); injection site pain using a 
subject-reported VAS; suicidality using the eC-SSRS, use of concomitant medications; changes 
in clinical laboratory results; vital sign measurements; 12-lead ECGs, which will be interpreted 
by a central facility; physical examination results; body weight, height, and body mass index 
(BMI), and abdominal fat measurement (waist-to-hip ratio). 
Clinical Outcome Assessments: 
Clinical outcome assessments will include the UDS for opioids and other drugs; self-reported use 
of illicit opioids, other drugs, and alcohol on the TLFB; COWS, SOWS, and Opioid Craving 
VAS. 
PK Assessments: 
Sparse plasma samples will be collected for population PK analysis from the roll-over subjects 
only. Once at least 75  roll-over subjects have completed Injection 6 (Week 25 Day 169), the 
sites will be notified that no more PK samples will be required to be collected from the roll-over 
subjects for the duration of the study. 
No PK samples will be collected from the de novo subjects. 
However, for all subjects (de novo and roll-over) throughout the study, a PK sample will be 
taken as soon as possible after any SAE is reported. If possible, an additional sample should be 


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collected when the SAE has been resolved. 
Health Economics and Outcomes Assessments:  
Health economics and outcomes assessments will include: BDI-II, BPI, EQ-5D-5L, SF-36v2, 
MSQ, HCRU, TEA, and ASI-Lite. 


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Statistical Methods:  
A Statistical Analysis Plan (SAP) will be prepared after the protocol is approved and before 
database lock occurs.  The SAP will provide further details regarding the definition of analysis 
endpoints, data handling rules, and the statistical methodology to be used to address all study 
objectives.  The SAP will also include formats for the summary and analysis tables, listings, and 
graphical displays. 
Determination of Sample Size: 
Approximately 300 de novo subjects as well as approximately 300 subjects who completed the 
RB-US-13-0001 study will be enrolled into this long-term safety study to ensure 100 subjects 
reach 1 year of treatment with RBP-6000. No power analysis will be done corresponding to the 
sample sizes, but the large numbers proposed are clinically acceptable to provide adequate and 
relevant clinical conclusions from this study. 
Safety Analyses: 
Safety variables will include AEs, local injection site tolerability (e.g., injection site grading); 
injection site pain using a subject-reported VAS; suicidality using the eC-SSRS, concomitant 
medications; changes in clinical laboratory results (hematology, chemistry and urinalysis); vital 
sign measurements; 12-lead ECGs, physical examination results; body weight, height, BMI, and 
abdominal fat measurement (waist-to-hip ratio).  Safety variables will be analyzed on the safety 
population using descriptive statistics for continuous endpoints (e.g., mean, median, SD, 
minimum and maximum) and frequency counts with percentages for discrete endpoints. 
Baseline is defined as the last non-missing value prior to SC injection on Day 1.  No imputation 
of missing values will be performed. 
Clinical Outcomes Assessments: 
COWS, SOWS and Opioid Craving VAS total scores will be summarized using descriptive 
statistics (mean, median, SD, minimum, maximum), including change from baseline.  Subjects’ 
self-reported illicit drug use from the TLFB will be summarized as descriptive statistics. 
The cumulative distribution function (CDF) of the percentage of urine samples negative for 
opioids, the CDF of the percentage of self-reports from the TLFB negative for illicit opioid use, 
and other outcome measures will be calculated. 
Population PK/PD Analysis: 
The population PK model established using the data collected in the double-blind, placebo-
controlled, efficacy study (Study RB-US-13-0001) will be refined using the PK samples 
collected in the present study to characterize the disposition of buprenorphine and 
norbuprenorphine following SC injections of RBP-6000, with the assessment of potential 
covariates affecting the PK of both compounds. Subsequently, the relationships between 
buprenorphine plasma concentrations and clinical outcomes assessments will be investigated. 
These relationships will be initially assessed in a descriptive manner, and, if applicable, 
appropriate PK/PD models will be developed to describe these relationships. A stand-alone 
modeling analysis plan will be generated, and the results will be reported in a standalone 
modeling report. 


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Health Economic and Outcomes Research Analyses: 
The health economic and outcomes research endpoints for this study are: BDI-II, BPI, EQ-5D-
5L, SF-36v2, MSQ, Health Insurance, HCRU, TEA, and ASI-Lite.  
Summary scores for these measures will be calculated, as appropriate. Categorical variables will 
be summarized using frequencies and percentages. Continuous measures will be summarized 
using descriptive statistics (mean, standard deviation, median, minimum, maximum) as 
appropriate. An analysis of change will be conducted. Supplementary analyses using general 
linear, mixed, or non-parametric methods will be performed as appropriate.  
A stand-alone SAP will be developed prior to database lock with full detail regarding health 
economics and outcomes analyses. 
Date of Original Approved Protocol: 14 April 2015 
Date of Amendment 1: 19 August 2015 
Date of Amendment 2: 11 September 2015 
Date of Amendment 3: 25 March 2016 
Date of Amendment 4: 04 August 2016 
 


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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................2 
LIST OF IN-TEXT TABLES ..................................................................................................14 
LIST OF IN-TEXT FIGURES.................................................................................................14 
LIST OF APPENDICES ..........................................................................................................14 
LIST OF ABBREVIATIONS ..................................................................................................16 
1 
INTRODUCTION ...........................................................................................................19 
1.1 
Opioid Use Disorder ..............................................................................................19 
1.2 
Buprenorphine........................................................................................................20 
1.3 
ATRIGEL Delivery System ...................................................................................20 
1.4 
Buprenorphine in the ATRIGEL Delivery System (RBP-6000) ...........................21 
1.4.1 
Summary of Nonclinical Data .....................................................................21 
1.4.2 
Summary of Previous Clinical Data ............................................................22 
1.4.3 
Pharmacokinetic/Pharmacodynamic Modeling of RBP-6000 .....................23 
1.5 
Rationale for Dose Selection .................................................................................24 
1.6 
Known and Potential Risks and Benefits ...............................................................27 
2 
STUDY OBJECTIVES ....................................................................................................28 
2.1 
Primary Objective ..................................................................................................28 
2.2 
Secondary Objectives.............................................................................................28 
2.3 
Tertiary Objectives.................................................................................................28 
3 
INVESTIGATIONAL PLAN ..........................................................................................29 
3.1 
Overall Study Design and Plan ..............................................................................29 
3.2 
Rationale for Study Design ....................................................................................34 
3.3 
Study Duration and Dates ......................................................................................34 
4 
STUDY POPULATION SELECTION ...........................................................................35 
4.1 
Study Population ....................................................................................................35 
4.2 
Inclusion Criteria ...................................................................................................35 
4.3 
Exclusion Criteria ..................................................................................................36 
4.4 
Day -1/Enrollment Criteria ....................................................................................38 
5 
STUDY TREATMENTS .................................................................................................39 
5.1 
Description of Treatments......................................................................................39 
5.1.1 
SUBOXONE Sublingual Film .....................................................................39 
5.1.2 
Investigational Medicinal Products..............................................................39 
5.2 
Treatments Administered .......................................................................................39 
5.2.1 
Run-In Treatment Period .............................................................................39 
5.2.1.1 
SUBOXONE Sublingual Film Induction (De novo Subjects) ...........39 
5.2.1.2 
SUBOXONE Sublingual Film Induction (Roll-over Subjects) .........40 


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5.2.2 
Dose Adjustment Period (All Subjects) .......................................................41 
5.2.3 
Active Study Treatment ...............................................................................41 
5.3 
Selection and Timing of Dose for Each Subject ....................................................42 
5.4 
Method of Assigning Subjects to Treatment Groups .............................................42 
5.5 
Blinding..................................................................................................................42 
5.6 
Concomitant Therapy.............................................................................................42 
5.6.1 
Permitted Concomitant Medications ............................................................43 
5.6.2 
Prohibited Concomitant Medications ..........................................................43 
5.7 
Restrictions ............................................................................................................44 
5.7.1 
Prior Therapy ...............................................................................................44 
5.7.2 
Subject Activity Restrictions .......................................................................44 
5.8 
Protocol Compliance ..............................................................................................44 
5.9 
Packaging and Labeling .........................................................................................44 
5.10 
Storage and Accountability ....................................................................................45 
5.11 
Investigational Product Retention at Study Site ....................................................45 
6 
STUDY PROCEDURES .................................................................................................47 
6.1 
Informed Consent...................................................................................................47 
6.1.1 
General Information .....................................................................................47 
6.2 
Medical History .....................................................................................................47 
6.3 
Physical Examination.............................................................................................47 
6.4 
Vital Signs ..............................................................................................................48 
6.5 
Electrocardiograms ................................................................................................48 
6.5.1 
12-Lead Electrocardiograms ........................................................................48 
6.6 
Clinical Laboratory Tests .......................................................................................49 
6.6.1 
Laboratory Parameters .................................................................................49 
6.6.2 
Sample Collection, Storage, and Shipping ..................................................51 
6.6.3 
Reference Ranges.........................................................................................51 
6.6.4 
Laboratory Results Review ..........................................................................51 
6.7 
Pharmacokinetic Assessments ...............................................................................51 
6.8 
Administration of Study Drug ...............................................................................51 
6.9 
Safety and Suicidality Assessments .......................................................................52 
6.9.1 
Local Injection Site Tolerability ..................................................................52 
6.9.1.1 
Injection Site Grading ........................................................................52 
6.9.1.2 
Injection Site Pain Visual Analogue Scale (VAS) .............................52 
6.9.2 
Suicidality ....................................................................................................53 
6.9.2.1 
Columbia Suicide Severity Rating Scale ...........................................53 
6.10 
Adverse Events Assessments .................................................................................53 
6.10.1 
Definition .....................................................................................................53 


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6.10.2 
Performing Adverse Events Assessments ....................................................54 
6.10.3 
Timing ..........................................................................................................54 
6.10.4 
Severity ........................................................................................................54 
6.10.5 
Relationship .................................................................................................55 
6.10.6 
Expectedness ................................................................................................55 
6.10.7 
Clinical Significance ....................................................................................55 
6.10.8 
Clinical Laboratory Adverse Events ............................................................56 
6.10.9 
Serious Adverse Events ...............................................................................56 
6.10.9.1 
Definition ...........................................................................................56 
6.10.9.2 
Reporting Serious Adverse Events ....................................................56 
6.10.10 Treatment-Emergent Adverse Events ..........................................................57 
6.10.11 Procedures and Follow-Up of Subjects with Ongoing SAEs or Experiencing 
SAEs after Completion of or Withdrawal from the Study ...........................57 
6.10.12 Pregnancy .....................................................................................................57 
6.11 
Clinical Outcome Assessments ..............................................................................58 
6.11.1 
Timeline Followback Interview ...................................................................58 
6.11.2 
Opioid Craving Visual Analog Scale ...........................................................58 
6.11.3 
Clinical Opiate Withdrawal Scale ................................................................58 
6.11.4 
Subjective Opiate Withdrawal Scale ...........................................................59 
6.12 
Health Economics and Outcomes Assessments .....................................................59 
6.12.1 
EuroQoL-5 Dimensions-5 Levels (EQ-5D-5L) and EQ-VAS.....................59 
6.12.2 
Medical Outcomes Study Short Form-36 (SF-36v2) ...................................59 
6.12.5 
Treatment Effectiveness Assessment (TEA) ...............................................60 
6.12.6 
Addiction Severity Index (ASI) Lite............................................................60 
6.12.7 
Beck Depression Inventory II (BDI-II)........................................................61 
6.12.8 
Brief Pain Inventory (BPI) Short Form .......................................................61 
6.13 
Concomitant Medication Assessments ..................................................................62 
6.14 
Removal of Subjects from the Study .....................................................................62 
6.14.1 
Early Removal of RBP-6000 .......................................................................63 
6.14.2 
Stopping Rules .............................................................................................63 
6.14.3 
Screen Failures .............................................................................................63 
6.15 
Other Study Procedures .........................................................................................64 
6.15.1 
Counseling/Behavioral Therapy ..................................................................64 
6.15.2 
Unscheduled Visits ......................................................................................64 
6.15.3 
Additional Care of Study Subjects Following Completion of the Study .....64 
6.15.4 
Treating Toxicity .........................................................................................64 
6.15.5 
Ancillary Medications ..................................................................................64 
6.16 
Appropriateness of Measurements .........................................................................65 


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7 
STUDY ACTIVITIES .....................................................................................................66 
8 
QUALITY CONTROL AND ASSURANCE .................................................................67 
8.1 
Quality Control ......................................................................................................67 
8.2 
Quality Assurance ..................................................................................................67 
9 
PLANNED STATISTICAL METHODS ........................................................................68 
9.1 
General Considerations ..........................................................................................68 
9.2 
Determination of Sample Size ...............................................................................68 
9.3 
Analysis Populations ..............................................................................................68 
9.3.1 
Safety Population .........................................................................................68 
9.3.2 
Clinical Outcome Assessment and PK Populations.....................................68 
9.4 
Demographics and Baseline Characteristics ..........................................................69 
9.5 
Primary Analysis ....................................................................................................69 
9.5.1 
Safety Endpoints ..........................................................................................69 
9.5.1.1 
Adverse Events ..................................................................................69 
9.5.1.2 
Laboratory Data .................................................................................69 
9.5.1.3 
Vital Signs ..........................................................................................69 
9.5.1.4 
Other Variables Related to Safety ......................................................69 
9.6 
Secondary Analysis ................................................................................................70 
9.6.1 
Clinical Outcomes Assessments ..................................................................70 
9.7 
Other Analyses .......................................................................................................70 
9.7.1 
PK/PD Modeling ..........................................................................................70 
9.7.2 
Health Economic and Outcomes Assessment ..............................................71 
9.8 
Handling of Missing Data ......................................................................................71 
9.9 
Subjects Who Withdraw from the Study ...............................................................72 
9.10 
Interim Analyses ....................................................................................................72 
10 ADMINISTRATIVE CONSIDERATIONS ....................................................................73 
10.1 
Investigators and Study Administrative Structure .................................................73 
10.1.1 
Indivior Inc...................................................................................................73 
10.1.2 
Investigational Site(s) ..................................................................................73 
10.1.3 
Laboratories .................................................................................................73 
10.2 
Institutional Review Board or Independent Ethics Committee Approval .............73 
10.3 
Ethical Conduct of the Study .................................................................................73 
10.4 
Subject Information and Consent...........................................................................74 
10.5 
Subject Confidentiality ..........................................................................................74 
10.6 
Study Monitoring ...................................................................................................75 
10.6.1 
Study and Site Closure .................................................................................75 
10.7 
Case Report Forms and Study Records .................................................................75 
10.8 
Data Monitoring Committee ..................................................................................76 


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10.9 
Protocol Deviations ................................................................................................76 
10.10 Access to Source Documentation ..........................................................................77 
10.11 Data Generation and Analysis ...............................................................................77 
10.11.1 Data Collection and Data Management .......................................................77 
10.11.2 Database Quality Assurance ........................................................................77 
10.12 Retention of Data ...................................................................................................78 
10.13 Financial Disclosure...............................................................................................78 
10.14 Publication and Disclosure Policy .........................................................................78 
11 REFERENCE LIST .........................................................................................................79 
11.1.1.1 
Subjective Effects .............................................................................118 
11.1.1.2 
Physiologic Effects ............................................................................119 
 
LIST OF IN-TEXT TABLES 
Table 1 
PK Parameters of the Simulated Typical PK Profile of Buprenorphine after 
Repeated RBP-6000 Injections for the Phase 3 Efficacy Study (RB-US-13-0001) ....26 
Table 2 
List of Laboratory Tests ...............................................................................50 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Model-Predicted Buprenorphine Plasma Concentrations and Mu-Opioid 
Receptor Occupancy in Each Treatment Group on RBP-6000 Following the Proposed 
Design of the Current Study ........................................................................................25 
Figure 2 
Study Overview:  De novo Subjects ............................................................32 
Figure 3 
Study Overview:  Roll-over Subjects from RB-US-13-0001 ......................33 
Figure 4 
Injection Locations.....................................................................................128 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events – Screening and SUBOXONE Film Induction ..83 
Appendix 2 
Schedule of Events – RBP-6000 Injection 1 – 3 Visits .....................86 
Appendix 3 
Schedule of Events – RBP-6000 Injection 4 – 6 Visits for all Subjects 
and End of Study/Early Termination and Follow-Up Visits for Roll-over Subjects ...89 
Appendix 4 
Schedule of Events – RBP-6000 Injection 7 – 9 Visits for de novo 
Subjects 
92 
Appendix 5 
Schedule of Events – RBP-6000 Injection 10 – 12 Visits and End of 
Study/Early Termination Visit and Follow-Up for de novo Subjects ..........................95 
Appendix 6 
Pharmacokinetic Sampling Schedule .................................................98 
Appendix 7 
SUBOXONE® (Buprenorphine/Naloxone) Sublingual Film Full 
Prescribing Information ...............................................................................................99 


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Appendix 8 
Study Drug Preparation, Administration, and Depot Removal 
Instructions 
127 
Appendix 9 
Prohibited Cytochrome P450 Inhibitors and Inducers .....................130 
Appendix 10 
Columbia Suicide Severity Rating Scale (eC-SSRS) -- 
Baseline/Screening Version .......................................................................................131 
Appendix 11 
Columbia Suicide Severity Rating Scale (eC-SSRS) -- Since Last 
Visit Version 
133 
Appendix 12 
Clinical Opiate Withdrawal Scale (COWS) ....................................135 
Appendix 13 
Subjective Opiate Withdrawal Scale (SOWS) .................................137 
Appendix 14 
Opioid Craving Visual Analog Scale (Opioid Craving VAS) .........138 
Appendix 15 
Injection Site Grading Scale ............................................................139 
Appendix 16 
Injection Site Pain Visual Analog Scale (Injection Site Pain VAS) 140 
Appendix 17 
Timeline Followback (TLFB) Interview .........................................141 
Appendix 18 
Euro QoL EQ-5D-5L Health Questionnaire ....................................142 
Appendix 19 
Short Form (36) Health Survey v2...................................................144 
Appendix 20 
Medication Satisfaction Questionnaire ............................................148 
Appendix 21 
Health Care Resource Utilization Questionnaire .............................149 
Appendix 22 
Treatment Effectiveness Assessment (TEA) ...................................151 
Appendix 23 
Addiction Severity Index (ASI) Lite................................................152 
Appendix 24 
Beck Depression Inventory II (BDI-II)............................................168 
Appendix 25 
Brief Pain Inventory (BPI) Short Form ...........................................169 
Appendix 26 
Sponsor Signatures...........................................................................170 
Appendix 27 
Investigator’s Signature ...................................................................171 
 


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LIST OF ABBREVIATIONS 
AE 
adverse event 
AIDS 
acquired immunodeficiency syndrome 
ANOVA 
analysis of variance 
ASI-Lite 
Addiction Severity Index - Lite 
AUC 
area under the plasma concentration-time curve 
BDI-II 
Beck Depression Inventory - II 
BMI 
body mass index 
BP 
blood pressure 
BPI 
Brief Pain Inventory Short Form 
Cavg 
average plasma concentration 
Cmax 
maximum plasma concentration 
Ctrough 
plasma concentration at trough, i.e. before the next injection  
CDF 
cumulative distribution function 
CNS 
central nervous system 
COWS 
Clinical Opiate Withdrawal Scale 
CRA 
clinical research associate 
DAWN 
Drug Abuse Warning Network 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
EC50 
concentration yielding 50% of the maximal effect 
eCRF 
electronic case report form 
e C-SSRS 
Electronic Columbia Suicide Severity Rating Scale 
Emax 
maximum effect 
ECG 
electrocardiogram 
ED 
emergency department 
EOS 
end of study 
ET 
early termination 
EQ-5D 
EuroQol EQ-5D (standard instrument) 
EQ-5D-5L 
EuroQol EQ-5D-5L (self-complete version) 


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EQ-VAS 
EQ-5D using visual analog scale 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B surface antigen  
hCG 
urine human chorionic gonadotropin 
HCl 
hydrochloride 
HCRU 
healthcare resource utilization  
HEOR 
health economics and outcomes research 
HIV 
human immunodeficiency virus 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation  
IEC 
independent ethics committee 
IM 
intramuscular 
IMP 
investigational medicinal product 
IND 
investigational new drug application (i.e., Notice of Claimed 
Investigational Exemption for a New Drug) 
INDV 
Indivior Inc. 
INR 
international normalized ratio 
IRB 
institutional review board 
IV 
intravenous 
IWRS 
interactive web response system 
MAR 
missing at random  
MCAR 
missing completely at random  
MMRM 
mixed model repeated measures 
MSQ 
Medication Satisfaction Questionnaire 
NMP 
N-methyl pyrrolidone 
NOAEL 
no observable adverse effect level 
OTC 
over-the-counter 


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PD 
pharmacodynamic or pharmacodynamics 
PE 
physical examination 
PK 
pharmacokinetic or pharmacokinetics 
PLG or PLGH 
poly (DL-lactide-co-glycolide)  
PET 
positron emission tomography  
PI 
Principal Investigator 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
RBP 
Reckitt Benckiser Pharmaceuticals Inc. 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SD 
standard deviation 
SF-36v2 
36-Item Short Form Health Survey, Version 2 
SL 
sublingual 
SOE 
schedule of events 
SOP 
standard operating procedure 
SOWS 
Subjective Opiate Withdrawal Scale 
tmax 
time to maximum plasma concentration 
TEA 
Treatment Effectiveness Assessment  
TEAE 
treatment-emergent adverse event 
TLFB 
timeline followback 
UDS 
urine drug screen 
ULN 
upper limit of normal 
US/USA 
United States/United States of America 
VAS 
visual analog scale 


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1 
INTRODUCTION 
1.1 
Opioid Use Disorder 
Opioid use disorder, as defined in the Diagnostic and Statistical Manual of Mental Disorders, 
Fifth Edition (DSM-5; American Psychiatric Association 2013), is a neurobehavioral syndrome 
characterized by the repeated, compulsive seeking or use of an opioid despite adverse social, 
psychological, and/or physical consequences.  Opioid use disorder is a medical illness with high 
costs to individuals, families, and society.  Direct and indirect costs attributable to illicit drug use 
are estimated in 3 principal areas: crime, productivity, and health (US Department of Justice, 
Economic Impact of Illicit Drug Use on American Society, 2011).  Approximately one-third of 
all acquired immunodeficiency syndrome (AIDS) cases diagnosed in the United States (US) 
through 2009 (Centers for Disease Control and Prevention: HIV/AIDS Surveillance Report, 
2009) and many cases of hepatitis C (National Institute on Drug Abuse 2000; Thomas 2001) 
were associated with injection drug use.   
The increasing abuse of and addiction to prescription opioids is another major concern.  
According to the Substance Abuse and Mental Health Services Administration’s Office of 
Applied Studies, the incidence of abuse of prescription opioid pain medications (narcotic 
analgesics) such as hydrocodone, oxycodone, meperidine, and propoxyphene has risen markedly 
in recent years (Crane 2003).  The incidence of emergency department (ED) visits related to 
these medications has been increasing since the 1990s and has more than doubled between 1994 
and 2001 (Crane 2003).  The most recently published data from the Drug Abuse Warning 
Network (Drug Abuse Warning Network, 2009: National Estimates of Drug-Related Emergency 
Department Visits, 2011) estimated that about 2.1 million ED visits resulted from drug misuse or 
abuse, which was the equivalent of 674.4 ED visits per year per 100,000 population.  Although 
the overall number of ED visits attributable to drug misuse or abuse was stable from 2004 to 
2009, increases were seen in ED visits involving nonmedical use of pharmaceuticals with no 
other drug involvement (117% increase).  An estimated 1,079,683 ED visits in 2009 involved the 
nonmedical use of prescription drugs, over-the-counter (OTC) medicines, or other types of 
pharmaceuticals, representing about a quarter of all drug-related ED visits and over half of ED 
visits for drug abuse or misuse.  Pain relievers were the most common type of drugs reported in 
the nonmedical use category of ED visits (47.8%).  Among specific types of pain relievers, 
narcotic pain relievers such as oxycodone, hydrocodone, and methadone (13.7%, 8.0%, and 
5.8%, respectively) were most prevalent (Drug Abuse Warning Network, 2009: National 
Estimates of Drug-Related Emergency Department Visits, 2011). 
The economic burden of prescription opioid abuse is very high.  Total US societal costs of 
prescription opioid abuse were estimated at $55.7 billion in 2007 (US dollars in 2009).  
Workplace costs accounted for $25.6 billion (46%), health care costs accounted for $25.0 billion 
(45%), and criminal justice costs accounted for $5.1 billion (9%) (Birnbaum 2011).  Mean 
annual direct health care costs for opioid abusers were more than 8 times higher than for 
nonabusers.  Hospital inpatient and physician outpatient costs accounted for 46% and 31% 
respectively, of opioid abusers' health care costs.  The high costs of opioid abuse are driven 
primarily by high comorbidity rates and high utilization rates of medical services and 
prescription drugs (White 2005).  It was also found that opioid use results in lower quality of life, 


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including significantly worse physical and psychological health, compared with the general 
population (Ryan 1996). 
Given the high costs of opioid addiction to individuals, families, and society, treatments for this 
disease therefore aim to reduce the use of prescription or illicit opioids as well as the risks 
associated with injection, including transmission of human immunodeficiency virus (HIV) and 
hepatitis C virus.  Implantable formulations of opioid receptor partial agonists and antagonists 
represent an innovative alternative to daily dosing regimens, and several delivery systems are 
currently in clinical trials (Ling 2010, Rosenthal 2013).  The goal of this study is to determine 
whether RBP-6000, which is a sustained release formulation of buprenorphine in the ATRIGEL® 
delivery system, is a safe and effective treatment for opioid use disorder. 
1.2 
Buprenorphine 
In the central nervous system (CNS), opioid receptors are found in high concentrations in the 
limbic system and the spinal cord. The natural ligands for these receptors are a group of 
neuropeptides known as endorphins. Opioid analgesics mimic the action of endorphins but have 
a more prolonged action because the analgesics are not subject to rapid local metabolism. 
Three major opioid receptor subclasses have been identified: mu, kappa, and delta.  These 
subclasses mediate distinct actions with natural endorphins and opioid analgesics.  Different 
endorphin and opioid analgesic ligands demonstrate different binding affinities for the various 
subclasses of receptors.   
Buprenorphine is a member of the large family of opioid analgesics used in the treatment of 
moderate and severe acute and chronic pain. Opioid receptors are found in both the CNS and the 
periphery. Buprenorphine is a partial agonist at the mu receptor, producing a sub-maximal 
response compared to that of a full agonist. Hence, buprenorphine provides a greater margin of 
safety regarding respiratory depression in comparison to full agonist opioids. Buprenorphine is 
also an antagonist at the kappa receptor (Cowan 1977, Jasinski 1978). 
Buprenorphine has been reported to have a lower physical dependence liability than pure agonist 
analgesics such as morphine, and at a sufficient dose, it can suppress opioid withdrawal signs 
and symptoms for at least 24 hours.  Limited euphoric and respiratory depressant effects have led 
to its therapeutic use as a pharmacotherapy for opioid use disorder. 
Selected pharmacokinetic (PK) parameters for buprenorphine when administered sublingually as 
buprenorphine/naloxone films are in the SUBOXONE sublingual film prescribing information 
(Appendix 7).  Further details on the PK of buprenorphine in the ATRIGEL delivery system are 
described in Section 1.4.2. 
1.3 
ATRIGEL Delivery System 
The ATRIGEL Delivery System is a sterile, polymeric solution of a biodegradable 
poly DL-lactide-co-glycolide (PLGH) copolymer, dissolved in the water-miscible, biocompatible 
solvent N-methyl pyrrolidone (NMP).  The polymers belong to a family of poly α-hydroxy acids 
that are used in medical devices such as resorbable sutures and degradable drug delivery 


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systems.  Polymerization, which is initiated with glycolic acid, leads to a linear polymer 
containing a carboxylic acid end group.  The ATRIGEL Delivery System can be formulated to 
deliver different active ingredients for various lengths of time. 
The ATRIGEL Delivery System is well characterized.  It is currently used in 7 approved 
products worldwide, including 4 ELIGARD® products (subcutaneous [SC] depot formulations of 
leuprolide acetate), ATRIDOX® (doxycycline hyclate applied to the periodontal pocket), the 
ATRISORB® Bioabsorbable Guided Tissue Regeneration Barrier for periodontal application, and 
the ATRISORB-D Barrier (ATRISORB with doxycycline) for periodontal guided tissue 
regeneration. 
Clinical studies with these products demonstrated that the ATRIGEL Delivery System was well 
tolerated and provided consistent sustained release of the incorporated drug over the designated 
dosing interval.  Injection site reactions are expected to be mild and appear early in treatment, as 
observed in previous local irritation ATRIGEL studies (RBP-6000 Investigator’s Brochure [IB] 
Edition 5, 18 May 2016). 
1.4 
Buprenorphine in the ATRIGEL Delivery System (RBP-6000) 
RBP-6000 is a subcutaneously injected depot product under development for the treatment of 
opioid addiction. It contains buprenorphine in the ATRIGEL Delivery System and provides 
sustained plasma levels of buprenorphine over a minimum of 28 days. There is no currently 
approved, parenterally administered, sustained-release buprenorphine formulation for the 
treatment of opioid use disorder. Such a formulation could offer advantages over existing 
buprenorphine products by improving subject compliance and reducing diversion, abuse, and 
unintended exposure (e.g., in pediatric exposure), and reduce chances of swallowing drug. 
The safety profile and clinical efficacy of RBP-6000 are expected to be similar to and 
comparable with that of buprenorphine or SUBOXONE sublingual treatment.  
1.4.1 
Summary of Nonclinical Data 
Nonclinical data suggest that toxicity from RBP-6000 is unlikely at the doses planned for this 
clinical study.  The no observable adverse effect levels (NOAELs) were determined to be 250 
mg/kg (rat) and 40 mg/kg (dog) following single SC injections of RBP-6000 in 4-week toxicity 
studies.  These levels are equivalent to human buprenorphine doses of 2419 mg and 1333 mg, 
respectively (based on 60 kg body weight and calculated according US Food and Drug 
Administration guidance [FDA 2005]).  These levels provide approximately 8.1x (rat) and 4.4x 
(dog) safety margins when compared to the 300-mg buprenorphine dose in humans (based on 
60 kg body weight and calculated according US Food and Drug Administration guidance 
[FDA 2005]).  Systemic effects seen in the rat and dog 4-week toxicity studies were related to 
the pharmacology of buprenorphine or local tolerance effects of the formulation as a result of 
high dose and volume, so the safety margins are considered acceptable. 
Chronic repeated-dose studies were conducted in rats and dogs dosed with RBP-6000 once every 
4 weeks for 6 or 9 months, respectively.  These studies demonstrated systemic effects consistent 
with buprenorphine administration, such as stained fur, aggressive behavior, decreased activity, 


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reduced food consumption and body weight gain, and abnormal feces.  Minimal to mild lung 
alveolar macrophage infiltration and pancreatic acinar cell apoptosis were seen with increased 
incidence in rats, but not dogs, treated with RBP-6000.  Injection site findings were seen in both 
species, characterized microscopically by minimal to moderate granuloma formation.  Injection 
volumes were high, being 2.73 mL/m2 in rats and 3.64 mL/ m2 in dogs, compared with a volume 
of 0.62 mL/ m2 at the highest proposed clinical dose, contributing to these local findings.  
Systemic chronic NOAELs were considered to be 10 mg/kg in rats and 40 mg/kg in dogs.   
Overall, the extensive preclinical data on both the buprenorphine and SUBOXONE products and 
nonclinical PK and toxicity studies in rats and dogs support the clinical development of 
RBP-6000.  Systemic exposure to buprenorphine is not considered to pose any significant safety 
concerns following SC administration of RBP-6000.  Additionally, this clinical study will be 
conducted in subjects who have a current diagnosis of opioid use disorder and who would thus 
be expected to have a certain degree of cross-tolerance to the opioid agonist effects of 
buprenorphine.  Minimal to moderate irritation at the injection site, seen in both rats and dogs, 
may warrant attention to ensure local tolerability (RBP-6000 IB, Edition 4, 24 February 2014). 
1.4.2 
Summary of Previous Clinical Data 
In the first-in-human trial to evaluate the safety, tolerability, and PK of RBP-6000, 12 subjects 
received a single SC injection of RBP-6000 containing 20 mg of buprenorphine.  Of these 
12 subjects, 6 subjects completed the study through Day 85.  The majority (94%) of 
treatment-emergent adverse events (TEAEs) were mild, 5.4% were moderate, and 1 was severe 
in intensity.  TEAEs considered related to the study drug included injection site pain, injection 
site warmth, and injection site bruising, erythema, and edema.  All subjects experienced mild to 
moderate symptoms of withdrawal at study entry, prior to study drug injection, and after study 
drug injection.  One serious adverse event (SAE) was reported.  The SAE was notably identified 
psychosocial stressors and intermittent withdrawal, for which the subject had prolonged 
hospitalization for treatment.  This SAE was not considered to be related to the study drug.  No 
respiratory depression, temperature elevations, clinically significant lowering of oxygen 
saturation, or electrocardiogram (ECG) abnormalities were observed.  There was 1 clinically 
significant laboratory adverse event (AE; elevated hepatic enzymes), which resolved.  No 
unexpected side effects occurred in the RBP-6000 depot formulation of buprenorphine 
(RBP-6000 IB, Edition 4, 24 February 2014).  Buprenorphine was rapidly absorbed over the first 
day and peaked on the second day, with a slow decrease in plasma concentrations thereafter that 
is consistent with the slow release of buprenorphine from the ATRIGEL Delivery System.   
The PK of 50, 100, and 200 mg buprenorphine (as RBP-6000) was also evaluated in a single-
ascending-dose study in 51 subjects (RB-US-11-0020).  In this study, median buprenorphine 
time to peak concentration (tmax) in the initial burst period was observed at 24 hours for all 3 
dosages.  Buprenorphine mean plasma terminal half-life increased slightly with the increase in 
dose from 50 mg to 200 mg (1078 hours [44.9 days] at 50 mg, 1376 hours at 100 mg, and 1573 
hours at 200 mg).  Buprenorphine exhibited overall geometric mean average concentration 
values of 0.356, 0.624, and 1.108 ng/mL, respectively with 50, 100 and 200 mg buprenorphine 
while overall geometric mean Cmax values of 0.999, 1.518, and 2.381 ng/mL were observed for 
buprenorphine doses of 50, 100, and 200 mg, respectively.  With an increase in dose of RBP-


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6000 from 50 to 200 mg, mean buprenorphine exposure parameters increased less than 
proportionally to dose (RBP-6000 IB, Edition 4, 24 February 2014).  A single SC injection of 
RBP-6000 was generally safe and well tolerated.  A total of 46 of 51 subjects (90.2%) had at 
least 1 TEAE.  A total of 30 of 51 subjects (58.8%) had TEAEs that were related to treatment 
with RBP-6000.  The majority of AEs were qualified as moderate in severity (68.6%).  
Two subjects reported TEAEs that were considered to be severe but unrelated to RBP-6000.  No 
subjects withdrew from the study because of an AE. 
The safety profile of multiple-dose SC injections of RBP-6000 containing 50 mg, 100 mg, 
200 mg, and 300 mg of buprenorphine in treatment-seeking, opioid-dependent subjects in an 
open-label, multiple-dose study has recently been examined.  The results suggest that all doses 
were safe and well-tolerated following a 13-day induction and stabilization on SUBUTEX.  In 
addition, a study investigating the blockade of subjective opioid effects demonstrated that RBP-
6000 was safe and well tolerated after the SC administration of 2 monthly 300-mg doses of 
buprenorphine in RBP-6000, following a 14-day induction and stabilization period on 
SUBOXONE Film. 
1.4.3 
Pharmacokinetic/Pharmacodynamic Modeling of RBP-6000 
A population PK model was developed to characterize the disposition of buprenorphine and 
norbuprenorphine following SC injection of RBP-6000 (Nasser 2014).  This model was built 
using plasma concentration data collected in 36 opioid-dependent subjects who received single 
doses (50 mg, 100 mg, and 200 mg) of RBP-6000 in the single-ascending-dose study (RB-US-
11-0020).  Analysis of the PK profiles of RBP-6000 revealed a complex and multi-phase 
absorption profile, presenting double peaks and a prolonged plasma terminal half-life.  These 
distinguishing features of the PK of RBP-6000 required the development of a complex structural 
PK model accounting for this dual absorption process: a first absorption process that was 
associated with an initial, rapid delivery from the SC injection site, and a second absorption 
process that was associated with the slow release of buprenorphine from the ATRIGEL Delivery 
System into the systemic circulation.  The population PK model accurately predicted the PK data 
after repeated doses of RBP-6000 in the multiple ascending dose study (RB-US-12-0005) and in 
the opioid blockade study (RB-US-13-0002).  
Another population PK/PD model was developed to characterize the link between buprenorphine 
plasma concentration and mu opioid receptor occupancy (Nasser 2014).  Individual data from 15 
heroin-dependent subjects were taken from two published clinical trials (Greenwald 2003; 
Greenwald 2007).  A saturable maximum effect (Emax) model with 0.67 ng/mL effective 
concentration at 50% of maximum (EC50) and 91% Emax best described mu opioid receptor 
occupancy versus buprenorphine plasma concentrations.  At buprenorphine concentrations 
greater than 2 ng/mL, saturation occurred on mu opioid receptor occupancy where a 4.5-fold 
increase in observed buprenorphine concentrations resulted in observed mu opioid receptor 
occupancy between 70% and 90%. 
Positron emission tomography (PET) scan data were obtained in 2 subjects participating in the 
multiple-ascending dose study RB-US-12-0005 (PET scan sub-study) and receiving either 200 or 
300 mg of RBP-6000.  The PET scans were conducted at 7 days and 28 days post-dose following 


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the 12th SC injection for the first subject receiving 200 mg, and following the 6th SC injection for 
the second subject receiving 300 mg.  Both subjects were considered to be at steady-state for 
buprenorphine at the time of the PET scan measurements.  The mu opioid receptor availabilities 
of four different regions in the brain were measured, and the mu opioid receptor occupancy in 
the whole brain was calculated as described in Greenwald et al. (2003). 
The subject receiving 200 mg of RBP-6000 in the PET scan sub-study showed 79% and 75% mu 
opioid receptor occupancy on Day 7 and Day 28, respectively, following the 12th SC injection of 
RBP-6000.  The subject receiving 300 mg of RBP-6000 in the PET scan sub-study showed 92% 
and 81% mu opioid receptor occupancy on Day 7 and Day 28, respectively, following the 6th SC 
injection of RBP-6000.  These values and the corresponding PK concentrations were in 
agreement with the model predictions and the previous individual observations used to build the 
population PK/PD model. 
Linear relationships were found between mu opioid receptor occupancy and opioid withdrawal 
symptoms, and between mu opioid receptor occupancy and hydromorphone agonist blockade, 
based on the data from 15 heroin-dependent subjects (Nasser 2014).  These data suggest that a 
mean buprenorphine plasma concentration of 2 ng/mL is able to provide 70 % mu opioid 
receptor occupancy associated with low reported agonist drug effects and withdrawal symptoms 
(scores ≤2). 
Model simulations indicated that the desired 70% mu opioid receptor occupancy may be 
achieved after multiple doses of 200 mg of RBP-6000 (Nasser 2014).  The 300 mg dose was 
considered to be a full opioid blockade dose. 
1.5 
Rationale for Dose Selection 
The results of the opioid blockade study (RB-US-13-0002) showed that 300 mg was a full opioid 
blocking dose (i.e., for the “drug liking” VAS scores the upper bound of the 95% confidence 
interval ≤11), which is consistent with PK/PD modeling and simulation results. The least means 
“drug liking” VAS scores in the opioid blockade study showed that the blockade was achieved 
from the first SC injection and was maintained after the second SC injection until week 12 (i.e., 2 
months after the second injection). 
The population PK and PK/PD models presented in Section 1.4.3 were used to simulate the 
double-blind efficacy study (RB-US-13-0001).  The results of these simulations are displayed in 
Figure 1 for the two treatment arms on RBP-6000 receiving either 6 SC injections of 300 mg 
(300 mg × 2 + 300  mg × 4), or 2 SC injections of 300 mg followed by 4 SC injections of 100 mg 
(300  mg ×2  + 100  mg × 4).  
 


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Figure 1 
Model-Predicted Buprenorphine Plasma Concentrations and Mu-
Opioid Receptor Occupancy in Each Treatment Group on RBP-
6000 Following the Proposed Design of the Current Study 
 
The blue line represents the median model prediction; the yellow areas represent the 5th and the 95th 
percentiles of the predictions; µ-ORO: mu opioid receptor occupancy; wks: weeks. 
The PK parameters calculated from the simulated typical PK profile of buprenorphine are listed 
in Table 1.  Average buprenorphine plasma concentration (Cavg) over the monthly dosing interval 
was 1.9 ng/mL after the first SC injection at 300 mg, and 3.1 ng/mL after the second SC 
injection at 300 mg.  
For the subjects receiving 6 monthly SC injections of RBP-6000 at 300 mg, the predicted Cavg 
value after the 4th SC injection was 5.1 ng/mL, which is close to mean value of 4.8 ng/mL 
observed in the multiple-ascending dose study.  The predicted Cavg value after the 6th SC 
injection was 6.0 ng/mL.  For the patients receiving 2 monthly SC injections at 300 mg followed 
by 4 monthly SC injections at 100 mg, the predicted Cavg after the 6th SC injection was 
2.6 ng/mL.  All these values were above the 2 ng/mL threshold for achieving the desired 
efficacy. 
Overall, the modeling and simulation work and the opioid blockade study have shown that the 
300 mg SC dose is an appropriate dose to assess for efficacy. The current study will therefore 
evaluate the long-term safety and tolerability of this dose. It is recognized, however, that some 
individuals may need lower doses based on genetic variations, abuse behavior, etc. Accordingly, 
subsequent doses of RBP-6000 may be adjusted down to 100 mg and back up to 300 mg based 
on the medical judgment of the Investigator. 
 


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Table 1 
PK Parameters of the Simulated Typical PK Profile of Buprenorphine after Repeated RBP-6000 
Injections for the Phase 3 Efficacy Study (RB-US-13-0001) 
Buprenorphine 
(ng/mL) 
SC Injection Number 
1 
2 
3 
4 
5 
6 
 
Cmax 
Cavg 
Cmax Ctrough Cavg 
Cmax 
Ctrough 
Cavg 
Cmax 
Ctrough 
Cavg 
Cmax 
Ctrough 
Cavg 
Cmax 
Ctrough 
Cavg 
300mgx2 + 
100mgx4 
2.9 
1.9 
4.2 
1.3 
3.1 
3.5 
2.5 
3.0 
3.6 
2.6 
3.0 
3.5 
2.5 
2.8 
3.2 
2.3 
2.6 
300mgx2 + 
300mgx4 
2.9 
1.9 
4.2 
1.3 
3.1 
5.4 
2.5 
4.3 
6.4 
3.5 
5.1 
7.1 
4.2 
5.7 
7.5 
4.6 
6.0 
Cmax: maximum plasma concentration; Cavg : average plasma concentration; Ctrough: plasma concentration at trough (ie, before the next injection). 
 
 


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1.6 
Known and Potential Risks and Benefits 
The AE profile of buprenorphine is well-characterized; commonly reported effects include 
constipation, nausea, vomiting, and headache.  Buprenorphine is approved for use by various 
routes of administration (e.g., SL, intramuscular [IM], intravenous [IV], transdermal, and rectal). 
Studies of buprenorphine receptor binding in human subjects have consistently and reproducibly 
established that buprenorphine is a highly lipophilic, mu-opioid receptor partial agonist with 
slow receptor association and dissociation kinetics.  Buprenorphine has an improved safety 
profile relative to mu-opioid receptor full agonists due to its partial agonist properties.  These 
attributes of buprenorphine allow it to perform well as substitution therapy for opioid-dependent 
individuals over short-term and long-term durations.  The experiments used to establish the 
binding profile of buprenorphine were consistent across differing parenteral routes of 
administration (IV, IM, and SL); therefore, RBP-6000 is expected to perform similarly when 
administered as a SC depot in the ATRIGEL Delivery System. 
The efficacy of buprenorphine in the treatment of opioid dependence has been well established 
(see for example, New Drug Applications 20-732; 20-733; 22-410).  Buprenorphine has been 
used for medically-supervised taper (i.e., detoxification) medication and as a long-term 
medication assisted therapy (i.e., maintenance).  A recent Cochrane Review meta-analysis 
revealed that buprenorphine is statistically significantly superior to placebo in the retention of 
subjects and reduction of opioid-positive urine tests, and that buprenorphine and methadone may 
be equally efficacious at adequate dose levels of both medications (Mattick 2008). 
A sustained-release formulation of buprenorphine using the ATRIGEL Delivery System offers a 
number of potential benefits relative to shorter-acting formulations, including improved subject 
compliance, reduced diversion and misuse, as well as a reduced risk to subjects, their families, 
and the community.  


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2 
STUDY OBJECTIVES 
Indivior Inc., formerly Reckitt Benckiser Pharmaceuticals Inc. (RBP), is developing RBP-6000, 
a long-acting formulation of buprenorphine for monthly SC administration, for the treatment of 
opioid use disorder.   
2.1 
Primary Objective 
To assess the long-term safety and tolerability of RBP-6000 subcutaneous (SC) injections in 
subjects with opioid use disorder. 
2.2 
Secondary Objectives 
To collect clinical outcome data with RBP-6000 SC injections in subjects with opioid use 
disorder. 
2.3 
Tertiary Objectives 
To evaluate the: 
• PK of RBP-6000,  
• Relationship between RBP-6000 PK and clinical outcome data, and 
• Impact of RBP-6000 on health and economic outcomes. 


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a multicenter, open-label, long-term safety study in which approximately 600 subjects 
diagnosed with opioid use disorder will be enrolled (approximately 300 subjects who did not 
participate in the RB-US-13-0001 study [hereafter referred to as “de novo” subjects] and 
approximately 300 subjects that completed the RB-US-13-0001 study [hereafter referred to as 
“roll-over” subjects]).  Subject participation will be based on the Investigator’s determination 
that initiation or continuation of study treatment is appropriate; and, that among subjects who are 
continuing from the RB-US-13-0001 study, there have been no significant protocol deviations or 
clinically relevant AEs that would preclude inclusion of the subject in this study. All subjects 
will need to provide written informed consent before any protocol-related procedures commence. 
At the Screening Visit (which is up to 3 days after the End of Study [EOS] Visit (Day 169 + 3]), 
for roll-over subjects), potential subjects will be reviewed for eligibility against inclusion and 
exclusion criteria, and eligible subjects will be enrolled into the trial.  
Before receiving the first injection of RBP-6000 in this safety study, all subjects will undergo a 
Run-In period with SUBOXONE® (buprenorphine/naloxone) sublingual film to avoid 
precipitating a withdrawal syndrome and to preserve the blind in subjects treated with placebo in 
the RB-US-13-0001 study. Subjects will be inducted onto SUBOXONE sublingual film 
consistent with the SUBOXONE sublingual film label; they will then complete a 1 to 11 day 
SUBOXONE sublingual film Dose Adjustment period (Section 5.2.1). SUBOXONE dose 
adjustments will be made based on COWS scores as well as physician judgment (Section 5.2.2).   
Once subjects meet the criteria (on Day -11 to Day -1) of no significant opioid craving (≤20 mm 
on the Opioid Craving Visual Analog Scale [VAS] and no significant withdrawal (≤ 12 on the 
Clinical Opiate Withdrawal Scale [COWS]) they may receive the first SC injection of RBP-6000 
(containing 300 mg buprenorphine). Subjects with significant withdrawal signs/symptoms 
(defined as >12 on the COWS) or significant cravings for opioids (defined as >20 mm on the 
Opioid Craving VAS) after the end of the 2-week SUBOXONE sublingual film Run-In period 
will not be eligible to continue in the study and will be referred for treatment.   
On Day 1 of the study (initiation of study drug injections), all subjects will receive a SC injection 
of 300 mg of buprenorphine in RBP-6000. Subsequent doses of RBP-6000 may be adjusted 
down to 100 mg and back up to 300 mg based on the medical judgment of the Investigator. After 
injection of RBP-6000, subjects will not be permitted to receive supplemental SUBOXONE 
sublingual film during the RBP-6000 treatment period. Subjects who require supplemental 
SUBOXONE sublingual film or other sublingual buprenorphine pharmacotherapy during the 
RBP-6000 treatment period will be withdrawn from the study and referred for appropriate 
treatment. 
Subjects will return to the clinic for monthly injection visits (every 28 - 2/+ 4 days) for a total of 
up to 12 injections for de novo subjects or for a total of 6 injections for roll-over subjects. ECG 
recordings and vital signs will be collected pre and post each SC injection. All ECGs will be 
interpreted by a central monitoring facility.  Subject-reported injection site pain Visual Analog 


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Scale scores (VAS) will be collected at various times up to 1 hour after each injection. Local 
injection site grading will be collected at various time points starting immediately after injection 
and will be evaluated for pain, tenderness, warmth, itching, erythema, inflammation or swelling, 
and bruising using a 4-point severity scale. At each visit after injections begin, the injection site 
will be assessed by site staff and will also be evaluated for evidence of attempts to remove the 
depot.  
Subjects will need to return to the clinic weekly for the first 5 weeks and biweekly (i.e., every 2 
weeks) until injection 6, and monthly for the rest of the study period for urine drug screens 
(UDS), Timeline Followback (TLFB) interviews, opioid craving VAS evaluation, COWS and 
subject reported outcomes (Subjective Opiate Withdrawal Scale [SOWS]). Subjects will 
continue to receive counseling (manual-guided behavioral therapy) during the study.  
Safety assessments will be collected at each visit and will include the following:  vital signs, 
electronic Columbia Suicide Severity Rating Scale (eC-SSRS) responses, ECGs, laboratory tests 
(hematology, chemistry, urinalysis, and pregnancy test), concomitant medications, and AEs.   
Sparse PK blood samples will be collected for population PK analysis for the roll-over subjects 
only. Once at least 75 roll-over subjects have completed Injection 6 (Week 25, Day 169) the sites 
will be notified that no more PK samples will be required to be collected from the roll-over 
subjects for the duration of the study. PK samples will not be collected for the de novo subjects. 
However, for all subjects (de novo and roll-over) throughout the study, a PK sample will be 
taken as soon as possible after any SAE is reported. If possible, an additional sample should be 
collected when the SAE has been resolved. ECGs will be performed before PK sample 
collection. The following depression, pain, and health economic outcome assessments will also 
be collected: Beck Depression Inventory (BDI-II), brief pain inventory (BPI), EuroQol EQ-5D-
5L (EQ-5D-5L), 36-Item Short Form Health Survey, Version 2 (SF-36v2), Medication 
Satisfaction Questionnaire (MSQ), healthcare resource utilization (HCRU), Treatment 
Effectiveness Assessment (TEA) and Addiction Severity Index Lite (ASI-Lite). 
Approximately 2 months prior to the scheduled EOS visit, the subject’s ongoing treatment 
options will be reviewed with the investigator. At the EOS, 2 transition treatment options may be 
offered if the subject is eligible: 
• Subjects who complete the RBP-6000 treatment period may be offered entry into an open 
label extension study of RBP-6000 (Study INDV-6000-301).  Eligibility will be based on 
meeting the inclusion and exclusion criteria and the medical judgment of the Investigator. 
• Subjects who do not meet the eligibility criteria of the extension study, or subjects who 
do not wish to enroll may alternatively enter a 4-week SUBOXONE transition period if 
deemed suitable by the investigator.  Subjects should be dosed using the Investigators 
medical judgement. Any additional unscheduled visits required by the subject for the 
SUBOXONE transition will not be compensated by the Sponsor.   


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Subjects that have not enrolled onto the INDV-6000-301 should be contacted by telephone 
approximately 4 weeks after EOS for a safety follow-up assessment of AEs and use of 
concomitant medications.   
A schematic depicting the study design for de novo subjects is in Figure 2 and a schematic for 
roll-over subjects is in Figure 3.  A complete list of procedures and assessments for subjects is in 
the Schedule of Events (SOE) in Appendix 1, Appendix 2, Appendix 3, Appendix 4, and 
Appendix 5. 


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Figure 2 
Study Overview:  De novo Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Injection No. 7 (Week 25/Day 169) 
Injection No. 8 (Week 29/Day 197)  
Injection No. 9 (Week 33/Day 225)  
 
Injection No. 10 (Week 37/Day 253)  
Injection No. 11 (Week 41/Day 281)  
Injection No. 12 (Week 45/Day 309)  
End of Study Visit (Week 49 / Day 337) 
Safety Follow up Telephone Call (Week 53 / Day 365) 
Injection No. 1 (Week 1/Day 1)  
 Followed by weekly assessment visits 
Injection No. 2 (Week 5/Day 29)  
Followed by biweekly assessment visits 
Injection No. 3 (Week 9/Day 57)  
Followed by biweekly assessment visits 
Injection No. 4 (Week 13/Day 85)  
Followed by biweekly assessment visits
Injection No. 5 (Week 17/Day 113)  
Followed by biweekly assessment visits 
Injection No. 6 (Week 21/Day 141)  
SUBOXONE Sublingual Film Run-In 
• 
Induction (3 days) 
Subjects complete daily visits on Day -14 to Day -12  
• 
Dose Adjustment (1-11 days) 
Subjects complete visits on Day -11, Day -8, Day -4, and Day -1 (all visits not required) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Early 
Termin
ation 
Subjects 
return 
to clinic 
for this 
visit 
Screening  
(Day -21 to Day -15)  
 


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Figure 3 
Study Overview:  Roll-over Subjects from RB-US-13-0001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Injection No. 1 (Week 1/Day 1) 
 Followed by weekly assessment visits 
Injection No. 2 (Week 5/Day 29)  
Followed by biweekly assessment visits 
Injection No. 3 (Week 9/Day 57)  
Followed by biweekly assessment visits 
Injection No. 4 (Week 13/Day 85)  
Followed by biweekly assessment visits 
Injection No. 5 (Week 17/Day 113)  
Followed by biweekly assessment visits 
Injection No. 6 (Week 21/Day 141)  
SUBOXONE Sublingual Film Run-In 
• 
Induction (3 days) 
Subjects complete daily visits on Day -14 to Day -12  
• 
Dose Adjustment (1-11 days) 
Subjects complete visits on Day -11, Day -8, Day -4, and Day -1 (all visits not required) 
End of Study Visit (Week 25 / Day 169) 
Safety Follow Up Telephone Call (Week 29 / Day 197) 
 
 
 
 
 
 
 
Early 
Termin
ation 
Subjects 
return to 
clinic 
for this 
visit 
Screening  
(Days -21 to -15 [Up to 3 days after EOS Visit/Day169 + 3 for Subject’s Completing  
Study RB-US-13-0001])  
Note: RB-US-13-0001 assessments completed at EOS/Day 169 will serve as screening 
assessments  


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3.2 
Rationale for Study Design 
This study is designed to assess the long-term safety, tolerability, and clinical outcomes of  
RBP-6000 SC injections in subjects with opioid use disorder.  The planned number of subjects 
was designed to ensure at least 100 subjects reach 1 year of treatment with RBP-6000 (as advised 
in the ICH-E1A Guideline - The Extent of Population Exposure to Assess Clinical Safety: For 
Drugs Intended for Long-term Treatment of Non-Life-Threatening Conditions).  The safety 
assessments used include evaluations of AEs, serious AEs (SAEs), discontinuations from study 
due to AEs; local injection site tolerability (e.g., injection site grading); injection site pain using a 
subject-reported VAS; suicidality using the eC-SSRS, concomitant medications; changes in 
clinical laboratory results; vital sign measurements; 12-lead ECGs, and physical examination 
results.  The instruments used to measure clinical outcomes (e.g., COWS, SOWS, Opioid 
Craving VAS, and eC-SSRS) were developed to measure the specific symptoms exhibited by 
and the challenges facing opioid-dependent individuals.   
3.3 
Study Duration and Dates 
The expected maximum duration of participation for de novo subjects is up to approximately 55 
weeks consisting of up to a 7-day screening period, up to a 14-day SUBOXONE sublingual film 
Run-In, up to a 48-week open-label treatment period, and a 4-week safety follow-up telephone 
call. 
The expected maximum duration of participation for roll-over subjects is up to approximately 31 
weeks, consisting of up to a 7-day screening period, up to a 14-day SUBOXONE sublingual film 
Run-In, a 24-week open-label treatment period, and a 4-week safety follow-up telephone call.  
Subjects who enroll in the INDV-6000-301 study at the EOS visit are not required to be 
contacted with a safety follow-up telephone call. 
Subjects who receive at least 1 dose of RBP-6000 and discontinue the trial for any reason will be 
required to complete the Early Termination (ET) visit. 
If a sufficient number of subjects reach 1 year of exposure to RBP-6000, the study may be 
stopped early, and all remaining subjects will complete EOS procedures. 
 


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4 
STUDY POPULATION SELECTION 
4.1 
Study Population 
Approximately 300 de novo subjects will be enrolled into this study as well as approximately 
300 roll-over subjects. The study population will consist of individuals diagnosed with opioid 
use disorder who are seeking treatment.  
4.2 
Inclusion Criteria 
A. De novo Subjects: Subjects who have not participated in Study RB-US-13-0001 must meet 
the following criteria to be enrolled in this study: 
1. Subjects seeking treatment for opioid use disorder who currently, and by medical history 
over the previous 3 months, meet the DSM-5 criteria for moderate or severe opioid use 
disorder.  
2. Subjects who provide written informed consent to participate in this study. 
3. Subjects who are an appropriate candidate for opioid partial-agonist treatment in the 
opinion of the Investigator or medically responsible physician. 
4. Either male or female. 
5. Age ≥ 18 to ≤ 65 years. 
6. Have a body mass index (BMI) of ≥ 18.0 to ≤ 35.0 kg/m2. 
7. Females: Women of childbearing potential (defined as all women who are not surgically 
sterile or postmenopausal for at least 1 year prior to informed consent), must have a 
negative pregnancy test prior to enrollment and must agree to use a medically acceptable 
means of contraception from screening through at least 6 months after the last dose of 
investigational medicinal product (IMP). 
Males: Subjects with female partners of child-bearing potential must agree to use 
medically acceptable contraception after signing the informed consent form (ICF) 
through at least 6 months after the last dose of IMP. Male subjects must also agree not to 
donate sperm during the study and for 6 months after receiving the last dose of IMP. 
The following methods of contraception are considered to be medically acceptable: 
established use of oral, injected or implanted hormonal contraception; placement of an 
intrauterine device or intrauterine system; use of a double-barrier method of 
contraception (condom or occlusive cap with use of a spermicide) or male sterilization.   
8. Subjects must agree not to take any buprenorphine products other than those administered 
during the current study throughout participation in the study. 
9. Subjects must be willing to adhere to study procedures. 
 
B. Roll-Over Subjects: Subjects who have successfully completed Study RB-US-13-0001 in its 
entirety must complete EOS/Day 169 assessments, which will serve as screening for this 
study. In addition, only the following criteria must be met to be enrolled in this study: 
1. Provide written consent to participate in this study. 
2. Be considered eligible in the medical judgment of the Investigator. 


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3. Females: Women of childbearing potential (defined as all women who are not surgically 
sterile or postmenopausal for at least 1 year prior to informed consent) must have a negative 
pregnancy test prior to enrollment and must agree to use a medically acceptable means of 
contraception from screening through at least 6 months after the last dose of IMP. 
Males: Subjects with female partners of child-bearing potential must agree to use medically 
acceptable contraception after signing the ICF through at least 6 months after the last dose of 
IMP. Male subjects must also agree not to donate sperm during the study and for 6 months 
after receiving the last dose of IMP. 
The following methods of contraception are considered to be medically acceptable:  
established use of oral, injected or implanted hormonal contraception; placement of an 
intrauterine device or intrauterine system; use of a double-barrier method of contraception 
(condom or occlusive cap with use of a spermicide) or male sterilization.   
4. Subjects must agree not to take any buprenorphine products other than those administered 
during the current study throughout participation in the study. 
5. Subjects must be willing to adhere to study procedures. 
 
4.3 
Exclusion Criteria 
A. De novo Subjects who meet any of the following criteria will be excluded from the study: 
1. Current diagnosis, other than opioid use disorder, requiring chronic opioid treatment. 
2. Current substance use disorder, as defined by DSM-5 criteria, with regard to any 
substances other than opioids, cocaine, cannabis, tobacco, or alcohol. 
3. Positive UDS result at screening for cocaine or cannabis AND meets DSM-5 criteria for 
either moderate or severe cocaine or cannabis use disorder, respectively. 
4. Meets DSM-5 criteria for moderate or severe alcohol use disorder. 
5. Treatment for opioid use disorder required by court order.   
6. Current incarceration or pending incarceration/legal action that could interfere with a 
subject’s ability to participate in the study. 
7. Pregnant or lactating females. 
8. Current use of prescription or OTC medications that are clinically relevant cytochrome 
P450 3A4 or cytochrome P450 2C8 inducers or inhibitors (e.g., rifampicin, azole 
antifungals [e.g., ketoconazole], macrolide antibiotics [e.g., erythromycin]) with the 
exception of marijuana.  More examples are provided in the excluded medications list 
(Appendix 9). 
9. History of suicidal ideation within 30 days prior to providing written informed consent as 
evidenced by answering “yes’ to questions 4 or 5 on the suicidal ideation portion of the 
eC-SSRS completed at the screening visit or history of a suicide attempt (per the eC-
SSRS) in the 6 months prior to informed consent. 
10. Current or history (within the 6 months prior to providing written informed consent) of 
chest pain or palpitation with either exertion or drug use, peripheral or generalized 
edema, clinically significant cardiovascular disease, including myocardial infarction, 
heart failure, uncontrolled hypertension, clinically significant orthostatic hypotension, 
endocarditis, or myocarditis.  
11. Clinically significant abnormal systolic blood pressure (BP) or diastolic BP, in the 
opinion of the Investigator. 


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12. Uncontrolled medical or psychiatric illness that, in the opinion of the Investigator or 
Sponsor, may place the subject at risk or interfere with outcome measures or a subject’s 
ability to participate in the study. 
13. Clinically significant abnormality (e.g., severe respiratory insufficiency) in past medical 
history or at the screening physical examination that, in the opinion of the Investigator or 
Sponsor, may place the subject at risk or interfere with outcome variables.   
14. History or presence of allergic or adverse response (including rash or anaphylaxis) to 
buprenorphine, naloxone, or the ATRIGEL Delivery System. 
15. Total bilirubin ≥ 1.5x the upper limit of normal (ULN), alanine aminotransferase (ALT) 
≥3xULN, aspartate aminotransferase (AST) ≥ 3xULN, serum creatinine > 2xULN, 
international normalized ratio (INR) >1.5xULN, lipase >3xULN, amylase >3xULN, or 
any abnormal pancreatic enzyme value above ULN that is associated with clinically 
significant, active pancreatic disorder. 
16. Congenital long QT syndrome, history of prolonged QT in the 3 months prior to 
screening, or a corrected QT interval (Fridericia’s – QTcF) >450 msec (male) or >470 
msec (female) or history of risk factors for Torsades de Pointes. 
17. Diagnosis of acquired immunodeficiency syndrome (AIDS). 
18. Affiliated with, or a family member of, site staff directly involved in the study. 
19. Unable, in the opinion of the Investigator or the medically responsible physician, to 
comply fully with the study requirements.   
20. Clinically significant anemia or low hemoglobin (levels < 9 g/dL) at Screening.  
21. Donation of > 250 mL of blood or plasma within the 30 days prior to providing written 
informed consent  
22. Participation in any other clinical trial within 30 days prior to informed consent  
23. Received medication-assisted treatment for opioid use disorder (e.g., methadone, 
buprenorphine) in the 90 days prior to providing written informed consent  
24. Previously received RBP-6000. 
25. Use of (within the past 30 days prior to providing written informed consent) or positive 
UDS result at screening for barbiturates, benzodiazepines, or methadone.  
 
B. Roll-Over Subjects who meet any of the following criteria will be excluded from the study: 
1. Discontinued early from Study RB-US-13-0001 
2. Experienced any major protocol deviations or adverse events during the RB-US-13-0001 
study which, in the opinion of the Investigator, could potentially compromise subject 
safety. 
3. Women of childbearing potential who have a positive pregnancy test at EOS/Day 169, 
who are pregnant or breastfeeding, seeking pregnancy, or failing to use adequate 
contraceptive methods during the study. 
 


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4.4 
Day -1/Enrollment Criteria 
Beginning on the 4th day of SUBOXONE sublingual film dosing (Study Day -11) through the 
14th day of dosing, subjects will be evaluated for Day -1 criteria.  Subjects must meet the 
following criteria in order to be enrolled: 
1. No allergic reaction to SUBOXONE sublingual film. 
2. Daily dose of SUBOXONE sublingual film between 8 mg/2 mg - 24 mg/6 mg (inclusive) 
buprenorphine/naloxone. 
3. COWS score of ≤ 12. 
4. Opioid Craving VAS score of ≤ 20 mm. 
 


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5 
STUDY TREATMENTS 
5.1 
Description of Treatments 
5.1.1 
SUBOXONE Sublingual Film 
SUBOXONE sublingual film is supplied as an orange rectangular sublingual film with a white 
printed logo.  Each SUBOXONE sublingual film contains buprenorphine HCl and naloxone HCl 
dihydrate at a 4:1 ratio expressed as the free bases.  Films are intended for SL administration and 
are available in 4 dosage strengths (2 mg/0.5 mg; 4 mg/1 mg; 8 mg/2 mg; and 12 mg/3 mg).   
5.1.2 
Investigational Medicinal Products 
RBP-6000 uses buprenorphine base in the ATRIGEL Delivery System, which is currently used 
in a number of approved commercial products.  RBP-6000 will be supplied as a single-syringe 
system, which is prefilled with RBP-6000.  The entire contents of the prefilled syringe will be 
administered.  (See Appendix 8: Study Drug Preparation and Dispensing Procedures for detailed 
dosage instructions).   
RBP-6000 is manufactured by Indivior Inc. according to Good Manufacturing Practice 
standards. 
All used syringes components will be disposed of in accordance with the site’s standard 
operating procedures (SOP) or pharmacy destruction policy. The site’s clinical research associate 
(CRA) will review the site’s SOP and/or pharmacy destruction policy.  All IMP packaging will 
be retained for CRA verification. 
5.2 
Treatments Administered 
5.2.1 
Run-In Treatment Period 
5.2.1.1 
SUBOXONE Sublingual Film Induction (De novo Subjects) 
De novo subjects will receive their first dose of SUBOXONE sublingual film on Induction 
Day 1.  Subjects will be started with an initial dose of 2 mg/0.5 mg or 4 mg/1 mg and may titrate 
upwards in 2 or 4 mg increments of buprenorphine, at approximately 2-hour intervals, under 
clinical supervision, to 8 mg/2 mg based on therapeutic response.  
On Induction Day 2, subjects with a COWS score > 12, or subjects reporting withdrawal 
signs/symptoms overnight, will receive a dose of SUBOXONE sublingual film equal to the total 
dose given on Induction Day 1 plus 4 mg. (For example, if a subject received a total dose of 8 
mg on Induction Day 1, the starting dose of buprenorphine for Induction Day 2 would be 12 mg).  
If the COWS score is still > 12 one hour later, another 4 mg dose can be given. The subject 
should not exceed a maximum dose of 16 mg/4 mg for Induction Day 2. Subsequent 
SUBOXONE sublingual film doses must be separated by at least 1 hour from the preceding dose. 
SUBOXONE sublingual film doses may also be adjusted downward if necessary.  


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On Induction Day 3, subjects will be titrated to therapeutic response based on COWS scores as 
well as physician judgment. Most subjects will only require a single dose on Induction Day 3 
which will equal the Induction Day 2 dose or the Induction Day 2 dose plus 4 mg buprenorphine. 
Additional doses may also be administered on Induction Day 3 (up to 24 mg). Subsequent 
SUBOXONE sublingual film doses must be separated by at least 1 hour from the preceding dose.  
Subjects should reach a daily dose of between 8 mg/2 mg and 24 mg/6 mg by Induction Day 3 
and continue on that dose through the remainder of the SUBOXONE sublingual film Run-In 
period, with additional dose adjustments if necessary.  
The SUBOXONE sublingual film(s) will be administered under the tongue, close to the base on 
the left or right side, until they are dissolved.  If an additional sublingual film is required, it 
should be placed on the opposite side from the first film.  Subjects should be instructed to hold 
the films under the tongue until they dissolve.  If a third film is required, it should be placed 
under the tongue after the first 2 films have dissolved.   
For more information about SUBOXONE sublingual film administration, please refer to the 
SUBOXONE Full Prescribing Information (See Appendix 7). 
5.2.1.2 
SUBOXONE Sublingual Film Induction (Roll-over Subjects) 
Following screening, roll-over subjects will be inducted on SUBOXONE sublingual film to 
achieve daily doses between 8 mg to 24 mg buprenorphine according to the SUBOXONE 
sublingual film prescribing instructions. Roll-over subjects may start their SUBOXONE run in 
on the same day that they complete the RB-US-13-0001 EOS visit (and up to 7 days after this 
date) provided they meet the appropriate inclusion criteria and do not meet any exclusion 
criteria. Subjects must be titrated to a minimum dose of 8 mg SUBOXONE by the end of the 3-
day Induction period regardless of their COWS scores and/or the presence or absence of 
withdrawal symptoms.   
Subjects will receive their first induction dose on Induction Day 1. Subjects should be started 
with an initial dose of 2 mg/0.5 mg or 4 mg/1 mg buprenorphine/naloxone and may titrate 
upwards in 2 or 4 mg increments of buprenorphine, at approximately 2-hour intervals, under 
supervision, to a total dose of up to 8 mg/2 mg buprenorphine/naloxone based on the control of 
acute withdrawal symptoms.  
On Induction Day 2, subjects with a score for COWS of > 12, or subjects reporting opioid 
withdrawal signs/symptoms overnight, should receive a dose of study drug equal to the total dose 
given on Induction Day 1 plus 4 mg.  If the COWS score is still > 12 one hour later, another 4 
mg dose can be given.  The subject should not exceed a maximum dose of 16 mg/4 mg 
buprenorphine/naloxone for Induction Day 2.  Subsequent SUBOXONE sublingual film doses 
must be separated by at least 1 hour from the preceding dose.  SUBOXONE sublingual film 
doses may also be adjusted downward if necessary.   
 
On Induction Day 3, subjects will be titrated to therapeutic response until a therapeutic dosage is 
reached, based on COWS scores as well as physician judgment. Most subjects will only require a 
single dose on Induction Day 3 which will equal the Induction Day 2 dose or the Induction Day 2 
dose plus 4 mg. Additional doses may also be administered on Induction Day 3 (up to 24 mg).  


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Subsequent SUBOXONE sublingual film doses must be separated by at least 1 hour from the 
preceding dose.  Although subjects should reach a daily dose of between 8 mg and 24 mg by 
Induction Day 3 and continue on that dose through the remainder of the SUBOXONE sublingual 
film Run-In period, dose adjustments may be necessary during the Run-In period.  
The SUBOXONE sublingual film(s) will be administered under the tongue, close to the base on 
the left or right side, until they are dissolved.  If an additional sublingual film is required, it 
should be placed on the opposite side from the first film.  Subjects should be instructed to hold 
the films under the tongue until they dissolve.  If a third film is required, it should be placed 
under the tongue after the first 2 films have dissolved.   
For more information about SUBOXONE sublingual film administration, please refer to the 
SUBOXONE Full Prescribing Information (See Appendix 7). 
5.2.2 
Dose Adjustment Period (All Subjects) 
Beginning at Day -11, subjects will be assessed to determine whether they meet Day -1 
/enrollment criteria as defined in Section 4.4.  Once subjects meet the enrollment criteria (no 
significant opioid craving (≤20 mm on the Opioid Craving Visual Analog Scale [VAS] and no 
significant withdrawal (≤ 12 on the Clinical Opiate Withdrawal Scale [COWS]), they are eligible 
to receive the first SC injection of RBP-6000 (containing 300 mg buprenorphine). Subjects with 
significant withdrawal signs/symptoms (defined as >12 on the COWS) or significant cravings for 
opioids (defined as >20 mm on the Opioid Craving VAS) after the end of the 2-week 
SUBOXONE sublingual film Run-In period will not be eligible to continue in the study and will 
be referred for treatment.   
5.2.3 Active Study Treatment 
On Day 1 of the study (initiation of study drug injections), all subjects will receive a SC injection 
of 300 mg of buprenorphine in RBP-6000. Subsequent doses of RBP-6000 may be adjusted 
down to 100 mg and back up to 300 mg based on the medical judgment of the Investigator.   All 
subjects will receive injections of RBP-6000 separated by 28 (- 2/+ 4) days.   
After injection of RBP-6000, subjects will not be permitted to receive supplemental 
SUBOXONE sublingual film during the RBP-6000 treatment period. Subjects who require 
supplemental SUBOXONE sublingual film or other sublingual buprenorphine pharmacotherapy 
during the RBP-6000 treatment period will be withdrawn from the study and referred for 
appropriate treatment. 
A single SC dose will be injected by an individual who is medically qualified to perform the 
procedure and delegated by the Principal Investigator to perform the task.  Injections of 
RBP-6000 will be administered in the abdominal area below the waist but above the hip bone; 
more specifically, injection should occur in the region where the body curves at the side to about 
2 inches from the middle of the abdomen with adequate amounts of subcutaneous tissue that 
does not have excessive pigment, nodules, lesions, or hair.  RBP-6000 will form a solid polymer 
depot that contains the buprenorphine.  As the depot degrades, buprenorphine will be released 


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into the systemic circulation at a consistent rate over an approximately 28-day period.  For 
detailed instructions on use, see Appendix 8. 
Approximately 2 months prior to the scheduled EOS visit, the subject’s ongoing treatment 
options will be reviewed with the investigator. At the EOS, 2 transition treatment options may be 
offered if the subject is eligible: 
• Subjects who complete the RBP-6000 treatment period may be offered entry into an open 
label extension study of RBP-6000 (Study INDV-6000-301).  Eligibility will be based on 
meeting the inclusion and exclusion criteria and the medical judgment of the Investigator. 
• Subjects who do not meet the eligibility criteria of the extension study, or subjects who 
do not wish to enroll may alternatively enter a 4-week SUBOXONE transition period if 
deemed suitable by the investigator.  Subjects should be dosed using the Investigators 
medical judgement. Any additional unscheduled visits required by the subject for the 
SUBOXONE transition will not be compensated by the Sponsor.   
5.3 
Selection and Timing of Dose for Each Subject 
The study schedule is designed so that each of the injections will be separated by a minimum of 
26 days and a maximum of 32 days (28 days - 2/+ 4 days) and will be given on alternate sides of 
the subject’s abdomen (see Appendix 8 and the Pharmacy Manual for detailed information on 
administration).   
5.4 
Method of Assigning Subjects to Treatment Groups 
When a de novo or roll-over subject signs the ICF, she/he will be assigned a unique subject 
number in numerical sequence, which will be used for the duration of the study. Roll-over 
subjects will retain the subject number assigned to them in the RB-US-13-0001 study. De novo 
subjects will be assigned a unique subject number, consisting of the site number followed by 9 
and a 3 digit number in numerical sequence (e.g., the first de novo subject screened at site # 001 
will be assigned the number 0019001).  The subject number will be recorded in the source 
document and electronic case report form (eCRF). 
All subjects will be assigned to receive the 300 mg RBP-6000 dose. Subsequent doses of 
RBP-6000 may be adjusted down to 100 mg and back up to 300 mg based on the medical 
judgment of the Investigator 
5.5 
Blinding 
Not applicable; this is an open-label study  
 
5.6 
Concomitant Therapy 
Concomitant therapies are defined as prescribed medications and OTC preparations, including 
herbal preparations and vitamins, other than study medication and supplementary medication that 
the subject receives within 30 days of screening and for the during the course of the study.  


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Concomitant medications that are ongoing at the time a subject rolls-over from the RB-US-13-
0001 study will be recorded in the eCRF. Any medication taken by the subject is to be reported 
by the subject and noted on the subject’s source document and concomitant medication page.  
Any changes in concomitant therapy during the study will be documented, including cessation of 
therapy, initiation of therapy, and dose changes.  
Roll-over subjects who started on a benzodiazepine during the RB-US-13-0001 study will be 
evaluated on a case-by-case basis for inclusion in the RB-US-13-0003 study.  The investigator 
will discuss these subjects with the medical monitor before enrolling into the RB-US-13-0003 
study. 
The Investigator or designee will also record any medications given for the treatment of AEs on 
the concomitant medication page.   
5.6.1 
Permitted Concomitant Medications 
Following screening and enrollment, ancillary medications (ibuprofen, acetaminophen, 
methocarbamol, hydroxyzine, and loperamide) may be administered to subjects to help alleviate 
signs and symptoms of opioid withdrawal as deemed necessary by the Investigator or medically 
qualified sub-investigator.  Details on acceptable administration of these medications and 
preparations are provided below: 
• Ibuprofen (400 mg orally) may be given every 4 to 6 hours as needed for pain up to a 
maximum of 2400 mg per day.  Subjects for whom ibuprofen is contraindicated or not 
tolerated may be given acetaminophen (325 to 1000 mg every 4 to 6 hours) as needed up 
to a maximum of 3000 mg per day.  Caution should be exercised when using 
acetaminophen concomitantly with other medications that have potential hepatotoxic 
effects.  Methocarbamol may also be given as needed for relief of muscle pain in 
clinically appropriate doses based on physician assessment. 
• Hydroxyzine (50 to 100 mg orally) may be given every 6 hours as needed for anxiety, 
nausea, or vomiting.  Additionally, hydroxyzine (50 to 100 mg orally) may be given at 
bedtime as needed for sleep.  The hydroxyzine daily dose should not exceed a maximum 
of 600 mg per day. 
• Loperamide (2 to 4 mg orally) may be given as needed for diarrhea up to a maximum of 
16 mg per day. 
5.6.2 
Prohibited Concomitant Medications 
Concomitant therapies subject to the restrictions indicated under Prohibited Concomitant 
Medications may be used only following approval by the Sponsor unless an immediate medical 
need necessitates their use.  These are listed below:   
• Use of buprenorphine. 
• Ongoing prescription that are clinically relevant P450 3A4 inducers or inhibitors, such as 
azole antifungals (e.g., ketoconazole) and macrolide antibiotics (e.g., erythromycin). 


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• Herbal supplements that have the potential to cause prolongation of the QTc interval.   
• Over-the-counter medications that have the potential to cause prolongation of the QTc 
interval.  This does not apply to over-the-counter medications listed under Concomitant 
Therapies above that are prescribed by the Investigator, or over-the counter medications 
that may be used by the Investigator for an immediate medical need that necessitates their 
use. The medical monitor should be consulted for any questions. 
• Medications, in the addition to those listed above, which may be expected to significantly 
interfere with the metabolism or excretion of buprenorphine that may be associated with 
a significant drug interaction with buprenorphine, or may pose a significant risk to 
subjects’ participation in the study. 
Other concomitant medications, OTC preparations, or therapies that are not allowed during study 
participation are listed in Appendix 9. 
5.7 
Restrictions 
5.7.1 
Prior Therapy 
All prior medications including OTC, dietary supplements, and herbal preparations taken by the 
subject within the 30 days prior to screening will be recorded. 
5.7.2 
Subject Activity Restrictions 
Subjects should be advised to avoid strenuous exercise. 
5.8 
Protocol Compliance 
This study involves the SC injection of multiple doses of RBP-6000 containing 100 or 300 mg of 
buprenorphine (see the Schedule of Events [SOE], Appendix 2).  The Investigator may terminate 
a subject based on the subject’s inability or willingness to comply with the protocol 
requirements. 
IMP will be administered by designated and qualified study personnel at the site.  The time and 
duration, the dose delivered, and any dosing observations will be recorded in source 
documentation.  The Investigator or designated individual will maintain a log of all study drugs 
dispensed and returned (if applicable).  Drug supplies will be inventoried and accounted 
throughout the study. 
5.9 
Packaging and Labeling 
RBP-6000 will be packaged and labeled in a manner consistent with the study design and 
applicable regulations.  The study medication will be provided to the investigator(s) by the 
Sponsor or contractor.   
The SUBOXONE sublingual film will be supplied as bulk films in the following buprenorphine 
dosage strengths: 2mg /0.5 mg; 4 mg/1 mg; 8 mg/2 mg; and 12 mg/3 mg.  Containers will be 


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labeled with a single panel disclosing the product name, lot number, contents, Sponsor name and 
address, route of administration, and appropriate precautionary statements. 
The study drug, RBP-6000, will be identified as an investigational compound. 
The following components will be used in the preparation of RBP-6000: 
• One sealed foil pouch containing a syringe prefilled with RBP-6000 and an oxygen 
absorber pack. 
• One sterile 19-gauge, 1 inch hypodermic safety needle. 
5.10 Storage and Accountability 
RBP-6000 should be stored under refrigerated conditions between 2-8ºC (36-46°F). Temperature 
excursions between 8 and 25°C (46 and 77°F) are permitted for a maximum duration of 48 
hours; Temperature excursions between 2 and -20°C (-4 and 36°F) are permitted for a maximum 
duration of 7 days. Temperature excursions outside of these ranges or timeframes should be 
reported to the Sponsor immediately and approval for use should be obtained. 
 
SUBOXONE sublingual films should be stored at 25°C (77°F) with excursions permitted 
between 15-30°C (59-86°F).  Temperature excursions outside of these ranges should be reported 
to the Sponsor immediately and approval for use should be obtained. 
 
The PI or designee is responsible for ensuring that all study drug received at the site is 
inventoried and accounted for throughout the study. Drug accountability is the responsibility of 
the PI or designee, with verification by the CRA. Study drug must be handled strictly in 
accordance with the protocol, handling guidelines and the label, and must be stored in a locked, 
limited access area under appropriate environmental conditions. The PI must ensure that proper 
conditions exist for storage of study treatments. The dispensing of study drug to the subject must 
be documented on the drug dispensing form. 
 
Unused study drug must be available for verification by the Sponsor’s site monitor during on-site 
monitoring visits. The return to the Sponsor of unused study drug will be documented on the 
Study Drug Return Form. 
 
The Investigator agrees not to supply RBP-6000 to any person except study personnel for SC 
injection of subjects in this study.   
5.11 Investigational Product Retention at Study Site 
The PI or medically-qualified designee agrees to conduct a study drug supply inventory for  
RBP-6000, to record results of this inventory, and to return all unused study drug to the Sponsor 
at times specified by Indivior. Indivior will arrange for the appropriate and timely destruction of 
all returned, unused RBP-6000. All used needles and syringes from RBP-6000 will be disposed 
of into an appropriate secure biohazard container per the standard operating procedures (SOPs) 
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All used IMP packaging (e.g. carton, foil pouch) will be retained at the study site until 
reconciliation is performed by the CRA. After reconciliation is completed, the used IMP 
packaging may be disposed of per the SOPs at the study site. 


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6 
STUDY PROCEDURES 
The SOE for this study is provided in Appendix 1, Appendix 2, Appendix 3, Appendix 4, and 
Appendix 5. 
For roll-over subjects, study procedures completed at EOS/Day 169 for study RB-US-13-0001 
will serve as screening assessments for the open-label study.   
6.1 
Informed Consent 
6.1.1 
General Information 
Prior to entering the study, the Investigator or designated individual must explain to each subject 
the nature of the study, its purpose, procedures, expected duration, alternative therapies 
available, and the benefits and risks involved in study participation. Subjects must be given the 
Institutional Review Board (IRB)-approved ICF version to review and the opportunity to ask 
questions. Subjects must be informed of their right to withdraw from the study at any time 
without prejudice. The potential subjects should be able to answer simple questions about the 
study after the ICF has been reviewed and explained. After this explanation and before any 
study-specific procedures have been performed, the subject must voluntarily sign and date the 
ICF to indicate the desire to participate in the study. Prior to participation in the study, the 
subject must receive a copy of the signed and dated ICF.  
Roll-over subjects will complete all Day 169/EOS procedures for study RB-US-13-0001 prior to 
signing the ICF for this study.  
6.2 
Medical History 
For de novo subjects, a detailed medical history will be obtained by the PI or medically qualified 
designee during the screening visit (Visit 1). This will include information regarding the 
subject’s full history of medical and psychiatric conditions, diagnoses, procedures, treatments, 
concomitant medications, demographic information, and use of tobacco, drugs of abuse, alcohol, 
and caffeine, and any other noteworthy medical information, including suicidality measured 
using the eC-SSRS. Any updates to medical history information that the PI or medically 
qualified designee becomes aware of will be captured throughout the study.  All prior 
medications, OTC health, and dietary supplements taken by the subject within 30 days will be 
recorded.  In addition, hospitalizations in the past 3 months and the reason for admission 
(medical/surgical/psychiatric/other) will be recorded.   
For roll-over subjects, medical history will not be obtained again. 
6.3 
Physical Examination 
A complete physical examination (PE) will be performed by the Investigator or medically 
qualified designee.  The physical examination will consist of an examination of the following:  
general appearance, skin, head, eyes, ears, nose, throat, neck (including thyroid), lymph nodes, 
chest and lungs, heart, abdomen, extremities, body weight, and a brief neurological assessment.  


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The examination will not include a pelvic, breast, or rectal examination.  If any clinically 
significant abnormal findings started before the date that informed consent was given, these 
findings should be recorded on the Medical History case report form (eCRF).   
If any clinically significant change from screening (Visit 1 for de novo subjects; Study RB-US-
13-0001 EOS visit (Day 169) for roll-over subjects) is noted, it will be reported as an AE and 
followed up to resolution or until reaching a stable end point. 
Weight (kg) will be assessed (in ordinary indoor clothing with shoes off) and will be recorded at 
screening as well as periodically throughout the study.  Height (cm) will be recorded at screening 
only.  BMI will be calculated at screening as well as periodically throughout the study.  BMI is 
defined as the subject’s weight in kg divided by the square of the subject’s height in meters 
(kg/m2).  The amount of abdominal fat will be measured using the waist-to-hip ratio and will be 
recorded at screening as well as periodically throughout the study.   
Procedures performed at Day 169/EOS in the RB-US-13-0001 study will not be repeated at the 
screening visit for roll-over subjects. 
Assessments are performed at the time points detailed in the SOEs (Appendix 1, Appendix 2, 
Appendix 3, Appendix 4, and Appendix 5). 
6.4 
Vital Signs 
Evaluation of vital signs will be performed after the subject has been supine for ≥ 3 minutes and 
will include a measurement of systolic and diastolic BP, pulse rate, pulse oximetry, respiratory 
rate, and oral temperature.   
If clinically significant findings, as determined by the Investigator or medically qualified sub-
investigator, occur in any vital sign measurement, that measurement will be captured as an AE 
and repeated at medically appropriate intervals until the value returns to an acceptable range, a 
specific diagnosis is established, or the condition is otherwise explained. 
Assessments will be recorded in the source documents and eCRF and will be performed at the 
time points detailed in the SOE (Appendix 1, Appendix 2, Appendix 3, Appendix 4, and 
Appendix 5). 
6.5 
Electrocardiograms 
6.5.1 
12-Lead Electrocardiograms 
Resting 12-lead ECGs will be recorded with the subject in supine position following a 10-minute 
rest period. For roll-over subjects, ECGs will be recorded prior to the PK blood sampling. 
(Appendix 6). 
Resting 12-lead ECGs will be recorded as indicated in the SOEs (Appendix 1, Appendix 2, 
Appendix 3, Appendix 4, and Appendix 5). ECGs recorded at screening will be recorded in 
triplicate, at approximately 2 - 5 minute intervals.  


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ECG intervals including HR, QT, QTcF, QTcB, RR, PR, QRS and T wave changes will be 
recorded.  ECGs will be reviewed by the Investigator during the visits for any immediate 
abnormalities. ECGs will also be reviewed by a central facility.   
The findings of the ECGs as determined by the central facility will be assessed by the 
Investigator and marked as normal, abnormal-not clinically significant, or abnormal-clinically 
significant.  All clinically significant abnormalities will be captured as AEs.  In the event that a 
clinically significant AE related to an ECG assessment occurs during the study, the Investigator 
should contact the Indivior Medical Monitor. 
6.6 
Clinical Laboratory Tests 
6.6.1 
Laboratory Parameters 
All clinical laboratory assessments will be performed by a clinical laboratory accredited by the 
College of American Pathologists or with a certificate of compliance (or certificate of waiver for 
CLIA-waived tests) issued by the Center for Medicare & Medicaid Services or Clinical 
Laboratory Improvement Amendments.  The laboratory assessments will include routine and 
screening laboratory tests.   
See the SOEs in Appendix 1, Appendix 2, Appendix 3, Appendix 4, and Appendix 5 for the 
timing of the specific required laboratory tests which are listed in Table 2.  
Any abnormal hematology, chemistry, or urinalysis test result deemed clinically significant by 
the Investigator will be repeated, including test results obtained on the final study day.  For any 
test abnormality deemed clinically significant, an AE will be recorded (unless the result was 
considered erroneous) and repeat analysis will be performed until resolution or until the 
Investigator determines that resolution of the laboratory abnormality is not expected.   
Subjects will be in a seated or supine position during blood collection.  Clinical laboratory panels 
are listed in Table 2. 


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Table 2 
List of Laboratory Tests 
Hematology: 
Hematocrit 
Hemoglobin  
Mean corpuscular hemoglobin  
Mean corpuscular hemoglobin concentration  
Mean corpuscular volume  
Platelet count 
Pancreatic enzymes 
Red blood cell count 
White blood cell count with differential 
 
Urinalysis: 
Appearance 
Bilirubin 
Color 
Glucose 
Ketones 
Leucocyte esterase 
Microscopic examination of sedimenta 
Nitrite 
Occult blood 
pH 
Protein 
Specific gravity 
Urobilinogen 
 
Hormone Panel: 
Adrenocorticotropic hormone (ACTH) Follicle Stimulating 
Hormone 
Testosterone (total and free) 
 
Pregnancy: 
Urine Pregnancy (only for females not postmenopausal or 
surgically sterile for at least 1 year) 
Serum Pregnancy 
 
Screening:    
Hemoglobin A1c  
HIV-1 and -2 antibodies 
PTT 
PT with INR 
Serum pregnancy 
 
Serum Chemistry: 
Albumin 
Alkaline phosphatase 
Alanine aminotransferase (ALT) 
Amylase 
Aspartate aminotransferase (AST) 
Blood urea nitrogen 
Calcium 
Calculated creatinine clearance 
Carbon dioxide 
Chloride 
Creatinine 
Creatine kinase and subtypes 
Gamma-glutamyl transferase 
Globulin 
Glucose (non-fasting) 
High-density lipoprotein (HDL) 
Immunoreactive trypsinogen 
Lactate dehydrogenase 
Lipase 
Low-density lipoprotein (LDL) 
Magnesium 
Phosphorus 
Potassium 
Sodium 
Total bilirubin 
Direct bilirubin 
Total cholesterol 
Total protein 
Triglycerides 
Uric acid 
 
Urine Drug Screen (UDS): 
Opioidsb 
Cocaine 
Amphetamines 
Methadone 
Cannabinoids 
Barbiturates 
Benzodiazepines 
Methamphetamine 
Phencyclidine 
Anti-HIV = human immunodeficiency virus antibodies; hCG = human chorionic gonadotropin; INR = 
international normalized ratio; IRT = immunoreactive trypsinogen; PT = prothrombin time; and PTT = 
partial thromboplastin time. 
a 
Microscopic examination of sediment will be performed only if the results of the urinalysis evaluation are 
positive (microscopic examination may include but is not limited to WBC count, RBC count, casts, and crystals). 
b 
Oxycodone may not show up in all opiate assays and should be assessed separately. 
   
 


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6.6.2 
Sample Collection, Storage, and Shipping 
All blood sampling will be by individual venipuncture or with the use of a saline lock.  Blood 
and urine sample collection and processing procedures will be outlined in a separate reference 
manual to be provided to the site. 
6.6.3 
Reference Ranges 
Up-to-date reference ranges for the above investigations must be obtained for the laboratory 
performing analyses prior to the start of the study and be updated as appropriate during the 
course of the study. 
6.6.4 
Laboratory Results Review 
The Investigator will review the results and comment on the laboratory results sheet for all 
abnormal values, identifying those that are abnormal but not clinically significant as well as 
those that are significantly abnormal.  The Investigator will sign and date the laboratory results 
sheet to indicate that the review has taken place. 
Clinical Laboratory Changes:  It is the Investigator’s responsibility to review the results of all 
laboratory tests as they become available.  This review will be documented by the Investigator 
on the laboratory report.  For each abnormal laboratory test result, the Investigator needs to 
ascertain if this is a clinically significant abnormal change from baseline for that individual 
subject.  
6.7 
Pharmacokinetic Assessments 
Blood samples for population PK analysis will be collected from roll-over subjects only at the 
time points indicated in the PK sampling schedule (Appendix 6). Once at least 75 roll-over 
subjects have completed Injection 6 (Week 25, Day 169) the sites will be notified that no more 
PK samples will be required to be collected from the roll-over subjects for the duration of the 
study. The plasma concentrations of buprenorphine and norbuprenorphine will be quantified 
using specific and validated liquid chromatography tandem mass spectrometry methods. A 
laboratory manual for PK sample collection, processing, storage, and shipping will be supplied. 
However, for all subjects (de novo and roll-over) throughout the study, a PK sample will be 
taken as soon as possible after any SAE is reported.  If possible, an additional sample should be 
collected when the SAE has been resolved. 
The exact times (to the minute) of PK blood sampling as well as the exact times of drug 
administration will be recorded in the source and eCRF.   
6.8 
Administration of Study Drug 
The study drug will be assigned by an IWRS system. Injections will be administered by a 
physician or suitably-qualified designee (e.g., physician, nurse, nurse practitioner, PA) who has 
been delegated to perform the task.  Study drug will be supplied only to subjects participating in 


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the study. The Investigator agrees not to allow the study drug to be administered from, nor stored 
at, any site other than the study site agreed upon with the Sponsor. 
See Appendix 7 for detailed descriptions of dosing for the SUBOXONE sublingual film. 
Detailed instructions for the preparation and administration of RBP-6000 are in Appendix 8. 
If at an injection visit there is a safety concern with administration of RBP-6000, after discussion 
with the medical monitor or sponsor, dosing can be delayed up to one week.  In the event this 
occurs, the subsequent doses will be delayed.  There must be at least 26 days between injections 
of study medication. 
All used syringe components will be disposed of into an appropriate secure biohazard container 
or per the SOPs at the study site. 
All used IMP packaging (e.g., carton, foil pouch) will be retained at the study site until the CRA 
conducts a visit to perform reconciliation.  After the reconciliation is completed, the used IMP 
packaging may then be disposed of per the SOPs at the study site. 
Unused IMP and returned SUBOXONE sublingual film must be available for verification by the 
Sponsor’s site monitor during on-site monitoring visits.  The return of unused or used returned 
IMP for destruction will be documented on the drug return form. 
6.9 
Safety and Suicidality Assessments 
Safety will be assessed by AEs, vital signs, ECGs, clinical laboratory assessments, local injection 
site grading scale, injection site pain VAS, and eC-SSRS responses. See the SOE for specific 
timing of assessments (Appendix 1, Appendix 2, Appendix 3, Appendix 4, and Appendix 5). 
6.9.1 
Local Injection Site Tolerability 
6.9.1.1 
Injection Site Grading 
Local injection site grading will be performed by the Investigator or a trained and qualified 
health care professional, according to the SOE in Appendix 2, Appendix 3, Appendix 4, and 
Appendix 5.  Injection sites will be assessed for pain, tenderness, erythema/redness, induration, 
or swelling.  Local injection site tolerability will be assigned a severity grade, including none 
(grade 0), mild (grade 1), moderate (grade 2), severe (grade 3), or potentially life threatening 
(grade 4) utilizing the Injection Site Grading Scale in Appendix 15.  The local injection site 
grading assessment will be completed electronically on injection days immediately after each 
injection (within 10 minutes) and at 1 hour (± 15 minutes). For Injection 1 only, local injection 
site grading will be completed 24 hours (±4 hours) after the injection. 
6.9.1.2 
Injection Site Pain Visual Analogue Scale (VAS)  
Injection site pain will be assessed by the subject at each injection visit electronically with a 
100mm VAS scale, where 0 represents no pain and 10 represents maximum pain (Appendix 16).  
The injection site-pain VAS scores will be obtained (after the completion of the injection) within 


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1 minute and then at 5, 10, 15, 30, and 60 minutes (±5 minutes).  The timing of the Injection Site 
Pain VAS should be measured from the end of the injection.  In addition to rating pain levels by 
marking on the line the point they feel best represents their perception of their current state, the 
subject will also answer the following question with either a Yes or No: Are you currently 
experiencing any burning or stinging at the injection site? 
6.9.2 
Suicidality 
6.9.2.1 
Columbia Suicide Severity Rating Scale 
The eC-SSRS will be administered according to the SOE in Appendix 1, Appendix 2, Appendix 
3, Appendix 4, and Appendix 5.  The eC-SSRS is a questionnaire designed for assessment of 
suicidal ideation and behavior in adolescents and adults (Posner 2011).  The questionnaire will 
be administered as an electronic, self-rated version (eC-SSRS).  Clinical trial versions of the 
questionnaire are available for trial screening and follow-up visits.  A sample section from the 
Baseline/Screening eC-SSRS and the follow-up eC-SSRS are presented in Appendix 10 and 
Appendix 11, respectively.   
If a subject becomes suicidal during the study, the investigator should provide the appropriate 
treatment to the subject.  If the suicidality is deemed to be related to IMP and it is within 14 days 
of an injection, the depot may be removed (Section 6.14.1).  
The eC-SSRS should be completed prior to SUBOXONE and RBP-6000 injection and at 
approximately the same time each day ±2 hours. 
If, there is a positive on the eC-SSRS after screening the subject will be evaluated by the 
investigator for continuation in the study.  If needed, the investigator can consult with the 
medical monitor on continuation in the study of subjects with a positive eC-SSRS. 
6.10 Adverse Events Assessments 
6.10.1 
Definition 
In accordance with ICH and US FDA guidance, any untoward medical occurrence incurred by a 
subject that occurs after the first study-related procedure to the completion of the last EOS/ET 
visit or start of treatment on the INDV-6000-301 study and is associated with the use of the drug, 
regardless of the presence of causal relationship, is a reportable AE.  AEs that are ongoing at the 
time a subject rolls-over from the RB-US-13-0001 study will be recorded in the eCRF. 
Abnormal results of diagnostic procedures, including laboratory test abnormalities, are 
considered AEs if they: 
• Result in discontinuation from the study, 
• Require treatment or any other therapeutic intervention, 
• Require further diagnostic evaluation (excluding a repetition of the same procedure to 
confirm the abnormality), or 


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• Are associated with clinical signs or symptoms that would have a significant clinical 
impact, as determined by the Investigator. 
6.10.2 
Performing Adverse Events Assessments 
The Investigator is ultimately responsible for assessing and reporting all AEs as outlined in the 
protocol.  The assessment of AEs may be delegated to a medically qualified sub-investigator, 
trained on this study protocol, who is listed on the FDA Form 1572 or equivalent document, and 
on the delegation of authority form. 
AEs should be volunteered by the subject or solicited from the subject using a standard 
statement, obtained from examination of the subject at a clinic visit, or from observations of 
clinically significant laboratory values or special examination abnormal values.  If an event 
assessed by one of the study scales requires intervention, or if in the opinion of the Investigator, 
it is clinically significant, then it will be reported as an AE. 
All AEs are to be assessed and recorded in a timely manner and followed to resolution or until 
the Investigator determines that there is not an anticipated resolution.  Each AE is to be 
documented with reference to severity, date of occurrence, duration, treatment, and outcome.  
Furthermore, each AE is to be classified as being serious or non-serious.  In addition, the 
Investigator must assess whether the AE is drug-related or not.  Changes in severity of AEs 
should be documented as one event at the maximum severity that occurred during the study. 
6.10.3 
Timing 
AEs will be captured from the time the subject gives informed consent until the subject 
completes the study. 
Surgical procedures, planned before enrollment of the subject in the study, are not considered 
AEs if the condition was known before study inclusion.  In this case the medical condition 
should be reported in the subject’s medical history.   
If a subject experiences the onset of an SAE within 30 days following study completion and in 
the opinion of the Investigator, that SAE is associated with the study, it will be followed and 
reported as described in Section 6.10.9.2. 
If a SAE occurs a PK sample will be taken as soon as possible after the event is reported.  If 
possible, an additional sample should be collected when the SAE has been resolved. 
6.10.4 
Severity 
Adverse events with changes in severity should be documented as one event at the maximum 
severity. 


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Intensity 
Definition 
Mild 
Causes transient or mild discomfort ; no limitation of usual activities; no 
medical intervention required 
Moderate 
Causes mild to moderate limitation in activity; some limitation of usual 
activities: no or minimal medical intervention or therapy is required. 
Severe 
Causes marked limitation in activity; some assistance is usually required; 
medical intervention or therapy is required; hospitalization is probable.   
 
The term “severe” is used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe); the event itself, however, may be of relatively minor medical significance 
(such as a severe headache). This is not the same as “serious,” which is based on subject/event 
outcome or action criteria usually associated with events that pose a threat to a subject’s life or 
functioning. Seriousness (not severity) serves as a guide for defining regulatory reporting 
obligations. 
6.10.5 
Relationship 
The Investigator or a medically qualified sub-investigator, trained on this study protocol, listed 
on the 1572 form or equivalent document and on the delegation of authority form is responsible 
for determining the AE relationship to the investigational product. 
The following categories will be used to define the relationship of an AE to the administration of 
the investigational product: 
 
Not Related: 
Data are available to identify a clear alternative cause for the AE other than 
the investigational product. 
Related: 
The cause of the AE is related to the investigational product and cannot be 
reasonably explained by other factors (e.g., the subject’s clinical state, 
concomitant therapy, and/or other interventions). 
 
6.10.6 
Expectedness 
An unexpected AE is any AE, the nature and severity of which is not consistent with the 
applicable product information (e.g., Investigator’s Brochure for an investigational product or 
product label/summary of product characteristics for an approved product). 
6.10.7 
Clinical Significance 
The Investigator or medically qualified sub-investigator, trained on this study protocol, listed on 
the 1572 form or equivalent document and on the delegation of authority form is responsible for 
determining clinical significance of abnormal assessment results (e.g., laboratory or ECG results) 
for the subject. 


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6.10.8 
Clinical Laboratory Adverse Events 
Changes in laboratory values or vital signs, or other safety parameters (e.g., ECG, neurological 
and clinical symptom assessments) as noted in the protocol are a subset of AEs and are 
reportable only if considered to be clinically significant by the investigator or medically qualified 
sub-investigator except that: 
• Baseline assessments are differentiated from AE/symptoms that are incurred post 
informed consent.  These baseline lab assessments, if determined to be clinically 
significant abnormal values, reflect the status of the subject prior to study participation.  
These clinically significant pre-dose abnormal assessments without clinical symptoms 
will not be reported as AEs.  
6.10.9 
Serious Adverse Events 
6.10.9.1 
Definition 
A SAE is defined as any AE occurring at any dose that results in any of the following outcomes:  
• death,  
• life-threatening AE, 
• hospitalization or prolongation of existing hospitalization,  
• a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or 
• a congenital anomaly or birth defect. 
“Important medical events may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.”  
6.10.9.2 
Reporting Serious Adverse Events 
All SAEs must be reported to the Sponsor by the Investigator or designee by email or fax within 
24 hours of discovery, using the form provided by the Sponsor. The SAE report should also be 
emailed to the Sponsor Medical Monitor. 
In the event of an SAE, the Investigator or designee will notify Medical Monitor and the Indivior 
Pharmacovigilance: 
Medical Monitor: 
 
 
24-hour emergency number: (866) 326-5053 
Email: VAIL@prahs.com 
Indivior Pharmacovigilance: 
Email: PatientSafetyNA@indivior.com  


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Fax: (804) 423-8951 
Indivior Inc. 
10710 Midlothian Turnpike, Suite 430 
Richmond, VA 23235 
 
The Investigator or designee must inform the IRB immediately regarding any AE (does not have 
to be causally related) that is both serious and unexpected; or that represents a series of AEs that 
on analysis is unanticipated, or occurs at an unanticipated frequency, or otherwise represents an 
unanticipated safety risk to the study subject. The IRB may subsequently choose to modify the 
informed consent or request changes to the protocol or Investigator’s Brochure.  A PK sample 
will be taken as soon as possible after any SAE is reported. If possible, an additional sample 
should be collected when the SAE has been resolved. 
6.10.10 Treatment-Emergent Adverse Events 
A TEAE is an AE that either commenced following initiation of study drug or was present prior 
to the initiation of study drug, but increased in frequency or severity following initiation of 
treatment, regardless of causality. 
6.10.11 Procedures and Follow-Up of Subjects with Ongoing SAEs or Experiencing 
SAEs after Completion of or Withdrawal from the Study 
Subjects with SAEs ongoing at the end of the study or after ET will be followed by the 
Investigator until stabilization or resolution.  If a subject experiences the onset of an SAE within 
a period of 30 days following study completion or withdrawal and, in the opinion of the 
Investigator or medically qualified sub-investigator, it is associated with the study, it will be 
followed up and reported as described for other SAEs. 
6.10.12 Pregnancy 
If a female subject believes she is pregnant (e.g., missed period, self-administered pregnancy 
test) the subject will be instructed to return to the clinical unit within 48 hours to undergo a 
serum pregnancy test.  If a pregnancy in a subject is confirmed at any time during the study 
through a serum pregnancy performed by the study laboratory, the subject will be discontinued 
from the study and will undergo all final study visit procedures (with the exception of a urine 
pregnancy test).  If the partner of a study subject becomes pregnant, the pregnancy will be 
reported to the clinical unit within 48 hours of the subject’s knowledge of the pregnancy.  The 
Investigator will attempt to collect pregnancy information on any female partner of a randomized 
male study subject who becomes pregnant while participating in this study.  After obtaining the 
necessary signed informed consent from the female partner directly, the Investigator will record 
pregnancy information on the appropriate form and submit it to Indivior or designated 
representative within 24 hours of learning of the partner’s pregnancy.   
All confirmed pregnancies that occur within this study will be followed until resolution (i.e., 
termination [voluntary or spontaneous]or birth).   


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Pregnancy ([study subject or the partner of a study subject] [without associated unexpected or 
adverse sequelae]) is not a reportable AE but must be reported to the Sponsor within 24 hours of 
the Investigator or study staff first being aware of the subject’s condition. 
6.11 Clinical Outcome Assessments 
Clinical outcome assessments will include the UDS for opioids and other drugs; self-reported use 
of illicit opioids, other drugs, and alcohol on the TLFB; COWS, SOWS, and Opioid Craving 
VAS. 
6.11.1 
Timeline Followback Interview 
The TLFB Interview will be administered according to the SOE in Appendix 1, Appendix 2, 
Appendix 3, Appendix 4, and Appendix 5. The TLFB Interview is a method to assess recent drug 
use and will be administered electronically.  The questionnaire should be administered by an 
interviewer.  The interview instrument asks subjects to retrospectively estimate their drug use in 
the 30 days prior to screen at the screening visit and since the last visit at all subsequent visits.  
Only occurrence of use is captured (i.e., used or did not use) (Fals-Stewart 2000). The interview 
takes approximately 10-30 minutes to complete and is appropriate for males and females 14 
years of age and older.  Drugs to be assessed in this study include opioids, methadone, 
buprenorphine, cocaine, barbiturates, benzodiazepines, amphetamines/methamphetamine, 
phencyclidine, and ethanol (Appendix 17). 
The timeline followback interview should be completed prior to SUBOXONE and RBP-6000 
injection and at approximately the same time each day ± 2 hours. 
6.11.2 
Opioid Craving Visual Analog Scale  
The Opioid Craving VAS will be administered electronically according to the SOE in Appendix 
1, Appendix 2, Appendix 3, Appendix 4, and Appendix 5.  A VAS is an instrument that 
measures a characteristic or attitude that is believed to range across a continuum of values and 
cannot easily be directly measured.  The amount of opioid craving that a subject feels for illicit 
opioids (not the buprenorphine used for treatment of opioid use disorder) can be recorded along a 
continuum from “no craving at all” to “strongest craving ever” (McMillan and Gilmore-Thomas 
1996).  Operationally, the VAS is a horizontal line, 100 millimeters (mm) in length, anchored by 
word descriptors at each end, as illustrated in Appendix 14.  The subject indicates the point on 
the line that he/she feels represents his/her perception of their current state.  The VAS score is 
the difference from the left hand end of the line to the point that the subject marks and will be 
electronically calculated. 
6.11.3 
Clinical Opiate Withdrawal Scale  
The COWS assessment will be administered electronically according to the SOE in Appendix 1, 
Appendix 2, Appendix 3, Appendix 4, and Appendix 5.  The COWS is an 11-item, validated 
instrument used to assess symptoms of opiate withdrawal (Wesson 2003, Tompkins 2009).  The 
score is the sum of the response to each of the 11 items.  The COWS is sometimes used by 
clinicians treating subjects with buprenorphine.  A score of 5 to 12 is considered mild, 13 to 24 is 


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moderate, 25 to 36 is moderately severe, and a score of exceeding 36 is considered severe 
withdrawal.  COWS scores will be electronically calculated.  Each subject should be assessed by 
the same qualified and trained individuals throughout the course of the study as much as 
possible.  This scale is presented in Appendix 12. 
6.11.4 
Subjective Opiate Withdrawal Scale 
The SOWS (Handlesman 1987) will be administered electronically according to the SOE in 
Appendix 1, Appendix 2, Appendix 3, Appendix 4, and Appendix 5.  The SOWS is a 16-item 
scale completed by the subject and used to assess the subject’s perception of opiate withdrawal 
symptoms.  SOWS scores will be electronically calculated.  This scale is presented in Appendix 
13. 
6.12 Health Economics and Outcomes Assessments 
Health economics and outcomes assessments will include: EQ 5D-5L, SF-36v2, MSQ, HCRU, 
TEA, ASI-Lite, BDI-II, and BPI.  
All questionnaires will be completed at the appropriate study visits as indicated in the following 
sections. 
6.12.1 
EuroQoL-5 Dimensions-5 Levels (EQ-5D-5L) and EQ-VAS 
The EQ-5D-5L will be used to record subjects’ health-related quality of life throughout the study 
at the time points indicated in the SOEs (Appendix 1, Appendix 2, Appendix 3, Appendix 4, and 
Appendix 5).  It will be administered electronically.  
The EQ-5D-5L is a widely-used, generic health-related quality of life instrument, which consists 
of 2 sections:  the EQ-5D-5L descriptive system and the EQ visual analogue scale (EQ VAS) 
(Appendix 18).  The EQ-5D-5L is comprised of 5 questions/dimensions (mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression) each of which can take 1 of 5 
responses.  The responses record 5 levels of severity (no problems/slight problems/moderate 
problems/severe problems/extreme problems) within a particular EQ-5D dimension.  EQ-5D -5L 
health states can be converted to a single summary index (range: 0-1) by using value sets that 
attaches values to each of the levels in each dimension.  The EQ-VAS is a standard, vertical, 20 -
cm visual analogue scale and will be used for recording a subject’s rating for their current health-
related quality of life state (Herdman 2007).   
6.12.2 
Medical Outcomes Study Short Form-36 (SF-36v2) 
The SF-36v2 is a generic, subject-reported outcome instrument used to assess quality of life, 
which will be administered electronically at the time points indicated in the SOEs (Appendix 1, 
Appendix 2, Appendix 3, Appendix 4, and Appendix 5).  
The SF-36v2 is a 36-question instrument, which assesses 8 health concepts: 1) limitations in 
physical activities because of health problems; 2) limitations in social activities because of 
physical or emotional problems; 3) limitations in usual role activities because of physical health 


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problems; 4) bodily pain; 5) general mental health (psychological distress and well-being); 6) 
limitations in usual role activities because of emotional problems; 7) vitality (energy and 
fatigue); and 8) general health perceptions (Appendix 19).  The scale score of each domain is 
calculated based on the summed score across items included in the domain and is rescaled to 0 to 
100 with higher scores indicating better health states. 
The SF-36v2 provides scores for each of the eight health domains and psychometrically-based 
physical component summary (PCS) and mental component summary (MCS) scores. The 
physical functioning, role physical, bodily pain, and general health can be used to construct a 
PCS score, while the vitality, social functioning, role emotional, and mental health scales are 
used to construct the MCS Scores (Ware 2007). 
6.12.3 
Medication Satisfaction Questionnaire (MSQ) 
The MSQ is a single-item, patient-rated questionnaire (Appendix 20) that evaluates patient 
satisfaction with opioid medication. (Vernon 2010).  Medication satisfaction will be measured 
with the MSQ at the time points indicated in the SOEs (Appendix 2, Appendix 3, Appendix 4, 
and Appendix 5) electronically. 
6.12.4 
Healthcare Resource Utilization (HCRU) Questionnaire 
The Healthcare Resource Utilization questionnaire will be completed by the Investigator or 
designee at the time points indicated in the SOEs (Appendix 1, Appendix 2, Appendix 3, 
Appendix 4, and Appendix 5).  The HCRU will be used to collect current health insurance status, 
hospitalizations; residential substance abuse treatment; general practitioner, specialist, and 
counseling visits; and ED visits (Appendix 21).  It will be administered electronically. 
The outpatient services captured on this questionnaire are ones conducted outside the study.  
Visits to the study site for scheduled study visits should not be reported here. 
6.12.5 
Treatment Effectiveness Assessment (TEA) 
The TEA is a patient-reported instrument which will be measured at the time points indicated in 
the SOEs (Appendix 1, Appendix 2, Appendix 3, Appendix 4, and Appendix 5). 
 
The TEA is a 4-item scale completed by the subject and used to assess the subject’s perception 
of treatment effectiveness (Ling 2012).  Patients respond to the TEA questions providing both 
numerical responses and brief feedback about their situation on four domains: substance use 
(drugs, alcohol, tobacco), health (e.g., physical, emotional health), lifestyle (e.g., housing or 
living situation, family, employment, relationships), and community (e.g., obeying laws and 
becoming a responsible member of society).  The TEA scale is presented in Appendix 22. 
6.12.6 
Addiction Severity Index (ASI) Lite 
The ASI Lite is a patient-reported instrument that is conducted via interview by a team member 
trained in the administration of the ASI Lite. ASI Lite will be administered at the time points 
indicated in the SOEs (Appendix 2, Appendix 3, Appendix 4, and Appendix 5). Given the nature 
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The ASI Lite, in an interview used to assess the subject’s addiction severity, covers 7 potential 
problem areas: medical, employment/support status, alcohol, drug, legal, family/social, and 
psychiatric problems (Strain 1996). The ASI Lite interview text is presented in Appendix 23. The 
ASI obtains lifetime information about problem behaviors, as well as problems within the 
previous 30 days. Of note, some items of the ASI Lite are only asked once at the initial visit; at 
subsequent time points only items indicated in the questionnaire should be administered.  
Below is a brief description of each of the scales that will be included within the trial:   
The medical status section of the ASI gathers basic information about the patient's medical 
history. It addresses information about lifetime hospitalizations, long-term medical problems and 
recent physical ailments.  The employment/support status section of the ASI gathers information 
about the resources a patient can record on a job application, as well as his or her current sources 
of income. Many items will have a 30-day recall period regarding current employment. The 
drug/alcohol section of the ASI gathers information about the patient's substance abuse history. It 
addresses information about current and lifetime substance abuse, consequences of abuse, 
periods of abstinence, treatment episodes, and financial burden of substance abuse. While 
lifetime versions of these items are also available, this would only be assessed at first interview.  
The legal status section of the ASI gathers information about the patient's legal history. It 
addresses information about probation or parole, charges, convictions, incarcerations or 
detainments, and illegal activities.  The family/social relationships section is designed to 
summarize the psychiatric, alcohol and drug abuse problems of the patient's relatives in each of 
the specified categories.  The psychiatric problem section gathers information on psychiatric 
symptoms experienced by the patient. 
6.12.7 
Beck Depression Inventory II (BDI-II) 
Depression is highly prevalent in patients with opioid use disorders.  Studies have been 
conducted using buprenorphine as a treatment for major depressive disorder.  
The Beck Depression Inventory II (BDI-II) is used to measure the severity of depression in 
adults and adolescents.  The BDI-II is scored on a 4 point Likert scale, each item ranging from 0-
3; it has a 2 week recall period, can be self-administered or administered by interview and takes 
5-10 minutes to complete.  
The strengths of the BDI-II include its ease of use; also, it is widely known and the results are 
easy to score and interpret.  The BDI-II has been successfully used to discriminate and measure 
depression in chronic pain patients on opioid therapy (Geisser 1997, Farren 2002, McCauley 
2014).   
The BDI-II assessment will be administered electronically according to the SOE in Appendix 1, 
Appendix 2, Appendix 3, Appendix 4, and Appendix 5.  This scale is presented in Appendix 24. 
Roll-over subjects who did not complete the BDI-II at EOS/Day 169 will complete this 
assessment at the screening visit. 
6.12.8 
Brief Pain Inventory (BPI) Short Form 
A substantial number of patients in the US with opioid use disorder began by using prescription 
pain medications and subsequently developed dependence. Many of these patients are concerned 


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at the beginning of therapy that their pain may worsen when they are no longer taking their 
opioid medication.   
The Brief Pain Inventory Short Form (BPI-SF) is used to measure the severity of pain and the 
impact of pain on daily functions in adults. The BPI-SF has a 24-hour recall period and can be 
self-administered or administered by an interviewer. It takes approximately 5 minutes to 
complete an instrument.  
The BPI has been widely used to measure pain severity among opioid users (Rosenblum 2003).  
BPI-SF consists of a combination of yes/no questions, an item based on human figure drawing, 
open-ended questions, and items based on a numeric rating scale.  Key strengths of the BPI-SF 
are that it is easy to administer and can provide rapid assessment of pain. BPI has been translated 
in many languages and is widely used. It captures all the components of pain: structural, intensity 
and its effect on patients.   
The BPI assessment will be administered electronically according to the SOE in Appendix 1, 
Appendix 2, Appendix 3, Appendix 4, and Appendix 5.  This scale is presented in Appendix 25.  
Roll-over subjects who did not complete the BPI at EOS/Day 169 will complete this assessment 
at the screening visit. 
6.13 Concomitant Medication Assessments 
The Investigator or designee will record any concomitant therapies given for 30 days prior to the 
start of and during the course of the study on the concomitant medication page of the subject’s 
source documentation and eCRF. Any changes in concomitant therapy during the study will also 
be documented, including cessation of therapy, initiation of therapy, and dose changes. 
6.14 Removal of Subjects from the Study 
Subjects will be free to withdraw at any time for any reason, or they may be withdrawn if 
necessary, to protect their health and safety or the integrity of the study data.   
The Investigator or medically qualified sub-investigator may choose to withdraw a subject from 
the study at any time.  Reasons for removing a subject from the study may include, but are not 
limited to the following: 
• Protocol deviation that might compromise data integrity, protocol compliance, or subject 
safety, 
• An AE is reported that compromises or potentially compromises subject safety, 
• The Sponsor or Investigator terminates the study, or 
• The subject requests to be discontinued from the study (i.e., subject declines further study 
participation). 
 
If a subject withdraws prematurely from the study after receiving IMP, the primary reason for 
withdrawal will be documented as 1 of the above, lost to follow-up, or other in the source 
documentation.  


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In the event a subject is lost to follow up, the site staff must make reasonable attempts to contact 
the subject.  A minimum of 2 documented telephone calls followed by a certified mailed letter is 
considered reasonable. 
6.14.1 
Early Removal of RBP-6000 
In the event of an emergency or if a subject withdraws or is withdrawn within the first 14 days of 
receiving an injection of RBP-6000, subjects may have the option to have the depot surgically 
removed by a physician delegated to perform surgery. The medically responsible physician 
should carefully discuss this option with subjects given the use of ATRIGEL Delivery System 
and the feasibility of extracting the depot. The surgical procedure requires a small incision in the 
abdomen where the depot was placed, removal of the depot with forceps, and suturing to close 
the incision.  The subject should have the EOS assessments performed at the time of early 
removal of RBP-6000. Subjects that have had an RBP-6000 depot removed should have follow-
up telephone contact(s) within 7 to 14 days to assess status and for resolution of related AEs. In 
the event a subject cannot be contacted for the follow-up telephone contact, a minimum of 2 
documented telephone calls followed by a certified mailed letter is considered reasonable. At this 
point, the subject may be considered lost to follow-up. 
The extracted RBP-6000 depot will be disposed of into an appropriate, secure biohazard 
container per the standard operating procedures (SOPs) at the study site.  
Detailed RBP-6000 depot removal instructions are in Appendix 8. 
6.14.2 
Stopping Rules 
The Investigator must contact the Sponsor immediately to discuss whether to suspend dosing if 
an AE or laboratory abnormalities indicates that continued dosing of subsequent subjects would 
not be tolerated or would jeopardize the subjects’ safety.  The Sponsor alone may suspend dosing 
at any time for any reason. 
Factors that must be considered for suspension of dosing include the frequency, severity, clinical 
significance, possible causality, and anticipated reversibility of all observed AEs or laboratory 
abnormalities for each specific SC injection group.  If dosing is suspended, the IRB will be 
notified in accordance with IRB requirements. 
6.14.3 
Screen Failures 
A screen failure subject is one from whom informed consent is obtained and is documented in 
writing (i.e., the subject signs the ICF) but who did not receive study medication. 
Rescreening of a de novo subject may be permitted after consultation with the study medical 
monitor. 


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6.15 Other Study Procedures 
6.15.1 
Counseling/Behavioral Therapy 
After enrollment, subjects will receive manual-guided, individual behavioral therapy once a 
week for 5 weeks, then bi-weekly (every 2 weeks) up until injection 6, at which point it will 
occur monthly to accompany the pharmacotherapy as indicated in the SOEs (Appendix 2, 
Appendix 3, Appendix 4, and Appendix 5). Behavioral therapy will continue through the end of 
the study (EOS/ET visit). It is at the Investigator’s discretion to provide additional behavioral 
counseling above this standard frequency. The reason(s) that additional counseling was provided 
should be documented in source documentation. Behavioral therapy can be conducted by any 
appropriately trained staff member at the site. 
An Individual Drug Counseling (IDC) reference manual will be provided to each site.   
6.15.2 
Unscheduled Visits 
If unscheduled visits occur, the Investigator must record the following in the subject’s source 
documentation: 
• Any AEs 
• Reason for unscheduled visit 
• Recording of any changes or additions to concomitant medications dose or regimen 
• COWS (if deemed appropriate) 
• Any clinical assessments deemed appropriate for the clinical care of the subject 
Unscheduled visits should not alter the timing of the routine study schedule. 
6.15.3 
Additional Care of Study Subjects Following Completion of the Study 
Each subject will be evaluated on his or her final study day.  Subjects who experience SAEs at 
the EOS, or experience the onset of an SAE after the final visit, will be followed up as described 
in Section 6.10.11.  No other additional care of study subjects will take place following 
completion of the study.  
6.15.4 
Treating Toxicity 
Treatment of suspected RBP-6000 toxicity should be at the judgment of the Investigator or 
medically-qualified sub-investigator and may include an attempt to remove the depot if toxicity 
is discovered within the first 14 days post injection.  Subjects who have had RBP-6000 removed 
will be followed up according to the procedures described in the SOE (EOS/ET Visit; Appendix 
3 and Appendix 5) and Section 6.14. 
6.15.5 
Ancillary Medications 
Treatment of signs and symptoms of opioid withdrawal after enrollment can be treated with 
ancillary medications allowed by the protocol, as clinically indicated by the Investigator or 


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physician Sub-Investigator.  Subjects whose symptoms are not manageable will be discontinued 
from the study and will be followed up according to the procedures described in the SOE 
(EOS/ET Visit; Appendix 3 and Appendix 5) and Section 6.14. 
6.16 Appropriateness of Measurements 
Within the study population of opioid-dependent subjects, certain common signs and symptoms 
are displayed that must be evaluated for safety and efficacy of treatment during clinical trials.  
The instruments used (e.g., COWS, SOWS, Opioid Craving VAS, and eC-SSRS) were 
developed to measure the specific symptoms exhibited by and challenges facing opioid-
dependent individuals. 


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7 
STUDY ACTIVITIES 
This study will be conducted as a fully non-residential (outpatient) study.  An overview of the 
study is shown in Figure 2 and Figure 3.  Details on procedures/activities for this study are 
provided in Section 6 and SOEs are provided in Appendix 1, Appendix 2, Appendix 3, Appendix 
4, and Appendix 5. 


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8 
QUALITY CONTROL AND ASSURANCE 
8.1 
Quality Control 
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study centers, review of protocol procedures with the investigators 
and associated personnel before the study, periodic monitoring visits by the Sponsor, and direct 
transmission of clinical laboratory data from a central laboratory into the Sponsor’s (or 
designee’s) database.  Written instructions will be provided for study drug preparation and 
dosing, collection, preparation, and shipment of blood, plasma, and urine samples.  Guidelines 
for eCRF completion will be provided and reviewed with study personnel before the start of the 
study.  The Sponsor (or designee) will review eCRFs for accuracy and completeness during on-
site monitoring visits and after transmission to the Sponsor (or designee).  Any discrepancies will 
be resolved with the Investigator or suitably qualified designee, as appropriate. 
8.2 
Quality Assurance 
This study will be organized, performed, and reported in compliance with the protocol, Standard 
Operating Procedures (SOPs), working practice documents, and applicable regulations and 
guidelines.   
In accordance with the standards defined in Sponsor SOPs and applicable regulatory 
requirements, clinical studies sponsored by Sponsor are subject to Sponsor Quality Audits at the 
study sites that will be conducted by personnel from an appropriate unit.  Site audits will be 
made periodically by the Sponsor’s (or contractor’s) qualified compliance auditing team, which 
is an independent function from the study conduct team.  Audits will include review of, but are 
not limited to, drug supply, presence of required documents, the informed consent process, and 
comparison of eCRFs with source documents.  The investigator agrees to participate with audits 
conducted at a reasonable time in a reasonable manner.  Full consultation with the Investigator 
will be made prior to and during such an audit, which will be conducted according to the Quality 
Assurance Unit SOPs.  In addition, this study is subject to inspection by regulatory authorities.  
If such a regulatory inspection occurs, the Investigator agrees to allow the regulatory inspector 
direct access to all relevant study documents.  The investigator should contact the Sponsor 
immediately if this occurs and must fully cooperate with the inspection conducted at a reasonable 
time in a reasonable manner. 


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9 
PLANNED STATISTICAL METHODS 
9.1 
General Considerations 
A Statistical Analysis Plan (SAP) will be prepared after the protocol is approved and before 
database lock occurs.  The SAP will provide further details regarding the definition of analysis 
endpoints, data handling rules, and the statistical methodology to be used to address all study 
objectives.  The SAP will also include formats for the summary and analysis tables, listings, and 
graphical displays. 
This section describes methods for sample size determination, analysis populations, and planned 
analyses for, safety, PK, and clinical outcomes endpoints.  Additional unplanned analyses may 
be required after all planned analyses have been completed.  Any unplanned analyses will be 
clearly identified in the clinical study report.  Any deviations from the analyses described below 
will be included in the SAP, which will form Appendix 16.1.9 of the clinical study report. 
Continuous variables will be summarized using descriptive statistics such as means, standard 
deviations (SD), medians, minimums, and maximums.  Categorical variables will be reported as 
frequency counts (including number missing) and the percentage of subjects in corresponding 
categories.  Individual subject data will be presented by subject in data listings.  Data listings will 
include all data collected from the initial screening visit to the end of study for all subjects 
enrolled.   
9.2 
Determination of Sample Size 
There is no formal sample size calculation. Approximately 300 de novo subjects as well as 
approximately 300 subjects who completed the RB-US-13-0001 efficacy study will be enrolled 
into this study to ensure at least 100 subjects reach 1 year of treatment with RBP-6000. 
9.3 
Analysis Populations 
The following populations will be used for data analyses: 
9.3.1 
Safety Population 
The Safety Population comprises all subjects who received at least 1 dose of RBP-6000 during 
the open-label treatment phase of the study. This population will be used for all safety analyses.   
9.3.2 
Clinical Outcome Assessment and PK Populations 
The Clinical Outcome Assessment population will include subjects who were dosed with 
RBP-6000 and have at least 1 post-dose Clinical Outcome Assessment value.  
The PK Population will include any subject who receives a dose of RBP-6000 or at least 1 dose 
of SUBOXONE sublingual film and has at least 1 sample collected post-dose.  
   


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9.4 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics (gender, race, age, weight, height) will be summarized 
by treatment group using descriptive statistics.  Qualitative variables (gender, race) will be 
summarized using frequencies while quantitative variables (age, weight, height) will be 
summarized using mean, SD, median, minimum, and maximum. 
9.5 
Primary Analysis 
9.5.1 
Safety Endpoints 
Safety variables will include AEs, local injection site tolerability (e.g., injection site grading); 
injection site pain using a subject-reported VAS; suicidality using the eC-SSRS, concomitant 
medications; changes in clinical laboratory results (hematology, chemistry and urinalysis); vital 
sign measurements; 12-lead ECGs, physical examination results; body weight, height, BMI, and 
abdominal fat measurement (waist-to-hip ratio). Safety variables will be analyzed using the 
safety population.  
Baseline is defined as the last non-missing value prior to SC injection on Day 1.  No imputation 
of missing values will be performed. 
9.5.1.1 
Adverse Events 
All AEs will be coded using the most up-to-date version of the Medical Dictionary for 
Regulatory Activities (MedDRA) and reported to the FDA. AEs that began more than 30 days 
after the last study subject assessment day will not be included in the safety analysis. Only 
TEAEs occurring post administration of RBP-6000 will be included in the safety analysis (See 
Section 6.10.10). 
The incidence of AEs (number and percent of subjects reporting the AE at least once during the 
study) will be summarized for all AEs, by the relationship to study drug and by severity. 
9.5.1.2 
Laboratory Data 
At each visit where clinical laboratory assessments are conducted, summary statistics for the 
absolute laboratory value and the changes from baseline will be presented.   
9.5.1.3 
Vital Signs 
Vital signs measurements will be assessed for clinical relevance and be performed as deemed 
medically necessary by research personnel.  Vital signs will be taken after the subject has 
completed a minimum 3-minute rest in the supine position.  Systolic and diastolic BP 
measurements will be assessed while supine throughout the trial. 
9.5.1.4 
Other Variables Related to Safety 
Results from 12-lead ECGs will be categorized as normal, abnormal clinically significant, or 
abnormal not clinically significant and will be summarized by time point using frequency counts 


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and percentages.  ECG interval measurements as well as change from baseline will also be 
summarized by time point using descriptive statistics (mean, median, SD, minimum, maximum).  
Additional analysis of ECG parameters will be outlined in the SAP. 
Medical history will be coded using MedDRA and summarized by treatment group as described 
for AEs (Section 9.5.1.1).  Body weight, height, BMI, and abdominal fat measurement (waist-to-
hip ratio) will be summarized using descriptive statistics (mean, median, SD, minimum, 
maximum), including change from baseline. 
Total eC-SSRS scores will be summarized using descriptive statistics (mean, median, SD, 
minimum, maximum), including change from baseline.  Subjects’ self-reported illicit drug use 
from the TLFB will be summarized as descriptive statistics. 
Prior and concomitant medications will be coded using the most recent version of the World 
Health Organization (WHO) Drug dictionary.  Incidence (number and percent of subjects 
reporting the medication at least once during the study) will be summarized for all concomitant 
medications. 
Local injection site tolerability as assessed by the Injection Site Grading scale will be 
summarized by category and severity using frequency counts and percentages similar to 
summaries for AEs (Section 9.5.1.1).  Injection Site Pain VAS scores will be summarized by 
dose, injection, and time point after injection.  The burning/stinging categorical variable 
(Yes/No) will be summarized by percent of responses in each treatment. 
9.6 
Secondary Analysis 
9.6.1 
Clinical Outcomes Assessments 
COWS, SOWS and Opioid Craving VAS total scores will be summarized using descriptive 
statistics (mean, median, SD, minimum, maximum), including change from baseline. Subjects’ 
self-reported illicit drug use from the TLFB will be summarized using descriptive statistics. 
The cumulative distribution function (CDF) of the percentage of urine samples negative for 
opioids and that of the percentage of self-reports from the TLFB negative for illicit opioid use 
will be calculated. Other outcome efficacy measures will be estimated using descriptive 
statistics.  
9.7 
Other Analyses 
9.7.1 
PK/PD Modeling 
The population PK model established using the data collected in the double-blind, placebo-
controlled, efficacy study (Study RB-US-13-0001) will be refined using the PK samples 
collected in the present study to characterize the disposition of buprenorphine and 
norbuprenorphine following SC injections of RBP-6000, with the assessment of potential 
covariates affecting the PK of both compounds.  Subsequently, the relationships between 
buprenorphine plasma concentrations and clinical outcomes assessments will be investigated.  


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These relationships will be initially assessed in a descriptive manner, and, if applicable, 
appropriate PK/PD models will be developed to describe these relationships.  A stand-alone 
modeling analysis plan will be generated, and the results will be reported in a standalone 
modeling report.  
9.7.2 
Health Economic and Outcomes Assessment 
The health economic and outcomes research endpoints for this study are: 
• EQ-5D-5L 
• SF-36v2  
• MSQ  
• HCRU  
• TEA 
• ASI Lite 
• BDI-II 
• BPI 
Summary scores for these measures will be calculated, as appropriate. Categorical variables will 
be summarized using frequencies and percentages. Continuous measures will be summarized 
using descriptive statistics (mean, standard deviation, median, minimum, maximum) as 
appropriate. An analysis of change will be conducted.  A stand-alone statistical analysis plan will 
be developed prior to database lock for health economics and outcomes research assessments.  
A separate stand-alone SAP will be developed prior to database lock with full detail regarding 
health economics and outcomes analyses. 
9.8 
Handling of Missing Data 
For dichotomous outcome measures such as UDS results (negative; non-negative) and self-
reports for illicit opioid use (negative; non-negative), any missing observation will be recorded 
as “non-negative.” For all continuous endpoints (e.g., COWS, SOWS, and VAS), the missing 
data mechanism will be assumed to be either missing completely at random (MCAR) or missing 
at random (MAR).  The missing data will not be imputed because the analysis method, mixed 
model for repeated measures (MMRM), does not require any imputation and no sensitivity 
analyses will be performed on these variables.  For time-to-event variables, if the event of 
interest is not observed prior to withdrawal or end of treatment, the observations will be censored 
at the time of withdrawal or at the end of treatment.  For example, if some subjects still have not 
had a urine sample negative for opioids combined with self-reports negative for illicit opioid use 
when the study ends or at the time of withdrawal from the study, then the time to first urine 
sample negative for opioids combined with self-reports negative for illicit opioid use will be 
censored at the last time they were assessed. 


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9.9 
Subjects Who Withdraw from the Study 
Subjects who withdraw after receiving RBP-6000 will not be replaced. 
9.10 Interim Analyses 
An Interim analysis will be performed once at least 100 subjects have completed the study. 
 


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10 ADMINISTRATIVE CONSIDERATIONS 
10.1 Investigators and Study Administrative Structure 
10.1.1 
Indivior Inc. 
Indivior Inc. 
10710 Midlothian Turnpike, Suite 430 
Richmond, VA 23235 
 
10.1.2 
Investigational Site(s) 
This study will be conducted at up to 50 sites in the US. 
10.1.3 
Laboratories 
The safety laboratory tests (serum chemistry, hematology, serology, and urinalysis), as well as 
the specialty laboratory tests (Bioanalytical and Pharmacokinetic) will be conducted at a central 
laboratory that is certified and accredited to perform the assigned assessments. 
Collection of safety laboratory samples is described in Section 6.6.2.  The Clinical Laboratory 
will provide normal ranges and collection, processing, and shipping instructions to the sites in a 
separate laboratory reference manual. 
10.2 Institutional Review Board or Independent Ethics Committee 
Approval 
The protocol will be reviewed by an independent, appropriately constituted, centralized IRB/ 
Independent Ethics Committee (IEC).  Study enrolment and protocol related procedures, which 
do not form part of the subject’s normal clinical treatment, will not be performed until the 
IRB/IEC of record has provided written approval of the protocol or a modification thereof.  The 
IRB/IEC must be constituted and operate in accordance with the principles and requirements of 
ICH GCP. 
Study drug can only be supplied to the Investigator after documentation on all ethical and legal 
requirements for starting the study has been received by the Sponsor.  This documentation must 
also include an IRB/IEC membership list that contains member’s occupations.  If the IRB/IEC 
will not disclose the names of the committee members, the IRB/IEC Federalwide Assurance 
Number may be accepted as a substitute for this list.  Formal approval by the IRB/IEC should 
mention the study title, study code, study site (or region or area of jurisdiction, as applicable), 
and any other documents reviewed.  It must mention the date on which the decision was made 
and must be officially signed by a committee member. 
10.3 Ethical Conduct of the Study 
The Investigator is responsible for ensuring that the clinical study is performed in accordance 
with the protocol, current ICH GCP guidelines, and applicable regulatory and country-specific 


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requirements.  GCP is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects.  
Compliance with this standard provides the public assurance that the rights, safety, and 
well-being of study subjects are protected and that the clinical study data are credible. 
10.4 Subject Information and Consent 
Prior to the subject incurring the first study related procedure, the Investigator or designated 
individual will explain to each subject the nature of the study, its purpose, procedures, expected 
duration, alternative therapies available, and the benefits and risks involved in study 
participation. It should also be mentioned that all informed consent documents and other 
documents used in the conduct of the study have been approved by an IRB/IEC. 
In the case of a non-medically qualified person conducting the consent process, he/she should 
have ready access to a medically qualified investigator to whom any questions from the study 
subject may be referred. Subjects will be given consent documents to review and the opportunity 
to ask questions. Subjects must be informed of their right to withdraw from the study at any time 
without prejudice.  
After this explanation and before any study-specific procedures have been performed, the subject 
must voluntarily sign and date the ICF to indicate he/she wishes to participate in study. The 
Investigator or the individual designated to conduct the consent discussion for the Investigator 
must also sign and date the ICF. The time (hour and minute) the consent is signed must also be 
recorded in the subject’s source notes, by the person obtaining consent from the subject. Verbal 
informed consent followed by a signed consent short form is not acceptable to Sponsor. 
Prior to participation in the study, the subject will receive a copy of the signed and dated ICF 
along with an emergency card with contact information for the Investigator and site staff in the 
event of a medical emergency during the study. 
10.5 Subject Confidentiality 
All subject-identifying documentation generated in this study must be considered confidential 
and must not be disclosed to any persons not directly concerned with the study without written 
permission from the subject.  However, authorized regulatory officials and Sponsor personnel (or 
their representatives) will be allowed full access to inspect and copy the records.  All subject 
bodily fluids, and/or other materials collected shall be used solely in accordance with this 
protocol and the informed consent signed by the subject, unless otherwise agreed to in writing by 
the Sponsor. 
Each subject will be identified by initials and an assigned subject number when reporting study 
information to any entity outside of the study center.  Data containing subject identification will 
not be removed from the study center without subject identifiers having been redacted. 
  


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10.6 Study Monitoring 
In accordance with applicable regulations, GCP, and Sponsor procedures, the clinical monitor(s) 
will periodically contact the site, including conducting on-site visits at intervals agreed by the 
Investigator and documented in the Clinical Monitoring Plan and the Site Initiation Visit Report.   
The clinical monitor(s) will contact the site prior to the start of the study to discuss the protocol 
and data collection procedures with site personnel.  In accordance with applicable regulations 
and GCP guidelines, the Investigator shall make available for direct access all study-related 
records upon request of the Sponsor, the Sponsor’s agents, clinical monitor(s), auditors, and/or 
IRB/IEC.  The Sponsor’s monitors will visit the site during the study in addition to maintaining 
frequent telephone and written communication.  The extent, nature, and frequency of on-site 
visits will be based on such considerations as the study objectives and/or endpoints, the purpose 
of the study, study design complexity, and enrolment rate.   
The Investigator must allow the clinical monitor(s) direct access to all relevant documents and to 
allocate his/her time and the time of his/her staff to the clinical monitor(s) to discuss findings and 
any relevant issues. 
10.6.1 
Study and Site Closure 
Upon completion of the study, study closeout activities must be conducted by the Sponsor or its 
designee in conjunction with the Investigator, as appropriate. 
In addition, the Sponsor reserves the right to temporarily suspend or prematurely discontinue this 
study at any time and for any reason.  If such action is taken, the Sponsor will discuss this with 
the Investigator (including the reason[s] for taking such action) at that time.  The Sponsor will 
also inform the regulatory authorities of the suspension or termination of the study and the 
reason(s) for the action.  If required by applicable regulations, the Investigator must inform the 
IRB/IEC promptly and provide the reason(s) for the suspension or termination.  If the study is 
prematurely discontinued, all study data and study drug remaining on site must be returned to the 
Sponsor or its designee. 
10.7 Case Report Forms and Study Records 
The Investigator is responsible for the quality of the data recorded in the electronic Case Report 
Forms (eCRFs). The data recorded should be a complete and accurate account of the subject’s 
record collected during the study. Study data are not to be gathered directly onto the eCRF but 
must be gathered onto primary source documents at the study site. Completion of source 
documents will precede the completion of the eCRF. Source data transfer into the eCRF should 
occur timely and on an ongoing basis. Source documents may be electronic, hard copy, or a 
combination of both. Source documents are defined as the results of original observations and 
activities of a clinical investigation. Source documents will include, but are not limited to, 
progress notes, electronic data, screening logs, and recorded data from automated instruments. 
All source documents pertaining to this study will be maintained by the investigators and made 
available for direct inspection by the authorized study personnel outlined in the ICF. The ePRO 


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tablet will be considered the source document for individual ePRO elements such as study-
specific scales when collected directly onto the tablet. 
Data collection will be completed according to the guidelines provided by Sponsor or its 
designee.   
For all subjects who signed an informed consent, all required data are to be recorded using 
source documents and reported on the eCRF, except for study scales that are recorded directly on 
the ePRO tablet.  Site staff will receive training on the eCRF completion guidelines and 
requirements for source documentation. 
Completed eCRFs will be reviewed by the study monitor in line with eCRF completion 
guidelines for the study to ensure completeness and consistency. The study monitor will review 
every subject’s eCRF with source data verification for at least all critical data points. The clinical 
management plan for this study will define the level of source data verification required for 
non-critical data points.  Any discrepancies found during the eCRF review will be clarified by 
the Investigator or designated individual. This includes eCRF reviews at the site by Sponsor or 
its designee, or during quality assurance review of the data.  
An explanation must be documented for any missing data.  Any changes to information in the 
study progress notes and other source documents will be initialled and dated on the day the 
change is made by a site staff member authorized to make the change.  Changes will be made by 
striking a single line through erroneous data (so as not to obliterate the original data), and clearly 
entering the correct data (e.g., wrong data right data).  If the reason for the change is not 
apparent, a brief explanation for the change will be written in the source documentation by the 
clinician. 
The Investigator must sign and date a declaration attesting to his/her responsibility for the quality 
of all data recorded, and that the data represents a complete and accurate record of each subject’s 
participation in the study.   
All eCRF entries, corrections, and alterations must be made by the Investigator or designated 
individual.  The Investigator or designated individual must adjust the eCRF (if applicable) and 
complete the query. 
10.8 Data Monitoring Committee 
Not applicable; there will be no data monitoring committee for this study. 
10.9 Protocol Deviations 
This study is intended to be conducted as described in this protocol.  At the outset of the study, a 
process for defining and handling protocol deviations will be established and defined in the 
medical management plan.  This will include determining which violations will be designated 
important and require immediate notification to the Sponsor.  In the event of a deviation from the 
protocol due to an emergency, accident, or mistake, the Investigator or designated individual 
must contact the Sponsor at the earliest possible time by telephone.  This will allow an early joint 


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decision regarding the subject’s continuation in the study.  This decision will be documented by 
the Investigator and the Sponsor, and reviewed by the monitor.  Deviations from the protocol are 
to be documented.  The Investigator or designated individual will be responsible for identifying 
and reporting all deviations, which are defined as isolated occurrences involving a procedure that 
did not follow the study protocol or study-specific procedure.  Deviations will be reported as 
required to the IRB and in the final study report. 
10.10 Access to Source Documentation 
The Investigator must agree to complete a subject identification and enrolment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
Sponsor site contact for completeness. The subject identification and enrollment log will be 
treated as confidential and will be filed by the Investigator in the investigator site file. To ensure 
subject confidentiality, no copy will be made. All reports and communications relating to the 
study will identify subjects by initials and assigned number only. The Investigator must also 
complete a subject-screening log, which reports on all subjects who were seen to determine 
eligibility for inclusion in the study. 
At a minimum, source documentation must be available for the following to confirm data 
collected in the eCRF: subject identification, eligibility, and study identification; study 
discussion and date of informed consent; dates of visits; results of safety and efficacy parameters 
as required by the protocol; record of all AEs; concomitant medications; study drug 
administered; date of study completion or early discontinuation, and reason for early 
discontinuation if applicable. 
10.11 Data Generation and Analysis 
10.11.1 Data Collection and Data Management 
Study specific data that has been outlined in the protocol will be entered into the clinical 
database by individual(s) designated by the Investigator in accordance with the CRF Completion 
Guidelines. Data is verified electronically using a series of on-line programmed edit checks that 
have been created by the Clinical Data Manager and programmed by the Clinical Data 
Programmer or Designee. Data discrepancies will be brought to the attention of the clinical team 
and investigated by the CRA and Site Study Coordinator. CRAs will review and verify all data 
collected in the eCRF against source documentation during scheduled monitoring visits. The 
CRA will work closely with the Site Study Coordinator to address any discrepancies which have 
been found so that proper resolutions can be made and documented into the clinical database. An 
audit trail within the system will track all changes made to the data. 
10.11.2 Database Quality Assurance  
The clinical database will be reviewed and checked for omissions, apparent errors, and values 
requiring further clarification using computerized and manual procedures.  Data queries 
requiring clarification will be generated and addressed by the investigational site.  Only 
authorized personnel will make corrections to the clinical database, and all corrections will be 
documented in an audit trail.   


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10.12 Retention of Data 
All documents pertaining to the study, including all versions of the approved study protocol, 
copy of the informed consent document and Health Insurance Portability and Accountability Act 
documents, completed eCRFs, source documents (subject records, subject diaries, hospital 
records, laboratory records, drug accountability records, etc.), and other study-related documents 
will be retained in the permanent archives of the study site. 
The Investigator must therefore notify and obtain approval in writing from the Sponsor prior to 
destruction of any study records or provide an opportunity for the Sponsor to collect such 
records.  If the investigator withdraws from the study (e.g., relocation, retirement) all study-
related records should be transferred, in a written agreement with the Sponsor, to a mutually 
agreed upon designee within a Sponsor-specified timeframe. 
10.13 Financial Disclosure 
Indivior requires, for each study, the disclosure of any financial interests from each investigator 
or sub-investigator, including financial interests of the spouse and each dependent child of the 
investigator who is directly involved in the treatment or evaluation of research subjects that 
could affect the reliability of data submitted to regulatory authorities. The collection of this 
financial interest information at the start of the study, as well as any updates should this 
information change, is required by the FDA when submitting a marketing application and is in 
line with the GCP requirement to consider any potential conflicts of interest. 
10.14 Publication and Disclosure Policy 
A clinical study report will be prepared following completion of the study.  The report will be a 
record of the total study conduct and will be subject to Sponsor approval and restrictions on 
distribution/disclosure.   
The study data will be owned by the Sponsor. Publication of any and all data will be at the 
discretion of the Sponsor. The Investigator will not disseminate, present, or publish any of the 
study data without the prior written Sponsor approval to do so. 


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Thomas J. Drug injectors sharing cookers and cotton increase their risk of hepatitis C (2001). 
NIDA Notes 16(3):9–11. 
Tompkins D, Bigelow G, Harrison J, Johnson R, Fudala P, Strain E (2009).  Concurrent 
validation of the Clinical Opiate Withdrawal Scale (COWS) and single-item indices against the 


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Confidential 
Clinical Institute Narcotic Assessment (CINA) opioid withdrawal instrument.  Drug Alcohol 
Depend. 105:154–159. 
United Nations Office on Drugs and Crime. World Drug Report 2012. Available at 
http://www.unodc.org/unodc/en/data-and-analysis/WDR-2012.html.  Accessed 29 February 
2016. 
U.S. Department of Health and Human Services, Food and Drug Administration, Center for 
Biologics Evaluation and Research, September 2007.  Guidance for Industry: Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials. [pdf] Available at: 
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInform
ation/Guidances/Vaccines/ucm091977.pdf.  Accessed 29 February 2016. 
U.S. Department of Health and Human Services, Food and Drug Administration, Center for 
Biologics Evaluation and Research, July 2005.  Guidance for Industry: Estimating the Maximum 
Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers [pdf] 
Available at: http://www.fda.gov/downloads/Drugs/.../Guidances/UCM078932.pdf Accessed 29 
February 2016. 
Vernon MK, Revicki DA, Awad AG, et al (2010).  Psychometric evaluation of the Medication 
Satisfaction Questionnaire (MSQ) to assess satisfaction with antipsychotic medication among 
schizophrenia patients. Schizophr Res. 118(1-3):271-278.  
Walsh SL, Preston KL, Stitzer ML, Cone EJ, Bigelow GE (1994).  Clinical pharmacology of 
buprenorphine: ceiling effects at high doses. Clin Pharmacol Ther. 55:569–580. 
Ware JE, Jr, Kosinski M, Bjorner JB, Turner-Bowker, DM, Gandek, B. and Maruish, ME 
(2007).  User's Manual for the SF-36v2TM Health Survey (2nd Ed). Lincoln, RI, QualityMetric 
Incorporated. 
White AG, Birnbaum HG, Mareva MN, et al (2005).  Direct costs of opioid abuse in an insured 
population in the United States. J Manag Care Pharm. 11(6):469-479. 
Umbricht A, Heustis M, Cone EJ, Preston KL (2004).  Effects of High-Dose Intravenous 
Buprenorphine in Experienced Opioid Abusers.  J Clin Psychopharmacol. 24(5):479-487. 
 


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Appendix 1 
Schedule of Events – Screening and SUBOXONE Film Induction 
Evaluation 
Screening 
Visit  
(Up to 3 days after 
EOS Visit/Day 169 
of RB-US-13-0001 
for roll-over 
subjects) 15 
SUBOXONE sublingual film 
Run-In 
Induction  
(3 days) 
Dose Adjustment  
(1 to 11 days) 
Days  
-21 to -15 
Day  
-14  
Day  
-13 
Day 
-12 
Day 
-11 
Day 
-8 
Day 
-4 
Day 
-1 
 
 
 
 
+1 day 
±1 day 
-1 day 
Informed Consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria Reviewed 
X 
 
 
 
 
 
 
 
IWRS 
X 
X 
X 
X 
X 
X 
X 
X 
Demographics 1 
X 
 
 
 
 
 
 
 
Medical History 1 
X 
 
 
 
 
 
 
 
eC-SSRS (Baseline Version) 
X 13 
 
 
 
 
 
 
 
Physical Examination 2 
X 13 
 
 
 
 
 
 
 
Vital Signs 3 
X 13 
X 
X 
X 
X 
X 
X 
X 
Body Weight 
X 13 
 
 
 
 
 
 
 
BMI Calculation 
X 13 
 
 
 
 
 
 
 
Hip-to-Waist Ratio 
X 13 
 
 
 
 
 
 
 
12-lead ECG (supine > 10 min) 4 
X 13 
 
 
 
 
 
 
 
Urine Drug Screen (UDS) 
X 13 
 
 
 
 
 
 
 
Urine Pregnancy Test 5 
 
X 
 
 
 
 
 
 
Screening Labs / Hormone Panel 
X 13 
 
 
 
 
 
 
 
Urinalysis/ Hematology/Serum Chemistry 
X 13 
 
 
 
 
 
 
 
Opioid Craving VAS 6 
X 13 
 
 
 
X 
X 
X 
X 
Clinical Opiate Withdrawal Scale (COWS) 6 
X 13 
X 
X 
X 
X 
X 
X 
X 
Subjective Opiate Withdrawal Scale (SOWS) 6 
X 13 
X 
X 
X 
X 
X 
X 
X 


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Evaluation 
Screening 
Visit  
(Up to 3 days after 
EOS Visit/Day 169 
of RB-US-13-0001 
for roll-over 
subjects) 15 
SUBOXONE sublingual film 
Run-In 
Induction  
(3 days) 
Dose Adjustment  
(1 to 11 days) 
Days  
-21 to -15 
Day  
-14  
Day  
-13 
Day 
-12 
Day 
-11 
Day 
-8 
Day 
-4 
Day 
-1 
 
 
 
 
+1 day 
±1 day 
-1 day 
BDI-II 
X 13,14 
 
 
 
 
 
 
 
BPI 
X 13, 14 
 
 
 
 
 
 
 
TLFB Interview 
X 13 
 
 
 
 
 
 
 
Concomitant Medications 
X 7, 13 
X 
X 
X 
X 
X 
X 
X 
AE Assessment 8 
X 13 
X 
X 
X 
X 
X 
X 
X 
Day -1 Criteria Reviewed 
 
 
 
 
X 9 
X 9 
X 9 
X 10 
SUBOXONE SL film administration 11 
 
X 
X 16 
X 16 
X 12 
X 12 
X 12 
X 12 
EQ-5D-5L 
X 13 
 
 
 
 
 
 
 
SF-36v2 
X 13 
 
 
 
 
 
 
 
Health Insurance 
X 13 
 
 
 
 
 
 
 
HCRU 
X 13 
 
 
 
 
 
 
 
TEA 
X 
 
 
 
 
 
 
 
AE = adverse event; BDI-II = Beck Depression Inventory II; BMI = body mass index; BPI = Brief Pain Inventory Short Form; COWS = Clinical Opiate 
Withdrawal Scale; eC-SSRS =  electronic Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; EQ-5D-5L =  EuroQol EQ-5D-5L;; 
HCRU = Healthcare resource utilization; IXRS=Interactive voice/web response system; MSQ =  Medication Satisfaction Questionnaire; SF-36v2 = 36-
Item Short Form Health Survey, Version 2; SL = sublingual; SOWS = subjective opiate withdrawal scale; TEA = Treatment Effectiveness Assessment; 
TLFB = Timeline Followback; VAS = Visual Analog Scale 
 
1. A complete medical and psychiatric history, including use of tobacco, drugs of abuse, alcohol and caffeine.  Update demographics for roll-over subjects. 
2. Complete examination (excluding pelvic, breast, and rectal), including general appearance, skin, head, eyes, ears, nose, throat, neck, thyroid, 
chest/lungs, heart, abdomen, lymph nodes, extremities, and a brief neurological assessment.   
3. Includes blood pressure (BP; supine ≥ 3 minutes), pulse oximetry, pulse rate, respiratory rate, oral temperature, and height (screening visit only).  Vital 
signs will be assessed within < 60 minutes before administration of SUBOXONE sublingual film. 


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4. 
Must be performed prior to labs 
5. Only for female subjects who are of childbearing potential (not postmenopausal or surgically sterile for at least 1 year). 
6. Assessments should be performed prior to each SUBOXONE SL film dosing and at approximately the same time each day (±2 hours).   
7. Include a review of previous (within 30 days prior to screen) and ongoing medications. 
8. A PK sample will be taken as soon as possible after any SAE is reported.  If possible, an additional sample should be collected when the SAE has been 
resolved. 
9. This visit becomes Day -1 if the following criteria are met: 
• 
No allergic reaction to SUBOXONE sublingual film 
• 
Daily dose of SUBOXONE sublingual film between 8 mg/2 mg - 24 mg/6 mg (inclusive) buprenorphine/naloxone. 
• 
COWS score of ≤ 12 
• 
Opioid Craving VAS score of ≤ 20 mm 
If Day -1 criteria are met, the subject will be scheduled the following day (Injection Visit 1/Day 1) to receive the first injection of RBP-6000 after 
enrollment criteria are met.  
10. If Day -1 criteria are not met after 14 days of SUBOXONE sublingual film treatment, and a subject still has significant withdrawal signs/symptoms and 
opioid cravings (COWS score >12 and Opioid Craving VAS >20 mm), they will not be eligible to continue in the study.  They will be provided with 
information on the options for opioid use disorder treatment. 
11. SUBOXONE SL film dosing should take place at the same time of day (± 2 hours).   
12. Subjects should not take their dose of SUBOXONE SL film until after it has been determined if they have met Day -1 criteria (footnote #10). 
13. RB-US-13-0001 roll-over subjects study procedures completed at EOS/Day 169 will serve as the screening assessments for Protocol RB-US-13-0003 
14. Roll-over subjects who did not complete the BDI-II and the BPI at EOS/Day 169 visit will complete these assessments at Screening for Protocol RB-
US-13-0003 only after consent for the RB-US-13-0003 is obtained. 
15. For roll-over subjects only and at the Investigator’s discretion: Induction can begin on the day of screening for subjects who meet study criteria. 
16. Subjects with a score for COWS of >12, or subjects reporting opioid withdrawal signs/symptoms overnight, may receive a dose of an additional 4 mg.  
If the COWS score is still >12 one hour later, another 4 mg dose can be given.  Subjects should not exceed a maximum dose of 16 mg/4 mg for 
Induction Day 2, or 24 mg/6 mg on subsequent days.   
 


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Appendix 2 
Schedule of Events – RBP-6000 Injection 1 – 3 Visits 
Evaluation 
Inj 1 
Post Inj 1 Assessments 
 
Inj 2 
Post 
Inj 2 
24hrs 
Post 
Inj 2 
Inj 3 
Post 
Inj 3 
24hrs 
Post 
Inj 3 
Wk1 
D 
1 
Wk1 
D 
2 
Wk2 
D 
8 
Wk3 
D 
15 
Wk4 
D 
22 
Wk5 
D 
29 
Wk5 
D 
30 
Wk7 
D 
43 
Wk9 
D 
57 
Wk9 
D 
58 
W11 
D 
71 
Window  
 
+1 
±2 
±2 
±2 
-2/ +4 
+1 
±4 
-2/ +4 
+1 
-2/ +4 
IWRS 
X 
 
 
 
 
X 
 
 
X 
 
 
Enrollment 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs 1 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
Body Weight 
X 
 
 
 
 
 
 
 
 
 
 
BMI Calculation 
X 
 
 
 
 
 
 
 
 
 
 
Hip-to-Waist Ratio 
X 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 2 
(supine > 10 min) 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
Hematology/ Serum Chemistry 3 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
Hormone Panel 3 
X 
 
 
 
 
 
 
 
 
 
 
Urinalysis 3 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
Urine Pregnancy Test 4 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
Urine Drug Screen 5 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
PK Sampling (Roll-over patients only) 6  
X 
 
 
X 
 
X 
 
X 
X 
 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X13 
X 
X 
X13 
X 
AE Assessment 7 
X 
X 
X 
X 
X 
X 
X13 
X 
X 
X13 
X 
eC-SSRS (Since last-visit-version) 7 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
TLFB Interview 7 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
Opioid Craving VAS  7 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
COWS 7 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
SOWS 7 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
BDI-II 7 
X 
 
 
 
 
X 
 
 
X 
 
 
BPI  7 
X 
 
 
 
 
X 
 
 
X 
 
 
RBP-6000 Injection 
X 
 
 
 
 
X 
 
 
X 
 
 
Injection Site Grading Scale 8 
X 
X 
 
 
 
X 
 
 
X 
 
 
Injection Site Pain VAS 9 
X 
 
 
 
 
X 
 
 
X 
 
 


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Evaluation 
Inj 1 
Post Inj 1 Assessments 
 
Inj 2 
Post 
Inj 2 
24hrs 
Post 
Inj 2 
Inj 3 
Post 
Inj 3 
24hrs 
Post 
Inj 3 
Wk1 
D 
1 
Wk1 
D 
2 
Wk2 
D 
8 
Wk3 
D 
15 
Wk4 
D 
22 
Wk5 
D 
29 
Wk5 
D 
30 
Wk7 
D 
43 
Wk9 
D 
57 
Wk9 
D 
58 
W11 
D 
71 
Window  
 
+1 
±2 
±2 
±2 
-2/ +4 
+1 
±4 
-2/ +4 
+1 
-2/ +4 
Injection Site Evaluation 10 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
Behavioral Therapy 11 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
EQ-5D-5L 7 
X 
 
 
 
 
 
 
 
X 
 
 
SF-36v2 7 
X 
 
 
 
 
 
 
 
X 
 
 
MSQ 7 
 
 
 
 
 
 
 
 
X 
 
 
Health Insurance  
X 
 
 
 
 
X 
 
 
X 
 
 
HCRU  
X 
 
 
 
 
X 
 
 
X 
 
 
TEA 
X 
 
 
 
 
X 
 
 
X 
 
 
ASI Lite 
X 
 
 
 
 
 
 
 
X12 
 
 
AE = adverse event; ASI = Addiction Severity Index; BDI-II = Beck Depression Inventory II; BMI = body mass index; BPI = Brief Pain Inventory Short Form; 
COWS = Clinical Opiate Withdrawal Scale; eC-SSRS = electronic Columbia Suicide Severity Rating Scale; D = Day; ECG = electrocardiogram; EQ-5D-5L =  
EuroQol EQ-5D-5L; HCRU = Healthcare resource utilization; Inj. = injection; IXRS=Interactive voice/web response system; MSQ =  Medication Satisfaction 
Questionnaire; PK = pharmacokinetic/pharmacokinetics; SF-36v2 = 36-Item Short Form Health Survey, Version 2; SC = subcutaneous; SOWS = subjective 
opiate withdrawal scale; TEA = Treatment Effectiveness Assessment; TLFB = Timeline Followback; VAS = Visual Analog Scale 
 
1. Includes blood pressure, pulse oximetry, pulse rate, respiratory rate, and oral temperature which must be taken after subject is supine ≥ 3 minutes. On 
injection day 1, vital signs will be taken ≤ 60 minutes prior to SC injection, and then 0.5 (± 15 minutes), and 2 hours post SC injection (± 15 minutes). 
For all subsequent injection days, vital signs will be taken ≤ 60 minutes prior to SC injection, and 1 hour post SC injection (± 15 minutes). For non-
injection days, vital signs will be taken at approximately the same time of day as the Day 1 pre-injection vital signs. 
2. On Injection day 1, an ECG will be performed ≤ 60 minutes prior to SC injection, and then 0.5 (± 15 minutes),and 2 hours post SC injection (± 30 
minutes). For all subsequent injection days, an ECG will be recorded ≤ 60 minutes prior to SC injection, and 1 hour post SC injection (± 30 minutes). 
For non-injection days, an ECG will be performed at approximately the same time of day as the Day 1 pre-injection ECG. All ECGs must be performed 
prior to laboratory assessments. 
3. On injection days blood and urine samples will be taken ≤ 60 minutes prior to SC injection and after the ECG has been performed. 
4. Only for female subjects who are of childbearing potential (not postmenopausal or surgically sterile for at least 1 year). 
5. An additional urine drug screen can be done if use is suspected.  Oxycodone may not show up in all opiate assays and should be assessed separately. 
6. PK samples taken for roll-over subjects only. See PK table (Appendix 6) for exact time points. However, a PK sample should be taken as soon as 
possible after any SAE is reported regardless if the patient is de novo or roll-over. If possible, an additional sample should be collected when the SAE 
has been resolved.  
7. Assessments should be performed prior to RBP-6000 injection and at approximately the same time each day ±2 hours. 


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8. Local injection site grading will be performed at time of SC injection (within 10 minutes), 1 hour (± 15 minutes). For Injection 1 only, the local injection 
site grading will also be taken 24 hours (±4 hours) post SC injection. 
9. Injection Site Pain VAS will be completed by the subject within 1 minute after the completion of the injection and then at 5, 10, 15, 30, and 60 minutes 
(± 5 minutes) post-completion of injection. 
10. Injection site will be evaluated for evidence of attempted removal.   
11. Additional unscheduled visits for behavioral therapy may be added at the Investigator’s discretion.  
12. Collect information for the Employment/Support Status, Alcohol, Drug, Legal, Family/Social, and Psychological section only. Follow-up version of the 
questionnaire (only circled items, no lifetime recall). 
13. Subjects should be contacted by telephone at 24 hrs (± 4 hours) and will be assessed for AEs and any changes to Con Meds. Subjects are not required to 
return to the site unless the investigator deems it medically necessary. 
 
 


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Appendix 3 
Schedule of Events – RBP-6000 Injection 4 – 6 Visits for all Subjects and End of 
Study/Early Termination and Follow-Up Visits for Roll-over Subjects 
Evaluation 
Inj 4 
Post 
Inj 4 
24hrs 
Post 
Inj 4 
Inj 5 
Post 
Inj 5 
24hrs 
Post 
Inj 5 
Inj 6 
Post 
Inj 6 
24hrs 
EOS/ET 13 
Safety  
Follow-Up 20 
Wk13 
D 
85 
Wk13 
D 
86 
W15 
D 
99 
Wk17 
D 
113 
Wk17 
D 
114 
Wk19 
D 
127 
Wk21 
D 
141 
Wk21 
D 
142 
Wk25 
D 
169 
Wk29 
D 
197 
Window  
-2/ +4 
+1 
±4 
-2/ +4 
+1 
±4 
-2/ +4 
+1 
-2/ +4 
-2/ +4 
IWRS 
X 
 
 
X 
 
 
X 
 
X14 
 
Vital Signs 1 
X 
 
X 
X 
 
X 
X 
 
X 
 
Body Weight 
X 
 
 
 
 
 
X 
 
X 
 
BMI Calculation 
X 
 
 
 
 
 
X 
 
X 
 
Hip-to-Waist Ratio 
X 
 
 
 
 
 
X 
 
X 
 
12-lead ECG (supine > 10 min) 2 
X 
 
X 
X 
 
X 
X 
 
X 
 
Hematology/ Serum Chemistry 3 
X 
 
X 
X 
 
X 
X 
 
X 
 
Hormone Panel 3 
X 
 
 
 
 
 
X 
 
X 
 
Urinalysis 3 
X 
 
X 
X 
 
X 
X 
 
X 
 
Urine Pregnancy  
Test 3 
X 
 
X 
X 
 
X 
X 
 
X 
 
Serum Pregnancy Test 4 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screen 5 
X 
 
X 
X 
 
X 
X 
 
X 
 
PK Sampling (Roll-over patients only) 6 
X 
 
X 
X 
 
X 
X 
 
X 
 
Concomitant Medications 
X 
  X 19 
X 
X 
X 19 
X 
X 
X 19 
X 
X 
AE Assessment 8 
X 
  X 19 
X 
X 
X 19 
X 
X 
X 19 
X 
X 
eC-SSRS (Since last-visit-version) 8 
X 
 
X 
X 
 
X 
X 
 
X 
 
TLFB Interview 8 
X 
 
X 
X 
 
X 
X 
 
X 
 
Opioid Craving VAS  8 
X 
 
X 
X 
 
X 
X 
 
X 
 
COWS  8 
X 
 
X 
X 
 
X 
X 
 
X 
 
SOWS  8 
X 
 
X 
X 
 
X 
X 
 
X 
 


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Evaluation 
Inj 4 
Post 
Inj 4 
24hrs 
Post 
Inj 4 
Inj 5 
Post 
Inj 5 
24hrs 
Post 
Inj 5 
Inj 6 
Post 
Inj 6 
24hrs 
EOS/ET 13 
Safety  
Follow-Up 20 
Wk13 
D 
85 
Wk13 
D 
86 
W15 
D 
99 
Wk17 
D 
113 
Wk17 
D 
114 
Wk19 
D 
127 
Wk21 
D 
141 
Wk21 
D 
142 
Wk25 
D 
169 
Wk29 
D 
197 
Window  
-2/ +4 
+1 
±4 
-2/ +4 
+1 
±4 
-2/ +4 
+1 
-2/ +4 
-2/ +4 
BDI-II 8 
X 
 
 
X 
 
 
X 
 
X 
 
BPI 8 
X 
 
 
X 
 
 
X 
 
X 
 
RBP-6000 Injection 
X 
 
 
X 
 
 
X 
 
 
 
Injection Site  
Grading Scale 9 
X 
 
 
X 
 
 
X 
 
 
 
Injection Site Pain VAS 10 
X 
 
 
X 
 
 
X 
 
 
 
Injection Site Evaluation 11 
X 
 
X 
X 
 
X 
X 
 
X 
 
Behavioral Therapy 12 
X 
 
X 
X 
 
X 
X 
 
X 
 
EQ-5D-5L 8 
 
 
 
 
 
 
X 
 
X 
 
SF-36v2 8 
 
 
 
 
 
 
X 
 
X 
 
MSQ 8 
 
 
 
 
 
 
X 
 
X 
 
Health Insurance 8 
X 
 
 
X 
 
 
X 
 
X 
 
HCRU  8 
X 
 
 
X 
 
 
X 
 
X 
 
TEA 8 
X 
 
 
X 
 
 
X 
 
X 
 
ASI Lite 
 
 
 
 
 
 
X17 
 
X18 
 
Physical Examination 15 
 
 
 
 
 
 
 
 
X 
 
Review of Treatment Options 16 
 
 
 
X 
 
 
X 
 
X 
 
Alternative Treatment Agreed 16 
 
 
 
 
 
 
 
 
X 
 
AE = adverse event; ASI = Addiction Severity Index; BDI-II = Beck Depression Inventory II; BMI = body mass index; BPI = Brief Pain Inventory Short Form; 
COWS = Clinical Opiate Withdrawal Scale; eC-SSRS = electronic Columbia Suicide Severity Rating Scale; D = Day; ECG = electrocardiogram; EOS/ET = End 
of Study/Early Termination; EQ-5D-5L =  EuroQol EQ-5D-5L; HCRU = Healthcare resource utilization; Inj. = injection; IXRS=Interactive voice/web response 
system; MSQ =  Medication Satisfaction Questionnaire; PK = pharmacokinetic/pharmacokinetics; SF-36v2 = 36-Item Short Form Health Survey, Version 2; SC 
= subcutaneous; SL = sublingual; SOWS = subjective opiate withdrawal scale; TEA = Treatment Effectiveness Assessment; TLFB = Timeline Followback; 
VAS = Visual Analog Scale. 
1. Includes blood pressure, pulse oximetry, pulse rate, respiratory rate, and oral temperature which must be taken after subject is supine ≥ 3 minutes. On 
days injections 2-12 are given, vital signs will be taken ≤ 60 minutes prior to SC injection, and 1 hour post SC injection (± 15 minutes). For non-
injection days, vital signs will be taken at approximately the same time of day as the Day 1 pre-injection vital signs. 


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2. On days injections 2-12 are given, an ECG will be performed ≤ 60 minutes prior to SC injection, and 1 hour post SC injection (± 30 minutes). For non-
injection days, an ECG will be performed at approximately the same time of day as the Day 1 pre-injection ECG. All ECGs must be performed prior to 
labs and PK samples. 
3. On injection days, blood and urine samples will be taken ≤ 60 minutes prior to SC injection and after the ECGs has been performed. 
4. Only for female subjects who are of childbearing potential (not postmenopausal or surgically sterile for at least 1 year). 
5. An additional urine drug screen can be done if use is suspected.  Oxycodone may not show up in all opiate assays and should be assessed separately. 
6. PK samples taken for roll-over subjects only. See PK table (Appendix 6) for exact time points. However, a PK sample should be taken as soon as 
possible after any SAE is reported regardless if the patient is de novo or roll-over. If possible, an additional sample should be collected when the SAE 
has been resolved.  
7. A PK sample will be taken as soon as possible after any SAE is reported.  If possible, an additional sample should be collected when the SAE has been 
resolved. 
8. Assessments should be performed prior to RBP-6000 injection and at approximately the same time each day ±2 hours. 
9. Local injection site grading will be performed at time of SC injection (within 10 minutes) and 1 hour (± 15 minutes.) 
10. Injection Site Pain VAS will be completed by the subject within 1 minute after completion of the injection and then at 5, 10, 15, 30, and 60 (± 5 
minutes) post-completion of injection. 
11. Injection site will be evaluated for evidence of attempted removal.   
12. Additional unscheduled visits for behavioral therapy may be added at the Investigator's discretion. 
13. For roll-over subjects, the procedures at Week 25/Day 169 will serve as the EOS assessments.  For de novo subjects who discontinued participation in 
the study after receiving RBP-6000, the procedures at Week 25/Day 169 will serve as the ET assessments. 
14. IXRS contacted to confirm study completion or discontinuation status (date and reason for discontinuation). 
15. Complete examination (excluding pelvic, breast, and rectal), including general appearance, skin, head, eyes, ears, nose, throat, neck, thyroid, 
chest/lungs, heart, abdomen, lymph nodes, extremities, and a brief neurological assessment.   
16. Subject’s alternative treatment options should be assessed up to two months before EOS. At the EOS visit, if eligible, subjects may enroll in study 
INDV-6000-301. Alternatively, subjects can start an optional 4 week SUBOXONE program (based on Investigator’s discretion).  
17. Collect information for the Employment/Support Status, Alcohol, Drug, Legal, Family/Social, and Psychological section only. Follow-up version of the 
questionnaire (only circled items, no lifetime recall). 
18. Complete all ASI-Lite scales. Follow-up version of the questionnaire (only circled items, no lifetime recall). 
19. Subjects should be contacted by telephone at 24 hrs (± 4 hours) and will be assessed for AEs and any changes to Con Meds. Subjects are not required to 
return to the site unless the investigator deems it medically necessary. 
20. Subjects should be contacted by telephone in order to assess for AEs or Con Meds. Subjects are not required to return to the site unless the investigator 
deems it medically necessary. Subjects enrolled onto INDV-6000-301 are not required to be contacted. 
 
  
 
 


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Appendix 4 
Schedule of Events – RBP-6000 Injection 7 – 9 Visits for de novo Subjects  
Evaluation 
Inj 7 
Post Inj 7 
24hrs 
Inj 8 
Post Inj 8 
24hrs 
Inj 9 
Post Inj 9 
24hrs 
Wk25 
D169 
Wk25 
D170 
Wk29 
D197 
Wk29 
D198 
Wk33 
D225 
Wk33 
D226 
Window  
-2/ +4 
+1 
-2/ +4 
+1 
-2/ +4 
+1 
IWRS 
X 
 
X 
 
X 
 
Vital Signs 1 
X 
 
X 
 
X 
 
Body Weight 
X 
 
 
 
 
 
BMI Calculation 
X 
 
 
 
 
 
Hip-to-Waist Ratio 
X 
 
 
 
 
 
12-lead ECG 2 
(supine > 10 min)  
X 
 
X 
 
X 
 
Hematology/ Serum Chemistry 3 
X 
 
X 
 
X 
 
Hormone Panel 3 
X 
 
 
 
 
 
Urinalysis  3 
X 
 
X 
 
X 
 
Urine Pregnancy Test  4 
X 
 
X 
 
X 
 
Urine Drug Screen 5 
X 
 
X 
 
X 
 
Concomitant Medications  
X 
X 13 
X 
X 13 
X 
X 13 
AE Assessment 6 
X 
X 13 
X 
X 13 
X 
X 13 
eC-SSRS (Since last-visit-version) 7 
X 
 
X 
 
X 
 
TLFB Interview 7 
X 
 
X 
 
X 
 
Opioid Craving  
VAS 7 
X 
 
X 
 
X 
 
COWS 7 
X 
 
X 
 
X 
 
SOWS 7 
X 
 
X 
 
X 
 
BDI-II 7 
X 
 
X 
 
X 
 
BPI 7 
X 
 
X 
 
X 
 
RBP-6000 Injection 
X 
 
X 
 
X 
 


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Evaluation 
Inj 7 
Post Inj 7 
24hrs 
Inj 8 
Post Inj 8 
24hrs 
Inj 9 
Post Inj 9 
24hrs 
Wk25 
D169 
Wk25 
D170 
Wk29 
D197 
Wk29 
D198 
Wk33 
D225 
Wk33 
D226 
Window  
-2/ +4 
+1 
-2/ +4 
+1 
-2/ +4 
+1 
Injection Site Grading Scale 8 
X 
 
X 
 
X 
 
Injection Site Pain VAS 9 
X 
 
X 
 
X 
 
Injection Site Evaluation 10 
X 
 
X 
 
X 
 
Behavioral Therapy 11 
X 
 
X 
 
X 
 
EQ-5D-5L 7 
 
 
 
 
X 
 
SF-36v2 7 
 
 
 
 
X 
 
MSQ 7 
 
 
 
 
X 
 
Health Insurance 7 
X 
 
X 
 
X 
 
HCRU  7 
X 
 
X 
 
X 
 
TEA 7 
X 
 
X 
 
X 
 
ASI Lite 
 
 
 
 
X12 
 
 
AE = adverse event; ASI = Addiction Severity Index; BDI-II = Beck Depression Inventory II; BMI = body mass index; BPI = Brief Pain Inventory Short 
Form; COWS = Clinical Opiate Withdrawal Scale; eC-SSRS = electronic Columbia Suicide Severity Rating Scale; D = Day; ECG = electrocardiogram; EQ-
5D-5L =  EuroQol EQ-5D-5L; HCRU = Healthcare resource utilization; Inj. = injection; IXRS=Interactive voice/web response system; MSQ =  Medication 
Satisfaction Questionnaire; PK = pharmacokinetic/pharmacokinetics; SF-36v2 = 36-Item Short Form Health Survey, Version 2; SC = subcutaneous; SOWS 
= subjective opiate withdrawal scale; TEA = Treatment Effectiveness Assessment; TLFB = Timeline Followback; VAS = Visual Analog Scale 
 
1. Includes blood pressure, pulse oximetry, pulse rate, respiratory rate, and oral temperature which must be taken after subject is supine ≥ 3 minutes. On 
days injections 2-12 are given, vital signs will be taken ≤ 60 minutes prior to SC injection, and 1 hour post SC injection (± 15 minutes). For non-
injection days, vital signs will be taken at approximately the same time of day as the Day 1 pre-injection vital signs. 
2. On days injections 2-12 are given, an ECG will be recorded ≤ 60 minutes prior to SC injection, and 1 hour post SC injection (± 30 minutes). For non-
injection days, an ECG will be performed at approximately the same time of day as the Day 1 pre-injection ECG. All ECGs must be performed prior to 
labs and PK samples. 
3. On injection days, blood and urine samples will be taken ≤ 60 minutes prior to SC injection and after the ECGs has been performed. 
4. Only for female subjects who are of childbearing potential (not postmenopausal or surgically sterile for at least 1 year). 
5. An additional urine drug screen can be done if use is suspected.  Oxycodone may not show up in all opiate assays and should be assessed separately. 
6. A PK sample will be taken as soon as possible after any SAE is reported.  If possible, an additional sample should be collected when the SAE has been 
resolved. 
7. Assessments should be performed prior to RBP-6000 injection and at approximately the same time each day ±2 hours. 


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     04 August 2016 
 
 
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8. Local injection site grading will be performed at time of SC injection (within 10 minutes) and 1 hour (± 15 minutes).  
9. Injection Site Pain VAS will be completed by the subject within 1 minute after the completion of the injection and then at 5, 10, 15, 30, and 60 minutes 
(± 5 minutes) post-completion of injection. 
10. Injection site will be evaluated for evidence of attempted removal.   
11. Additional unscheduled visits for behavioral therapy may be added at the Investigator’s discretion. 
12. Collect information for the Employment/Support Status, Alcohol, Drug, Legal, Family/Social, and Psychological section only. Follow-up version of the 
questionnaire (only circled items, no lifetime recall). 
13. Subjects should be contacted by telephone at 24 hrs (± 4 hours) and will be assessed for AEs and any changes to Con Meds. Subjects are not required to 
return to the site unless the investigator deems it medically necessary. 
 


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     04 August 2016 
 
 
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Appendix 5 
Schedule of Events – RBP-6000 Injection 10 – 12 Visits and End of Study/Early 
Termination Visit and Follow-Up for de novo Subjects  
Evaluation 
Inj 10 
Post Inj 
10 24hrs 
Inj 11 
Post Inj 
11 24hrs 
Inj 12 
Post Inj 
12 24hrs 
EOS/ET 12 
Safety 
Follow-Up 19 
Wk37 
D253 
Wk37 
D254 
Wk41 
D281 
Wk41 
D282 
Wk45 
D309 
Wk45 
D310 
Wk49 
D337 
Wk53 
D365 
Window  
-2/ +4 
+1 
-2/ +4 
+1 
-2/ +4 
+1 
-2/ +4 
-2/ +4 
IWRS 
X 
 
X 
 
X 
 
X13 
 
Vital Signs 1 
X 
 
X 
 
X 
 
X 
 
Body Weight 
X 
 
 
 
X 
 
X 
 
BMI Calculation 
X 
 
 
 
X 
 
X 
 
Hip-to-Waist Ratio 
X 
 
 
 
X 
 
X 
 
12-lead ECG (supine > 10 min) 2 
X 
 
X 
 
X 
 
X 
 
Hematology/ Serum Chemistry 3  
X 
 
X 
 
X 
 
X 
 
Hormone Panel 3 
X 
 
 
 
X 
 
X 
 
Urinalysis 3 
X 
 
X 
 
X 
 
X 
 
Urine Pregnancy Test 4 
X 
 
X 
 
X 
 
X 
 
Serum Pregnancy Test 4 
 
 
 
 
 
 
 
 
Urine Drug Screen 5 
X 
 
X 
 
X 
 
X 
 
Concomitant Medications 
X 
X18 
X 
X18 
X 
X18 
X 
X 
AE Assessment 6 
X 
X18 
X 
X18 
X 
X18 
X 
X 
eC-SSRS (Since last-visit-version) 7 
X 
 
X 
 
X 
 
X 
 
TLFB Interview 7 
X 
 
X 
 
X 
 
X 
 
Opioid Craving VAS 7 
X 
 
X 
 
X 
 
X 
 
COWS 7 
X 
 
X 
 
X 
 
X 
 
SOWS 7 
X 
 
X 
 
X 
 
X 
 
BDI-II 7 
X 
 
X 
 
X 
 
X 
 
BPI 7 
X 
 
X 
 
X 
 
X 
 


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Evaluation 
Inj 10 
Post Inj 
10 24hrs 
Inj 11 
Post Inj 
11 24hrs 
Inj 12 
Post Inj 
12 24hrs 
EOS/ET 12 
Safety 
Follow-Up 19 
Wk37 
D253 
Wk37 
D254 
Wk41 
D281 
Wk41 
D282 
Wk45 
D309 
Wk45 
D310 
Wk49 
D337 
Wk53 
D365 
Window  
-2/ +4 
+1 
-2/ +4 
+1 
-2/ +4 
+1 
-2/ +4 
-2/ +4 
RBP-6000 Injection 
X 
 
X 
 
X 
 
 
 
Injection Site Grading Scale 8 
X 
 
X 
 
X 
 
 
 
Injection Site Pain VAS 9 
X 
 
X 
 
X 
 
 
 
Injection Site Evaluation 10 
X 
 
X 
 
X 
 
X 
 
Behavioral Therapy 11 
X 
 
X 
 
X 
 
X 
 
EQ-5D-5L 7 
 
 
 
 
X 
 
X 
 
SF-36v2  7 
 
 
 
 
X 
 
X 
 
MSQ 7 
 
 
 
 
X 
 
X 
 
Health Insurance 7 
X 
 
X 
 
X 
 
X 
 
HCRU  7 
X 
 
X 
 
X 
 
X 
 
TEA 7 
X 
 
X 
 
X 
 
X 
 
ASI Lite 
 
 
 
 
X16 
 
X17 
 
Physical Examination 14 
 
 
 
 
 
 
X 
 
Review of Treatment Options 15 
 
 
X 
 
X 
 
X 
 
Alternative Treatment Agreed 15 
 
 
 
 
 
 
X 
 
 
AE = adverse event; ASI = Addiction Severity Index; BDI-II = Beck Depression Inventory II; BMI = body mass index; BPI = Brief Pain Inventory Short Form; 
COWS = Clinical Opiate Withdrawal Scale; eC-SSRS = electronic Columbia Suicide Severity Rating Scale; D = Day; ECG = electrocardiogram; EOS/ET = End 
of Study/Early Termination;EQ-5D-5L =  EuroQol EQ-5D-5L; HCRU = Healthcare resource utilization; Inj. = injection; IXRS=Interactive voice/web response 
system; MSQ =  Medication Satisfaction Questionnaire; PK = pharmacokinetic/pharmacokinetics; SF-36v2 = 36-Item Short Form Health Survey, Version 2; SC 
= subcutaneous; SL = sublingual; SOWS = subjective opiate withdrawal scale; TEA = Treatment Effectiveness Assessment; TLFB = Timeline Followback; 
VAS = Visual Analog Scale. 
 
1. Includes blood pressure, pulse oximetry, pulse rate, respiratory rate, and oral temperature which must be taken after subject is supine ≥ 3 minutes. On days 
injections 2-12 are given, vital signs will be taken ≤ 60 minutes prior to SC injection, and 1 hour post SC injection (± 15 minutes). For non-injection days, 
vital signs will be taken at approximately the same time of day as the Day 1 pre-injection vital signs. 


RBP-6000 
 
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Clinical Study Protocol: RB-US-13-0003 
 
     04 August 2016 
 
 
Confidential 
Page 97 of 171 
2. On days injections 2-12 are given, an ECG will be recorded ≤ 60 minutes prior to SC injection, and 1 hour post SC injection (± 30 minutes). For non-
injection days, an ECG will be performed at approximately the same time of day as the Day 1 pre-injection ECG. All ECGs must be performed prior to labs 
and PK samples. 
3. On injection days, blood and urine samples will be taken ≤ 60 minutes prior to SC injection and after the ECGs has been performed. 
4. Only for female subjects who are of childbearing potential (not postmenopausal or surgically sterile for at least 1 year). 
5. An additional urine drug screen can be done if use is suspected.  Oxycodone may not show up in all opiate assays and should be assessed separately. 
6. A PK sample will be taken as soon as possible after any SAE is reported.  If possible, an additional sample should be collected when the SAE has been 
resolved. 
7. Assessments should be performed prior to RBP-6000 injection and at approximately the same time each day ±2 hours. 
8. Local injection site grading will be performed at time of SC injection (within 10 minutes) and 1 hour (± 15 minutes).  
9. Injection Site Pain VAS will be completed by the subject within 1 minute after the completion of the injection and then at 5, 10, 15, 30, and 60 minutes (± 5 
minutes) post-completion of injection. 
10. Injection site will be evaluated for evidence of attempted removal. 
11. Additional unscheduled visits for behavioral therapy may be added at the Investigator’s discretion. 
12. For de novo subjects who discontinue participation in this study after receiving RBP-6000, the procedures at Week 49/Day 337 will serve as the ET 
assessments. 
13. IXRS contacted to confirm study completion or discontinuation status (date and reason for discontinuation). 
14. Complete examination (excluding pelvic, breast, and rectal), including general appearance, skin, head, eyes, ears, nose, throat, neck, thyroid, chest/lungs, 
heart, abdomen, lymph nodes, extremities, and a brief neurological assessment.   
15. Subject’s alternative treatment options should be assessed up to two months before EOS. At the EOS visit, if eligible, subjects may enroll in study INDV-
6000-301. Alternatively, subjects can start an optional 4 week SUBOXONE program (based on Investigator’s discretion).  
16. Collect information for the Employment/Support Status, Alcohol, Drug, Legal, Family/Social, and Psychological section only. Follow-up version of the 
questionnaire (only circled items, no lifetime recall). 
17. Complete all ASI-Lite scales. Follow-up version of the questionnaire (only circled items, no lifetime recall). 
18. Subjects should be contacted by telephone at 24 hrs (± 4 hours) and will be assessed for AEs and any changes to Con Meds. Subjects are not required to 
return to the site unless the investigator deems it medically necessary. 
19. Subjects should be contacted by telephone in order to assess for AEs or Con Meds. Subjects are not required to return to the site unless the investigator 
deems it medically necessary. Subjects enrolled onto INDV-6000-301 are not required to be contacted.  
 


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Appendix 6 
Pharmacokinetic Sampling Schedule 
Sample 
Number1 
Sample 
Class 
Time 
Study Phase 
Comments 
1 
PK 
Day 1 
Treatment phase (SC) 
Within 1 hour prior to 1st SC injection  
2 
PK 
Day 15 
Treatment phase (SC) 
Post 1st SC injection 
3 
PK 
Day 29 
Treatment phase (SC) 
Within 1 hour prior to 2nd SC injection  
4 
PK 
Day 43 
Treatment phase (SC) 
Post 2nd SC injection 
5 
PK 
Day 57 
Treatment phase (SC) 
Within 1 hour prior to 3rd SC injection  
6 
PK 
Day 71 
Treatment phase (SC) 
Post 3rd SC injection 
7 
PK 
Day 85 
Treatment phase (SC) 
Within 1 hour prior to 4th SC injection  
8 
PK 
Day 99 
Treatment phase (SC) 
Post 4th SC injection 
9 
PK 
Day 113 
Treatment phase (SC) 
Within 1 hour prior to 5th SC injection 
10 
PK 
Day 127 
Treatment phase (SC) 
Post 5th SC injection 
11 
PK 
Day 141 
Treatment phase (SC) 
Within 1 hour prior to 6th SC injection 
12 
PK 
Day 169 or 
ET Visit 
Treatment phase (SC) 
Post 6th SC injection 
PK = pharmacokinetic/pharmacokinetics; SC = subcutaneous 
1  Blood samples for PK analysis will be collected from roll-over subjects only (not de novo). Once at least 75  
roll-over subjects have completed Injection 6 (Week 25, Day 169) no more PK samples will be required to be 
collected from the roll-over subjects for the duration of the study. 
However, for all subjects (de novo and roll-over), a PK sample will be taken as soon as possible after any SAE is 
reported. If possible, an additional sample should be collected when the SAE has been resolved. 
 


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Appendix 7 SUBOXONE® 
(Buprenorphine/Naloxone) 
Sublingual Film Full 
Prescribing Information 
HIGHLIGHTS OF PRESCRIBING INFORMATION 
These highlights do not include all the information needed to use 
SUBOXONE safely and effectively.  See full prescribing information for 
SUBOXONE. 
 
SUBOXONE® (buprenorphine and naloxone) sublingual film, for sublingual 
or buccal use  CIII 
Initial U.S. Approval: 2002 
----------------------------------RECENT MAJOR CHANGES--------------------------------- 
Dosage and Administration, Method 
      of Administration (2.3) 
 
 
 
09/2015 
Warnings and Precautions, Neonatal Opioid 
      Withdrawal Syndrome (5.5)  
 
 
06/2016 
----------------------------------INDICATIONS AND USAGE--------------------------------- 
SUBOXONE sublingual film is a partial-opioid agonist indicated for treatment 
of opioid dependence.  Prescription use of this product is limited under the 
Drug Addiction Treatment Act. (1) 
------------------------------DOSAGE AND ADMINISTRATION----------------------------- 
• For patients dependent on short-acting opioid products who are in opioid 
withdrawal; on Day 1, administer up to 8 mg/2 mg SUBOXONE sublingual 
film (in divided doses).  On Day 2, administer up to 16 mg/4 mg of 
SUBOXONE sublingual film as a single dose. (2.1) 
• For patients dependent on methadone or long-acting opioid products, 
induction onto sublingual buprenorphine monotherapy is recommended 
on Days 1 and 2 of treatment. (2.1) 
• For maintenance treatment, the target dosage of SUBOXONE sublingual 
film is usually 16 mg/4 mg as a single daily dose. (2.2) 
• Sublingual Administration: Place one film under the tongue, close to the 
base on the left or right side, and allow to completely dissolve.   
Buccal Administration: Place one film on the inside of the left or right 
cheek and allow to completely dissolve. 
• SUBOXONE sublingual film must be administered whole.  Do not cut, 
chew, or swallow SUBOXONE sublingual film (2.3) 
-----------------------------DOSAGE FORMS AND STRENGTHS---------------------------- 
Sublingual film:  2 mg buprenorphine with 0.5 mg naloxone, 4 mg 
buprenorphine with 1 mg naloxone, 8 mg buprenorphine with 2 mg naloxone 
and 12 mg buprenorphine with 3 mg naloxone. (3)  
-------------------------------------CONTRAINDICATIONS------------------------------------ 
Hypersensitivity to buprenorphine or naloxone. (4) 
-------------------------------WARNINGS AND PRECAUTIONS----------------------------- 
• Buprenorphine can be abused in a similar manner to other opioids. 
Clinical monitoring appropriate to the patient’s level of stability is 
essential. Multiple refills should not be prescribed early in treatment or 
without appropriate patient follow-up visits. (5.1)  
• Significant respiratory depression and death have occurred in association 
with buprenorphine, particularly when taken by the intravenous (IV) 
route in combination with benzodiazepines or other CNS depressants 
(including alcohol). (5.2) 
• Consider dose reduction of CNS depressants, SUBOXONE sublingual film, 
or both in situations of concomitant prescription. (5.3) 
• Store SUBOXONE sublingual film safely out of the sight and reach of 
children. Buprenorphine can cause severe, possibly fatal, respiratory 
depression in children. (5.4)   
• Neonatal opioid withdrawal syndrome (NOWS) is an expected and 
treatable outcome of prolonged use of opioids during pregnancy (5.5) 
• Chronic administration produces opioid-type physical dependence.  
Abrupt discontinuation or rapid dose taper may result in opioid 
withdrawal syndrome. (5.6) 
• Monitor liver function tests prior to initiation and during treatment and 
evaluate suspected hepatic events. (5.7) 
• Do not administer SUBOXONE sublingual film to patients with known 
hypersensitivity to buprenorphine or naloxone. (5.8) 
• An opioid withdrawal syndrome is likely to occur with parenteral misuse 
of SUBOXONE sublingual film by individuals physically dependent on full 
opioid agonists, or by sublingual or buccal administration before the 
agonist effects of other opioids have subsided. (5.9) 
• SUBOXONE sublingual film is not appropriate as an analgesic. There have 
been reported deaths of opioid naïve individuals who received a 2 mg 
sublingual dose. (5.10) 
• Buprenorphine/naloxone products are not recommended in patients 
with severe hepatic impairment and may not be appropriate for patients 
with moderate hepatic impairment (5.11) 
• Caution patients about the risk of driving or operating hazardous 
machinery. (5.12) 
-------------------------------------ADVERSE REACTIONS------------------------------------- 
Adverse events commonly observed with the sublingual/buccal 
administration of the SUBOXONE sublingual film were oral hypoesthesia, 
glossodynia, oral mucosal erythema, headache, nausea, vomiting, 
hyperhidrosis, constipation, signs and symptoms of withdrawal, insomnia, 
pain, and peripheral edema. (6.1)     
To report SUSPECTED ADVERSE REACTIONS, contact Indivior Inc. at 1-877-
782-6966 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 
--------------------------------------DRUG INTERACTIONS----------------------------------- 
• Monitor patients starting or ending CYP3A4 inhibitors or inducers for 
potential over or under dosing.  (7.1)  
• Use caution in prescribing SUBOXONE sublingual film for patients 
receiving benzodiazepines or other CNS depressants and warn patients 
against concomitant self-administration/misuse. (7.3) 
---------------------------------USE IN SPECIFIC POPULATIONS---------------------------- 
• 
Pregnancy: Based on animal data, may cause fetal harm. (8.1) 
• 
Nursing mothers: Caution should be exercised when administered to a 
nursing woman. (8.3) 
• 
Safety and effectiveness of SUBOXONE sublingual film in patients below 
the age of 16 has not been established. (8.4) 
• 
Administer SUBOXONE sublingual film with caution to elderly or 
debilitated patients. (8.5) 
• 
Buprenorphine/naloxone products are not recommended in patients 
with severe hepatic impairment and may not be appropriate for 
patients with moderate hepatic impairment.  (8.6) 
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. 
Revised:  6/2016


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FULL PRESCRIBING INFORMATION: CONTENTS* 
1 
INDICATIONS AND USAGE 
2 
DOSAGE AND ADMINISTRATION 
 
        2.1 
Induction 
 
        2.2 
Maintenance 
 
        2.3 
Method of Administration 
 
        2.4 
Clinical Supervision 
 
        2.5 
Patients With Hepatic Impairment 
 
        2.6 
Unstable Patients 
        2.7 
Stopping Treatment 
        2.8 
Switching Between Buprenorphine or 
Buprenorphine and Naloxone Sublingual Tablets 
and SUBOXONE Sublingual Film 
        2.9 
Switching Between SUBOXONE Sublingual Film 
Strengths 
        2.10 Switching Between Sublingual and Buccal Sites 
of  Administrations 
3 
DOSAGE FORMS AND STRENGTHS 
4 
CONTRAINDICATIONS 
5 
WARNINGS AND PRECAUTIONS 
        5.1 
Abuse Potential 
        5.2 
Respiratory Depression  
        5.3 
CNS Depression  
        5.4 
Unintentional Pediatric Exposure 
        5.5 
Neonatal Opioid Withdrawal Syndrome 
        5.6 
Dependence 
        5.7 
Hepatitis, Hepatic Events 
        5.8 
Allergic Reactions  
        5.9 
Precipitation of Opioid Withdrawal Signs and 
Symptoms 
        5.10 Use in Opioid Naïve Patients 
        5.11 Use in Patients With Impaired Hepatic Function 
        5.12 Impairment of Ability to Drive or Operate 
Machinery  
        5.13 Orthostatic Hypotension 
        5.14 Elevation of Cerebrospinal Fluid Pressure  
        5.15 Elevation of Intracholedochal Pressure 
        5.16 Effects in Acute Abdominal Conditions 
        5.17 General Precautions 
6 
ADVERSE REACTIONS 
        6.1 
Clinical Trials Experience 
        6.2 
Postmarketing Experience
 
7 
DRUG INTERACTIONS   
        7.1 
Cytochrome P-450 3A4 (CYP3A4) Inhibitors and 
Inducers 
 
        7.2 
Antiretrovirals 
 
        7.3 
Benzodiazepines 
8 
USE IN SPECIFIC POPULATIONS 
 
        8.1 
Pregnancy 
 
        8.3 
Nursing Mothers 
 
        8.4 
Pediatric Use 
 
        8.5 
Geriatric Use  
        8.6 
Hepatic Impairment 
        8.7  
Renal Impairment 
9 
DRUG ABUSE AND DEPENDENCE 
 
        9.1 
Controlled Substance 
        9.2 
Abuse 
 
        9.3 
Dependence 
10 
OVERDOSAGE 
11 
DESCRIPTION 
12 
CLINICAL PHARMACOLOGY 
 
        12.1 Mechanism of Action 
 
        12.2 Pharmacodynamics 
 
        12.3 Pharmacokinetics 
13 
NONCLINICAL TOXICOLOGY 
        13.1 Carcinogenesis, Mutagenesis, Impairment of 
Fertility 
16 
HOW SUPPLIED / STORAGE AND HANDLING 
17 
PATIENT COUNSELING INFORMATION 
        Safe Use 
        Disposal of Unused SUBOXONE Sublingual Films 
 
 
* 
Sections or subsections omitted from the full 
prescribing information are not listed. 


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Clinical Study Protocol: RB-US-13-0003 
 
04 August 2016 
 
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FULL PRESCRIBING INFORMATION 
1 
INDICATIONS AND USAGE 
SUBOXONE sublingual film is indicated for treatment of opioid dependence and should be used as part 
of a complete treatment plan to include counseling and psychosocial support.  
Under the Drug Addiction Treatment Act (DATA) codified at 21 U.S.C. 823(g), prescription use of this 
product in the treatment of opioid dependence is limited to physicians who meet certain qualifying 
requirements, and who have notified the Secretary of Health and Human Services (HHS) of their intent 
to prescribe this product for the treatment of opioid dependence and have been assigned a unique 
identification number that must be included on every prescription.   
2 
DOSAGE AND ADMINISTRATION 
2.1 
Induction  
Prior to induction, consideration should be given to the type of opioid dependence (i.e., long- or short-
acting opioid products), the time since last opioid use, and the degree or level of opioid dependence.  To 
avoid precipitating an opioid withdrawal syndrome, the first dose of buprenorphine/naloxone should be 
started only when objective signs of moderate withdrawal appear. 
On Day 1, an induction dosage of up to 8 mg/2 mg SUBOXONE sublingual film is recommended.  
Clinicians should start with an initial dose of 2 mg/0.5 mg or 4 mg/1 mg buprenorphine/naloxone and 
may titrate upwards in 2 or 4 mg increments of buprenorphine, at approximately 2-hour intervals, under 
supervision, to 8 mg/2 mg buprenorphine/naloxone based on the control of acute withdrawal 
symptoms.   
On Day 2, a single daily dose of up to 16 mg/4 mg SUBOXONE sublingual film is recommended.  
Because the exposure to naloxone is somewhat higher after buccal than after sublingual administration, 
it is recommended that the sublingual site of administration be used during induction to minimize 
exposure to naloxone, to reduce the risk of precipitated withdrawal. 
 
Medication should be prescribed in consideration of the frequency of visits. Provision of multiple refills 
is not advised early in treatment or without appropriate patient follow-up visits. 
Patients dependent on methadone or long-acting opioid products 
Patients dependent upon methadone or long-acting opioid products may be more susceptible to 
precipitated and prolonged withdrawal during induction than those on short-acting opioid products.  
Buprenorphine/naloxone combination products have not been evaluated in adequate and well-
controlled studies for induction in patients on long-acting opioid products, and contain naloxone, which 
is absorbed in small amounts by the sublingual route and could cause worse precipitated and prolonged 
withdrawal.  For this reason, buprenorphine monotherapy is recommended in patients taking long-
acting opioids when used according to approved administration instructions.  Following induction, the 
patient may then be transitioned to once-daily SUBOXONE sublingual film. 
Patients dependent on heroin or other short-acting opioid products  
Patients dependent on heroin or short-acting opioid products may be inducted with either SUBOXONE 
sublingual film or with sublingual buprenorphine monotherapy.  The first dose of SUBOXONE sublingual 


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film or buprenorphine should be administered when objective signs of moderate opioid withdrawal 
appear, and not less than 6 hours after the patient last used an opioid. 
It is recommended that an adequate maintenance dose, titrated to clinical effectiveness, be achieved as 
rapidly as possible.  In some studies, a too-gradual induction over several days led to a high rate of drop-
out of buprenorphine patients during the induction period. 
 2.2 
Maintenance  
For maintenance, SUBOXONE sublingual film may be administered buccally or sublingually. The dosage 
of SUBOXONE sublingual film from Day 3 onwards should be progressively adjusted in 
increments/decrements of 2 mg/0.5 mg or 4 mg/1 mg buprenorphine/naloxone to a level that holds the 
patient in treatment and suppresses opioid withdrawal signs and symptoms. 
 
After treatment induction and stabilization, the maintenance dose of SUBOXONE sublingual film is 
generally in the range of 4 mg/1 mg buprenorphine/naloxone to 24 mg/6 mg buprenorphine/naloxone 
per day depending on the individual patient and clinical response.  The recommended target dosage of 
SUBOXONE sublingual film during maintenance is 16 mg/4 mg buprenorphine/naloxone/day as a single 
daily dose.  Dosages higher than 24 mg/6 mg daily have not been demonstrated to provide a clinical 
advantage.  
2.3 
Method of Administration 
SUBOXONE sublingual film must be administered whole.  Do not cut, chew, or swallow SUBOXONE 
sublingual film. 
Sublingual Administration 
Place one film under the tongue, close to the base on the left or right side.  If an additional film is 
necessary to achieve the prescribed dose, place an additional film sublingually on the opposite side from 
the first film.  Place the film in a manner to minimize overlapping as much as possible.  The film must be 
kept under the tongue until the film is completely dissolved.  If a third film is necessary to achieve the 
prescribed dose, place it under the tongue on either side after the first 2 films have dissolved. 
Buccal Administration 
Place one film on the inside of the right or left cheek.  If an additional film is necessary to achieve the 
prescribed dose, place an additional film on the inside of the opposite cheek.  The film must be kept on 
the inside of the cheek until the film is completely dissolved.  If a third film is necessary to achieve the 
prescribed dose, place it on the inside of the right or left cheek after the first two films have dissolved. 
SUBOXONE sublingual film should NOT be moved after placement. Proper administration technique 
should be demonstrated to the patient.  
2.4  
Clinical Supervision  
Treatment should be initiated with supervised administration, progressing to unsupervised 
administration as the patient’s clinical stability permits.  SUBOXONE sublingual film is subject to 
diversion and abuse.  When determining the prescription quantity for unsupervised administration, 
consider the patient’s level of stability, the security of his or her home situation, and other factors likely 
to affect the ability to manage supplies of take-home medication. 
 


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Ideally patients should be seen at reasonable intervals (e.g., at least weekly during the first month of 
treatment) based upon the individual circumstances of the patient. Medication should be prescribed in 
consideration of the frequency of visits.  Provision of multiple refills is not advised early in treatment or 
without appropriate patient follow-up visits.  Periodic assessment is necessary to determine compliance 
with the dosing regimen, effectiveness of the treatment plan, and overall patient progress.   
 
Once a stable dosage has been achieved and patient assessment (e.g., urine drug screening) does not 
indicate illicit drug use, less frequent follow-up visits may be appropriate. A once-monthly visit schedule 
may be reasonable for patients on a stable dosage of medication who are making progress toward their 
treatment objectives. Continuation or modification of pharmacotherapy should be based on the 
physician’s evaluation of treatment outcomes and objectives such as: 
 
1.  Absence of medication toxicity. 
 
2.  Absence of medical or behavioral adverse effects. 
 
3.  Responsible handling of medications by the patient. 
 
4.  Patient’s compliance with all elements of the treatment plan (including recovery-oriented activities, 
psychotherapy, and/or other psychosocial modalities). 
 
5.  Abstinence from illicit drug use (including problematic alcohol and/or benzodiazepine use).  
 
If treatment goals are not being achieved, the physician should re-evaluate the appropriateness of 
continuing the current treatment.  
 
2.5  
Patients With Hepatic Impairment  
Severe hepatic impairment results in a reduced clearance of naloxone to a much greater extent than 
buprenorphine, and moderate hepatic impairment also results in a reduced clearance of naloxone to a 
greater extent than buprenorphine. Because the doses of this fixed combination product cannot be 
individually titrated, the combination product should generally be avoided in patients with severe 
hepatic impairment and may not be appropriate for patients with moderate hepatic impairment [see 
Warnings and Precautions (5.11)]. 
 
2.6 
Unstable Patients 
Physicians will need to decide when they cannot appropriately provide further management for 
particular patients.  For example, some patients may be abusing or dependent on various drugs, or 
unresponsive to psychosocial intervention such that the physician does not feel that he/she has the 
expertise to manage the patient.  In such cases, the physician may want to assess whether to refer the 
patient to a specialist or more intensive behavioral treatment environment.  Decisions should be based 
on a treatment plan established and agreed upon with the patient at the beginning of treatment. 
 
Patients who continue to misuse, abuse, or divert buprenorphine products or other opioids should be 
provided with, or referred to, more intensive and structured treatment. 


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2.7 
Stopping Treatment 
The decision to discontinue therapy with SUBOXONE sublingual film after a period of maintenance 
should be made as part of a comprehensive treatment plan.  Taper patients to avoid opioid withdrawal 
signs and symptoms. 
 
2.8 
Switching Between Buprenorphine or Buprenorphine and Naloxone Sublingual Tablets and 
SUBOXONE Sublingual Film 
Patients being switched between buprenorphine and naloxone or buprenorphine only sublingual tablets 
and SUBOXONE sublingual film should be started on the corresponding dosage of the previously 
administered product.  However, dosage adjustments may be necessary when switching between 
buprenorphine products.  Not all strengths and combinations of the SUBOXONE sublingual films are 
bioequivalent to the SUBOXONE (buprenorphine and naloxone) sublingual tablets as observed in 
pharmacokinetic studies [see Clinical Pharmacology (12.3)].  Therefore, systemic exposures of 
buprenorphine and naloxone may be different when patients are switched from tablets to film or vice-
versa. Patients should be monitored for symptoms related to over-dosing or under-dosing. 
 
2.9 
Switching Between SUBOXONE Sublingual Film Strengths 
As indicated in Table 1, the sizes and the compositions of the four units of SUBOXONE sublingual films, 
i.e.,  
2 mg/0.5 mg, 4 mg/1 mg, 8 mg/2 mg and the 12 mg/3 mg units, are different from one another. If 
patients switch between various combinations of lower and higher strength units of SUBOXONE 
sublingual films to obtain the same total dose, (e.g., from three 4 mg/1 mg units to a single 12 mg/3 mg 
unit, or vice-versa), systemic exposures of buprenorphine and naloxone may be different and patients 
should be monitored for over-dosing or under-dosing.  For this reason, pharmacist should not substitute 
one or more film strengths for another without approval of the prescriber. 
 
Table 1.  Comparison of Available SUBOXONE Sublingual Film Strengths by Dimensions and Drug 
Concentrations. 
 
SUBOXONE sublingual film unit strength 
(buprenorphine/naloxone) 
SUBOXONE sublingual 
film unit dimensions 
Buprenorphine 
Concentration 
% (w/w) 
Naloxone 
Concentration 
% (w/w) 
2 mg/0.5 mg 
22.0 mm x 12.8 mm 
5.4 
1.53 
4 mg/1 mg  
(2 times the length of the 2 mg/0.5 mg unit) 
22.0 mm x 25.6 mm 
5.4 
1.53 
8 mg/2 mg  
22.0 mm x 12.8 mm 
17.2 
4.88 
12 mg/3 mg 
(1.5 times the length of the 8 mg/2 mg unit) 
22.0 mm X 19.2 mm 
17.2 
4.88 


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2.10 Switching Between Sublingual and Buccal Sites of Administration 
The systemic exposure of buprenorphine between buccal and sublingual administration of SUBOXONE 
sublingual film is similar.  Therefore, once induction is complete, patients can switch between buccal 
and sublingual administration without significant risk of under or overdosing.  
3 
DOSAGE FORMS AND STRENGTHS 
SUBOXONE sublingual film is supplied as an orange rectangular film with a white printed logo in four 
dosage strengths: 
• 
buprenorphine/naloxone 2 mg/0.5 mg,  
• 
buprenorphine/naloxone 4 mg/1 mg, 
• 
buprenorphine/naloxone 8 mg/2 mg and 
• 
buprenorphine/naloxone 12 mg/3 mg 
4 
CONTRAINDICATIONS 
SUBOXONE sublingual film should not be administered to patients who have been shown to be 
hypersensitive to buprenorphine or naloxone as serious adverse reactions, including anaphylactic shock, 
have been reported [see Warnings and Precautions (5.7)]. 
5 
WARNINGS AND PRECAUTIONS 
5.1 
Abuse Potential  
Buprenorphine can be abused in a manner similar to other opioids, legal or illicit. Prescribe and dispense 
buprenorphine with appropriate precautions to minimize risk of misuse, abuse, or diversion, and ensure 
appropriate protection from theft, including in the home. Clinical monitoring appropriate to the 
patient’s level of stability is essential. Multiple refills should not be prescribed early in treatment or 
without appropriate patient follow-up visits [see Drug Abuse and Dependence (9.2)]. 
5.2 
Respiratory Depression  
Buprenorphine, particularly when taken by the IV route, in combination with benzodiazepines or other 
CNS depressants (including alcohol), has been associated with significant respiratory depression and 
death.  Many, but not all, post-marketing reports regarding coma and death associated with the 
concomitant use of buprenorphine and benzodiazepines involved misuse by self-injection. Deaths have 
also been reported in association with concomitant administration of buprenorphine with other 
depressants such as alcohol or other CNS depressant drugs.  Patients should be warned of the potential 
danger of self-administration of benzodiazepines or other depressants while under treatment with 
SUBOXONE sublingual film [see Drug Interactions (7.3)]. 
In the case of overdose, the primary management should be the re-establishment of adequate 
ventilation with mechanical assistance of respiration, if required.  Naloxone may be of value for the 
management of buprenorphine overdose. Higher than normal doses and repeated administration may 
be necessary. 
SUBOXONE sublingual film should be used with caution in patients with compromised respiratory 
function (e.g., chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, 
hypoxia, hypercapnia, or pre-existing respiratory depression). 


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5.3 
CNS Depression  
Patients receiving buprenorphine in the presence of opioid analgesics, general anesthetics, 
benzodiazepines, phenothiazines, other tranquilizers, sedative/hypnotics, or other CNS depressants 
(including alcohol) may exhibit increased CNS depression.  Consider dose reduction of CNS depressants, 
SUBOXONE sublingual film, or both in situations of concomitant prescription [see Drug Interactions 
(7.3)]. 
5.4 
Unintentional Pediatric Exposure 
Buprenorphine can cause severe, possibly fatal, respiratory depression in children who are accidentally 
exposed to it.  Store buprenorphine-containing medications safely out of the sight and reach of children. 
5.5 
Neonatal Opioid Withdrawal Syndrome 
Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use 
of opioids during pregnancy, whether that use is medically-authorized or illicit. Unlike opioid withdrawal 
syndrome in adults, NOWS may be life-threatening if not recognized and treated in the neonate. 
Healthcare professionals should observe newborns for signs of NOWS and manage accordingly [see 
Specific Populations (8.1)].Advise pregnant women receiving opioid addiction treatment with 
SUBOXONE of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment 
will be available [see Specific Populations (8.1)]. This risk must be balanced against the risk of untreated 
opioid addiction which often results in continued or relapsing illicit opioid use and is associated with 
poor pregnancy outcomes. Therefore, prescribers should discuss the importance and benefits of 
management of opioid addiction throughout pregnancy. 
5.6 
Dependence 
Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces 
physical dependence of the opioid type, characterized by withdrawal signs and symptoms upon abrupt 
discontinuation or rapid taper.  The withdrawal syndrome is typically milder than seen with full agonists 
and may be delayed in onset.  Buprenorphine can be abused in a manner similar to other opioids.  This 
should be considered when prescribing or dispensing buprenorphine in situations when the clinician is 
concerned about an increased risk of misuse, abuse, or diversion [see Drug Abuse and Dependence 
(9.3)]. 
5.7 
Hepatitis, Hepatic Events 
Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving 
buprenorphine in clinical trials and through post-marketing adverse event reports.  The spectrum of 
abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports 
of death, hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy.  In many 
cases, the presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C 
virus, concomitant usage of other potentially hepatotoxic drugs, and ongoing injecting drug use may 
have played a causative or contributory role.  In other cases, insufficient data were available to 
determine the etiology of the abnormality.  Withdrawal of buprenorphine has resulted in amelioration 
of acute hepatitis in some cases; however, in other cases no dose reduction was necessary.  The 
possibility exists that buprenorphine had a causative or contributory role in the development of the 
hepatic abnormality in some cases.  Liver function tests, prior to initiation of treatment, are 
recommended to establish a baseline.  Periodic monitoring of liver function during treatment is also 
recommended.  A biological and etiological evaluation is recommended when a hepatic event is 
suspected.  Depending on the case, SUBOXONE sublingual film may need to be carefully discontinued to 


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prevent withdrawal signs and symptoms and a return by the patient to illicit drug use, and strict 
monitoring of the patient should be initiated.  
5.8 
Allergic Reactions  
Cases of hypersensitivity to buprenorphine and naloxone containing products have been reported both 
in clinical trials and in the post-marketing experience.  Cases of bronchospasm, angioneurotic edema, 
and anaphylactic shock have been reported. The most common signs and symptoms include rashes, 
hives, and pruritus.  A history of hypersensitivity to buprenorphine or naloxone is a contraindication to 
the use of SUBOXONE sublingual film.  
5.9 
Precipitation of Opioid Withdrawal Signs and Symptoms  
Because it contains naloxone, SUBOXONE sublingual film is likely to produce withdrawal signs and 
symptoms if misused parenterally by individuals dependent on full opioid agonists such as heroin, 
morphine, or methadone.  Because of the partial agonist properties of buprenorphine, SUBOXONE 
sublingual film may precipitate opioid withdrawal signs and symptoms in such persons if administered 
before the agonist effects of the opioid have subsided.  
5.10 
Use in Opioid Naïve Patients 
There have been reported deaths of opioid naïve individuals who received a 2 mg dose of 
buprenorphine as a sublingual tablet for analgesia. SUBOXONE sublingual film is not appropriate as an 
analgesic. 
5.11 
Use in Patients With Impaired Hepatic Function 
Buprenorphine/naloxone products are not recommended in patients with severe hepatic impairment 
and may not be appropriate for patients with moderate hepatic impairment.  Because hepatic 
impairment results in a reduced clearance of naloxone to a much greater extent than buprenorphine, 
the doses of buprenorphine and naloxone in this fixed-dose combination product cannot be individually 
titrated. Therefore, patients with severe hepatic impairment will be exposed to substantially higher 
levels of naloxone than patients with normal hepatic function. This may result in an increased risk of 
precipitated withdrawal at the beginning of treatment (induction) and may interfere with 
buprenorphine’s efficacy throughout treatment.  In patients with moderate hepatic impairment, the 
differential reduction of naloxone clearance compared to buprenorphine clearance is not as great as in 
subjects with severe hepatic impairment.  Therefore, buprenorphine/naloxone products are not 
recommended for initiation of treatment (induction) in patients with moderate hepatic impairment due 
to the increased risk of precipitated withdrawal. However, buprenorphine/naloxone products may be 
used with caution for maintenance treatment in patients with moderate hepatic impairment who have 
initiated treatment on a buprenorphine product without naloxone. However, patients should be 
carefully monitored and consideration given to the possibility of naloxone interfering with 
buprenorphine’s efficacy [see Use in Specific Populations (8.6)]. 
5.12 
Impairment of Ability to Drive or Operate Machinery  
SUBOXONE sublingual film may impair the mental or physical abilities required for the performance of 
potentially dangerous tasks such as driving a car or operating machinery, especially during treatment 
induction and dose adjustment.  Patients should be cautioned about driving or operating hazardous 
machinery until they are reasonably certain that SUBOXONE sublingual film therapy does not adversely 
affect his or her ability to engage in such activities.   


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5.13 
Orthostatic Hypotension 
Like other opioids, SUBOXONE sublingual film may produce orthostatic hypotension in ambulatory 
patients. 
5.14 
Elevation of Cerebrospinal Fluid Pressure  
Buprenorphine, like other opioids, may elevate cerebrospinal fluid pressure and should be used with 
caution in patients with head injury, intracranial lesions, and other circumstances when cerebrospinal 
pressure may be increased.  Buprenorphine can produce miosis and changes in the level of 
consciousness that may interfere with patient evaluation. 
5.15 
Elevation of Intracholedochal Pressure 
Buprenorphine has been shown to increase intracholedochal pressure, as do other opioids, and thus 
should be administered with caution to patients with dysfunction of the biliary tract. 
5.16 
Effects in Acute Abdominal Conditions 
As with other opioids, buprenorphine may obscure the diagnosis or clinical course of patients with acute 
abdominal conditions. 
5.17 
General Precautions 
SUBOXONE sublingual film should be administered with caution in debilitated patients and those with 
myxedema or hypothyroidism, adrenal cortical insufficiency (e.g., Addison's disease); CNS depression or 
coma; toxic psychoses; prostatic hypertrophy or urethral stricture; acute alcoholism; delirium tremens; 
or kyphoscoliosis. 
6 
ADVERSE REACTIONS 
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 
the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and 
may not reflect the rates observed in practice.   
6.1 
Clinical Trials Experience 
The safety of SUBOXONE sublingual film is supported by clinical trials using SUBUTEX (buprenorphine) 
sublingual tablets and SUBOXONE (buprenorphine and naloxone) sublingual tablets, and other trials 
using buprenorphine sublingual solutions, as well as an open-label study in 194 patients treated with 
SUBOXONE sublingual film administered sublingually and 188 patients treated with the film 
administered buccally.  In total, safety data from clinical studies are available from over 3000 opioid-
dependent subjects exposed to buprenorphine at doses in the range used in the treatment of opioid 
dependence.  Few differences in the adverse event profile were noted with regard to sublingually and 
bucally administered SUBOXONE sublingual film, SUBOXONE (buprenorphine and naloxone) sublingual 
tablets, SUBUTEX (buprenorphine) sublingual tablets and a buprenorphine ethanolic sublingual solution.   
The most common adverse event (>1%) associated with the sublingual administration of the SUBOXONE 
sublingual film was oral hypoesthesia. Other adverse events were constipation, glossodynia, oral 
mucosal erythema, vomiting, intoxication, disturbance in attention, palpitations, insomnia, withdrawal 
syndrome, hyperhidrosis, and blurred vision. 
The most common adverse events associated with the buccal administration were similar to those 
observed with sublingual administration of the film. 


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Other adverse event data were derived from larger, controlled studies of SUBOXONE (buprenorphine 
and naloxone) sublingual tablets and SUBUTEX (buprenorphine) tablets and of buprenorphine sublingual 
solution.  In a comparative study of SUBOXONE (buprenorphine and naloxone) sublingual tablets and 
SUBUTEX (buprenorphine) sublingual tablets, adverse event profiles were similar for subjects treated 
with 16 mg/4 mg SUBOXONE (buprenorphine and naloxone) sublingual tablets or 16 mg SUBUTEX 
(buprenorphine) sublingual tablets.  The following adverse events were reported to occur by at least 5% 
of patients in a 4 week study of SUBOXONE (buprenorphine and naloxone) sublingual tablets and 
SUBUTEX (buprenorphine) sublingual tablets. 
 
Table 2.  Adverse Events (≥ 5%) by Body System and Treatment Group in a 4 Week Study 
Body System/ Adverse Event 
(COSTART Terminology) 
SUBOXONE 
(buprenorphine and 
naloxone) sublingual 
tablets 
16 mg/4 mg/day 
N=107 
n (%) 
SUBUTEX 
(buprenorphine) 
sublingual tablets 
16 mg/day 
N=103 
n (%) 
Placebo 
N=107 
n (%) 
Body as a Whole 
Asthenia 
7 (6.5%) 
5 (4.9%) 
7 (6.5%) 
Chills 
8 (7.5%) 
8 (7.8%) 
8 (7.5%) 
Headache 
39 (36.4%) 
30 (29.1%) 
24 (22.4%) 
Infection 
6 (5.6%) 
12 (11.7%) 
7 (6.5%) 
Pain 
24 (22.4%) 
19 (18.4%) 
20 (18.7%) 
Pain abdomen 
12 (11.2%) 
12 (11.7%) 
7 (6.5%) 
Pain back 
4 (3.7%) 
8 (7.8%) 
12 (11.2%) 
Withdrawal syndrome 
27 (25.2%) 
19 (18.4%) 
40 (37.4%) 
Cardiovascular System 
Vasodilation 
10 (9.3%) 
4 (3.9%) 
7 (6.5%) 
Digestive System 
Constipation 
13 (12.1%) 
8 (7.8%) 
3 (2.8%) 
Diarrhea 
4 (3.7%) 
5 (4.9%) 
16 (15.0%) 
Nausea 
16 (15.0%) 
14 (13.6%) 
12 (11.2%) 
Vomiting 
8 (7.5%) 
8 (7.8%) 
5 (4.7%) 
Nervous System 
Insomnia 
15 (14.0%) 
22 (21.4%) 
17 (15.9%) 
Respiratory System 
Rhinitis 
5 (4.7%) 
10 (9.7%) 
14 (13.1%) 


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Skin And Appendages 
Sweating 
15 (14.0%) 
13 (12.6%) 
11 (10.3%) 
Abbreviations: COSTART = Coding Symbols for Thesaurus of Adverse Reaction Terms. 
The adverse event profile of buprenorphine was also characterized in the dose-controlled study of a 
buprenorphine ethanolic solution, over a range of doses in four months of treatment.  Table 3 shows 
adverse events reported by at least 5% of subjects in any dose group in the dose-controlled trial. 
 
Table 3.  Adverse Events (≥5%) by Body System and Treatment Group in a 16 Week Study 
Body 
System/ 
Adverse 
Event 
(COSTART 
Terminology) 
Buprenorphine Dose 
Very 
Low* 
N=184 
n (%) 
Low* 
N=180 
n (%) 
Moderate* 
N=186 
n (%) 
High* 
N=181 
n (%) 
Total* 
N=731 
n (%) 
Body as a Whole 
Abscess 
9 (5%) 
2 (1%) 
3 (2%) 
2 (1%) 
16 (2%) 
Asthenia 
26 (14%) 
28 (16%) 
26 (14%) 
24 (13%) 
104 
(14%) 
Chills 
11 (6%) 
12 (7%) 
9 (5%) 
10 (6%) 
42 (6%) 
Fever 
7 (4%) 
2 (1%) 
2 (1%) 
10 (6%) 
21 (3%) 
Flu syndrome 4 (2%) 
13 (7%) 
19 (10%) 
8 (4%) 
44 (6%) 
Headache 
51 (28%) 
62 (34%) 
54 (29%) 
53 (29%) 
220 
(30%) 
Infection 
32 (17%) 
39 (22%) 
38 (20%) 
40 (22%) 
149 
(20%) 
Injury 
accidental 
5 (3%) 
10 (6%) 
5 (3%) 
5 (3%) 
25 (3%) 
Pain 
47 (26%) 
37 (21%) 
49 (26%) 
44 (24%) 
177 
(24%) 
Pain back 
18 (10%) 
29 (16%) 
28 (15%) 
27 (15%) 
102 
(14%) 
Withdrawal 
syndrome 
45 (24%) 
40 (22%) 
41 (22%) 
36 (20%) 
162 
(22%) 
Digestive System 
Constipation 
10 (5%) 
23 (13%) 
23 (12%) 
26 (14%) 
82 (11%) 
Diarrhea 
19 (10%) 
8 (4%) 
9 (5%) 
4 (2%) 
40 (5%) 
Dyspepsia 
6 (3%) 
10 (6%) 
4 (2%) 
4 (2%) 
24 (3%) 


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Nausea 
12 (7%) 
22 (12%) 
23 (12%) 
18 (10%) 
75 (10%) 
Vomiting 
8 (4%) 
6 (3%) 
10 (5%) 
14 (8%) 
38 (5%) 
Nervous System 
Anxiety 
22 (12%) 
24 (13%) 
20 (11%) 
25 (14%) 
91 (12%) 
Depression 
24 (13%) 
16 (9%) 
25 (13%) 
18 (10%) 
83 (11%) 
Dizziness 
4 (2%) 
9 (5%) 
7 (4%) 
11 (6%) 
31 (4%) 
Insomnia 
42 (23%) 
50 (28%) 
43 (23%) 
51 (28%) 
186 
(25%) 
Nervousness 
12 (7%) 
11 (6%) 
10 (5%) 
13 (7%) 
46 (6%) 
Somnolence 
5 (3%) 
13 (7%) 
9 (5%) 
11 (6%) 
38 (5%) 
Respiratory System 
Cough 
increase 
5 (3%) 
11 (6%) 
6 (3%) 
4 (2%) 
26 (4%) 
Pharyngitis 
6 (3%) 
7 (4%) 
6 (3%) 
9 (5%) 
28 (4%) 
Rhinitis 
27 (15%) 
16 (9%) 
15 (8%) 
21 (12%) 
79 (11%) 
Skin and Appendages 
Sweat 
23 (13%) 
21 (12%) 
20 (11%) 
23 (13%) 
87 (12%) 
Special Senses 
Runny eyes 
13 (7%) 
9 (5%) 
6 (3%) 
6 (3%) 
34 (5%) 
*Sublingual solution.  Doses in this table cannot necessarily be delivered in tablet form, but for 
comparison purposes: 
1 mg solution would be less than a tablet dose of 2 mg 
4 mg solution approximates a 6 mg tablet dose 
8 mg solution approximates a 12 mg tablet dose 
16 mg solution approximates a 24 mg tablet dose 
The safety of SUBOXONE sublingual film during treatment induction is supported by a clinical trial using 
16 patients treated with SUBOXONE sublingual film and 18 treated with a buprenorphine-only 
sublingual film.  Few differences in the adverse event profiles were noted between SUBOXONE 
sublingual film and the buprenorphine-only sublingual film.   
The most common adverse event occurring during treatment induction and the 3 days following 
induction using SUBOXONE sublingual film was restlessness. Other adverse events were anxiety, 
piloerection, stomach discomfort, irritability, headache, rhinorrhea, cold sweat, arthralgia, and 
lacrimation increased. 
Four subjects left the study early on the first day of sublingual film administration.  However, there was 
not evidence to suggest that any of the four subjects experienced precipitated withdrawal secondary to 
the administration of buprenorphine or buprenorphine/naloxone sublingual films.  


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6.2 
Postmarketing Experience 
The following adverse reactions have been identified during post-approval use of SUBOXONE sublingual 
film. Because these reactions are reported voluntarily from a population of uncertain size, it is not 
always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 
The most frequently reported postmarketing adverse events were peripheral edema, stomatitis, 
glossitis, and blistering and ulceration of the mouth or tongue.  
7 
DRUG INTERACTIONS 
7.1 
Cytochrome P-450 3A4 (CYP3A4) Inhibitors and Inducers 
Buprenorphine is metabolized to norbuprenorphine primarily by cytochrome CYP3A4; therefore, 
potential interactions may occur when SUBOXONE sublingual film is given concurrently with agents that 
affect CYP3A4 activity.  The concomitant use of SUBOXONE sublingual film with CYP3A4 inhibitors (e.g., 
azole antifungals such as ketoconazole, macrolide antibiotics such as erythromycin, and HIV protease 
inhibitors) should be monitored and may require dose-reduction of one or both agents. 
The interaction of buprenorphine with CYP3A4 inducers has not been studied; therefore, it is 
recommended that patients receiving SUBOXONE sublingual film be monitored for signs and symptoms 
of opioid withdrawal if inducers of CYP3A4 (e.g., efavirenz, phenobarbital, carbamazepine, phenytoin, 
rifampicin) are coadministered [see Clinical Pharmacology (12.3)]. 
7.2 
Antiretrovirals 
Three classes of antiretroviral agents have been evaluated for CYP3A4 interactions with buprenorphine.  
Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme 
pathway, thus no interactions with buprenorphine are expected.  Non-nucleoside reverse transcriptase 
inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine and etravirine are 
known CYP3A inducers whereas delavirdine is a CYP3A inhibitor. Significant pharmacokinetic 
interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in 
clinical studies, but these pharmacokinetic interactions did not result in any significant 
pharmacodynamic effects. It is recommended that patients who are on chronic buprenorphine 
treatment have their dose monitored if NNRTIs are added to their treatment regimen.  Studies have 
shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, 
lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant 
pharmacodynamic effects.  Other PIs with CYP3A4 inhibitory activity (atazanavir and 
atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine and patients in 
one study reported increased sedation. Symptoms of opioid excess have been found in post-marketing 
reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly.  
Monitoring of patients taking buprenorphine and atazanavir with and without ritonavir is 
recommended, and dose reduction of buprenorphine may be warranted. 
7.3 
Benzodiazepines 
There have been a number of postmarketing reports regarding coma and death associated with the 
concomitant use of buprenorphine and benzodiazepines.  In many, but not all, of these cases, 
buprenorphine was misused by self-injection.  Preclinical studies have shown that the combination of 
benzodiazepines and buprenorphine altered the usual ceiling effect on buprenorphine-induced 
respiratory depression, making the respiratory effects of buprenorphine appear similar to those of full 


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opioid agonists.  SUBOXONE sublingual film should be prescribed with caution to patients taking 
benzodiazepines or other drugs that act on the CNS, regardless of whether these drugs are taken on the 
advice of a physician or are being abused/misused.  Patients should be warned that it is extremely 
dangerous to self-administer non-prescribed benzodiazepines while taking SUBOXONE sublingual film, 
and should also be cautioned to use benzodiazepines concurrently with SUBOXONE sublingual film only 
as directed by their physician. 
8 
USE IN SPECIFIC POPULATIONS 
8.1 
Pregnancy 
 
Risk Summary  
There are no adequate and well-controlled studies of SUBOXONE sublingual film or 
buprenorphine/naloxone in pregnant women. Limited published data on use of buprenorphine, the 
active ingredient in SUBOXONE sublingual film, in pregnancy, have not shown an increased risk of major 
malformations. All pregnancies, regardless of drug exposure, have a background risk of 2% to 4% for 
major birth defects, and 15% to 20% for pregnancy loss. Reproductive and developmental studies in rats 
and rabbits identified adverse events at clinically relevant doses. Pre- and postnatal development 
studies in rats demonstrated dystocia, increased neonatal deaths, and developmental delays. No clear 
teratogenic effects were seen with a range of doses equivalent to or greater than the human dose. 
However, in a few studies, some events such as acephalus, omphalocele, and skeletal abnormalities 
were observed but these findings were not clearly treatment-related. Embryofetal death was also 
observed in both rats and rabbits. 
SUBOXONE sublingual film should be used during pregnancy only if the potential benefit justifies the 
potential risk to the fetus.  
Clinical Considerations 
Disease-associated maternal and embryo-fetal risk 
 
Untreated opioid addiction in pregnancy is associated with adverse obstetrical outcomes such as low 
birth weight, preterm birth, and fetal death. In addition, untreated opioid addiction often results in 
continued or relapsing illicit opioid use. 
Fetal/neonatal adverse reactions 
 
Neonatal opioid withdrawal syndrome may occur in newborn infants of mothers who are receiving 
treatment with SUBOXONE. 
Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, 
high pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight. Signs of neonatal withdrawal 
usually occur in the first days after birth. The duration and severity of neonatal opioid withdrawal 
syndrome may vary. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage 
accordingly [see Warnings and Precautions (5.5)]. 
Labor or Delivery 
As with all opioids, use of buprenorphine prior to delivery may result in respiratory depression in the 
newborn. Closely monitor neonates for signs of respiratory depression. An opioid antagonist such as 
naloxone should be available for reversal of opioid induced respiratory depression in the neonate. 


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Data 
Human Data 
Studies have been conducted to evaluate neonatal outcomes in women exposed to buprenorphine 
during pregnancy. Limited published data on malformations from trials, observational studies, case 
series, and case reports on buprenorphine use in pregnancy have not shown an increased risk of major 
malformations. Based on these studies the incidence of neonatal abstinence syndrome is not clear and 
there does not appear to be a dose-response relationship. 
Animal Data 
Effects on embryo-fetal development were studied in Sprague-Dawley rats and Russian white rabbits 
following oral (1:1) and intramuscular (IM) (3:2) administration of mixtures of buprenorphine and 
naloxone.  Following oral administration to rats and rabbits, no teratogenic effects were observed at 
buprenorphine doses up to 250 mg/kg/day and 40 mg/kg/day, respectively (estimated exposure 
approximately 150 times and 50 times, respectively, the recommended human daily sublingual dose of 
16 mg on a mg/m² basis).  No definitive drug-related teratogenic effects were observed in rats and 
rabbits at IM doses up to 30 mg/kg/day (estimated exposure approximately 20 times and 35 times, 
respectively, the recommended human daily dose of 16 mg on a mg/m² basis).  Acephalus was observed 
in one rabbit fetus from the low-dose group and omphalocele was observed in two rabbit fetuses from 
the same litter in the mid-dose group; no findings were observed in fetuses from the high-dose group.  
Following oral administration of buprenorphine to rats, dose-related post-implantation losses, 
evidenced by increases in the numbers of early resorptions with consequent reductions in the numbers 
of fetuses, were observed at doses of 10 mg/kg/day or greater (estimated exposure approximately 
6 times the recommended human daily sublingual dose of 16 mg on a mg/m² basis).  In the rabbit, 
increased post-implantation losses occurred at an oral dose of 40 mg/kg/day.  Following IM 
administration in the rat and the rabbit, post-implantation losses, as evidenced by decreases in live 
fetuses and increases in resorptions, occurred at 30 mg/kg/day.   
Buprenorphine was not teratogenic in rats or rabbits after IM or subcutaneous (SC) doses up to 5 
mg/kg/day (estimated exposure was approximately 3 and 6 times, respectively, the recommended 
human daily sublingual dose of 16 mg on a mg/m2 basis), after IV doses up to 0.8 mg/kg/day (estimated 
exposure was approximately 0.5 times and equal to, respectively, the recommended human daily 
sublingual dose of 16 mg on a mg/m2 basis), or after oral doses up to 160 mg/kg/day in rats (estimated 
exposure was approximately 95 times the recommended human daily sublingual dose of 16 mg on a 
mg/m2 basis) and 25 mg/kg/day in rabbits (estimated exposure was approximately 30 times the 
recommended human daily sublingual dose of 16 mg on a mg/m2 basis). Significant increases in skeletal 
abnormalities (e.g., extra thoracic vertebra or thoraco-lumbar ribs) were noted in rats after SC 
administration of 1 mg/kg/day and up (estimated exposure was approximately 0.6 times the 
recommended human daily sublingual dose of 16 mg on a mg/m2 basis), but were not observed at oral 
doses up to 160 mg/kg/day.  Increases in skeletal abnormalities in rabbits after IM administration of 5 
mg/kg/day (estimated exposure was approximately 6 times the recommended human daily sublingual 
dose of 16 mg on a mg/m2 basis) or oral administration of 1 mg/kg/day or greater (estimated exposure 
was approximately equal to the recommended human daily sublingual dose of 16 mg on a mg/m2 basis) 
were not statistically significant. 
In rabbits, buprenorphine produced statistically significant pre-implantation losses at oral doses of 1 
mg/kg/day or greater and post-implantation losses that were statistically significant at IV doses of 0.2 
mg/kg/day or greater (estimated exposure approximately 0.3 times the recommended human daily 
sublingual dose of 16 mg on a mg/m2 basis). 


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Dystocia was noted in pregnant rats treated intramuscularly with buprenorphine 5 mg/kg/day 
(approximately 3 times the recommended human daily sublingual dose of 16 mg on a mg/m² basis).  
Fertility, peri-, and post-natal development studies with buprenorphine in rats indicated increases in 
neonatal mortality after oral doses of 0.8 mg/kg/day and up (approximately 0.5 times the recommended 
human daily sublingual dose of 16 mg on a mg/m² basis), after IM doses of 0.5 mg/kg/day and up 
(approximately 0.3 times the recommended human daily sublingual dose of 16 mg on a mg/m² basis), 
and after SC doses of 0.1 mg/kg/day and up (approximately 0.06 times the recommended human daily 
sublingual dose of 16 mg on a mg/m² basis).  An apparent lack of milk production during these studies 
likely contributed to the decreased pup viability and lactation indices.  Delays in the occurrence of 
righting reflex and startle response were noted in rat pups at an oral dose of 80 mg/kg/day 
(approximately 50 times the recommended human daily sublingual dose of 16 mg on a mg/m² basis). 
8.3 
Nursing Mothers 
Risk Summary 
Based on two studies in 13 lactating women, buprenorphine and its metabolite norbuprenorphine are 
present in low levels in human milk and infant urine, and available data have not shown adverse 
reactions in breastfed infants. There are no data on the combination product buprenorphine/naloxone 
in breastfeeding, however oral absorption of naloxone is minimal. Caution should be exercised when 
SUBOXONE sublingual film is administered to a nursing woman. The developmental and health benefits 
of breastfeeding should be considered along with the mother’s clinical need for SUBOXONE sublingual 
film and any potential adverse effects on the breastfed child from the drug or from the underlying 
maternal condition. 
Clinical Considerations 
Advise the nursing mother taking SUBOXONE sublingual film to monitor the infant for increased 
drowsiness and breathing difficulties. 
Data 
Based on limited data from a study of 6 lactating women who were taking a median oral dose of 
buprenorphine of 0.29 mg/kg/day 5 to 8 days after delivery, breast milk contained a median infant dose 
of 0.42 mcg/kg/day of buprenorphine and 0.33 mcg/kg/day of norbuprenorphine, which are equal to 
0.2% and 0.12% of the maternal weight-adjusted dose. 
Based on limited data from a study of 7 lactating women who were taking a median oral dose of 
buprenorphine of 7 mg/day an average of 1.12 months after delivery, the mean milk concentrations of 
buprenorphine and norbuprenorphine were 3.65 mcg/L and 1.94 mcg/L respectively. Based on the 
limited data from this study, and assuming milk consumption of 150 mL/kg/day, an exclusively breastfed 
infant would receive an estimated mean of 0.55 mcg/kg/day of buprenorphine and 0.29 mcg/kg/day of 
norbuprenorphine, which are 0.38% and 0.18% of the maternal weight-adjusted dose. 
No adverse reactions were observed in the infants in these two studies. 
8.4 
Pediatric Use 
The safety and effectiveness of SUBOXONE sublingual film have not been established in pediatric 
patients.  This product is not appropriate for the treatment of neonatal abstinence syndrome in 
neonates, because it contains naloxone, an opioid antagonist.  


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8.5 
Geriatric Use 
Clinical studies of SUBOXONE sublingual film, SUBOXONE (buprenorphine and naloxone) sublingual 
tablets, or SUBUTEX (buprenorphine) sublingual tablets did not include sufficient numbers of subjects 
aged 65 and over to determine whether they responded differently than younger subjects.  Other 
reported clinical experience has not identified differences in responses between the elderly and younger 
patients.  In general, dose selection for an elderly patient should be cautious, usually starting at the low 
end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac 
function, and of concomitant disease or other drug therapy. 
8.6 
Hepatic Impairment 
The effect of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone has been 
evaluated in a pharmacokinetic study. Both drugs are extensively metabolized in the liver. While no 
clinically significant changes have been observed in subjects with mild hepatic impairment; the plasma 
levels have been shown to be higher and half-life values have been shown to be longer for both 
buprenorphine and naloxone in subjects with moderate and severe hepatic impairment. The magnitude 
of the effects on naloxone are greater than that on buprenorphine in both moderately and severely 
impaired subjects. The difference in magnitude of the effects on naloxone and buprenorphine are 
greater in subjects with severe hepatic impairment than in subjects with moderate hepatic impairment, 
and therefore the clinical impact of these effects is likely to be greater in patients with severe hepatic 
impairment than in patients with moderate hepatic impairment. Buprenorphine/naloxone products 
should be avoided in patients with severe hepatic impairment and may not be appropriate for patients 
with moderate hepatic impairment [see Warnings and Precautions (5.11) and Clinical Pharmacology 
(12.3)].    
8.7 
Renal Impairment  
No differences in buprenorphine pharmacokinetics were observed between 9 dialysis-dependent and 
6 normal patients following IV administration of 0.3 mg buprenorphine.  The effects of renal failure on 
naloxone pharmacokinetics are unknown. 
9 
DRUG ABUSE AND DEPENDENCE 
9.1 
Controlled Substance 
Buprenorphine is a Schedule III narcotic under the Controlled Substances Act. 
Under the Drug Addiction Treatment Act (DATA) codified at 21 U.S.C. 823(g), prescription use of this 
product in the treatment of opioid dependence is limited to physicians who meet certain qualifying 
requirements, and who have notified the Secretary of Health and Human Services (HHS) of their intent 
to prescribe this product for the treatment of opioid dependence and have been assigned a unique 
identification number that must be included on every prescription. 
9.2 
Abuse 
Buprenorphine, like morphine and other opioids, has the potential for being abused and is subject to 
criminal diversion. This should be considered when prescribing or dispensing buprenorphine in 
situations when the clinician is concerned about an increased risk of misuse, abuse, or diversion.  
Healthcare professionals should contact their state professional licensing board or state controlled 
substances authority for information on how to prevent and detect abuse or diversion of this product. 


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Patients who continue to misuse, abuse, or divert buprenorphine products or other opioids should be 
provided with or referred for more intensive and structured treatment.   
Abuse of buprenorphine poses a risk of overdose and death.  This risk is increased with the abuse of 
buprenorphine and alcohol and other substances, especially benzodiazepines. 
The physician may be able to more easily detect misuse or diversion by maintaining records of 
medication prescribed including date, dose, quantity, frequency of refills, and renewal requests of 
medication prescribed. 
Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and 
proper handling and storage of the medication are appropriate measures that help to limit abuse of 
opioid drugs. 
9.3 
Dependence  
Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces 
physical dependence of the opioid type, characterized by moderate withdrawal signs and symptoms 
upon abrupt discontinuation or rapid taper.  The withdrawal syndrome is typically milder than seen with 
full agonists and may be delayed in onset [see Warnings and Precautions (5.5)]. 
Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use 
of opioids during pregnancy [see Warnings and Precautions (5.5)]. 
10 
OVERDOSAGE 
The manifestations of acute overdose include pinpoint pupils, sedation, hypotension, respiratory 
depression, and death.  
In the event of overdose, the respiratory and cardiac status of the patient should be monitored 
carefully.  When respiratory or cardiac functions are depressed, primary attention should be given to the 
re-establishment of adequate respiratory exchange through provision of a patent airway and institution 
of assisted or controlled ventilation.  Oxygen, IV fluids, vasopressors, and other supportive measures 
should be employed as indicated. 
In the case of overdose, the primary management should be the re-establishment of adequate 
ventilation with mechanical assistance of respiration, if required.  Naloxone may be of value for the 
management of buprenorphine overdose.  Higher than normal doses and repeated administration 
may be necessary.  
11 
DESCRIPTION 
SUBOXONE (buprenorphine and naloxone) sublingual film is an orange film, imprinted with a logo 
identifying the product and strength in white ink.  It contains buprenorphine HCl, a mu-opioid receptor 
partial agonist and a kappa-opioid receptor antagonist, and naloxone HCl dihydrate, an opioid receptor 
antagonist, at a ratio of 4:1 (ratio of free bases).  It is intended for sublingual or buccal administration 
and is available in four dosage strengths, 2 mg buprenorphine with 0.5 mg naloxone, 4 mg 
buprenorphine with 1 mg naloxone,  8 mg buprenorphine with 2 mg naloxone and 12 mg buprenorphine 
with 3 mg naloxone.  Each film also contains polyethylene oxide, hydroxypropyl methylcellulose, 
maltitol, acesulfame potassium, lime flavor, citric acid, sodium citrate, FD&C yellow #6, and white ink. 
Chemically, buprenorphine HCl is (2S)-2-[17-Cyclopropylmethyl-4,5α-epoxy-3-hydroxy-6-methoxy-
6α,14-ethano-14α-morphinan-7α-yl]-3,3-dimethylbutan-2-ol hydrochloride.  It has the following 
chemical structure: 


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• HCl 
Buprenorphine HCl has the molecular formula C29 H41 NO4 • HCl and the molecular weight is 504.10.  It is 
a white or off-white crystalline powder, sparingly soluble in water, freely soluble in methanol, soluble in 
alcohol, and practically insoluble in cyclohexane. 
Chemically, naloxone HCl dihydrate is 17-Allyl-4,5 α -epoxy-3, 14-dihydroxymorphinan-6-one 
hydrochloride dihydrate.  It has the following chemical structure:  
HCl • 2H2O 
Naloxone hydrochloride dihydrate has the molecular formula C19H21NO4 • HCl • 2H2O and the molecular 
weight is 399.87.  It is a white to slightly off-white powder and is freely soluble in water, soluble in 
alcohol, and practically insoluble in toluene and ether.   
12 
CLINICAL PHARMACOLOGY 
12.1 
Mechanism of Action 
SUBOXONE sublingual film contains buprenorphine and naloxone.  Buprenorphine is a partial agonist at 
the mu-opioid receptor and an antagonist at the kappa-opioid receptor. Naloxone is a potent antagonist 
at mu-opioid receptors and produces opioid withdrawal signs and symptoms in individuals physically 
dependent on full opioid agonists when administered parenterally.  
12.2 
Pharmacodynamics 
11.1.1.1 
Subjective Effects 
Comparisons of buprenorphine to full opioid agonists such as methadone and hydromorphone suggest 
that sublingual buprenorphine produces typical opioid agonist effects which are limited by a ceiling 
effect.  
In opioid-experienced subjects who were not physically dependent, acute sublingual doses of 
buprenorphine/naloxone tablets produced opioid agonist effects which reached a maximum between 
doses of 8 mg/2 mg and 16 mg/4 mg buprenorphine/naloxone.   
HO
N
O
OH
O


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Opioid agonist ceiling-effects were also observed in a double-blind, parallel group, dose-ranging 
comparison of single doses of buprenorphine sublingual solution (1, 2, 4, 8, 16, or 32 mg), placebo and a 
full agonist control at various doses.  The treatments were given in ascending dose order at intervals of 
at least one week to 16 opioid-experienced subjects who were not physically dependent.  Both active 
drugs produced typical opioid agonist effects.  For all measures for which the drugs produced an effect, 
buprenorphine produced a dose-related response.  However, in each case, there was a dose that 
produced no further effect.  In contrast, the highest dose of the full agonist control always produced the 
greatest effects.  Agonist objective rating scores remained elevated for the higher doses of 
buprenorphine (8 mg to 32 mg) longer than for the lower doses and did not return to baseline until 48 
hours after drug administration.  The onset of effects appeared more rapidly with buprenorphine than 
with the full agonist control, with most doses nearing peak effect after 100 minutes for buprenorphine 
compared to 150 minutes for the full agonist control. 
11.1.1.2 
Physiologic Effects 
Buprenorphine in IV (2, 4, 8, 12 and 16 mg) and sublingual (12 mg) doses has been administered to 
opioid-experienced subjects who were not physically dependent to examine cardiovascular, respiratory, 
and subjective effects at doses comparable to those used for treatment of opioid dependence.  
Compared to placebo, there were no statistically significant differences among any of the treatment 
conditions for blood pressure, heart rate, respiratory rate, O2 saturation, or skin temperature across 
time.  Systolic BP was higher in the 8 mg group than placebo (3 hour AUC values).  Minimum and 
maximum effects were similar across all treatments.  Subjects remained responsive to low voice and 
responded to computer prompts. Some subjects showed irritability, but no other changes were 
observed.  
The respiratory effects of sublingual buprenorphine were compared with the effects of methadone in a 
double-blind, parallel group, dose ranging comparison of single doses of buprenorphine sublingual 
solution (1, 2, 4, 8, 16, or 32 mg) and oral methadone (15, 30, 45, or 60 mg) in non-dependent, opioid-
experienced volunteers. In this study, hypoventilation not requiring medical intervention was reported 
more frequently after buprenorphine doses of 4 mg and higher than after methadone. Both drugs 
decreased O2 saturation to the same degree. 
Effect of Naloxone 
Physiologic and subjective effects following acute sublingual administration of buprenorphine tablets 
and buprenorphine/naloxone tablets were similar at equivalent dose levels of buprenorphine.  Naloxone 
had no clinically significant effect when administered by the sublingual route, although blood levels of 
the drug were measurable.  Buprenorphine/naloxone, when administered sublingually to an opioid-
dependent cohort, was recognized as an opioid agonist, whereas when administered intramuscularly, 
combinations of buprenorphine with naloxone produced opioid antagonist actions similar to naloxone.  
This finding suggests that the naloxone in buprenorphine/naloxone tablets may deter injection of 
buprenorphine/naloxone tablets by persons with active substantial heroin or other full mu-opioid 
dependence.  However, clinicians should be aware that some opioid-dependent persons, particularly 
those with a low level of full mu-opioid physical dependence or those whose opioid physical 
dependence is predominantly to buprenorphine, abuse buprenorphine/naloxone combinations by the 
intravenous or intranasal route.  In methadone-maintained patients and heroin-dependent subjects, IV 
administration of buprenorphine/naloxone combinations precipitated opioid withdrawal signs and 
symptoms and was perceived as unpleasant and dysphoric.  In morphine-stabilized subjects, 
intravenously administered combinations of buprenorphine with naloxone produced opioid antagonist 
and withdrawal signs and symptoms that were ratio-dependent; the most intense withdrawal signs and 
symptoms were produced by 2:1 and 4:1 ratios, less intense by an 8:1 ratio.   


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12.3 
Pharmacokinetics 
Absorption   
In several pharmacokinetic studies following the administration of different dosages, a dose of one or 
two of the 2 mg/0.5 mg SUBOXONE sublingual films administered  sublingually or buccally showed 
comparable relative bioavailability to the same total dose of SUBOXONE sublingual tablets. In contrast, 
one 8 mg/2 mg and one 12 mg/3 mg SUBOXONE sublingual films administered  sublingually or buccally 
showed higher relative bioavailability for both buprenorphine and naloxone compared to the same total 
dose of SUBOXONE sublingual tablets.  A combination of one 8 mg/2 mg and two 2 mg/0.5 mg  
SUBOXONE sublingual films (total dose of 12 mg/ 3 mg) administered sublingually  showed comparable 
relative bioavailability to the same total dose of SUBOXONE sublingual tablets, while buccally 
administered SUBOXONE sublingual films showed higher relative bioavailability. Table 4, below, 
illustrates the relative increase in exposure to buprenorphine and naloxone associated with SUBOXONE 
sublingual films compared to SUBOXONE tablets, and shows the effect of route of administration  [see 
Dosage and Administration (2.8 and 2.9)]. 
Across relevant  pharmacokinetic studies, the pharmacokinetic parameters and exposures derived from 
the buccal and sublingual administrations of SUBOXONE sublingual film were comparable to one 
another. 
 
Table 4. Changes in Pharmacokinetic Parameters for SUBOXONE Sublingual Film Administered 
Sublingually or Buccally in Comparison to SUBOXONE Sublingual Tablet 


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Dosage 
PK 
Parameter 
Increase in Buprenorphine 
PK 
Parameter 
Increase in Naloxone 
Film 
Sublingual 
Compared 
to Tablet 
Sublingual 
Film 
Buccal 
Compared 
to Tablet 
Sublingual 
Film 
Buccal 
Compared 
to Film 
Sublingual 
Film 
Sublingual 
Compared 
to Tablet 
Sublingual 
Film 
Buccal 
Compared 
to Tablet 
Sublingual 
Film 
Buccal 
Compared 
to Film 
Sublingual 
1 x 2 
mg/0.5 
mg 
Cmax  
22% 
25% 
- 
Cmax  
- 
- 
- 
AUC0-last  
-  
19% 
- 
AUC0-last 
- 
-  
- 
2 x 2 
mg/0.5 
mg 
Cmax 
- 
21% 
21% 
Cmax 
- 
17% 
21% 
AUC0-last 
- 
23% 
16% 
AUC0-last 
- 
22% 
24% 
1 x 8 
mg/2 
mg 
Cmax  
28% 
34% 
- 
Cmax 
41% 
54% 
- 
AUC0-last 
20% 
25% 
- 
AUC0-last 
30% 
43% 
- 
1 x 12 
mg/3 
mg 
Cmax 
37% 
47% 
- 
Cmax 
57% 
72% 
9% 
AUC0-last 
21% 
29% 
- 
AUC0-last 
45% 
57% 
- 
1 x 8 
mg/2 
mg plus 
2 x 2 
mg/0.5 
mg 
Cmax 
- 
27% 
13% 
Cmax 
17% 
38% 
19% 
AUC0-last 
- 
23% 
- 
AUC0-last 
- 
30% 
19% 
1 x 16 
mg/4 
mg film 
Cmax 
34% 
29% 
7% 
Cmax 
44% 
46% 
9% 
AUC0-last 
32% 
- 
- 
AUC0-last 
49% 
36% 
3% 
Note: 1. the 16 mg/4 mg strength film is not marketed; it is compositionally proportional to the 8 mg/2 mg 
strength film and has the same size of 2 x 8 mg/2 mg film. 2. – represents no change when the 90% confidence 
intervals for the geometric mean ratios of the Cmax and AUC0-last values are within the 80% to 125% limit. 3. 
There are no data for the 4 mg/1 mg strength film; it is compositionally proportional to 2 mg/0.5 mg strength film 
and has the same size of 2 x 2 mg/0.5 mg film strength. 
 
Distribution  
Buprenorphine is approximately 96% protein bound, primarily to alpha and beta globulin. 
Naloxone is approximately 45% protein bound, primarily to albumin. 
Elimination 
Buprenorphine is metabolized and eliminated in urine and feces. Naloxone undergoes metabolism as 
well. When SUBOXONE sublingual film is administered sublingually or buccally, buprenorphine has a 
mean elimination half-life ranging from 24 to 42 hours and naloxone has a mean elimination half-life 
ranging from 2 to 12 hours. 
Metabolism 
Buprenorphine undergoes both N-dealkylation to norbuprenorphine and glucuronidation.  The N-
dealkylation pathway is mediated primarily by the CYP3A4.  Norbuprenorphine, the major metabolite, 
can further undergo glucuronidation. Norbuprenorphine has been found to bind opioid receptors in 


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vitro; however, it has not been studied clinically for opioid-like activity. Naloxone undergoes direct 
glucuronidation to naloxone-3-glucuronide as well as N-dealkylation, and reduction of the 6-oxo group. 
Excretion 
A mass balance study of buprenorphine showed complete recovery of radiolabel in urine (30%) and 
feces (69%) collected up to 11 days after dosing.  Almost all of the dose was accounted for in terms of 
buprenorphine, norbuprenorphine, and two unidentified buprenorphine metabolites.  In urine, most of 
buprenorphine and norbuprenorphine was conjugated (buprenorphine, 1% free and 9.4% conjugated; 
norbuprenorphine, 2.7% free and 11% conjugated).  In feces, almost all of the buprenorphine and 
norbuprenorphine were free (buprenorphine, 33% free and 5% conjugated; norbuprenorphine, 21% free 
and 2% conjugated). Based on all studies performed with sublingually and buccally administered 
SUBOXONE sublingual film, buprenorphine has a mean elimination half-life from plasma ranging from 24 
to 42 hours and naloxone has a mean elimination half-life from plasma ranging from 2 to 12 hours. 
DRUG-DRUG INTERACTIONS 
CYP3A4 Inhibitors and Inducers:  Subjects receiving SUBOXONE sublingual film should be monitored if 
inhibitors of CYP3A4 such as azole antifungal agents (e.g., ketoconazole), macrolide antibiotics (e.g., 
erythromycin) or HIV protease inhibitors and may require dose-reduction of one or both agents.  The 
interaction of buprenorphine with all CYP3A4 inducers has not been studied, therefore it is 
recommended that patients receiving SUBOXONE sublingual film be monitored for signs and symptoms 
of opioid withdrawal if inducers of CYP3A4 (e.g., phenobarbital, carbamazepine, phenytoin, rifampicin) 
are coadministered [see Drug Interactions (7.1)].  
Buprenorphine has been found to be a CYP2D6 and CYP3A4 inhibitor and its major metabolite, 
norbuprenorphine, has been found to be a moderate CYP2D6 inhibitor in in vitro studies employing 
human liver microsomes. However, the relatively low plasma concentrations of buprenorphine and 
norbuprenorphine resulting from therapeutic doses are not expected to raise significant drug-drug 
interaction concerns.  
SPECIAL POPULATIONS: 
Hepatic Impairment: In a pharmacokinetic study, the disposition of buprenorphine and naloxone were 
determined after administering a SUBOXONE 2.0/0.5 mg (Buprenorphine/Naloxone) sublingual tablet in 
subjects with varied degrees of hepatic impairment as indicated by Child-Pugh criteria. The disposition 
of buprenorphine and naloxone in patients with hepatic impairment were compared to disposition in 
subjects with normal hepatic function.  
 
In subjects with mild hepatic impairment, the changes in mean Cmax, AUC0-last, and half-life values of both 
buprenorphine and naloxone were not clinically significant. No dosing adjustment is needed in patients 
with mild hepatic impairment. 
 
For subjects with moderate and severe hepatic impairment, mean Cmax, AUC0-last, and half-life values of 
both buprenorphine and naloxone were increased; the effects on naloxone are greater than that on 
buprenorphine (Table 5).  
 
Table 5.  Changes in Pharmacokinetic Parameters in Subjects With Moderate and Severe Hepatic 
Impairment 
Hepatic 
PK Parameters 
Increase in buprenorphine 
Increase in naloxone 
compared to healthy 


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Impairment 
compared to healthy subjects 
subjects 
Moderate 
Cmax 
8% 
170% 
AUC0-last 
64% 
218% 
Half-life 
35% 
165% 
Severe 
Cmax 
72% 
1030% 
AUC0-last 
181% 
1302% 
Half-life 
57% 
122% 
 
The difference in magnitude of the effects on naloxone and buprenorphine are greater in subjects with 
severe hepatic impairment than subjects with moderate hepatic impairment, and therefore the clinical 
impact of these effects is likely to be greater in patients with severe hepatic impairment than in patients 
with moderate hepatic impairment. Buprenorphine/naloxone products should be avoided in patients 
with severe hepatic impairment and may not be appropriate for patients with moderate hepatic 
impairment [see Warnings and Precautions (5.11) and Use in Specific Populations (8.6)]. 
 
HCV infection: In subjects with HCV infection but no sign of hepatic impairment, the changes in the 
mean Cmax, AUC0-last, and half-life values of buprenorphine and naloxone were not clinically significant in 
comparison to healthy subjects without HCV infection.  No dosing adjustment is needed in patients with 
HCV infection. 
13 
NONCLINICAL TOXICOLOGY 
13.1 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
Carcinogenicity   
Carcinogenicity data on SUBOXONE sublingual film are not available. 
A carcinogenicity study of buprenorphine/naloxone (4:1 ratio of the free bases) was performed in 
Alderley Park rats.  Buprenorphine/naloxone was administered in the diet at doses of approximately 7, 
31, and 123 mg/kg/day for 104 weeks (estimated exposure was approximately 4, 18, and 44 times the 
recommended human sublingual dose of 16 mg/4 mg buprenorphine/naloxone based on buprenorphine 
AUC comparisons).  A statistically significant increase in Leydig cell adenomas was observed in all dose 
groups.  No other drug-related tumors were noted. 
Carcinogenicity studies of buprenorphine were conducted in Sprague-Dawley rats and CD-1 mice. 
Buprenorphine was administered in the diet to rats at doses of 0.6, 5.5, and 56 mg/kg/day (estimated 
exposure was approximately 0.4, 3, and 35 times the recommended human daily sublingual dose of 16 
mg on a mg/m2 basis) for 27 months.  As in the buprenorphine/naloxone carcinogenicity study in rats, 
statistically significant dose-related increases in Leydig cell tumors occurred.  In an 86 week study in 
CD-1 mice, buprenorphine was not carcinogenic at dietary doses up to 100 mg/kg/day (estimated 
exposure was approximately 30 times the recommended human daily sublingual dose of 16 mg on a 
mg/m2 basis). 
Mutagenicity  
The 4:1 combination of buprenorphine and naloxone was not mutagenic in a bacterial mutation assay 
(Ames test) using four strains of S. typhimurium and two strains of E. coli.  The combination was not 


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clastogenic in an in vitro cytogenetic assay in human lymphocytes or in an IV micronucleus test in the 
rat.  
Buprenorphine was studied in a series of tests utilizing gene, chromosome, and DNA interactions in both 
prokaryotic and eukaryotic systems.  Results were negative in yeast (S. cerevisiae) for recombinant, gene 
convertant, or forward mutations; negative in Bacillus subtilis “rec” assay, negative for clastogenicity in 
CHO cells, Chinese hamster bone marrow and spermatogonia cells, and negative in the mouse 
lymphoma L5178Y assay. 
Results were equivocal in the Ames test: negative in studies in two laboratories, but positive for frame 
shift mutation at a high dose (5 mg/plate) in a third study.  Results were positive in the Green-Tweets (E. 
coli) survival test, positive in a DNA synthesis inhibition (DSI) test with testicular tissue from mice, for 
both in vivo and in vitro incorporation of [3H]thymidine, and positive in unscheduled DNA synthesis 
(UDS) test using testicular cells from mice. 
Impairment of Fertility  
Dietary administration of buprenorphine in the rat at dose levels of 500 ppm or greater (equivalent to 
approximately 47 mg/kg/day or greater; estimated exposure approximately 28 times the recommended 
human daily sublingual dose of 16 mg on a mg/m2 basis) produced a reduction in fertility demonstrated 
by reduced female conception rates.  A dietary dose of 100 ppm (equivalent to approximately 10 
mg/kg/day; estimated exposure approximately 6 times the recommended human daily sublingual dose 
of 16 mg on a mg/m2 basis) had no adverse effect on fertility. 
16 
HOW SUPPLIED / STORAGE AND HANDLING 
SUBOXONE sublingual film is supplied as an orange rectangular film with a white printed logo in child-
resistant polyester/foil laminated pouches: 
• 
NDC 12496-1202-3 (buprenorphine/naloxone 2 mg/0.5 mg/film; content expressed in terms of 
free base) - 30 films per carton 
• 
NDC 12496-1204-3 (buprenorphine/naloxone 4 mg/1 mg/film; content expressed in terms of 
free base) - 30 films per carton 
• 
NDC 12496-1208-3 (buprenorphine/naloxone 8 mg/2 mg/film; content expressed in terms of 
free base) - 30 films per carton 
• 
NDC 12496-1212-3 (buprenorphine/naloxone 12 mg/3 mg/film; content expressed in terms of 
free base) - 30 films per carton 
Store at 25°C (77°F), excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room 
Temperature]. 
Patients should be advised to store buprenorphine-containing medications safely and out of sight and 
reach of children.   
Rx only 


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17 
PATIENT COUNSELING INFORMATION 
See FDA-approved patient labeling (Medication Guide). 
SUBOXONE sublingual film must be administered whole.  Advise patients not to cut, chew, or swallow 
SUBOXONE sublingual film  
Safe Use 
Before initiating treatment with SUBOXONE sublingual film, explain the points listed below to 
caregivers and patients. Instruct patients to read the Medication Guide each time SUBOXONE 
sublingual film is dispensed because new information may be available. 
• 
Patients should be warned that it is extremely dangerous to self-administer non-prescribed 
benzodiazepines or other CNS depressants (including alcohol) while taking SUBOXONE sublingual 
film.  Patients prescribed benzodiazepines or other CNS depressants should be cautioned to use 
them only as directed by their physician [see Warnings and Precautions (5.2), Drug Interactions 
(7.3)]. 
• 
Patients should be advised that SUBOXONE sublingual film contains an opioid that can be a target 
for people who abuse prescription medications or street drugs.  Patients should be cautioned to 
keep their films in a safe place, and to protect them from theft. 
• 
Patients should be instructed to keep SUBOXONE sublingual film in a secure place, out of the sight 
and reach of children.  Accidental or deliberate ingestion by a child may cause respiratory 
depression that can result in death.  Patients should be advised that if a child is exposed to 
SUBOXONE sublingual film, medical attention should be sought immediately.   
• 
Patients should be advised never to give SUBOXONE sublingual film to anyone else, even if he or she 
has the same signs and symptoms.  It may cause harm or death. 
• 
Patients should be advised that selling or giving away this medication is against the law. 
• 
Patients should be cautioned that SUBOXONE sublingual film may impair the mental or physical 
abilities required for the performance of potentially dangerous tasks such as driving or operating 
machinery.  Caution should be taken especially during drug induction and dose adjustment and until 
individuals are reasonably certain that buprenorphine therapy does not adversely affect their ability 
to engage in such activities [see Warnings and Precautions (5.11)]. 
• 
Patients should be advised not to change the dosage of SUBOXONE sublingual film without 
consulting their physician. 
• 
Patients should be advised to take SUBOXONE sublingual film once a day. 
• 
Patients should be advised that if they miss a dose of SUBOXONE they should take it as soon as they 
remember. If it is almost time for the next dose, they should skip the missed dose and take the next 
dose at the regular time. 
• 
Patients should be informed that SUBOXONE sublingual film can cause drug dependence and that 
withdrawal signs and symptoms may occur when the medication is discontinued. 
• 
Patients seeking to discontinue treatment with buprenorphine for opioid dependence should be 
advised to work closely with their physician on a tapering schedule and should be apprised of the 
potential to relapse to illicit drug use associated with discontinuation of opioid agonist/partial 
agonist medication-assisted treatment. 


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• 
Patients should be cautioned that, like other opioids, SUBOXONE sublingual film may produce 
orthostatic hypotension in ambulatory individuals [see Warnings and Precautions (5.12)]. 
• 
Patients should inform their physician if any other prescription medications, over-the-counter 
medications, or herbal preparations are prescribed or currently being used [see Drug Interactions 
(7.1, 7.2 and 7.3)]. 
• 
Advise women that if they are pregnant while being treated with SUBOXONE, the baby may have 
signs of withdrawal at birth and that withdrawal is treatable [see Warnings and Precautions (5.5),  
Specific Populations (8.1)]. 
• 
Advise women who are breastfeeding to monitor the infant for drowsiness and difficulty breathing 
[see Use in Specific Populations (8.3)].   
• 
Patients should inform their family members that, in the event of emergency, the treating physician 
or emergency room staff should be informed that the patient is physically dependent on an opioid 
and that the patient is being treated with SUBOXONE sublingual film. 
• 
Refer to the Medication Guide for additional information regarding the counseling information. 
 
Disposal of Unused SUBOXONE Sublingual Films 
 
Unused SUBOXONE sublingual films should be disposed of as soon as they are no longer needed. 
Unused films should be flushed down the toilet.  
 
Manufactured for Indivior Inc. 
Richmond, VA 23235 by: 
MonoSol Rx, LLC, 
Warren, NJ 07059 
 
Distributed by: 
Indivior Inc. 
Richmond, VA 23235 


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Appendix 8 Study Drug Preparation, Administration, and Depot Removal 
Instructions 
RBP-6000 PREPARATION AND DOSING PROCEDURE 
• 100 MG BUPRENORPHINE 
• 300 MG BUPRENORPHINE  
 
IMPORTANT:  Only qualified study personnel can prepare the study drug.  Protective gloves 
(latex or nitrile) should be worn when preparing and dosing RBP-6000.  Remove the product 
from the refrigerator at least 15 minutes before use to allow the product to reach room 
temperature before dosing.  Product may be left at room temperature up to 8 hours prior to use.  
If product is not used that day it should be marked appropriately.   
   
FOLLOW THE INSTRUCTIONS AS DIRECTED TO ENSURE PROPER DOSING 
Preparation of the Product Prior to Administration:  
The following components will be used in the preparation of RBP-6000: 
• One sealed foil pouch containing a syringe pre-filled with RBP-6000 and an oxygen 
absorber pack.  
• One sterile 19-gauge, 1 inch hypodermic safety needle 
 
1. On a clean field, open the foil pouch and remove the contents. Discard the oxygen absorber 
pack.   The pouch must be retained for accountability. 
2. Un-cap the pre-filled RBP-6000 syringe and attach the safety needle cartridge by pushing in 
and turning the needle until it is finger tight. Do not strip the threaded fitting by over-
tightening the needle. Position the sheath at 90 degrees to the needle.  Pull off the needle 
cartridge cover.   More complete documentation on the usage of the SurGuard2 safety needle 
can be found in the included instruction sheet.  
3. While holding the syringe vertically with the tip upwards, expel air bubbles by stroking the 
plunger up and down. 
4. The product is now ready for administration.  Carefully recap the needle. 
Administration Procedure: 
IMPORTANT: Once prepared (removed from foil pouch), the product must be 
administered within a maximum of 30 minutes. 
 
Choose an injection site below the waist but above the hip bone; from where the body curves at 
the side to about 2 inches from the middle of the abdomen with adequate amounts of 
subcutaneous tissue that does not have excessive pigment, nodules, lesions, or hair.  Since you 
can vary the injection site with a subcutaneous injection, choose an area that has not recently 
been used.   
 
Possible injection site locations and an injection rotation pattern are shown in Figure 4.  
Injections should be started based on where the last injection in RB-US-13-0001 was given for 
roll-over subjects. 


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Figure 4 
Injection Locations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. Cleanse the injection-site area with an alcohol swab.   
 
2. Using the thumb and forefinger of your non-dominant hand, grab and bunch the area of skin 
around the injection site. 
 
3. Using your dominant hand, insert approximately half the needle length quickly. The 
approximate angle you use will depend on the amount and fullness of the subcutaneous tissue 
and the length of the needle. 
 
4. After the needle is inserted, release the skin with your nondominant hand. 
 
5. Pull back on the plunger to check for blood.  If blood is present in the syringe, do not inject.  
Withdraw the needle and discard all components safely in an appropriate biohazard 
container.  Repeat the “Preparation of the Product Prior to Administration” procedures and 
the “Administration Procedure” using a different abdominal injection site with another 
syringe of RBP-6000 and associated components. 
 
6. Inject the product using a slow, steady push. Press down on the plunger until the syringe is 
empty. 
 
7. Withdraw the needle at the same angle used for insertion. Do not rub the injection area.  If 
there is bleeding, apply minimal pressure with a gauze pad or bandage.  Engage the safety 
sheath on the needle as per the SurGuard2 needle instructions.   
 
8. Discard all components safely in an appropriate biohazard container. 
 
Hipbones 
Waist 
1 / 5 
2 / 6 
3 
4 


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PROCEDURE FOR REMOVAL OF THE RBP-6000 DEPOT 
 
In the event of an emergency or if a subject withdraws or is withdrawn within the first 14 days of 
receiving an injection of RBP-6000, subjects may have the option to have the depot surgically 
removed by a physician delegated to perform surgery. The medically responsible physician 
should carefully discuss this option with subjects given the use of ATRIGEL Delivery System 
and the feasibility of extracting the depot. 
 
The following surgical procedure should be followed: 
 
1. 
Palpate the depot and surrounding area to confirm its exact location. 
2. 
Cleanse the area with an antiseptic solution (e.g., Betadine).   
3. 
Infiltrate the area with a local anesthesia (e.g., Lidocaine 1% or a lidocaine/adrenaline 
[epinephrine] mixture) and wait for it to take effect. 
4. 
Cover the area with a sterile drape. 
5. 
Incise the skin up to the subcutaneous tissues using a scalpel.  
6. 
Using blunt and sharp dissection, identify the plane between the depot and surrounding 
subcutaneous tissues.  Once the plane is identified, separate the superficial 25% of the 
circumference of the depot with blunt dissection.  
7. 
Gently lift the incised ellipse of skin and depot with forceps.   
8. 
Once the depot is removed, ensure hemostasis, and close the skin with non-absorbable 
sutures.   
9. 
The extracted RBP-6000 depot will be disposed of into an appropriate, secure biohazard 
container per the SOP at the study site. 
 


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Appendix 9 
Prohibited Cytochrome P450 Inhibitors and Inducers 
The following medications are prohibited during the study: 
Cytochrome 
P450 3A4 
Inhibitors 
Cytochrome 
P450 3A4 
Inducers 
Cytochrome 
P450 2C8 
Inhibitors 
Cytochrome 
P450 2C8 
Inducers 
Amiodarone 
Ketoconazole 
Barbiturates 
Gemifibrozil 
Rifampicin 
Amprenavir 
Metronidazole 
Carbamazepine 
Trimethoprim 
 
Aprepitant 
Mibefradil 
Dexamethasone 
Glitazones 
 
Chloramphenicol Miconazole 
Efavirenz 
Montelukast 
 
Cimetidine 
Mifepristone 
Ethosuximide 
Quercetin 
 
Ciprofloxacin 
Nefazodone 
Glucocorticoids 
 
 
Clarithromycin 
Nelfinavir 
Glutethimide 
 
 
Clotrimazole 
Nicardipine 
Modafinil 
 
 
Cyclosporine 
Norfloxacin 
Nevirapine 
 
 
Delavirdine 
Norfluoxetine 
Oxcarbazepine 
 
 
Diethyl-
dithiocarbamate 
Propofol 
Phenobarbital 
 
 
Diltiazem 
Quinine 
Phenytoin 
 
 
Ethinyl estradiol 
Ritonavir 
Pioglitazone 
 
 
Erythromycin 
Saquinavir 
Primidone 
 
 
Fluconazole 
Sertraline 
Rifabutin 
 
 
Fluoxetine 
Starfruit 
Rifampin 
 
 
Fluvoxamine 
Telithromycin 
Hypericum 
perforatum 
 
 
Gestodene 
Troleandomycin 
Sulfadimidine 
 
 
Grapefruit juice 
Verapamil 
Sulfinpyrazone 
 
 
Imatinib 
Voriconazole 
Troglitazone 
 
 
Indinavir 
Zafirlukast 
Troleandomycin 
 
 
Itraconazole 
 
 
 
 
Source:  http://medicine.iupui.edu/clinpharm/ddis/clinical-table/ 


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Appendix 10 
Columbia Suicide Severity Rating Scale (eC-SSRS) -- 
Baseline/Screening Version 
 
 


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Appendix 11 
Columbia Suicide Severity Rating Scale (eC-SSRS) -- 
Since Last Visit Version 
 


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Appendix 12 
Clinical Opiate Withdrawal Scale (COWS) 
 
0 - Pulse rate 80 or below
1 - Pulse rate 81 - 100
2 - Pulse rate 101 - 120
4 - Pulse rate greater than 120
1. Resting Pulse Rate:
Measured after patient is sitting or lying for one minute.
0 - No GI symptoms
1 - Stomach cramps
2 - Nausea or loose stool
3 - Vomiting or diarrhea
5 - Multiple episodes of diarrhea or vomiting
2. GI upset: Over last 1/2 hour.
0 - No report of chills or flushing
1 - Subjective report of chills or flushing
2 - Flushed or observable moistness on face
3 - Beads of sweat on brow or face
4 - Sweat streaming off face
3. Sweating:
Over past 1/2 hour not accounted for by room temperature or patient activity.
0 - No tremor
1 - Tremor can be felt, but not observed
2 - Slight tremor observable
4 - Gross tremor or muscle twitching
4. Tremor:
Observation of outstretched hands.
0 - Able to sit still
1 - Reports difficulty sitting still, but is able to do so
3 - Frequent shifting or extraneous movements of legs/arms
5 - Unable to sit still for more than a few seconds
5. Restlessness:
For each item, mark the choice that best describes the subject's signs or symptom. Rate on just the
apparent relationship to opiate withdrawal. For example, if heart rate is increased because the patient was
jogging just prior to assessment, the increased pulse rate would not add to the score.
beats/min
Observation during assessment.
0 - No yawning
1 - Yawning once or twice during assessment
2 - Yawning three or more times during assessment
4 - Yawning several times/minute
6. Yawning: Observation durring assessment.
 
 


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0 - Not present
1 - Nasal stuffiness or unusually moist eyes
2 - Nose running or tearing
4 - Nose constantly running or tears streaming down cheeks
11. Runny nose or tearing:
0 - None
1 - Patient reports increasing irritability or anxiousness
2 - Patient obviously irritable or anxious
4 - Patient so irritable or anxious that participation in the assessment is difficult
8. Anxiety or Irritability:
0 - Not present
1 - Mild diffuse discomfort
2 - Patient reports severe diffuse aching of joints/muscle
4 - Patient is rubbing joints or muscles and is unable to sit still because of discomfort
9. Bone or Joint aches:
0 - Skin is smooth
3 - Piloerection of skin can be felt or hairs standing up on arms
5 - Prominent piloerection
10. Gooseflesh skin:
0 - Pupils pinned or normal size for room light
1 - Pupils possibly larger than normal for room light
2 - Pupils moderately dilated
5 - Pupils so dilated that only the rim of the iris is visible
7. Pupil Size:
If patient was having pain previously, only the additional component attributed to opiate
withdrawal is scored.
Not accounted for by cold symptoms or allergies.
TOTAL SCORE (sum of all 11 items):
Score Interpretation: 5 - 12= Mild, 13 - 24= Moderate, 25 - 36=Moderately Severe, More than 36= Severe Withdrawal


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Appendix 13 
Subjective Opiate Withdrawal Scale (SOWS) 
 
Modified from : Handelsman L, Cochrane KJ, Aronson MJ, Ness R, Rubenstein KJ, Kanof PD 
(1987). Two new rating scales for opiate withdrawal.  Am J Drug Alcohol Abuse 13:293-308. 


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Appendix 14 
Opioid Craving Visual Analog Scale (Opioid Craving VAS) 
 
No craving 
_________________________________________Strongest craving ever 
100 mm scale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 15 Injection Site Grading Scale 
 
Injection 
Site 
Reactions 
None 
(Grade 0) 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Pain 
None 
Does not 
interfere with 
activity 
Repeated use of non-
narcotic pain reliever 
> 24 hours or 
interferes with 
activity  
Any use of narcotic 
pain reliever or 
prevents daily 
activity 
Emergency room  
(ER) visit or  
hospitalization  
Tenderness 
None 
Mild discomfort 
to touch. 
Discomfort with 
movement. 
Significant 
discomfort at rest  
ER visit or 
hospitalization 
Erythema/ 
Redness* 
(quantitative) 
None 
2.5 – 5 cm 
5.1 – 10 cm 
> 10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration ** 
None 
2.5 – 5 cm and 
does not 
interfere  
with activity  
5.1 – 10 cm or  
interferes with  
activity  
> 10 cm or  
prevents daily  
activity  
Necrosis  
Swelling ** 
(subjective) 
None 
2.5 – 5 cm and 
does not 
interfere  
with activity  
5.1 – 10 cm or  
interferes with  
activity  
> 10 cm or  
prevents daily  
activity  
Necrosis  
 
* In addition to grading the measured local reaction at the greatest single diameter, the measurement should be  
recorded as a continuous variable.  
** Induration/Swelling should be evaluated and graded using the functional scale as well as the actual measurement.  
 
Modified from:   
U.S. Department of Health and Human Services, Food and Drug Administration, Center for 
Biologics Evaluation and Research, September 2007.  Guidance for Industry: Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials. [pdf] Available at: 
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInform
ation/Guidances/Vaccines/ucm091977.pdf.  Accessed 14 April 2015. 


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Appendix 16 
Injection Site Pain Visual Analog Scale (Injection Site Pain 
VAS) 
How would you rate your injection site pain today? 
 
                  No  _________________________________________ Pain as bad  
                  Pain                                                                                  as it could be 
 
 
 
 
 
Please answer the following question by checking the box with either a “Yes” or “No”: 
Are you currently experiencing any burning or stinging at the injection site? 
 
 
 
 
YES   
 
 
 
NO 
 


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Appendix 17 
Timeline Followback (TLFB) Interview 
 
 
Ethanol 


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Appendix 18 
Euro QoL EQ-5D-5L Health Questionnaire 
 


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Appendix 19 
Short Form (36) Health Survey v2 
 


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Appendix 20 
Medication Satisfaction Questionnaire  
Overall, how satisfied are you with your current opioid dependence medication? 
 
1 = extremely dissatisfied 
2 = very dissatisfied 
3 = somewhat dissatisfied 
4 = neither satisfied nor dissatisfied 
5 = somewhat satisfied 
6 = very satisfied 
7 = extremely satisfied 
 


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Appendix 21 
Health Care Resource Utilization Questionnaire 
HEALTH INSURANCE 
Primary Health Insurance  
(Please check all  that apply) 
 Commercial (for example, Blue Cross Blue  
Shield,  Aetna, Humana, United, Cigna) 
 Medicare 
 Medicaid 
 Veterans Affairs 
 Workers compensation 
 Other insurance 
 Self-pay / Out of pocket/No insurance 
 
 
INPATIENT ADMISSIONS 
 
• 
Please list in the table below all inpatient admissions in the past 30 days.  If patient is currently 
hospitalized, please check the box in the “Ongoing” column. 
• 
If patient has had no previous hospitalizations in the past 30 days, please check the 
appropriate box below. 
 No hospitalizations since the last study visit 
Admission Date  
(dd / mmm / yyyy) 
Discharge Date 
(dd / mmm / yyyy) 
Ongoing? 
Type of Admission 
1. 
_ _ / _ _ _ / _ _ _ _ 
_ _ / _ _ _ / _ _ _ _ 
 
Medical 
Surgical 
Psychiatric 
Other 
2. 
_ _ / _ _ _ / _ _ _ _ 
_ _ / _ _ _ / _ _ _ _ 
 
 Medical 
Surgical 
Psychiatric 
Other 
3. 
_ _ / _ _ _ / _ _ _ _ 
_ _ / _ _ _ / _ _ _ _ 
 
 Medical 
Surgical 
Psychiatric 
Other 
 


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EMERGENCY ROOM VISITS  
• 
Please list how many times the patient has been to the Emergency Room in the past 30 days. 
Type of Problem 
Number of Visits 
Substance abuse-related 
visits 
Other medical problems 
visits 
 
 
OUTPATIENT SERVICES 
• 
Please list how many times the patient has seen 1 of the following health professionals in the 
past 30 days. The outpatient services captured on this questionnaire are ones conducted 
outside the study 
Health Professional 
Number of Visits 
General practitioner / Internist 
visits 
Addiction Medicine Specialist 
visits 
Therapist / Counselor 
visits 
Other: Specialist 
visits 
Other:  Non-Specialist  
visits 
 


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Appendix 22 
Treatment Effectiveness Assessment (TEA) 
 
 


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Appendix 23 
Addiction Severity Index (ASI) Lite 
 


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Appendix 24 
Beck Depression Inventory II (BDI-II) 
To be supplied by Indivior Inc.   
http://www.pearsonclinical.com/psychology/products/100000159/beck-depression-inventoryii-
bdi-ii.html?Pid=015-8018-370&Mode=summary#tab-details 


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Appendix 25 
Brief Pain Inventory (BPI) Short Form 
To be supplied by Indivior Inc.   
http://www.mdanderson.org/education-and-research/departments-programs-and-
labs/departments-and-divisions/symptom-research/symptom-assessment-
tools/BPI_UserGuide.pdf 


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Appendix 26 
Sponsor Signatures 
Study Title: 
An Open-Label, Long-Term Safety and Tolerability Study of Depot 
Buprenorphine (RBP-6000) in Treatment-Seeking Subjects With 
Opioid Use Disorder 
Study Number: 
RB-US-13-0003 
Final Date: 
04 August 2016 
 
 
This clinical study protocol was subject to critical review and has been approved by the Sponsor 
and contracted Medical Monitor.   
 
 
Signed: 
 
 
Date:  
 
 
Sr. Vice President, Global Clinical Development 
Indivior Inc. 
 
 
 
 
 
Signed: 
 
Date:  
 
  
Medical Monitor  
PRA Health Sciences. 


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Appendix 27 
Investigator’s Signature 
Study Title: 
An Open-Label, Long-Term Safety and Tolerability Study of Depot 
Buprenorphine (RBP-6000) in Treatment-Seeking Subjects With 
Opioid Use Disorder 
Study Number: 
RB-US-13-0003 
Final Date: 
04 August 2016 
 
I have read the protocol described above. I agree to comply with all applicable regulations and to 
conduct the study as described in the protocol.   
 
 
 
 
 
Signed: 
 
 
Date:  
 
Printed Name and Credentials: 
Title: 
Site Name: 
Address: 
Telephone: 
 
 
 
 

Prot_002.pdf: 
 
 
 
 
 
 
 
 
 
 
 
Study Title 
An Open-Label, Long-Term Safety and Tolerability Study of Depot 
Buprenorphine (RBP-6000) in Treatment-Seeking Subjects With 
Opioid Use Disorder 
NCT Number 
NCT02510014 
Date 
September 11, 2015 
 


Clinical Study Protocol: RB-US-13-0003 
Study Title: 
An Open-Label, Long-Term Safety and Tolerability Study of Depot 
Buprenorphine (RBP-6000) in Treatment-Seeking Subjects With 
Opioid Use Disorder 
Study Number: 
RB-US-13-0003 
Study Phase: 
3 
Product Name: 
RBP-6000 
IND Number: 
107,607 
Indication: 
Treatment of Opioid Use Disorder 
Investigators: 
Multicenter 
Sponsor: 
Indivior Inc. 
 
10710 Midlothian Turnpike, Suite 430 
Richmond, VA 23235 
 
Sponsor Contact: 
 Clinical Development Manager 
 
 
Medical Monitor: 
 
 
 
Date 
Original Protocol: 
14 April 2015 
Amendment 1: 
19 August 2015 
Amendment 2: 
11 September 2015 
 
 
 
 
 
 
 
Confidentiality Statement 
The information contained in this document is privileged and confidential. Do not copy, 
circulate, or otherwise distribute without written authorization from  
Indivior Inc. 


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SYNOPSIS 
Sponsor:  
Indivior Inc., formerly Reckitt Benckiser Pharmaceuticals Inc. (RBP) 
Name of Finished Product: 
RBP-6000, 18% buprenorphine sterile solution for subcutaneous (SC) injection 
Name of Active Ingredient: 
Buprenorphine 
Name of Inactive Ingredient:  
ATRIGEL® Delivery System 
Study Title: 
An Open-Label, Long-Term Safety and Tolerability Study of Depot Buprenorphine (RBP-6000) 
in Treatment-Seeking Subjects With Opioid Use Disorder 
Study Number: 
RB-US-13-0003 
Study Phase: Phase 3 
Primary Objective: 
To assess the long-term safety and tolerability of RBP-6000 subcutaneous (SC) injections in 
subjects with opioid use disorder. 
Secondary Objective: 
To collect clinical outcome data with RBP-6000 SC injections in subjects with opioid use 
disorder. 
Tertiary Objectives:  
To evaluate the: 
• Pharmacokinetics (PK) of RBP-6000,  
• Relationships between RBP-6000 PK and clinical outcome data, and 
• Impact of RBP-6000 on health and economic outcomes. 
Study Design: 
This is a multicenter, open-label, long-term safety study in which approximately 600 subjects 
diagnosed with opioid use disorder will be enrolled (approximately 300 subjects who did not 
participate in Study RB-US-13-0001, the double-blind, placebo-controlled efficacy study of 
RBP-6000 [hereafter referred to as “de novo” subjects], and 300 subjects who completed the RB-
US-13-0001 study [hereafter referred to as “roll-over” subjects]).  Subject participation will be 
based on the Investigator’s determination that initiation or continuation of study treatment is 
appropriate; and, for subjects who participated in RB-US-13-0001, that there have been no 
significant protocol deviations or clinically relevant adverse events (AEs) that would preclude 
inclusion of the subject in this study. All subjects will provide written informed consent before 
any protocol-related procedures commence. At the Screening Visit (which is up to 3 days after 
the End of Study [EOS] Visit [Day 169 + 3] for roll-over subjects), potential subjects will be 


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reviewed for eligibility against inclusion and exclusion criteria, and eligible subjects will be 
enrolled into the trial.  
SUBOXONE Sublingual Film Run-In:  Induction 
De novo Subjects: 
De novo subjects will initially be inducted onto SUBOXONE® (buprenorphine/naloxone) 
sublingual film for 3 days according to the SUBOXONE sublingual film prescribing 
information.  They will receive their first dose of SUBOXONE sublingual film on Induction 
Day 1 after it is confirmed that the subject meets eligibility criteria and has a Clinical Opiate 
Withdrawal Scale (COWS) score > 12.  Subjects will be started with an initial dose of 2 mg/0.5 
mg (buprenorphine/naloxone) or 4 mg/1 mg and may titrate upwards in 2 or 4 mg increments of 
buprenorphine, at approximately 2-hour intervals, under clinical supervision, to 8 mg/2 mg based 
on therapeutic response.  
On Induction Day 2, subjects with a COWS score > 12 or subjects reporting withdrawal 
signs/symptoms overnight will receive a dose of SUBOXONE sublingual film equal to the total 
dose given on Induction Day 1 plus 4 mg.  (For example, if a subject received a total dose of 8 
mg of buprenorphine on Induction Day 1, the starting dose for Induction Day 2 would be 12 mg).  
If the COWS score is still > 12 one hour later, another 4 mg dose can be given. The subject 
should not exceed a maximum dose of 16 mg buprenorphine for Induction Day 2. Subsequent 
SUBOXONE sublingual film doses must be separated by at least 1 hour from the preceding dose. 
SUBOXONE sublingual film doses may also be adjusted downward if necessary.  
On Induction Day 3, subjects will be titrated to therapeutic response based on COWS scores as 
well as physician judgment. Most subjects will only require a single dose on Induction Day 3, 
which will equal the Induction Day 2 dose or the Induction Day 2 dose plus 4 mg buprenorphine. 
Additional doses may also be administered on Induction Day 3 (up to 24 mg/6 mg). Subsequent 
SUBOXONE sublingual film doses must be separated by at least 1 hour from the preceding dose.  
Subjects should reach a daily dose of between 8 mg and 24 mg buprenorphine by Induction Day 
3 and continue on that dose through the remainder of the SUBOXONE sublingual film Run-In 
period, with additional dose adjustments if necessary.  
Roll-over Subjects: 
Following screening, roll-over subjects will be inducted onto SUBOXONE sublingual film to 
achieve daily doses between 8 mg to 24 mg buprenorphine according to the SUBOXONE 
sublingual film prescribing information.  
Subjects will receive their first induction dose on Induction Day 1. Subjects should be started 
with an initial dose of 2 mg/0.5 mg (buprenorphine/naloxone) or 4 mg/1 mg and may titrate 
upwards in 2 or 4 mg increments of buprenorphine, at approximately 2-hour intervals, under 
supervision, to a total dose of up to 8 mg/2 mg based on the control of acute withdrawal 
symptoms.  
On Induction Day 2, subjects with a score for COWS of >12, or subjects reporting opioid 
withdrawal signs/symptoms overnight, should receive a dose of study drug equal to the total dose 
given on Induction Day 1 plus 4 mg.  If the COWS score is still >12 one hour later, another 4 mg 
dose can be given.  The subject should not exceed a maximum dose of 16 mg/4 mg for Induction 
Day 2.  Subsequent SUBOXONE sublingual film doses must be separated by at least 1 hour 
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necessary.   
On Induction Day 3, subjects will be titrated to therapeutic response until a therapeutic dosage is 
reached, based on COWS scores as well as physician judgment. Most subjects will only require a 
single dose on Induction Day 3 which will equal the Induction Day 2 dose or the Induction Day 2 
dose plus 4 mg. Additional doses may also be administered on Induction Day 3 (up to 24 mg).  
Subsequent SUBOXONE sublingual film doses must be separated by at least 1 hour from the 
preceding dose.  Although subjects should reach a daily dose of between 8 mg and 24 mg by 
Induction Day 3 and continue on that dose through the remainder of the SUBOXONE sublingual 
film Run-In period, dose adjustments may be necessary during the Run-In period.  
Roll-over subjects must be titrated to a minimum dose of 8 mg SUBOXONE by the end of the 
3-day Induction period regardless of their COWS scores and/or the presence or absence of 
withdrawal symptoms.   
The SUBOXONE sublingual film(s) will be administered under the tongue, close to the base on 
the left or right side, until they are dissolved.  If an additional sublingual film is required, it 
should be placed on the opposite side from the first film.  Subjects should be instructed to hold 
the films under the tongue until they dissolve.  If a third film is required, it should be placed 
under the tongue after the first 2 films have dissolved.   
SUBOXONE Sublingual Film Run-In:  Dose Adjustment (All Subjects) 
After the daily induction visits, all subjects will begin a 1-to 11-day SUBOXONE sublingual 
film dose adjustment period.  Subjects will return to the clinic at 3- to 4-day intervals for Opioid 
Craving Visual Analog Scale (VAS), COWS, and Subjective Opiate Withdrawal Scale (SOWS) 
assessments.  SUBOXONE sublingual film will be dispensed at each visit for at home dosing.  
Beginning on the 4th day of SUBOXONE sublingual film dosing, subjects will be evaluated for 
Day -1 criteria, which are identical to the criteria required for enrollment on Day 1.  These 
criteria include the following: no allergic reaction to SUBOXONE sublingual film, a daily dose 
of SUBOXONE sublingual film between 8 mg and 24 mg (inclusive) buprenorphine, a COWS 
score of ≤ 12, and an Opioid Craving VAS score of ≤ 20 mm. 
Open-Label Treatment with RBP-6000: 
On Day 1 of the study (first dose of RBP-6000), all subjects who meet enrollment criteria will 
receive a SC injection of 300 mg of buprenorphine in RBP-6000. Subsequent doses of RBP-6000 
may be adjusted down to 100 mg and back up to 300 mg based on the medical judgment of the 
Investigator. After injection of RBP-6000, subjects will not be permitted to receive supplemental 
SUBOXONE sublingual film during the RBP-6000 treatment period. Subjects who require 
supplemental SUBOXONE sublingual film or other sublingual buprenorphine pharmacotherapy 
during the RBP-6000 treatment period will be withdrawn from the study and referred for 
appropriate treatment. 
Subjects will return to the clinic for monthly injection visits (every 28 ±2 days) for a total of up 
to 12 injections for de novo subjects or for a total of 6 injections for roll-over subjects. 
Electrocardiogram (ECG) recordings and vital signs will be collected pre and post each SC 
injection. Subject-reported injection site pain Visual Analog Scale scores (VAS) will be 
collected at various times for 1 hour after each injection. Local injection site grading will be 
collected at various time points starting immediately after injection; the injection site will 
evaluated for pain, tenderness, warmth, itching, erythema, inflammation or swelling, and 


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bruising using a 4-point severity scale. At each visit after injections begin, the injection site will 
be assessed by site staff for potential reaction and will also be evaluated for evidence of attempts 
to remove the depot. 
Subjects will return to the clinic weekly for the first 5 weeks and then biweekly (i.e., every 2 
weeks) through to injection 6. After injection 6, visits will be monthly for the rest of the study 
period for urine drug screens (UDS), Timeline Followback (TLFB) interviews, opioid craving 
VAS evaluation, COWS and subject reported outcomes (Subjective Opiate Withdrawal Scale 
[SOWS]). Subjects will continue to receive counseling (manual-guided behavioral therapy) 
during the study.  
Safety assessments will be collected at each injection visit and/or at injection follow-up visits 
and will include the following: vital signs, electronic Columbia Suicide Severity Rating Scale 
(eC-SSRS) responses, ECGs, laboratory tests (hematology, chemistry, urinalysis, and pregnancy 
test), use of concomitant medications, and the frequency of AEs.  
Sparse PK blood samples will be collected for population PK analysis from the roll-over subjects 
only. PK samples for population PK analysis are not required from the de novo subjects. ECGs 
will be performed before PK sample collection. The following health economic and outcome 
assessments will also be collected: Beck Depression Inventory (BDI-II), brief pain inventory 
(BPI), EuroQol EQ-5D-5L (EQ-5D-5L), 36-Item Short Form Health Survey, Version 2 (SF-
36v2), Medication Satisfaction Questionnaire (MSQ), healthcare resource utilization (HCRU), 
Treatment Effectiveness Assessment (TEA), and Addiction Severity Index Lite (ASI). 
 
For all subjects (de novo and roll-over), a PK sample will be taken as soon as possible after any 
SAE is reported. If possible, an additional sample should be collected when the SAE has been 
resolved. 
 
SUBOXONE Transition Period/Safety Follow-up: 
At the end of the RBP-6000 treatment period, subjects will enter a 4-week SUBOXONE 
transition period/safety follow-up where they will receive the same dose of SUBOXONE 
sublingual film that they received at Day -1, and their ongoing treatment options will be 
reviewed. 
Study Population:  
Approximately 300 de novo subjects will be enrolled into this study, as well as approximately 
300 roll-over subjects. The study population will consist of individuals diagnosed with opioid 
use disorder who are seeking treatment.  
Test Product, Dose, and Mode of Administration:  
300 mg buprenorphine in RBP-6000, subcutaneous injection 
100 mg buprenorphine in RBP-6000, subcutaneous injection 
Duration of Study Treatment:  
This will be a multiple-dose study, with the first investigational product administration 
(RBP-6000 containing 300 mg buprenorphine) on Day 1. The expected maximum duration of 
participation for de novo subjects is up to approximately 55 weeks, consisting of up to 7 days of 
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treatment period, and a 4-week follow-up period. The expected maximum duration of 
participation for roll-over subjects is up to approximately 31 weeks, consisting of up to a 7-day 
screening period, up to 14 days SUBOXONE sublingual film Run-In, a 24-week open-label 
treatment period, and a 4-week follow-up period. 
Safety Assessments: 
Safety objectives for this study are to evaluate the safety and tolerability of RBP-6000 (100 mg 
and 300 mg) SC injection treatment in subjects with opioid use disorder. Safety assessments will 
include the following: frequency of all AEs, serious AEs (SAEs), discontinuations from study 
due to AEs; local injection site tolerability (e.g., injection site grading); injection site pain using a 
subject-reported VAS; suicidality using the eC-SSRS, use of concomitant medications; changes 
in clinical laboratory results; vital sign measurements; 12-lead ECGs, which will be interpreted 
by a central facility; physical examination results; body weight, height, and body mass index 
(BMI), and abdominal fat measurement (waist-to-hip ratio). 
Clinical Outcome Assessments: 
Clinical outcome assessments will include the UDS for opioids and other drugs; self-reported use 
of illicit opioids, other drugs, and alcohol on the TLFB; COWS, SOWS, and Opioid Craving 
VAS. 
PK Assessments: 
Sparse plasma samples will be collected for population PK analysis from the roll-over subjects 
only. No PK samples will be collected from the de novo subjects. 
Health Economics and Outcomes Assessments:  
Health economics and outcomes assessments will include: BDI-II, BPI, EQ-5D-5L, SF-36v2, 
MSQ, HCRU, TEA, and ASI-Lite. 


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Statistical Methods:  
A Statistical Analysis Plan (SAP) will be prepared after the protocol is approved and before 
database lock occurs.  The SAP will provide further details regarding the definition of analysis 
endpoints, data handling rules, and the statistical methodology to be used to address all study 
objectives.  The SAP will also include formats for the summary and analysis tables, listings, and 
graphical displays. 
Determination of Sample Size: 
Approximately 300 de novo subjects as well as approximately 300 subjects who completed the 
RB-US-13-0001 study will be enrolled into this long-term safety study to ensure 100 subjects 
reach 1 year of treatment with RBP-6000. No power analysis will be done corresponding to the 
sample sizes, but the large numbers proposed are clinically acceptable to provide adequate and 
relevant clinical conclusions from this study. 
Safety Analyses: 
Safety variables will include AEs, local injection site tolerability (e.g., injection site grading); 
injection site pain using a subject-reported VAS; suicidality using the eC-SSRS, concomitant 
medications; changes in clinical laboratory results (hematology, chemistry and urinalysis); vital 
sign measurements; 12-lead ECGs, physical examination results; body weight, height, BMI, and 
abdominal fat measurement (waist-to-hip ratio).  Safety variables will be analyzed on the safety 
population using descriptive statistics for continuous endpoints (e.g., mean, median, SD, 
minimum and maximum) and frequency counts with percentages for discrete endpoints. 
Baseline is defined as the last non-missing value prior to SC injection on Day 1.  No imputation 
of missing values will be performed. 
Clinical Outcomes Assessments: 
COWS, SOWS and Opioid Craving VAS total scores will be summarized using descriptive 
statistics (mean, median, SD, minimum, maximum), including change from baseline.  Subjects’ 
self-reported illicit drug use from the TLFB will be summarized as descriptive statistics. 
The cumulative distribution function (CDF) of the percentage of urine samples negative for 
opioids, the CDF of the percentage of self-reports from the TLFB negative for illicit opioid use, 
and other outcome measures will be calculated. 
Population PK/PD Analysis: 
The population PK model established using the data collected in the double-blind, placebo-
controlled, efficacy study (Study RB-US-13-0001) will be refined using the sparse PK samples 
collected in the present study for the roll-over subjects to characterize the disposition of 
buprenorphine and norbuprenorphine following SC injections of RBP-6000, with the assessment 
of potential covariates affecting the PK of both compounds. Subsequently, the relationships 
between buprenorphine plasma concentrations and clinical outcomes assessments will be 
investigated. These relationships will be initially assessed in a descriptive manner, and, if 
applicable, appropriate PK/PD models will be developed to describe these relationships. A stand-
alone modeling analysis plan will be generated, and the results will be reported in a standalone 
modeling report. 


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Health Economic and Outcomes Research Analyses: 
The health economic and outcomes research endpoints for this study are: BDI-II, BPI, EQ-5D-
5L, SF-36v2, MSQ, Health Insurance, HCRU, TEA, and ASI-Lite.  
Summary scores for these measures will be calculated, as appropriate. Categorical variables will 
be summarized using frequencies and percentages. Continuous measures will be summarized 
using descriptive statistics (mean, standard deviation, median, minimum, maximum) as 
appropriate. An analysis of change will be conducted. Supplementary analyses using general 
linear, mixed, or non-parametric methods will be performed as appropriate.  
A stand-alone SAP will be developed prior to database lock with full detail regarding health 
economics and outcomes analyses. 
Date of Original Approved Protocol: 14 April 2015 
Date of Amendment 1: 19 August 2015 
Date of Amendment 2: 11 September 2015 
 


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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................2 
LIST OF IN-TEXT TABLES ..................................................................................................13 
LIST OF IN-TEXT FIGURES.................................................................................................13 
LIST OF APPENDICES ..........................................................................................................13 
LIST OF ABBREVIATIONS ..................................................................................................15 
1 
INTRODUCTION ...........................................................................................................18 
1.1 
Opioid Use Disorder ..............................................................................................18 
1.2 
Buprenorphine........................................................................................................19 
1.3 
ATRIGEL Delivery System ...................................................................................19 
1.4 
Buprenorphine in the ATRIGEL Delivery System (RBP-6000) ...........................20 
1.4.1 
Summary of Nonclinical Data .....................................................................20 
1.4.2 
Summary of Previous Clinical Data ............................................................21 
1.4.3 
Pharmacokinetic/Pharmacodynamic Modeling of RBP-6000 .....................22 
1.5 
Rationale for Dose Selection .................................................................................23 
1.6 
Known and Potential Risks and Benefits ...............................................................26 
2 
STUDY OBJECTIVES ....................................................................................................27 
2.1 
Primary Objective ..................................................................................................27 
2.2 
Secondary Objectives.............................................................................................27 
2.3 
Tertiary Objectives.................................................................................................27 
3 
INVESTIGATIONAL PLAN ..........................................................................................28 
3.1 
Overall Study Design and Plan ..............................................................................28 
3.2 
Rationale for Study Design ....................................................................................32 
3.3 
Study Duration and Dates ......................................................................................32 
4 
STUDY POPULATION SELECTION ...........................................................................33 
4.1 
Study Population ....................................................................................................33 
4.2 
Inclusion Criteria ...................................................................................................33 
4.3 
Exclusion Criteria ..................................................................................................34 
4.4 
Day -1/Enrollment Criteria ....................................................................................36 
5 
STUDY TREATMENTS .................................................................................................37 
5.1 
Description of Treatments......................................................................................37 
5.1.1 
SUBOXONE Sublingual Film .....................................................................37 
5.1.2 
Investigational Medicinal Products..............................................................37 
5.2 
Treatments Administered .......................................................................................37 
5.2.1 
Run-In Treatment Period .............................................................................37 
5.2.1.1 
SUBOXONE Sublingual Film Induction (De novo Subjects) ...........37 
5.2.1.2 
SUBOXONE Sublingual Film Induction (Roll-over Subjects) .........38 


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5.2.2 
Dose Adjustment Period (All Subjects) .......................................................39 
5.2.3 
Active Study Treatment ...............................................................................39 
5.2.4 
SUBOXONE Transition Period/Safety Follow-up ......................................40 
5.3 
Selection and Timing of Dose for Each Subject ....................................................40 
5.4 
Method of Assigning Subjects to Treatment Groups .............................................40 
5.5 
Blinding..................................................................................................................40 
5.6 
Concomitant Therapy.............................................................................................40 
5.6.1 
Permitted Concomitant Medications ............................................................41 
5.6.2 
Prohibited Concomitant Medications ..........................................................41 
5.7 
Restrictions ............................................................................................................42 
5.7.1 
Prior Therapy ...............................................................................................42 
5.7.2 
Subject Activity Restrictions .......................................................................42 
5.8 
Protocol Compliance ..............................................................................................42 
5.9 
Packaging and Labeling .........................................................................................42 
5.10 
Storage and Accountability ....................................................................................42 
5.11 
Investigational Product Retention at Study Site ....................................................43 
6 
STUDY PROCEDURES .................................................................................................44 
6.1 
Informed Consent...................................................................................................44 
6.1.1 
General Information .....................................................................................44 
6.2 
Medical History .....................................................................................................44 
6.3 
Physical Examination.............................................................................................44 
6.4 
Vital Signs ..............................................................................................................45 
6.5 
Electrocardiograms ................................................................................................45 
6.5.1 
12-Lead Electrocardiograms ........................................................................45 
6.6 
Clinical Laboratory Tests .......................................................................................46 
6.6.1 
Laboratory Parameters .................................................................................46 
6.6.2 
Sample Collection, Storage, and Shipping ..................................................48 
6.6.3 
Reference Ranges.........................................................................................48 
6.6.4 
Laboratory Results Review ..........................................................................48 
6.6.5 
Good Laboratory Practice Compliance ........................................................48 
6.7 
Pharmacokinetic Assessments ...............................................................................48 
6.8 
Administration of Study Drug ...............................................................................49 
6.9 
Safety and Suicidality Assessments .......................................................................49 
6.9.1 
Local Injection Site Tolerability ..................................................................49 
6.9.1.1 
Injection Site Grading ........................................................................49 
6.9.1.2 
Injection Site Pain Visual Analogue Scale (VAS) .............................50 
6.9.2 
Suicidality ....................................................................................................50 
6.9.2.1 
Columbia Suicide Severity Rating Scale ...........................................50 


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6.10 
Adverse Events Assessments .................................................................................50 
6.10.1 
Definition .....................................................................................................50 
6.10.2 
Performing Adverse Events Assessments ....................................................51 
6.10.3 
Timing ..........................................................................................................51 
6.10.4 
Severity ........................................................................................................51 
6.10.5 
Relationship .................................................................................................52 
6.10.6 
Expectedness ................................................................................................52 
6.10.7 
Clinical Significance ....................................................................................52 
6.10.8 
Clinical Laboratory Adverse Events ............................................................53 
6.10.9 
Serious Adverse Events ...............................................................................53 
6.10.9.1 
Definition ...........................................................................................53 
6.10.9.2 
Reporting Serious Adverse Events ....................................................53 
6.10.10 Treatment-Emergent Adverse Events ..........................................................54 
6.10.11 Procedures and Follow-Up of Subjects with Ongoing SAEs or Experiencing 
SAEs after Completion of or Withdrawal from the Study ...........................54 
6.10.12 Pregnancy .....................................................................................................54 
6.11 
Clinical Outcome Assessments ..............................................................................55 
6.11.1 
Timeline Followback Interview ...................................................................55 
6.11.2 
Opioid Craving Visual Analog Scale ...........................................................55 
6.11.3 
Clinical Opiate Withdrawal Scale ................................................................55 
6.11.4 
Subjective Opiate Withdrawal Scale ...........................................................56 
6.12 
Health Economics and Outcomes Assessments .....................................................56 
6.12.1 
EuroQoL-5 Dimensions-5 Levels (EQ-5D-5L) and EQ-VAS.....................56 
6.12.2 
Medical Outcomes Study Short Form-36 (SF-36v2) ...................................56 
6.12.5 
Treatment Effectiveness Assessment (TEA) ...............................................57 
6.12.6 
Addiction Severity Index (ASI) Lite............................................................57 
6.12.7 
Beck Depression Inventory II (BDI-II)........................................................58 
6.12.8 
Brief Pain Inventory (BPI) Short Form .......................................................58 
6.13 
Concomitant Medication Assessments ..................................................................59 
6.14 
Removal of Subjects from the Study .....................................................................59 
6.14.1 
Early Removal of RBP-6000 .......................................................................60 
6.14.2 
Stopping Rules .............................................................................................60 
6.14.3 
Screen Failures .............................................................................................60 
6.15 
Other Study Procedures .........................................................................................60 
6.15.1 
Counseling/Behavioral Therapy ..................................................................60 
6.15.2 
Unscheduled Visits ......................................................................................61 
6.15.3 
Additional Care of Study Subjects Following Completion of the Study .....61 
6.15.4 
Treating Toxicity .........................................................................................61 


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6.15.5 
Ancillary Medications ..................................................................................61 
6.16 
Appropriateness of Measurements .........................................................................62 
7 
STUDY ACTIVITIES .....................................................................................................63 
8 
QUALITY CONTROL AND ASSURANCE .................................................................64 
8.1 
Quality Control ......................................................................................................64 
8.2 
Quality Assurance ..................................................................................................64 
9 
PLANNED STATISTICAL METHODS ........................................................................65 
9.1 
General Considerations ..........................................................................................65 
9.2 
Determination of Sample Size ...............................................................................65 
9.3 
Analysis Populations ..............................................................................................65 
9.3.1 
Safety Population .........................................................................................65 
9.3.2 
Clinical Outcome Assessment and PK Populations.....................................65 
9.4 
Demographics and Baseline Characteristics ..........................................................66 
9.5 
Primary Analysis ....................................................................................................66 
9.5.1 
Safety Endpoints ..........................................................................................66 
9.5.1.1 
Adverse Events ..................................................................................66 
9.5.1.2 
Laboratory Data .................................................................................66 
9.5.1.3 
Vital Signs ..........................................................................................66 
9.5.1.4 
Other Variables Related to Safety ......................................................66 
9.6 
Secondary Analysis ................................................................................................67 
9.6.1 
Clinical Outcomes Assessments ..................................................................67 
9.7 
Other Analyses .......................................................................................................67 
9.7.1 
PK/PD Modeling ..........................................................................................67 
9.7.2 
Health Economic and Outcomes Assessment ..............................................68 
9.8 
Handling of Missing Data ......................................................................................68 
9.9 
Subjects Who Withdraw from the Study ...............................................................69 
9.10 
Interim Analyses ....................................................................................................69 
10 ADMINISTRATIVE CONSIDERATIONS ....................................................................70 
10.1 
Investigators and Study Administrative Structure .................................................70 
10.1.1 
Indivior Inc...................................................................................................70 
10.1.2 
Investigational Site(s) ..................................................................................70 
10.1.3 
Laboratories .................................................................................................70 
10.2 
Institutional Review Board or Independent Ethics Committee Approval .............70 
10.3 
Ethical Conduct of the Study .................................................................................70 
10.4 
Subject Information and Consent...........................................................................71 
10.5 
Subject Confidentiality ..........................................................................................71 
10.6 
Study Monitoring ...................................................................................................72 
10.6.1 
Study and Site Closure .................................................................................72 


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10.7 
Case Report Forms and Study Records .................................................................72 
10.8 
Data Monitoring Committee ..................................................................................73 
10.9 
Protocol Deviations ................................................................................................73 
10.10 Access to Source Documentation ..........................................................................74 
10.11 Data Generation and Analysis ...............................................................................74 
10.11.1 Data Collection and Data Management .......................................................74 
10.11.2 Database Quality Assurance ........................................................................74 
10.12 Retention of Data ...................................................................................................75 
10.13 Financial Disclosure...............................................................................................75 
10.14 Publication and Disclosure Policy .........................................................................75 
11 REFERENCE LIST .........................................................................................................76 
 
LIST OF IN-TEXT TABLES 
Table 1 
PK Parameters of the Simulated Typical PK Profile of Buprenorphine after 
Repeated RBP-6000 Injections for the Phase 3 Efficacy Study (RB-US-13-0001) ....25 
Table 2 
List of Laboratory Tests ...............................................................................47 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Model-Predicted Buprenorphine Plasma Concentrations and Mu-Opioid 
Receptor Occupancy in Each Treatment Group on RBP-6000 Following the Proposed 
Design of the Current Study ........................................................................................24 
Figure 2 
Study Overview:  De novo Subjects ............................................................30 
Figure 3 
Study Overview:  Roll-over Subjects from RB-US-13-0001 ......................31 
Figure 4 
Injection Locations.....................................................................................124 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events – Screening and SUBOXONE Film Induction ..80 
Appendix 2 
Schedule of Events – RBP-6000 Injection 1 – 3 Visits .....................83 
Appendix 3 
Schedule of Events – RBP-6000 Injection 4 – 6 Visits for all Subjects 
and End of Study/Early Termination and Follow-Up Visits for Roll-over Subjects ...86 
Appendix 4 
Schedule of Events – RBP-6000 Injection 7 – 9 Visits for de novo 
Subjects  
90 
Appendix 5 
Schedule of Events – RBP-6000 Injection 10 – 12 Visits and End of 
Study/Early Termination Visit and Follow-Up for de novo Subjects  .........................93 
Appendix 6 
Pharmacokinetic Sampling Schedule .................................................96 
Appendix 7 
SUBOXONE® (Buprenorphine/Naloxone) Sublingual Film Full 
Prescribing Information ...............................................................................................97 


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Appendix 8 
Study Drug Preparation, Administration, and Depot Removal 
Instructions 
123 
Appendix 9 
Prohibited Cytochrome P450 Inhibitors and Inducers .....................126 
Appendix 10 
Columbia Suicide Severity Rating Scale (eC-SSRS) -- 
Baseline/Screening Version .......................................................................................127 
Appendix 11 
Columbia Suicide Severity Rating Scale (eC-SSRS) -- Since Last 
Visit Version 
129 
Appendix 12 
Clinical Opiate Withdrawal Scale (COWS) ....................................131 
Appendix 13 
Subjective Opiate Withdrawal Scale (SOWS) .................................133 
Appendix 14 
Opioid Craving Visual Analog Scale (Opioid Craving VAS) .........134 
Appendix 15 
Injection Site Grading Scale ............................................................135 
Appendix 16 
Injection Site Pain Visual Analog Scale (Injection Site Pain VAS) 136 
Appendix 17 
Timeline Followback (TLFB) Interview .........................................137 
Appendix 18 
Euro QoL EQ-5D-5L Health Questionnaire ....................................138 
Appendix 19 
Short Form (36) Health Survey v2...................................................140 
Appendix 20 
Medication Satisfaction Questionnaire ............................................144 
Appendix 21 
Health Care Resource Utilization Questionnaire .............................145 
Appendix 22 
Treatment Effectiveness Assessment (TEA) ...................................147 
Appendix 23 
Addiction Severity Index (ASI) Lite................................................148 
Appendix 24 
Beck Depression Inventory II (BDI-II)............................................164 
Appendix 25 
Brief Pain Inventory (BPI) Short Form ...........................................165 
Appendix 26 
Sponsor Signatures...........................................................................166 
Appendix 27 
Investigator’s Signature ...................................................................167 
 


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LIST OF ABBREVIATIONS 
AE 
adverse event 
AIDS 
acquired immunodeficiency syndrome 
ANOVA 
analysis of variance 
ASI-Lite 
Addiction Severity Index - Lite 
AUC 
area under the plasma concentration-time curve 
BDI-II 
Beck Depression Inventory - II 
BMI 
body mass index 
BP 
blood pressure 
BPI 
Brief Pain Inventory Short Form 
Cavg 
average plasma concentration 
Cmax 
maximum plasma concentration 
Ctrough 
plasma concentration at trough, i.e. before the next injection  
CDF 
cumulative distribution function 
CNS 
central nervous system 
COWS 
Clinical Opiate Withdrawal Scale 
CRA 
clinical research associate 
DAWN 
Drug Abuse Warning Network 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
EC50 
concentration yielding 50% of the maximal effect 
eCRF 
electronic case report form 
e C-SSRS 
Electronic Columbia Suicide Severity Rating Scale 
Emax 
maximum effect 
ECG 
electrocardiogram 
ED 
emergency department 
EOS 
end of study 
ET 
early termination 
EQ-5D 
EuroQol EQ-5D (standard instrument) 
EQ-5D-5L 
EuroQol EQ-5D-5L (self-complete version) 


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EQ-VAS 
EQ-5D using visual analog scale 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B surface antigen  
hCG 
urine human chorionic gonadotropin 
HCl 
hydrochloride 
HCRU 
healthcare resource utilization  
HEOR 
health economics and outcomes research 
HIV 
human immunodeficiency virus 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation  
IEC 
independent ethics committee 
IM 
intramuscular 
IMP 
investigational medicinal product 
IND 
investigational new drug application (i.e., Notice of Claimed 
Investigational Exemption for a New Drug) 
INR 
international normalized ratio 
IRB 
institutional review board 
IV 
intravenous 
IWRS 
interactive web response system 
MAR 
missing at random  
MCAR 
missing completely at random  
MMRM 
mixed model repeated measures 
MSQ 
Medication Satisfaction Questionnaire 
NMP 
N-methyl pyrrolidone 
NOAEL 
no observable adverse effect level 
OTC 
over-the-counter 


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PD 
pharmacodynamic or pharmacodynamics 
PE 
physical examination 
PK 
pharmacokinetic or pharmacokinetics 
PLG or PLGH 
poly (DL-lactide-co-glycolide)  
PET 
positron emission tomography  
PI 
Principal Investigator 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
RBP 
Reckitt Benckiser Pharmaceuticals Inc. 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SD 
standard deviation 
SF-36v2 
36-Item Short Form Health Survey, Version 2 
SL 
sublingual 
SOE 
schedule of events 
SOP 
standard operating procedure 
SOWS 
Subjective Opiate Withdrawal Scale 
tmax 
time to maximum plasma concentration 
TEA 
Treatment Effectiveness Assessment  
TEAE 
treatment-emergent adverse event 
TLFB 
timeline followback 
UDS 
urine drug screen 
ULN 
upper limit of normal 
US/USA 
United States/United States of America 
VAS 
visual analog scale 


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1 
INTRODUCTION 
1.1 
Opioid Use Disorder 
Opioid use disorder, as defined in the Diagnostic and Statistical Manual of Mental Disorders, 
Fifth Edition (DSM-5; American Psychiatric Association 2013), is a neurobehavioral syndrome 
characterized by the repeated, compulsive seeking or use of an opioid despite adverse social, 
psychological, and/or physical consequences.  Opioid use disorder is a medical illness with high 
costs to individuals, families, and society.  Direct and indirect costs attributable to illicit drug use 
are estimated in 3 principal areas: crime, productivity, and health (US Department of Justice, 
Economic Impact of Illicit Drug Use on American Society, 2011).  Approximately one-third of 
all acquired immunodeficiency syndrome (AIDS) cases diagnosed in the United States (US) 
through 2009 (Centers for Disease Control and Prevention: HIV/AIDS Surveillance Report, 
2009) and many cases of hepatitis C (National Institute on Drug Abuse 2000; Thomas 2001) 
were associated with injection drug use.   
The increasing abuse of and addiction to prescription opioids is another major concern.  
According to the Substance Abuse and Mental Health Services Administration’s Office of 
Applied Studies, the incidence of abuse of prescription opioid pain medications (narcotic 
analgesics) such as hydrocodone, oxycodone, meperidine, and propoxyphene has risen markedly 
in recent years (Crane 2003).  The incidence of emergency department (ED) visits related to 
these medications has been increasing since the 1990s and has more than doubled between 1994 
and 2001 (Crane 2003).  The most recently published data from the Drug Abuse Warning 
Network (Drug Abuse Warning Network, 2009: National Estimates of Drug-Related Emergency 
Department Visits, 2011) estimated that about 2.1 million ED visits resulted from drug misuse or 
abuse, which was the equivalent of 674.4 ED visits per year per 100,000 population.  Although 
the overall number of ED visits attributable to drug misuse or abuse was stable from 2004 to 
2009, increases were seen in ED visits involving nonmedical use of pharmaceuticals with no 
other drug involvement (117% increase).  An estimated 1,079,683 ED visits in 2009 involved the 
nonmedical use of prescription drugs, over-the-counter (OTC) medicines, or other types of 
pharmaceuticals, representing about a quarter of all drug-related ED visits and over half of ED 
visits for drug abuse or misuse.  Pain relievers were the most common type of drugs reported in 
the nonmedical use category of ED visits (47.8%).  Among specific types of pain relievers, 
narcotic pain relievers such as oxycodone, hydrocodone, and methadone (13.7%, 8.0%, and 
5.8%, respectively) were most prevalent (Drug Abuse Warning Network, 2009: National 
Estimates of Drug-Related Emergency Department Visits, 2011). 
The economic burden of prescription opioid abuse is very high.  Total US societal costs of 
prescription opioid abuse were estimated at $55.7 billion in 2007 (US dollars in 2009).  
Workplace costs accounted for $25.6 billion (46%), health care costs accounted for $25.0 billion 
(45%), and criminal justice costs accounted for $5.1 billion (9%) (Birnbaum 2011).  Mean 
annual direct health care costs for opioid abusers were more than 8 times higher than for 
nonabusers.  Hospital inpatient and physician outpatient costs accounted for 46% and 31% 
respectively, of opioid abusers' health care costs.  The high costs of opioid abuse are driven 
primarily by high comorbidity rates and high utilization rates of medical services and 
prescription drugs (White 2005).  It was also found that opioid use results in lower quality of life, 


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including significantly worse physical and psychological health, compared with the general 
population (Ryan 1996). 
Given the high costs of opioid addiction to individuals, families, and society, treatments for this 
disease therefore aim to reduce the use of prescription or illicit opioids as well as the risks 
associated with injection, including transmission of human immunodeficiency virus (HIV) and 
hepatitis C virus.  Implantable formulations of opioid receptor partial agonists and antagonists 
represent an innovative alternative to daily dosing regimens, and several delivery systems are 
currently in clinical trials (Ling 2010, Rosenthal 2013).  The goal of this study is to determine 
whether RBP-6000, which is a sustained release formulation of buprenorphine in the ATRIGEL® 
delivery system, is a safe and effective treatment for opioid use disorder. 
1.2 
Buprenorphine 
In the central nervous system (CNS), opioid receptors are found in high concentrations in the 
limbic system and the spinal cord. The natural ligands for these receptors are a group of 
neuropeptides known as endorphins. Opioid analgesics mimic the action of endorphins but have 
a more prolonged action because the analgesics are not subject to rapid local metabolism. 
Three major opioid receptor subclasses have been identified: mu, kappa, and delta.  These 
subclasses mediate distinct actions with natural endorphins and opioid analgesics.  Different 
endorphin and opioid analgesic ligands demonstrate different binding affinities for the various 
subclasses of receptors.   
Buprenorphine is a member of the large family of opioid analgesics used in the treatment of 
moderate and severe acute and chronic pain. Opioid receptors are found in both the CNS and the 
periphery. Buprenorphine is a partial agonist at the mu receptor, producing a sub-maximal 
response compared to that of a full agonist. Hence, buprenorphine provides a greater margin of 
safety regarding respiratory depression in comparison to full agonist opioids. Buprenorphine is 
also an antagonist at the kappa receptor (Cowan 1977, Jasinski 1978). 
Buprenorphine has been reported to have a lower physical dependence liability than pure agonist 
analgesics such as morphine, and at a sufficient dose, it can suppress opioid withdrawal signs 
and symptoms for at least 24 hours.  Limited euphoric and respiratory depressant effects have led 
to its therapeutic use as a pharmacotherapy for opioid use disorder. 
Selected pharmacokinetic (PK) parameters for buprenorphine when administered sublingually as 
buprenorphine/naloxone films are in the SUBOXONE sublingual film prescribing information 
(Appendix 7).  Further details on the PK of buprenorphine in the ATRIGEL delivery system are 
described in Section 1.4.2. 
1.3 
ATRIGEL Delivery System 
The ATRIGEL Delivery System is a sterile, polymeric solution of a biodegradable 
poly DL-lactide-co-glycolide (PLGH) copolymer, dissolved in the water-miscible, biocompatible 
solvent N-methyl pyrrolidone (NMP).  The polymers belong to a family of poly α-hydroxy acids 
that are used in medical devices such as resorbable sutures and degradable drug delivery 


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systems.  Polymerization, which is initiated with glycolic acid, leads to a linear polymer 
containing a carboxylic acid end group.  The ATRIGEL Delivery System can be formulated to 
deliver different active ingredients for various lengths of time. 
The ATRIGEL Delivery System is well characterized.  It is currently used in 7 approved 
products worldwide, including 4 ELIGARD® products (subcutaneous [SC] depot formulations of 
leuprolide acetate), ATRIDOX® (doxycycline hyclate applied to the periodontal pocket), the 
ATRISORB® Bioabsorbable Guided Tissue Regeneration Barrier for periodontal application, and 
the ATRISORB-D Barrier (ATRISORB with doxycycline) for periodontal guided tissue 
regeneration. 
Clinical studies with these products demonstrated that the ATRIGEL Delivery System was well 
tolerated and provided consistent sustained release of the incorporated drug over the designated 
dosing interval.  Injection site reactions are expected to be mild and appear early in treatment, as 
observed in previous local irritation ATRIGEL studies (RBP-6000 Investigator’s Brochure [IB], 
Edition 4, 24 February 2014). 
1.4 
Buprenorphine in the ATRIGEL Delivery System (RBP-6000) 
RBP-6000 is a subcutaneously injected depot product under development for the treatment of 
opioid addiction. It contains buprenorphine in the ATRIGEL Delivery System and provides 
sustained plasma levels of buprenorphine over a minimum of 28 days. There is no currently 
approved, parenterally administered, sustained-release buprenorphine formulation for the 
treatment of opioid use disorder. Such a formulation could offer advantages over existing 
buprenorphine products by improving subject compliance and reducing diversion, abuse, and 
unintended exposure (e.g., in pediatric exposure), and reduce chances of swallowing drug. 
The safety profile and clinical efficacy of RBP-6000 are expected to be similar to and 
comparable with that of buprenorphine or SUBOXONE sublingual treatment.  
1.4.1 
Summary of Nonclinical Data 
Nonclinical data suggest that toxicity from RBP-6000 is unlikely at the doses planned for this 
clinical study.  The no observable adverse effect levels (NOAELs) were determined to be 250 
mg/kg (rat) and 40 mg/kg (dog) following single SC injections of RBP-6000 in 4-week toxicity 
studies.  These levels are equivalent to human buprenorphine doses of 2419 mg and 1333 mg, 
respectively (based on 60 kg body weight and calculated according US Food and Drug 
Administration guidance [FDA 2005]).  These levels provide approximately 8.1x (rat) and 4.4x 
(dog) safety margins when compared to the 300-mg buprenorphine dose in humans (based on 
60 kg body weight and calculated according US Food and Drug Administration guidance 
[FDA 2005]).  Systemic effects seen in the rat and dog 4-week toxicity studies were related to 
the pharmacology of buprenorphine or local tolerance effects of the formulation as a result of 
high dose and volume, so the safety margins are considered acceptable. 
Chronic repeated-dose studies were conducted in rats and dogs dosed with RBP-6000 once every 
4 weeks for 6 or 9 months, respectively.  These studies demonstrated systemic effects consistent 
with buprenorphine administration, such as stained fur, aggressive behavior, decreased activity, 


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reduced food consumption and body weight gain, and abnormal feces.  Minimal to mild lung 
alveolar macrophage infiltration and pancreatic acinar cell apoptosis were seen with increased 
incidence in rats, but not dogs, treated with RBP-6000.  Injection site findings were seen in both 
species, characterized microscopically by minimal to moderate granuloma formation.  Injection 
volumes were high, being 2.73 mL/m2 in rats and 3.64 mL/ m2 in dogs, compared with a volume 
of 0.62 mL/ m2 at the highest proposed clinical dose, contributing to these local findings.  
Systemic chronic NOAELs were considered to be 10 mg/kg in rats and 40 mg/kg in dogs.   
Overall, the extensive preclinical data on both the buprenorphine and SUBOXONE products and 
nonclinical PK and toxicity studies in rats and dogs support the clinical development of 
RBP-6000.  Systemic exposure to buprenorphine is not considered to pose any significant safety 
concerns following SC administration of RBP-6000.  Additionally, this clinical study will be 
conducted in subjects who have a current diagnosis of opioid use disorder and who would thus 
be expected to have a certain degree of cross-tolerance to the opioid agonist effects of 
buprenorphine.  Minimal to moderate irritation at the injection site, seen in both rats and dogs, 
may warrant attention to ensure local tolerability (RBP-6000 IB, Edition 4, 24 February 2014). 
1.4.2 
Summary of Previous Clinical Data 
In the first-in-human trial to evaluate the safety, tolerability, and PK of RBP-6000, 12 subjects 
received a single SC injection of RBP-6000 containing 20 mg of buprenorphine.  Of these 
12 subjects, 6 subjects completed the study through Day 85.  The majority (94%) of 
treatment-emergent adverse events (TEAEs) were mild, 5.4% were moderate, and 1 was severe 
in intensity.  TEAEs considered related to the study drug included injection site pain, injection 
site warmth, and injection site bruising, erythema, and edema.  All subjects experienced mild to 
moderate symptoms of withdrawal at study entry, prior to study drug injection, and after study 
drug injection.  One serious adverse event (SAE) was reported.  The SAE was notably identified 
psychosocial stressors and intermittent withdrawal, for which the subject had prolonged 
hospitalization for treatment.  This SAE was not considered to be related to the study drug.  No 
respiratory depression, temperature elevations, clinically significant lowering of oxygen 
saturation, or electrocardiogram (ECG) abnormalities were observed.  There was 1 clinically 
significant laboratory adverse event (AE; elevated hepatic enzymes), which resolved.  No 
unexpected side effects occurred in the RBP-6000 depot formulation of buprenorphine 
(RBP-6000 IB, Edition 4, 24 February 2014).  Buprenorphine was rapidly absorbed over the first 
day and peaked on the second day, with a slow decrease in plasma concentrations thereafter that 
is consistent with the slow release of buprenorphine from the ATRIGEL Delivery System.   
The PK of 50, 100, and 200 mg buprenorphine (as RBP-6000) was also evaluated in a single-
ascending-dose study in 51 subjects (RB-US-11-0020).  In this study, median buprenorphine 
time to peak concentration (tmax) in the initial burst period was observed at 24 hours for all 3 
dosages.  Buprenorphine mean plasma terminal half-life increased slightly with the increase in 
dose from 50 mg to 200 mg (1078 hours [44.9 days] at 50 mg, 1376 hours at 100 mg, and 1573 
hours at 200 mg).  Buprenorphine exhibited overall geometric mean average concentration 
values of 0.356, 0.624, and 1.108 ng/mL, respectively with 50, 100 and 200 mg buprenorphine 
while overall geometric mean Cmax values of 0.999, 1.518, and 2.381 ng/mL were observed for 
buprenorphine doses of 50, 100, and 200 mg, respectively.  With an increase in dose of RBP-


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6000 from 50 to 200 mg, mean buprenorphine exposure parameters increased less than 
proportionally to dose (RBP-6000 IB, Edition 4, 24 February 2014).  A single SC injection of 
RBP-6000 was generally safe and well tolerated.  A total of 46 of 51 subjects (90.2%) had at 
least 1 TEAE.  A total of 30 of 51 subjects (58.8%) had TEAEs that were related to treatment 
with RBP-6000.  The majority of AEs were qualified as moderate in severity (68.6%).  
Two subjects reported TEAEs that were considered to be severe but unrelated to RBP-6000.  No 
subjects withdrew from the study because of an AE. 
The safety profile of multiple-dose SC injections of RBP-6000 containing 50 mg, 100 mg, 
200 mg, and 300 mg of buprenorphine in treatment-seeking, opioid-dependent subjects in an 
open-label, multiple-dose study has recently been examined.  The results suggest that all doses 
were safe and well-tolerated following a 13-day induction and stabilization on SUBUTEX.  In 
addition, a study investigating the blockade of subjective opioid effects demonstrated that RBP-
6000 was safe and well tolerated after the SC administration of 2 monthly 300-mg doses of 
buprenorphine in RBP-6000, following a 14-day induction and stabilization period on 
SUBOXONE Film. 
1.4.3 
Pharmacokinetic/Pharmacodynamic Modeling of RBP-6000 
A population PK model was developed to characterize the disposition of buprenorphine and 
norbuprenorphine following SC injection of RBP-6000 (Nasser 2014).  This model was built 
using plasma concentration data collected in 36 opioid-dependent subjects who received single 
doses (50 mg, 100 mg, and 200 mg) of RBP-6000 in the single-ascending-dose study (RB-US-
11-0020).  Analysis of the PK profiles of RBP-6000 revealed a complex and multi-phase 
absorption profile, presenting double peaks and a prolonged plasma terminal half-life.  These 
distinguishing features of the PK of RBP-6000 required the development of a complex structural 
PK model accounting for this dual absorption process: a first absorption process that was 
associated with an initial, rapid delivery from the SC injection site, and a second absorption 
process that was associated with the slow release of buprenorphine from the ATRIGEL Delivery 
System into the systemic circulation.  The population PK model accurately predicted the PK data 
after repeated doses of RBP-6000 in the multiple ascending dose study (RB-US-12-0005) and in 
the opioid blockade study (RB-US-13-0002).  
Another population PK/PD model was developed to characterize the link between buprenorphine 
plasma concentration and mu opioid receptor occupancy (Nasser 2014).  Individual data from 15 
heroin-dependent subjects were taken from two published clinical trials (Greenwald 2003; 
Greenwald 2007).  A saturable maximum effect (Emax) model with 0.67 ng/mL effective 
concentration at 50% of maximum (EC50) and 91% Emax best described mu opioid receptor 
occupancy versus buprenorphine plasma concentrations.  At buprenorphine concentrations 
greater than 2 ng/mL, saturation occurred on mu opioid receptor occupancy where a 4.5-fold 
increase in observed buprenorphine concentrations resulted in observed mu opioid receptor 
occupancy between 70% and 90%. 
Positron emission tomography (PET) scan data were obtained in 2 subjects participating in the 
multiple-ascending dose study RB-US-12-0005 (PET scan sub-study) and receiving either 200 or 
300 mg of RBP-6000.  The PET scans were conducted at 7 days and 28 days post-dose following 


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the 12th SC injection for the first subject receiving 200 mg, and following the 6th SC injection for 
the second subject receiving 300 mg.  Both subjects were considered to be at steady-state for 
buprenorphine at the time of the PET scan measurements.  The mu opioid receptor availabilities 
of four different regions in the brain were measured, and the mu opioid receptor occupancy in 
the whole brain was calculated as described in Greenwald et al. (2003). 
The subject receiving 200 mg of RBP-6000 in the PET scan sub-study showed 79% and 75% mu 
opioid receptor occupancy on Day 7 and Day 28, respectively, following the 12th SC injection of 
RBP-6000.  The subject receiving 300 mg of RBP-6000 in the PET scan sub-study showed 92% 
and 81% mu opioid receptor occupancy on Day 7 and Day 28, respectively, following the 6th SC 
injection of RBP-6000.  These values and the corresponding PK concentrations were in 
agreement with the model predictions and the previous individual observations used to build the 
population PK/PD model. 
Linear relationships were found between mu opioid receptor occupancy and opioid withdrawal 
symptoms, and between mu opioid receptor occupancy and hydromorphone agonist blockade, 
based on the data from 15 heroin-dependent subjects (Nasser 2014).  These data suggest that a 
mean buprenorphine plasma concentration of 2 ng/mL is able to provide 70 % mu opioid 
receptor occupancy associated with low reported agonist drug effects and withdrawal symptoms 
(scores ≤2). 
Model simulations indicated that the desired 70% mu opioid receptor occupancy may be 
achieved after multiple doses of 200 mg of RBP-6000 (Nasser 2014).  The 300 mg dose was 
considered to be a full opioid blockade dose. 
1.5 
Rationale for Dose Selection 
The results of the opioid blockade study (RB-US-13-0002) showed that 300 mg was a full opioid 
blocking dose (i.e., for the “drug liking” VAS scores the upper bound of the 95% confidence 
interval ≤11), which is consistent with PK/PD modeling and simulation results. The least means 
“drug liking” VAS scores in the opioid blockade study showed that the blockade was achieved 
from the first SC injection and was maintained after the second SC injection until week 12 (i.e., 2 
months after the second injection). 
The population PK and PK/PD models presented in Section 1.4.3 were used to simulate the 
double-blind efficacy study (RB-US-13-0001).  The results of these simulations are displayed in 
Figure 1 for the two treatment arms on RBP-6000 receiving either 6 SC injections of 300 mg 
(300 mg × 2 + 300  mg × 4), or 2 SC injections of 300 mg followed by 4 SC injections of 100 mg 
(300  mg ×2  + 100  mg × 4).  
 


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Figure 1 
Model-Predicted Buprenorphine Plasma Concentrations and Mu-
Opioid Receptor Occupancy in Each Treatment Group on RBP-
6000 Following the Proposed Design of the Current Study 
 
The blue line represents the median model prediction; the yellow areas represent the 5th and the 95th 
percentiles of the predictions; µ-ORO: mu opioid receptor occupancy; wks: weeks. 
The PK parameters calculated from the simulated typical PK profile of buprenorphine are listed 
in Table 1.  Average buprenorphine plasma concentration (Cavg) over the monthly dosing interval 
was 1.9 ng/mL after the first SC injection at 300 mg, and 3.1 ng/mL after the second SC 
injection at 300 mg.  
For the subjects receiving 6 monthly SC injections of RBP-6000 at 300 mg, the predicted Cavg 
value after the 4th SC injection was 5.1 ng/mL, which is close to mean value of 4.8 ng/mL 
observed in the multiple-ascending dose study.  The predicted Cavg value after the 6th SC 
injection was 6.0 ng/mL.  For the patients receiving 2 monthly SC injections at 300 mg followed 
by 4 monthly SC injections at 100 mg, the predicted Cavg after the 6th SC injection was 
2.6 ng/mL.  All these values were above the 2 ng/mL threshold for achieving the desired 
efficacy. 
Overall, the modeling and simulation work and the opioid blockade study have shown that the 
300 mg SC dose is an appropriate dose to assess for efficacy. The current study will therefore 
evaluate the long-term safety and tolerability of this dose. It is recognized, however, that some 
individuals may need lower doses based on genetic variations, abuse behavior, etc. Accordingly, 
subsequent doses of RBP-6000 may be adjusted down to 100 mg and back up to 300 mg based 
on the medical judgment of the Investigator. 
 


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Table 1 
PK Parameters of the Simulated Typical PK Profile of Buprenorphine after Repeated RBP-6000 
Injections for the Phase 3 Efficacy Study (RB-US-13-0001) 
Buprenorphine 
(ng/mL) 
SC Injection Number 
1 
2 
3 
4 
5 
6 
 
Cmax 
Cavg 
Cmax Ctrough Cavg 
Cmax 
Ctrough 
Cavg 
Cmax 
Ctrough 
Cavg 
Cmax 
Ctrough 
Cavg 
Cmax 
Ctrough 
Cavg 
300mgx2 + 
100mgx4 
2.9 
1.9 
4.2 
1.3 
3.1 
3.5 
2.5 
3.0 
3.6 
2.6 
3.0 
3.5 
2.5 
2.8 
3.2 
2.3 
2.6 
300mgx2 + 
300mgx4 
2.9 
1.9 
4.2 
1.3 
3.1 
5.4 
2.5 
4.3 
6.4 
3.5 
5.1 
7.1 
4.2 
5.7 
7.5 
4.6 
6.0 
Cmax: maximum plasma concentration; Cavg : average plasma concentration; Ctrough: plasma concentration at trough (ie, before the next injection). 
 
 


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1.6 
Known and Potential Risks and Benefits 
The AE profile of buprenorphine is well-characterized; commonly reported effects include 
constipation, nausea, vomiting, and headache.  Buprenorphine is approved for use by various 
routes of administration (e.g., SL, intramuscular [IM], intravenous [IV], transdermal, and rectal). 
Studies of buprenorphine receptor binding in human subjects have consistently and reproducibly 
established that buprenorphine is a highly lipophilic, mu-opioid receptor partial agonist with 
slow receptor association and dissociation kinetics.  Buprenorphine has an improved safety 
profile relative to mu-opioid receptor full agonists due to its partial agonist properties.  These 
attributes of buprenorphine allow it to perform well as substitution therapy for opioid-dependent 
individuals over short-term and long-term durations.  The experiments used to establish the 
binding profile of buprenorphine were consistent across differing parenteral routes of 
administration (IV, IM, and SL); therefore, RBP-6000 is expected to perform similarly when 
administered as a SC depot in the ATRIGEL Delivery System. 
The efficacy of buprenorphine in the treatment of opioid dependence has been well established 
(see for example, New Drug Applications 20-732; 20-733; 22-410).  Buprenorphine has been 
used for medically-supervised taper (i.e., detoxification) medication and as a long-term 
medication assisted therapy (i.e., maintenance).  A recent Cochrane Review meta-analysis 
revealed that buprenorphine is statistically significantly superior to placebo in the retention of 
subjects and reduction of opioid-positive urine tests, and that buprenorphine and methadone may 
be equally efficacious at adequate dose levels of both medications (Mattick 2008). 
A sustained-release formulation of buprenorphine using the ATRIGEL Delivery System offers a 
number of potential benefits relative to shorter-acting formulations, including improved subject 
compliance, reduced diversion and misuse, as well as a reduced risk to subjects, their families, 
and the community.  


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2 
STUDY OBJECTIVES 
Indivior Inc., formerly Reckitt Benckiser Pharmaceuticals Inc. (RBP), is developing RBP-6000, 
a long-acting formulation of buprenorphine for monthly SC administration, for the treatment of 
opioid use disorder.   
2.1 
Primary Objective 
To assess the long-term safety and tolerability of RBP-6000 subcutaneous (SC) injections in 
subjects with opioid use disorder. 
2.2 
Secondary Objectives 
To collect clinical outcome data with RBP-6000 SC injections in subjects with opioid use 
disorder. 
2.3 
Tertiary Objectives 
To evaluate the: 
• PK of RBP-6000,  
• Relationship between RBP-6000 PK and clinical outcome data, and 
• Impact of RBP-6000 on health and economic outcomes. 


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a multicenter, open-label, long-term safety study in which approximately 600 subjects 
diagnosed with opioid use disorder will be enrolled (approximately 300 subjects who did not 
participate in the RB-US-13-0001 study [hereafter referred to as “de novo” subjects] and 
approximately 300 subjects that completed the RB-US-13-0001 study [hereafter referred to as 
“roll-over subjects”]).  Subject participation will be based on the Investigator’s determination 
that initiation or continuation of study treatment is appropriate; and, that among subjects who are 
continuing from the RB-US-13-0001 study, there have been no significant protocol deviations or 
clinically relevant AEs that would preclude inclusion of the subject in this study. All subjects 
will need to provide written informed consent before any protocol-related procedures commence. 
At the Screening Visit (which is up to 3 days after the End of Study [EOS] Visit (Day 169 + 3]), 
for roll-over subjects), potential subjects will be reviewed for eligibility against inclusion and 
exclusion criteria, and eligible subjects will be enrolled into the trial.  
Before receiving the first injection of RBP-6000 in this safety study, all subjects will undergo a 
Run-In period with SUBOXONE® (buprenorphine/naloxone) sublingual film to avoid 
precipitating a withdrawal syndrome and to preserve the blind in subjects treated with placebo in 
the RB-US-13-0001 study. Subjects will be inducted onto SUBOXONE sublingual film 
consistent with the SUBOXONE sublingual film label; they will then complete a 1 to 11 day 
SUBOXONE sublingual film Dose Adjustment period (Section 5.2.1). SUBOXONE dose 
adjustments will be made based on COWS scores as well as physician judgment (Section 5.2.2).   
Once subjects meet the criteria (on Day -11 to Day -1) of no significant opioid craving (≤20 mm 
on the Opioid Craving Visual Analog Scale [VAS] and no significant withdrawal (≤ 12 on the 
Clinical Opiate Withdrawal Scale [COWS]) they may receive the first SC injection of RBP-6000 
(containing 300 mg buprenorphine). Subjects with significant withdrawal signs/symptoms 
(defined as >12 on the COWS) or significant cravings for opioids (defined as >20 mm on the 
Opioid Craving VAS) after the end of the 2-week SUBOXONE sublingual film Run-In period 
will not be eligible to continue in the study and will be referred for treatment.   
On Day 1 of the study (initiation of study drug injections), all subjects will receive a SC injection 
of 300 mg of buprenorphine in RBP-6000. Subsequent doses of RBP-6000 may be adjusted 
down to 100 mg and back up to 300 mg based on the medical judgment of the Investigator. After 
injection of RBP-6000, subjects will not be permitted to receive supplemental SUBOXONE 
sublingual film during the RBP-6000 treatment period. Subjects who require supplemental 
SUBOXONE sublingual film or other sublingual buprenorphine pharmacotherapy during the 
RBP-6000 treatment period will be withdrawn from the study and referred for appropriate 
treatment. 
Subjects will return to the clinic for monthly injection visits (every 28 ±2 days) for a total of up 
to 12 injections for de novo subjects or for a total of 6 injections for roll-over subjects. ECG 
recordings and vital signs will be collected pre and post each SC injection. All ECGs will be 
interpreted by a central monitoring facility.  Subject-reported injection site pain Visual Analog 


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Scale scores (VAS) will be collected at various times up to 1 hour after each injection. Local 
injection site grading will be collected at various time points starting immediately after injection 
and will be evaluated for pain, tenderness, warmth, itching, erythema, inflammation or swelling, 
and bruising using a 4-point severity scale. At each visit after injections begin, the injection site 
will be assessed by site staff and will also be evaluated for evidence of attempts to remove the 
depot.  
Subjects will need to return to the clinic weekly for the first 5 weeks and biweekly (i.e., every 2 
weeks) until injection 6, and monthly for the rest of the study period for urine drug screens 
(UDS), Timeline Followback (TLFB) interviews, opioid craving VAS evaluation, COWS and 
subject reported outcomes (Subjective Opiate Withdrawal Scale [SOWS]). Subjects will 
continue to receive counseling (manual-guided behavioral therapy) during the study.  
Safety assessments will be collected at each injection visit and/or at injection follow-up visits 
and will include the following:  vital signs, electronic Columbia Suicide Severity Rating Scale 
(eC-SSRS) responses, ECGs, laboratory tests (hematology, chemistry, urinalysis, and pregnancy 
test), concomitant medications, and AEs.   
Sparse PK blood samples will be collected for population PK analysis for the roll-over subjects 
only. PK samples will not be collected for the de novo subjects. ECGs will be performed before 
PK sample collection. The following depression, pain, and health economic outcome 
assessments will also be collected: Beck Depression Inventory (BDI-II), brief pain inventory 
(BPI), EuroQol EQ-5D-5L (EQ-5D-5L), 36-Item Short Form Health Survey, Version 2 (SF-
36v2), Medication Satisfaction Questionnaire (MSQ), healthcare resource utilization (HCRU), 
Treatment Effectiveness Assessment (TEA) and Addiction Severity Index Lite (ASI-Lite). 
At the end of the RBP-6000 treatment period, subjects will enter a 4-week SUBOXONE 
transition period/safety follow-up where they will receive the same dose of SUBOXONE that 
they received at Day -1 and their ongoing treatment options will be reviewed. 
A schematic depicting the study design for de novo subjects is in Figure 2 and a schematic for 
roll-over subjects is in Figure 3.  A complete list of procedures and assessments for subjects is in 
the Schedule of Events (SOE) in Appendix 1, Appendix 2, Appendix 3, Appendix 4, and 
Appendix 5. 


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Figure 2 
Study Overview:  De novo Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Injection No. 7 (Week 25/Day 169) 
Injection No. 8 (Week 29/Day 197)  
Injection No. 9 (Week 33/Day 225)  
 
Injection No. 10 (Week 37/Day 253)  
Injection No. 11 (Week 41/Day 281)  
Injection No. 12 (Week 45/Day 309)  
SUBOXONE - Sublingual Film Transition (Day 337) 
End of Study Visit (Day 365)/Early Termination (Up to Day 365) 
Subjects return to clinic for this visit 
Injection No. 1 (Week 1/Day 1)  
 Followed by weekly assessment visits 
Injection No. 2 (Week 5/Day 29)  
Followed by biweekly assessment visits 
Injection No. 3 (Week 9/Day 57)  
Followed by biweekly assessment visits 
Injection No. 4 (Week 13/Day 85)  
Followed by biweekly assessment visits
Injection No. 5 (Week 17/Day 113)  
Followed by biweekly assessment visits 
Injection No. 6 (Week 21/Day 141)  
SUBOXONE Sublingual Film Run-In 
• 
Induction (3 days) 
Subjects complete daily visits on Day -14 to Day -12  
• 
Dose Adjustment (1-11 days) 
Subjects complete visits on Day -11, Day -8, Day -4, and Day -1 (all visits not required) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Early 
Termin
ation 
Subjects 
return 
to clinic 
for this 
visit 
Screening  
(Day -21 to Day -15)  
 


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Figure 3 
Study Overview:  Roll-over Subjects from RB-US-13-0001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Injection No. 1 (Week 1/Day 1) 
 Followed by weekly assessment visits 
Injection No. 2 (Week 5/Day 29)  
Followed by biweekly assessment visits 
Injection No. 3 (Week 9/Day 57)  
Followed by biweekly assessment visits 
Injection No. 4 (Week 13/Day 85)  
Followed by biweekly assessment visits 
Injection No. 5 (Week 17/Day 113)  
Followed by biweekly assessment visits 
Injection No. 6 (Week 21/Day 141)  
SUBOXONE Sublingual Film Run-In 
• 
Induction (3 days) 
Subjects complete daily visits on Day -14 to Day -12  
• 
Dose Adjustment (1-11 days) 
Subjects complete visits on Day -11, Day -8, Day -4, and Day -1 (all visits not required) 
SUBOXONE 
Sublingual Film 
Transition 
(Day 169) 
End of Study Visit (Day 197)/Early Termination (Up to Day 197) 
Subjects return to clinic for this visit 
 
 
 
 
 
 
 
Early 
Termin
ation 
Subjects 
return to 
clinic 
for this 
visit 
Screening  
(Days -21 to -15 [Up to 3 days after EOS Visit/Day169 + 3 for Subject’s Completing  
Study RB-US-13-0001])  
Note: RB-US-13-0001 assessments completed at EOS/Day 169 will serve as screening 
assessments  


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3.2 
Rationale for Study Design 
This study is designed to assess the long-term safety, tolerability, and clinical outcomes of  
RBP-6000 SC injections in subjects with opioid use disorder.  The planned number of subjects 
was designed to ensure at least 100 subjects reach 1 year of treatment with RBP-6000 (as advised 
in the ICH-E1A Guideline - The Extent of Population Exposure to Assess Clinical Safety: For 
Drugs Intended for Long-term Treatment of Non-Life-Threatening Conditions).  The safety 
assessments used include evaluations of AEs, serious AEs (SAEs), discontinuations from study 
due to AEs; local injection site tolerability (e.g., injection site grading); injection site pain using a 
subject-reported VAS; suicidality using the eC-SSRS, concomitant medications; changes in 
clinical laboratory results; vital sign measurements; 12-lead ECGs, and physical examination 
results.  The instruments used to measure clinical outcomes (e.g., COWS, SOWS, Opioid 
Craving VAS, and eC-SSRS) were developed to measure the specific symptoms exhibited by 
and the challenges facing opioid-dependent individuals.   
3.3 
Study Duration and Dates 
The expected maximum duration of participation for de novo subjects is up to approximately 55 
weeks consisting of up to a 7-day screening period, up to a 14-day SUBOXONE sublingual film 
Run-In, up to a 48-week open-label treatment period, and a 4-week follow-up and transition 
period when subjects will receive the same dose of SUBOXONE that they received at Day -1 
and their ongoing treatment options will be reviewed. 
The expected maximum duration of participation for roll-over subjects is up to approximately 31 
weeks, consisting of up to a 7-day screening period, up to a 14-day SUBOXONE sublingual film 
Run-In, a 24-week open-label treatment period, and a 4-week follow-up and transition period 
when they will receive the same dose of SUBOXONE that they received at Day -1 and their 
ongoing treatment options will be reviewed. 
If a sufficient number of subjects reach 1 year of exposure to RBP-6000, the study may be 
stopped early, and all remaining subjects will complete EOS procedures and enter the 
SUBOXONE Transition Period/Safety Follow-up. 
Subjects who receive at least 1 dose of RBP-6000 and discontinue the trial for any reason will be 
required to complete the Early Termination (ET) visit. 


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4 
STUDY POPULATION SELECTION 
4.1 
Study Population 
Approximately 300 de novo subjects will be enrolled into this study as well as approximately 
300 roll-over subjects. The study population will consist of individuals diagnosed with opioid 
use disorder who are seeking treatment.  
4.2 
Inclusion Criteria 
A. De novo Subjects: Subjects who have not participated in Study RB-US-13-0001 must meet 
the following criteria to be enrolled in this study: 
1. Subjects seeking treatment for opioid use disorder who currently, and by medical history 
over the previous 3 months, meet the DSM-5 criteria for moderate or severe opioid use 
disorder.  
2. Subjects who provide written informed consent to participate in this study. 
3. Subjects who are an appropriate candidate for opioid partial-agonist treatment in the 
opinion of the Investigator or medically responsible physician. 
4. Either male or female. 
5. Age ≥ 18 to ≤ 65 years. 
6. Have a body mass index (BMI) of ≥ 18.0 to ≤ 35.0 kg/m2. 
7. Females: Women of childbearing potential (defined as all women who are not surgically 
sterile or postmenopausal for at least 1 year prior to informed consent), must have a 
negative pregnancy test prior to enrollment and must agree to use a medically acceptable 
means of contraception from screening through at least 6 months after the last dose of 
investigational medicinal product (IMP). 
Males: Subjects with female partners of child-bearing potential must agree to use 
medically acceptable contraception after signing the informed consent form (ICF) 
through at least 6 months after the last dose of IMP. Male subjects must also agree not to 
donate sperm during the study and for 6 months after receiving the last dose of IMP. 
The following methods of contraception are considered to be medically acceptable: 
established use of oral, injected or implanted hormonal contraception; placement of an 
intrauterine device or intrauterine system; use of a double-barrier method of 
contraception (condom or occlusive cap with use of a spermicide) or male sterilization.   
8. Subjects must agree not to take any buprenorphine products other than those administered 
during the current study throughout participation in the study. 
9. Subjects must be willing to adhere to study procedures. 
 
B. Roll-Over Subjects: Subjects who have successfully completed Study RB-US-13-0001 in its 
entirety must complete EOS/Day 169 assessments, which will serve as screening for this 
study. In addition, only the following criteria must be met to be enrolled in this study: 
1. Provide written consent to participate in this study. 
2. Be considered eligible in the medical judgment of the Investigator. 


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3. Females: Women of childbearing potential (defined as all women who are not surgically 
sterile or postmenopausal for at least 1 year prior to informed consent) must have a negative 
pregnancy test prior to enrollment and must agree to use a medically acceptable means of 
contraception from screening through at least 6 months after the last dose of IMP. 
Males: Subjects with female partners of child-bearing potential must agree to use medically 
acceptable contraception after signing the ICF through at least 6 months after the last dose of 
IMP. Male subjects must also agree not to donate sperm during the study and for 6 months 
after receiving the last dose of IMP. 
The following methods of contraception are considered to be medically acceptable:  
established use of oral, injected or implanted hormonal contraception; placement of an 
intrauterine device or intrauterine system; use of a double-barrier method of contraception 
(condom or occlusive cap with use of a spermicide) or male sterilization.   
4. Subjects must agree not to take any buprenorphine products other than those administered 
during the current study throughout participation in the study. 
5. Subjects must be willing to adhere to study procedures. 
 
4.3 
Exclusion Criteria 
A. De novo Subjects who meet any of the following criteria will be excluded from the study: 
1. Current diagnosis, other than opioid use disorder, requiring chronic opioid treatment. 
2. Current substance use disorder, as defined by DSM-5 criteria, with regard to any 
substances other than opioids, cocaine, cannabis, tobacco, or alcohol. 
3. Positive UDS result at screening for cocaine or cannabis AND meets DSM-5 criteria for 
either moderate or severe cocaine or cannabis use disorder, respectively. 
4. Meets DSM-5 criteria for moderate or severe alcohol use disorder. 
5. Treatment for opioid use disorder required by court order.   
6. Current incarceration or pending incarceration/legal action that could interfere with a 
subject’s ability to participate in the study. 
7. Pregnant or lactating females. 
8. Current use of prescription or OTC medications that are clinically relevant cytochrome 
P450 3A4 or cytochrome P450 2C8 inducers or inhibitors (e.g., rifampicin, azole 
antifungals [e.g., ketoconazole], macrolide antibiotics [e.g., erythromycin]) with the 
exception of marijuana.  More examples are provided in the excluded medications list 
(Appendix 9). 
9. History of suicidal ideation within 30 days prior to providing written informed consent as 
evidenced by answering “yes’ to questions 4 or 5 on the suicidal ideation portion of the 
eC-SSRS completed at the screening visit or history of a suicide attempt (per the eC-
SSRS) in the 6 months prior to informed consent. 
10. Current or history (within the 6 months prior to providing written informed consent) of 
chest pain or palpitation with either exertion or drug use, peripheral or generalized 
edema, clinically significant cardiovascular disease, including myocardial infarction, 
heart failure, uncontrolled hypertension, clinically significant orthostatic hypotension, 
endocarditis, or myocarditis.  
11. Clinically significant abnormal systolic blood pressure (BP) or diastolic BP, in the 
opinion of the Investigator. 


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12. Uncontrolled medical or psychiatric illness that, in the opinion of the Investigator or 
Sponsor, may place the subject at risk or interfere with outcome measures or a subject’s 
ability to participate in the study. 
13. Clinically significant abnormality (e.g., severe respiratory insufficiency) in past medical 
history or at the screening physical examination that, in the opinion of the Investigator or 
Sponsor, may place the subject at risk or interfere with outcome variables.   
14. History or presence of allergic or adverse response (including rash or anaphylaxis) to 
buprenorphine, naloxone, or the ATRIGEL Delivery System. 
15. Total bilirubin ≥ 1.5x the upper limit of normal (ULN), alanine aminotransferase (ALT) 
≥3xULN, aspartate aminotransferase (AST) ≥ 3xULN, serum creatinine > 2xULN, 
international normalized ratio (INR) >1.5xULN, lipase >3xULN, amylase >3xULN, or 
any abnormal pancreatic enzyme value above ULN that is associated with clinically 
significant, active pancreatic disorder. 
16. Congenital long QT syndrome, history of prolonged QT in the 3 months prior to 
screening, or a corrected QT interval (Fridericia’s – QTcF) >450 msec (male) or >470 
msec (female) or history of risk factors for Torsades de Pointes. 
17. Diagnosis of acquired immunodeficiency syndrome (AIDS). 
18. Affiliated with, or a family member of, site staff directly involved in the study. 
19. Unable, in the opinion of the Investigator or the medically responsible physician, to 
comply fully with the study requirements.   
20. Clinically significant anemia or low hemoglobin (levels < 9 g/dL) at Screening.  
21. Donation of > 250 mL of blood or plasma within the 30 days prior to providing written 
informed consent  
22. Participation in any other clinical trial within 30 days prior to informed consent  
23. Received medication-assisted treatment for opioid use disorder (e.g., methadone, 
buprenorphine) in the 90 days prior to providing written informed consent  
24. Previously received RBP-6000. 
25. Use of (within the past 30 days prior to providing written informed consent) or positive 
UDS result at screening for barbiturates, benzodiazepines, or  methadone.. 
 
B. Roll-Over Subjects who meet any of the following criteria will be excluded from the study: 
1. Discontinued early from Study RB-US-13-0001 
2. Experienced any major protocol deviations or adverse events during the RB-US-13-0001 
study which, in the opinion of the Investigator, could potentially compromise subject 
safety. 
3. Women of childbearing potential who have a positive pregnancy test at EOS/Day 169, 
who are pregnant or breastfeeding, seeking pregnancy, or failing to use adequate 
contraceptive methods during the study. 
 


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4.4 
Day -1/Enrollment Criteria 
Beginning on the 4th day of SUBOXONE sublingual film dosing (Study Day -11) through the 
14th day of dosing, subjects will be evaluated for Day -1 criteria.  Subjects must meet the 
following criteria in order to be enrolled: 
1. No allergic reaction to SUBOXONE sublingual film. 
2. Daily dose of SUBOXONE sublingual film between 8 mg/2 mg - 24 mg/6 mg (inclusive) 
buprenorphine/naloxone. 
3. COWS score of ≤ 12. 
4. Opioid Craving VAS score of ≤ 20 mm. 
 


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5 
STUDY TREATMENTS 
5.1 
Description of Treatments 
5.1.1 
SUBOXONE Sublingual Film 
SUBOXONE sublingual film is supplied as an orange rectangular sublingual film with a white 
printed logo.  Each SUBOXONE sublingual film contains buprenorphine HCl and naloxone HCl 
dihydrate at a 4:1 ratio expressed as the free bases.  Films are intended for SL administration and 
are available in 4 dosage strengths (2 mg/0.5 mg; 4 mg/1 mg; 8 mg/2 mg; and 12 mg/3 mg).   
5.1.2 
Investigational Medicinal Products 
RBP-6000 uses buprenorphine base in the ATRIGEL Delivery System, which is currently used 
in a number of approved commercial products.  RBP-6000 will be supplied as a single-syringe 
system, which is prefilled with RBP-6000.  The entire contents of the prefilled syringe will be 
administered.  (See Appendix 8: Study Drug Preparation and Dispensing Procedures for detailed 
dosage instructions).   
RBP-6000 is manufactured by Indivior Inc. according to Good Manufacturing Practice 
standards. 
All used syringes components will be disposed of in accordance with the site’s standard 
operating procedures (SOP) or pharmacy destruction policy. The site’s clinical research associate 
(CRA) will review the site’s SOP and/or pharmacy destruction policy.  All IMP packaging will 
be retained for CRA verification. 
5.2 
Treatments Administered 
5.2.1 
Run-In Treatment Period 
5.2.1.1 
SUBOXONE Sublingual Film Induction (De novo Subjects) 
De novo subjects will receive their first dose of SUBOXONE sublingual film on Induction 
Day 1.  Subjects will be started with an initial dose of 2 mg/0.5 mg or 4 mg/1 mg and may titrate 
upwards in 2 or 4 mg increments of buprenorphine, at approximately 2-hour intervals, under 
clinical supervision, to 8 mg/2 mg based on therapeutic response.  
On Induction Day 2, subjects with a COWS score > 12, or subjects reporting withdrawal 
signs/symptoms overnight, will receive a dose of SUBOXONE sublingual film equal to the total 
dose given on Induction Day 1 plus 4 mg. (For example, if a subject received a total dose of 8 
mg on Induction Day 1, the starting dose of buprenorphine for Induction Day 2 would be 12 mg).  
If the COWS score is still > 12 one hour later, another 4 mg dose can be given. The subject 
should not exceed a maximum dose of 16 mg/4 mg for Induction Day 2. Subsequent 
SUBOXONE sublingual film doses must be separated by at least 1 hour from the preceding dose. 
SUBOXONE sublingual film doses may also be adjusted downward if necessary.  


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On Induction Day 3, subjects will be titrated to therapeutic response based on COWS scores as 
well as physician judgment. Most subjects will only require a single dose on Induction Day 3 
which will equal the Induction Day 2 dose or the Induction Day 2 dose plus 4 mg buprenorphine. 
Additional doses may also be administered on Induction Day 3 (up to 24 mg). Subsequent 
SUBOXONE sublingual film doses must be separated by at least 1 hour from the preceding dose.  
Subjects should reach a daily dose of between 8 mg/2 mg and 24 mg/6 mg by Induction Day 3 
and continue on that dose through the remainder of the SUBOXONE sublingual film Run-In 
period, with additional dose adjustments if necessary.  
The SUBOXONE sublingual film(s) will be administered under the tongue, close to the base on 
the left or right side, until they are dissolved.  If an additional sublingual film is required, it 
should be placed on the opposite side from the first film.  Subjects should be instructed to hold 
the films under the tongue until they dissolve.  If a third film is required, it should be placed 
under the tongue after the first 2 films have dissolved.   
For more information about SUBOXONE sublingual film administration, please refer to the 
SUBOXONE Full Prescribing Information (See Appendix 7). 
5.2.1.2 
SUBOXONE Sublingual Film Induction (Roll-over Subjects) 
Following screening, roll-over subjects will be inducted on SUBOXONE sublingual film to 
achieve daily doses between 8 mg to 24 mg buprenorphine according to the SUBOXONE 
sublingual film prescribing instructions. Subjects must be titrated to a minimum dose of 8 mg 
SUBOXONE by the end of the 3-day Induction period regardless of their COWS scores and/or 
the presence or absence of withdrawal symptoms.   
Subjects will receive their first induction dose on Induction Day 1. Subjects should be started 
with an initial dose of 2 mg/0.5 mg or 4 mg/1 mg buprenorphine/naloxone and may titrate 
upwards in 2 or 4 mg increments of buprenorphine, at approximately 2-hour intervals, under 
supervision, to a total dose of up to 8 mg/2 mg buprenorphine/naloxone based on the control of 
acute withdrawal symptoms.  
On Induction Day 2, subjects with a score for COWS of > 12, or subjects reporting opioid 
withdrawal signs/symptoms overnight, should receive a dose of study drug equal to the total dose 
given on Induction Day 1 plus 4 mg.  If the COWS score is still > 12 one hour later, another 4 
mg dose can be given.  The subject should not exceed a maximum dose of 16 mg/4 mg 
buprenorphine/naloxone for Induction Day 2.  Subsequent SUBOXONE sublingual film doses 
must be separated by at least 1 hour from the preceding dose.  SUBOXONE sublingual film 
doses may also be adjusted downward if necessary.   
 
On Induction Day 3, subjects will be titrated to therapeutic response until a therapeutic dosage is 
reached, based on COWS scores as well as physician judgment. Most subjects will only require a 
single dose on Induction Day 3 which will equal the Induction Day 2 dose or the Induction Day 2 
dose plus 4 mg. Additional doses may also be administered on Induction Day 3 (up to 24 mg).  
Subsequent SUBOXONE sublingual film doses must be separated by at least 1 hour from the 
preceding dose.  Although subjects should reach a daily dose of between 8 mg and 24 mg by 


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Induction Day 3 and continue on that dose through the remainder of the SUBOXONE sublingual 
film Run-In period, dose adjustments may be necessary during the Run-In period.  
The SUBOXONE sublingual film(s) will be administered under the tongue, close to the base on 
the left or right side, until they are dissolved.  If an additional sublingual film is required, it 
should be placed on the opposite side from the first film.  Subjects should be instructed to hold 
the films under the tongue until they dissolve.  If a third film is required, it should be placed 
under the tongue after the first 2 films have dissolved.   
For more information about SUBOXONE sublingual film administration, please refer to the 
SUBOXONE Full Prescribing Information (See Appendix 7). 
5.2.2 
Dose Adjustment Period (All Subjects) 
Beginning at Day -11, subjects will be assessed to determine whether they meet Day -1 
/enrollment criteria as defined in Section 4.4.  Once subjects meet the enrollment criteria (no 
significant opioid craving (≤20 mm on the Opioid Craving Visual Analog Scale [VAS] and no 
significant withdrawal (≤ 12 on the Clinical Opiate Withdrawal Scale [COWS]), they are eligible 
to receive the first SC injection of RBP-6000 (containing 300 mg buprenorphine). Subjects with 
significant withdrawal signs/symptoms (defined as >12 on the COWS) or significant cravings for 
opioids (defined as >20 mm on the Opioid Craving VAS) after the end of the 2-week 
SUBOXONE sublingual film Run-In period will not be eligible to continue in the study and will 
be referred for treatment.   
5.2.3 Active Study Treatment 
On Day 1 of the study (initiation of study drug injections), all subjects will receive a SC injection 
of 300 mg of buprenorphine in RBP-6000. Subsequent doses of RBP-6000 may be adjusted 
down to 100 mg and back up to 300 mg based on the medical judgment of the Investigator.   All 
subjects will receive injections of RBP-6000 separated by 28 (± 2) days.   
After injection of RBP-6000, subjects will not be permitted to receive supplemental 
SUBOXONE sublingual film during the RBP-6000 treatment period. Subjects who require 
supplemental SUBOXONE sublingual film or other sublingual buprenorphine pharmacotherapy 
during the RBP-6000 treatment period will be withdrawn from the study and referred for 
appropriate treatment. 
A single SC dose will be injected by an individual who is medically qualified to perform the 
procedure and delegated by the Principal Investigator to perform the task.  Injections of 
RBP-6000 will be administered in the abdominal area below the waist but above the hip bone; 
more specifically, injection should occur in the region where the body curves at the side to about 
2 inches from the middle of the abdomen with adequate amounts of subcutaneous tissue that 
does not have excessive pigment, nodules, lesions, or hair.  RBP-6000 will form a solid polymer 
depot that contains the buprenorphine.  As the depot degrades, buprenorphine will be released 
into the systemic circulation at a consistent rate over an approximately 28-day period.  For 
detailed instructions on use, see Appendix 8. 


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5.2.4 
SUBOXONE Transition Period/Safety Follow-up 
At the end of the RBP-6000 open-label treatment period, subjects will enter a 4-week 
SUBOXONE transition period/safety follow-up where they will receive the same dose of 
SUBOXONE that they received at Day -1, and their ongoing treatment options will be reviewed. 
5.3 
Selection and Timing of Dose for Each Subject 
The study schedule is designed so that each of the injections will be separated by a maximum of 
30 days (28 days ± 2 days) and will be given on alternate sides of the subject’s abdomen (see 
Appendix 8 and the Pharmacy Manual for detailed information on administration).   
5.4 
Method of Assigning Subjects to Treatment Groups 
When a de novo or roll-over subject signs the ICF, she/he will be assigned a unique subject 
number in numerical sequence, which will be used for the duration of the study. Roll-over 
subjects will retain the subject number assigned to them in the RB-US-13-0001 study. De novo 
subjects will be assigned a unique subject number, consisting of the site number followed by 9 
and a 3 digit number in numerical sequence (e.g., the first de novo subject screened at site # 001 
will be assigned the number 0019001).  The subject number will be recorded in the source 
document and electronic case report form (eCRF). 
All subjects will be assigned to receive the 300 mg RBP-6000 dose. Subsequent doses of 
RBP-6000 may be adjusted down to 100 mg and back up to 300 mg based on the medical 
judgment of the Investigator 
5.5 
Blinding 
Not applicable; this is an open-label study  
 
5.6 
Concomitant Therapy 
Concomitant therapies are defined as prescribed medications and OTC preparations, including 
herbal preparations and vitamins, other than study medication and supplementary medication that 
the subject receives within 30 days of screening and for the during the course of the study.  Any 
medication taken by the subject is to be reported by the subject and noted on the subject’s source 
document and concomitant medication page.  Any changes in concomitant therapy during the 
study will be documented, including cessation of therapy, initiation of therapy, and dose 
changes. 
Roll-over subjects who started on a benzodiazepine during the RB-US-13-0001 study will be 
evaluated on a case-by-case basis for inclusion in the RB-US-13-0003 study.  The investigator 
will discuss these subjects with the medical monitor before enrolling into the RB-US-13-0003 
study. 
The Investigator or designee will also record any medications given for the treatment of AEs on 
the concomitant medication page.   


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5.6.1 
Permitted Concomitant Medications 
Following screening and enrollment, ancillary medications (ibuprofen, acetaminophen, 
methocarbamol, hydroxyzine, and loperamide) may be administered to subjects to help alleviate 
signs and symptoms of opioid withdrawal as deemed necessary by the Investigator or medically 
qualified sub-investigator.  Details on acceptable administration of these medications and 
preparations are provided below: 
• Ibuprofen (400 mg orally) may be given every 4 to 6 hours as needed for pain up to a 
maximum of 2400 mg per day.  Subjects for whom ibuprofen is contraindicated or not 
tolerated may be given acetaminophen (325 to 1000 mg every 4 to 6 hours) as needed up 
to a maximum of 3000 mg per day.  Caution should be exercised when using 
acetaminophen concomitantly with other medications that have potential hepatotoxic 
effects.  Methocarbamol may also be given as needed for relief of muscle pain in 
clinically appropriate doses based on physician assessment. 
• Hydroxyzine (50 to 100 mg orally) may be given every 6 hours as needed for anxiety, 
nausea, or vomiting.  Additionally, hydroxyzine (50 to 100 mg orally) may be given at 
bedtime as needed for sleep.  The hydroxyzine daily dose should not exceed a maximum 
of 600 mg per day. 
• Loperamide (2 to 4 mg orally) may be given as needed for diarrhea up to a maximum of 
16 mg per day. 
5.6.2 
Prohibited Concomitant Medications 
Concomitant therapies subject to the restrictions indicated under Prohibited Concomitant 
Medications may be used only following approval by the Sponsor unless an immediate medical 
need necessitates their use.  These are listed below:   
• Use of buprenorphine. 
• Ongoing prescription that are clinically relevant P450 3A4 inducers or inhibitors, such as 
azole antifungals (e.g., ketoconazole) and macrolide antibiotics (e.g., erythromycin). 
• Herbal supplements that have the potential to cause prolongation of the QTc interval.   
• Over-the-counter medications that have the potential to cause prolongation of the QTc 
interval.  This does not apply to over-the-counter medications listed under Concomitant 
Therapies above that are prescribed by the Investigator, or over-the counter medications 
that may be used by the Investigator for an immediate medical need that necessitates their 
use. The medical monitor should be consulted for any questions. 
• Medications, in the addition to those listed above, which may be expected to significantly 
interfere with the metabolism or excretion of buprenorphine that may be associated with 
a significant drug interaction with buprenorphine, or may pose a significant risk to 
subjects’ participation in the study. 
Other concomitant medications, OTC preparations, or therapies that are not allowed during study 
participation are listed in Appendix 9. 


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5.7 
Restrictions 
5.7.1 
Prior Therapy 
All prior medications including OTC, dietary supplements, and herbal preparations taken by the 
subject within the 30 days prior to screening will be recorded. 
5.7.2 
Subject Activity Restrictions 
Subjects should be advised to avoid strenuous exercise. 
5.8 
Protocol Compliance 
This study involves the SC injection of multiple doses of RBP-6000 containing 100 or 300 mg of 
buprenorphine (see the SOE, Appendix 2).  The Investigator may terminate a subject based on 
the subject’s inability or willingness to comply with the protocol requirements. 
IMP will be administered by designated and qualified study personnel at the site.  The time and 
duration, the dose delivered, and any dosing observations will be recorded in source 
documentation.  The Investigator or designated individual will maintain a log of all study drugs 
dispensed and returned (if applicable).  Drug supplies will be inventoried and accounted 
throughout the study. 
5.9 
Packaging and Labeling 
RBP-6000 will be packaged and labeled in a manner consistent with the study design and 
applicable regulations.  The study medication will be provided to the investigator(s) by the 
Sponsor or contractor.   
The SUBOXONE sublingual film will be supplied as bulk films in the following buprenorphine 
dosage strengths: 2mg /0.5 mg; 4 mg/1 mg; 8 mg/2 mg; and 12 mg/3 mg.  Containers will be 
labeled with a single panel disclosing the product name, lot number, contents, Sponsor name and 
address, route of administration, and appropriate precautionary statements. 
The study drug, RBP-6000, will be identified as an investigational compound. 
The following components will be used in the preparation of RBP-6000: 
• One sealed foil pouch containing a syringe prefilled with RBP-6000 and an oxygen 
absorber pack. 
• One sterile 19-gauge, 1-inch hypodermic safety needle. 
5.10 Storage and Accountability 
RBP-6000 should be stored under refrigerated conditions between 2-8ºC (36-46°F).  
SUBOXONE sublingual films should be stored at 25°C (77°F) with excursions permitted 


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between 15-30°C (59-86°F).  Temperature excursions outside of these ranges should be reported 
to the Sponsor immediately and approval for use should be obtained. 
 
The PI or designee is responsible for ensuring that all study drug received at the site is 
inventoried and accounted for throughout the study. Drug accountability is the responsibility of 
the PI or designee, with verification by the CRA. Study drug must be handled strictly in 
accordance with the protocol, handling guidelines and the label, and must be stored in a locked, 
limited access area under appropriate environmental conditions. The PI must ensure that proper 
conditions exist for storage of study treatments. The dispensing of study drug to the subject must 
be documented on the drug dispensing form. 
 
Unused study drug must be available for verification by the Sponsor’s site monitor during on-site 
monitoring visits. The return to the Sponsor of unused study drug will be documented on the 
Study Drug Return Form. 
 
The Investigator agrees not to supply RBP-6000 to any person except study personnel for SC 
injection of subjects in this study.   
5.11 Investigational Product Retention at Study Site 
The PI or medically-qualified designee agrees to conduct a study drug supply inventory for  
RBP-6000, to record results of this inventory, and to return all unused study drug to the Sponsor 
at times specified by RBP. RBP will arrange for the appropriate and timely destruction of all 
returned, unused RBP-6000. All used needles and syringes from RBP-6000 will be disposed of 
into an appropriate secure biohazard container per the standard operating procedures (SOPs) at 
the clinical site.  
All used IMP packaging (e.g. carton, foil pouch) will be retained at the study site until 
reconciliation is performed by the CRA.  After reconciliation is completed, the used IMP 
packaging may be disposed of per the SOPs at the study site. 


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6 
STUDY PROCEDURES 
The schedule of events for this study is provided in Appendix 1, Appendix 2, Appendix 3, 
Appendix 4, and Appendix 5. 
For roll-over subjects, study procedures completed at EOS/Day 169 will serve as screening 
assessments for the open-label study.   
6.1 
Informed Consent 
6.1.1 
General Information 
Prior to entering the study, the Investigator or designated individual will explain to each subject 
the nature of the study, its purpose, procedures, expected duration, alternative therapies 
available, and the benefits and risks involved in study participation. Subjects will be given the 
Institutional Review Board (IRB)-approved ICF to review and the opportunity to ask questions.  
Subjects will be informed of their right to withdraw from the study at any time without prejudice.  
The potential subjects should be able to answer simple questions about the study after the ICF 
has been reviewed and explained.  After this explanation and before any study-specific 
procedures have been performed, the subject will voluntarily sign and date the ICF to indicate 
the desire to participate in the study.  Prior to participation in the study, the subject will receive a 
copy of the signed and dated ICF.   
Roll-over subjects will complete all Day 169/EOS procedures prior to signing the ICF 
6.2 
Medical History 
For de novo subjects, a detailed medical history will be obtained by the PI or medically qualified 
designee during the screening visit (Visit 1). This will include information regarding the 
subject’s full history of medical and psychiatric conditions, diagnoses, procedures, treatments, 
concomitant medications, demographic information, and use of tobacco, drugs of abuse, alcohol, 
and caffeine, and any other noteworthy medical information, including suicidality measured 
using the eC-SSRS. Any updates to medical history information that the PI or medically 
qualified designee becomes aware of will be captured throughout the study.  All prior 
medications, OTC health, and dietary supplements taken by the subject within 30 days will be 
recorded.  In addition, hospitalizations in the past 3 months and the reason for admission 
(medical/surgical/psychiatric/other) will be recorded.   
For roll-over subjects medical history will not be re-obtained, except for new information. 
6.3 
Physical Examination 
A complete physical examination (PE) will be performed by the Investigator or medically 
qualified designee.  The physical examination will consist of an examination of the following:  
general appearance, skin, head, eyes, ears, nose, throat, neck (including thyroid), lymph nodes, 
chest and lungs, heart, abdomen, extremities, body weight, and a brief neurological assessment.  
The examination will not include a pelvic, breast, or rectal examination.  If any clinically 


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significant abnormal findings started before the date that informed consent was given, these 
findings should be recorded on the Medical History case report form (eCRF).   
If any clinically significant change from screening (Visit 1 for de novo subjects; Study RB-US-
13-0001 EOS visit (Day 169) for roll-over subjects) is noted, it will be reported as an AE and 
followed up to resolution or until reaching a stable end point. 
Weight (kg) will be assessed (in ordinary indoor clothing with shoes off) and will be recorded at 
screening as well as periodically throughout the study.  Height (cm) will be recorded at screening 
only.  BMI will be calculated at screening as well as periodically throughout the study.  BMI is 
defined as the subject’s weight in kg divided by the square of the subject’s height in meters 
(kg/m2).  The amount of abdominal fat will be measured using the waist-to-hip ratio and will be 
recorded at screening as well as periodically throughout the study.   
Procedures performed at Day 169/EOS in the RB-US-13-0001 study will not be repeated at the 
screening visit for roll-over subjects. 
Assessments are performed at the time points detailed in the SOEs (Appendix 1, Appendix 2, 
Appendix 3, Appendix 4, and Appendix 5). 
6.4 
Vital Signs 
Evaluation of vital signs will be performed after the subject has been supine for ≥ 3 minutes and 
will include a measurement of systolic and diastolic BP, pulse rate, pulse oximetry, respiratory 
rate, and oral temperature.   
If clinically significant findings, as determined by the Investigator or medically qualified sub-
investigator, occur in any vital sign measurement, that measurement will be captured as an AE 
and repeated at medically appropriate intervals until the value returns to an acceptable range, a 
specific diagnosis is established, or the condition is otherwise explained. 
Assessments will be recorded in the source documents and eCRF and will be performed at the 
time points detailed in the SOE (Appendix 1, Appendix 2, Appendix 3, Appendix 4, and 
Appendix 5). 
6.5 
Electrocardiograms 
6.5.1 
12-Lead Electrocardiograms 
Resting 12-lead ECGs will be recorded with the subject in supine position following a 10-minute 
rest period. For roll-over subjects, ECGs will be recorded prior to the PK blood sampling. 
(Appendix 6). 
Resting 12-lead ECGs will be recorded as indicated in the SOEs (Appendix 1, Appendix 2, 
Appendix 3, Appendix 4, and Appendix 5). ECGs recorded at screening will be recorded in 
triplicate, at approximately 2 - 5 minute intervals.  


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ECG intervals including HR, QT, QTcF, QTcB, RR, PR, QRS and T wave changes will be 
recorded.  ECGs will be reviewed by the Investigator during the visits for any immediate 
abnormalities. ECGs will also be reviewed by a central facility.   
The findings of the ECGs as determined by the central facility will be assessed by the 
Investigator and marked as normal, abnormal-not clinically significant, or abnormal-clinically 
significant.  All clinically significant abnormalities will be captured as AEs.  In the event that a 
clinically significant AE related to an ECG assessment occurs during the study, the Investigator 
should contact the Indivior Medical Monitor. 
6.6 
Clinical Laboratory Tests 
6.6.1 
Laboratory Parameters 
All clinical laboratory assessments will be performed by a clinical laboratory accredited by the 
College of American Pathologists or with a certificate of compliance (or certificate of waiver for 
CLIA-waived tests) issued by the Center for Medicare & Medicaid Services or Clinical 
Laboratory Improvement Amendments.  The laboratory assessments will include routine and 
screening laboratory tests.   
See the SOEs in Appendix 1, Appendix 2, Appendix 3, Appendix 4, and Appendix 5 for the 
timing of the specific required laboratory tests which are listed in Table 2.  
Any abnormal hematology, chemistry, or urinalysis test result deemed clinically significant by 
the Investigator will be repeated, including test results obtained on the final study day.  For any 
test abnormality deemed clinically significant, an AE will be recorded (unless the result was 
considered erroneous) and repeat analysis will be performed until resolution or until the 
Investigator determines that resolution of the laboratory abnormality is not expected.   
Subjects will be in a seated or supine position during blood collection.  Clinical laboratory panels 
are listed in Table 2. 


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Table 2 
List of Laboratory Tests 
Hematology: 
Hematocrit 
Hemoglobin  
Mean corpuscular hemoglobin  
Mean corpuscular hemoglobin concentration  
Mean corpuscular volume  
Platelet count 
Pancreatic enzymes 
Red blood cell count 
White blood cell count with differential 
 
Urinalysis: 
Appearance 
Bilirubin 
Color 
Glucose 
Ketones 
Leucocyte esterase 
Microscopic examination of sedimenta 
Nitrite 
Occult blood 
pH 
Protein 
Specific gravity 
Urobilinogen 
 
Hormone Panel: 
Adrenocorticotropic hormone (ACTH) Follicle Stimulating 
Hormone 
Testosterone (total and free) 
 
Pregnancy: 
Urine Pregnancy (only for females not postmenopausal or 
surgically sterile for at least 1 year) 
Serum Pregnancy 
 
Screening:    
Hemoglobin A1c  
HIV-1 and -2 antibodies 
PTT 
PT with INR 
Serum pregnancy 
 
Serum Chemistry: 
Albumin 
Alkaline phosphatase 
Alanine aminotransferase (ALT) 
Amylase 
Aspartate aminotransferase (AST) 
Blood urea nitrogen 
Calcium 
Calculated creatinine clearance 
Carbon dioxide 
Chloride 
Creatinine 
Creatine kinase and subtypes 
Gamma-glutamyl transferase 
Globulin 
Glucose (non-fasting) 
High-density lipoprotein (HDL) 
Immunoreactive trypsinogen 
Lactate dehydrogenase 
Lipase 
Low-density lipoprotein (LDL) 
Magnesium 
Phosphorus 
Potassium 
Sodium 
Total bilirubin 
Direct bilirubin 
Total cholesterol 
Total protein 
Triglycerides 
Uric acid 
 
Urine Drug Screen (UDS): 
Opioidsb 
Cocaine 
Amphetamines 
Methadone 
Cannabinoids 
Barbiturates 
Benzodiazepines 
Methamphetamine 
Phencyclidine 
Anti-HIV = human immunodeficiency virus antibodies; hCG = human chorionic gonadotropin; INR = 
international normalized ratio; IRT = immunoreactive trypsinogen; PT = prothrombin time; and PTT = 
partial thromboplastin time. 
a 
Microscopic examination of sediment will be performed only if the results of the urinalysis evaluation are 
positive (microscopic examination may include but is not limited to WBC count, RBC count, casts, and crystals). 
b 
Oxycodone may not show up in all opiate assays and should be assessed separately. 
   
 


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6.6.2 
Sample Collection, Storage, and Shipping 
All blood sampling will be by individual venipuncture or with the use of a saline lock.  Blood 
and urine sample collection and processing procedures will be outlined in a separate reference 
manual to be provided to the site. 
6.6.3 
Reference Ranges 
Up-to-date reference ranges for the above investigations must be obtained for the laboratory 
performing analyses prior to the start of the study and be updated as appropriate during the 
course of the study. 
6.6.4 
Laboratory Results Review 
The Investigator will review the results and comment on the laboratory results sheet for all 
abnormal values, identifying those that are abnormal but not clinically significant as well as 
those that are significantly abnormal.  The Investigator will sign and date the laboratory results 
sheet to indicate that the review has taken place. 
Clinical Laboratory Changes:  It is the Investigator’s responsibility to review the results of all 
laboratory tests as they become available.  This review will be documented by the Investigator 
on the laboratory report.  For each abnormal laboratory test result, the Investigator needs to 
ascertain if this is a clinically significant abnormal change from baseline for that individual 
subject.  
6.6.5 
Good Laboratory Practice Compliance 
Confirmation of compliance with Good Laboratory Practice (GLP) will be obtained from the 
designated Bioanalytical Laboratory prior to the start of the study. 
6.7 
Pharmacokinetic Assessments 
Blood samples for population PK analysis will be collected from roll-over subjects only at the 
time points indicated in the PK sampling schedule (Appendix 6). The plasma concentrations of 
buprenorphine and norbuprenorphine will be quantified using specific and validated liquid 
chromatography tandem mass spectrometry methods. A laboratory manual for PK sample 
collection, processing, storage, and shipping will be supplied. 
For all subjects (de novo and roll-over), a PK sample will be taken as soon as possible after any 
SAE is reported.  If possible, an additional sample should be collected when the SAE has been 
resolved. 
The exact times (to the minute) of PK blood sampling as well as the exact times of drug 
administration will be recorded in the source and eCRF.   


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6.8 
Administration of Study Drug 
The study drug will be assigned by an IWRS system. Injections will be administered by a 
physician or suitably-qualified designee (e.g., physician, nurse, nurse practitioner, PA) who has 
been delegated to perform the task.  Study drug will be supplied only to subjects participating in 
the study. The Investigator agrees not to allow the study drug to be administered from, nor stored 
at, any site other than the study site agreed upon with the Sponsor. 
See Appendix 7 for detailed descriptions of dosing for the SUBOXONE sublingual film. 
Detailed instructions for the preparation and administration of RBP-6000 are in Appendix 8. 
If at an injection visit there is a safety concern with administration of RBP-6000 or placebo, after 
discussion with the medical monitor or sponsor, dosing can be delayed up to one week.  In the 
event this occurs, the subsequent doses will be delayed.  There must be at least 26 days between 
injections of study medication. 
All used syringe components will be disposed of into an appropriate secure biohazard container 
or per the SOPs at the study site. 
All used IMP packaging (e.g., carton, foil pouch) will be retained at the study site until the CRA 
conducts a visit to perform reconciliation.  After the reconciliation is completed, the used IMP 
packaging may then be disposed of per the SOPs at the study site. 
Unused IMP and returned SUBOXONE sublingual film must be available for verification by the 
Sponsor’s site monitor during on-site monitoring visits.  The return of unused or used returned 
IMP for destruction will be documented on the drug return form. 
6.9 
Safety and Suicidality Assessments 
Safety will be assessed by AEs, vital signs,  ECGs, clinical laboratory assessments, local 
injection site grading scale, injection site pain VAS, and eC-SSRS responses. See the SOE for 
specific timing of assessments (Appendix 1, Appendix 2, Appendix 3, Appendix 4, and 
Appendix 5). 
6.9.1 
Local Injection Site Tolerability 
6.9.1.1 
Injection Site Grading 
Local injection site grading will be performed by the Investigator or a trained and qualified 
health care professional, according to the SOE in Appendix 2, Appendix 3, Appendix 4, and 
Appendix 5.  Injection sites will be assessed for pain, tenderness, erythema/redness, induration, 
or swelling.  Local injection site tolerability will be assigned a severity grade, including none 
(grade 0), mild (grade 1), moderate (grade 2), severe (grade 3), or potentially life threatening 
(grade 4) utilizing the Injection Site Grading Scale in Appendix 15.  The local injection site 
grading assessment will be completed electronically on injection days immediately after each 
injection (within 10 minutes) and at 1 hour (± 15 minutes) and 24 hours (± 4 hours) after each 
injection. 


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6.9.1.2 
Injection Site Pain Visual Analogue Scale (VAS)  
Injection site pain will be assessed by the subject at each injection visit electronically with a 
100mm VAS scale, where 0 represents no pain and 10 represents maximum pain (Appendix 16).  
The injection site-pain VAS scores will be obtained (after the completion of the injection) within 
1 minute and then at 5, 10, 15, 30, and 60 minutes (±5 minutes).  The timing of the Injection Site 
Pain VAS should be measured from the end of the injection.  In addition to rating pain levels by 
marking on the line the point they feel best represents their perception of their current state, the 
subject will also answer the following question with either a Yes or No: Are you currently 
experiencing any burning or stinging at the injection site? 
6.9.2 
Suicidality 
6.9.2.1 
Columbia Suicide Severity Rating Scale 
The eC-SSRS will be administered according to the SOE in Appendix 1, Appendix 2, Appendix 
3, Appendix 4, and Appendix 5.  The eC-SSRS is a questionnaire designed for assessment of 
suicidal ideation and behavior in adolescents and adults (Posner 2011).  The questionnaire will 
be administered as an electronic, self-rated version (eC-SSRS).  Clinical trial versions of the 
questionnaire are available for trial screening and follow up visits.  A sample section from the 
Baseline/Screening eC-SSRS and the follow up eC-SSRS are presented in Appendix 10 and 
Appendix 11, respectively.   
If a subject becomes suicidal during the study, the investigator should provide the appropriate 
treatment to the subject.  If the suicidality is deemed to be related to IMP and it is within 14 days 
of an injection, the depot may be removed (Section 6.14.1).  
The eC-SSRS should be completed prior to SUBOXONE and RBP-6000 injection and at 
approximately the same time each day ±2 hours. 
If, there is a positive on the eC-SSRS after screening the subject will be evaluated by the 
investigator for continuation in the study.  If needed, the investigator can consult with the 
medical monitor on continuation in the study of subjects with a positive eC-SSRS. 
6.10 Adverse Events Assessments 
6.10.1 
Definition 
In accordance with ICH and US FDA guidance, any untoward medical occurrence incurred by a 
subject that occurs after the first study-related procedure to the completion of the protocol-
defined safety surveillance period and is associated with the use of the drug, regardless of the 
presence of causal relationship, is a reportable AE.   
Abnormal results of diagnostic procedures, including laboratory test abnormalities, are 
considered AEs if they: 
• Result in discontinuation from the study, 


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• Require treatment or any other therapeutic intervention, 
• Require further diagnostic evaluation (excluding a repetition of the same procedure to 
confirm the abnormality), or 
• Are associated with clinical signs or symptoms that would have a significant clinical 
impact, as determined by the Investigator. 
6.10.2 
Performing Adverse Events Assessments 
The Investigator is ultimately responsible for assessing and reporting all AEs as outlined in the 
protocol.  The assessment of AEs may be delegated to a medically qualified sub-investigator, 
trained on this study protocol, who is listed on the FDA Form 1572 or equivalent document, and 
on the delegation of authority form. 
AEs should be volunteered by the subject or solicited from the subject using a standard 
statement, obtained from examination of the subject at a clinic visit, or from observations of 
clinically significant laboratory values or special examination abnormal values.  If an event 
assessed by one of the study scales requires intervention, or if in the opinion of the Investigator, 
it is clinically significant, then it will be reported as an AE. 
All AEs are to be assessed and recorded in a timely manner and followed to resolution or until 
the Investigator determines that there is not an anticipated resolution.  Each AE is to be 
documented with reference to severity, date of occurrence, duration, treatment, and outcome.  
Furthermore, each AE is to be classified as being serious or non-serious.  In addition, the 
Investigator must assess whether the AE is drug-related or not.  Changes in severity of AEs 
should be documented as one event at the maximum severity that occurred during the study. 
6.10.3 
Timing 
AEs will be captured from the time the subject gives informed consent until the subject 
completes the study. 
Surgical procedures, planned before enrollment of the subject in the study, are not considered 
AEs if the condition was known before study inclusion.  In this case the medical condition 
should be reported in the subject’s medical history.   
If a subject experiences the onset of an SAE within 30 days following study completion and in 
the opinion of the Investigator, that SAE is associated with the study, it will be followed and 
reported as described in Section 6.10.9.2. 
If a SAE occurs a PK sample will be taken as soon as possible after the event is reported.  If 
possible, an additional sample should be collected when the SAE has been resolved. 
6.10.4 
Severity 
Adverse events with changes in severity should be documented as one event at the maximum 
severity. 


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Intensity 
Definition 
Mild 
Causes transient or mild discomfort ; no limitation of usual activities; no 
medical intervention required 
Moderate 
Causes mild to moderate limitation in activity; some limitation of usual 
activities: no or minimal medical intervention or therapy is required. 
Severe 
Causes marked limitation in activity; some assistance is usually required; 
medical intervention or therapy is required; hospitalization is probable.   
 
The term “severe” is used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe); the event itself, however, may be of relatively minor medical significance 
(such as a severe headache). This is not the same as “serious,” which is based on subject/event 
outcome or action criteria usually associated with events that pose a threat to a subject’s life or 
functioning. Seriousness (not severity) serves as a guide for defining regulatory reporting 
obligations. 
6.10.5 
Relationship 
The Investigator or a medically qualified sub-investigator, trained on this study protocol, listed 
on the 1572 form or equivalent document and on the delegation of authority form is responsible 
for determining the AE relationship to the investigational product. 
The following categories will be used to define the relationship of an AE to the administration of 
the investigational product: 
 
Not Related: 
Data are available to identify a clear alternative cause for the AE other than 
the investigational product. 
Related: 
The cause of the AE is related to the investigational product and cannot be 
reasonably explained by other factors (e.g., the subject’s clinical state, 
concomitant therapy, and/or other interventions). 
 
6.10.6 
Expectedness 
An unexpected AE is any AE, the nature and severity of which is not consistent with the 
applicable product information (e.g., Investigator’s Brochure for an investigational product or 
product label/summary of product characteristics for an approved product). 
6.10.7 
Clinical Significance 
The Investigator or medically qualified sub-investigator, trained on this study protocol, listed on 
the 1572 form or equivalent document and on the delegation of authority form is responsible for 
determining clinical significance of abnormal assessment results (e.g., laboratory or ECG results) 
for the subject. 


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6.10.8 
Clinical Laboratory Adverse Events 
Changes in laboratory values or vital signs, or other safety parameters (e.g., ECG, neurological 
and clinical symptom assessments) as noted in the protocol are a subset of AEs and are 
reportable only if considered to be clinically significant by the investigator or medically qualified 
sub-investigator except that: 
• Baseline assessments are differentiated from AE/symptoms that are incurred post 
informed consent.  These baseline lab assessments, if determined to be clinically 
significant abnormal values, reflect the status of the subject prior to study participation.  
These clinically significant pre-dose abnormal assessments without clinical symptoms 
will not be reported as AEs.  
6.10.9 
Serious Adverse Events 
6.10.9.1 
Definition 
A SAE is defined as any AE occurring at any dose that results in any of the following outcomes:  
• death,  
• life-threatening AE, 
• hospitalization or prolongation of existing hospitalization,  
• a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or 
• a congenital anomaly or birth defect. 
“Important medical events may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.”  
6.10.9.2 
Reporting Serious Adverse Events 
All SAEs will be reported to the Sponsor by the Investigator or designee by email or fax within 
24 hours of discovery, using the form provided by the Sponsor.  The SAE report should also be 
emailed to the Sponsor Medical Monitor. 
In the event of an SAE, the Investigator or designee will notify Indivior Pharmacovigilance: 
Email: PatientSafetyNA@indivior.com  
Fax: (804) 423-8951 
Indivior Inc. 
10710 Midlothian Turnpike, Suite 430 
Richmond, VA 23235 
 
In the event that medical discussion is required for an SAE, the Sponsor Medical Monitor should 
be contacted: 


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The Investigator or designee must inform the IRB immediately regarding any AE (does not have 
to be causally related) that is both serious and unexpected; or that represents a series of AEs that 
on analysis is unanticipated, or occurs at an unanticipated frequency, or otherwise represents an 
unanticipated safety risk to the study subject. The IRB may subsequently choose to modify the 
informed consent or request changes to the protocol or Investigator’s Brochure.  A PK sample 
will be taken as soon as possible after any SAE is reported. If possible, an additional sample 
should be collected when the SAE has been resolved. 
6.10.10 Treatment-Emergent Adverse Events 
A TEAE is an AE that either commenced following initiation of study drug or was present prior 
to the initiation of study drug, but increased in frequency or severity following initiation of 
treatment, regardless of causality. 
6.10.11 Procedures and Follow-Up of Subjects with Ongoing SAEs or Experiencing 
SAEs after Completion of or Withdrawal from the Study 
Subjects with SAEs ongoing at the end of the study or after ET will be followed by the 
Investigator until stabilization or resolution.  If a subject experiences the onset of an SAE within 
a period of 30 days following study completion or withdrawal and, in the opinion of the 
Investigator or medically qualified sub-investigator, it is associated with the study, it will be 
followed up and reported as described for other SAEs. 
6.10.12 Pregnancy 
If a female subject believes she is pregnant (e.g., missed period, self-administered pregnancy 
test) the subject will be instructed to return to the clinical unit within 48 hours to undergo a 
serum pregnancy test.  If a pregnancy in a subject is confirmed at any time during the study 
through a serum pregnancy performed by the study laboratory, the subject will be discontinued 
from the study and will undergo all final study visit procedures (with the exception of a urine 
pregnancy test).  If the partner of a study subject becomes pregnant, the pregnancy will be 
reported to the clinical unit within 48 hours of the subject’s knowledge of the pregnancy.   
All confirmed pregnancies that occur within this study will be followed until resolution (i.e., 
termination [voluntary or spontaneous] or birth).   
Pregnancy ([study subject or the partner of a study subject] [without associated unexpected or 
adverse sequelae]) is not a reportable AE but must be reported to the Sponsor within 24 hours of 
the Investigator or study staff first being aware of the subject’s condition. 


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6.11 Clinical Outcome Assessments 
Clinical outcome assessments will include the UDS for opioids and other drugs; self-reported use 
of illicit opioids, other drugs, and alcohol on the TLFB; COWS, SOWS, and Opioid Craving 
VAS. 
6.11.1 
Timeline Followback Interview 
The TLFB Interview will be administered according to the SOE in Appendix 1, Appendix 2, 
Appendix 3, Appendix 4, and Appendix 5. The TLFB Interview is a method to assess recent drug 
use and will be administered electronically.  The questionnaire should be administered by an 
interviewer.  The interview instrument asks subjects to retrospectively estimate their drug use in 
the 30 days prior to screen at the screening visit and since the last visit at all subsequent visits.  
Only occurrence of use is captured (i.e., used or did not use) (Fals-Stewart 2000). The interview 
takes approximately 10-30 minutes to complete and is appropriate for males and females 14 
years of age and older.  Drugs to be assessed in this study include opioids, methadone, 
buprenorphine, cocaine, barbiturates, benzodiazepines, amphetamines/methamphetamine, 
phencyclidine, and ethanol (Appendix 17). 
The timeline followback interview should be completed prior to SUBOXONE and RBP-6000 
injection and at approximately the same time each day ± 2 hours. 
6.11.2 
Opioid Craving Visual Analog Scale  
The Opioid Craving VAS will be administered electronically according to the SOE in Appendix 
1, Appendix 2, Appendix 3, Appendix 4, and Appendix 5.  A VAS is an instrument that 
measures a characteristic or attitude that is believed to range across a continuum of values and 
cannot easily be directly measured.  The amount of opioid craving that a subject feels for illicit 
opioids (not the buprenorphine used for treatment of opioid use disorder) can be recorded along a 
continuum from “no craving at all” to “strongest craving ever” (McMillan and Gilmore-Thomas 
1996).  Operationally, the VAS is a horizontal line, 100 millimeters (mm) in length, anchored by 
word descriptors at each end, as illustrated in Appendix 14.  The subject indicates the point on 
the line that he/she feels represents his/her perception of their current state.  The VAS score is 
the difference from the left hand end of the line to the point that the subject marks and will be 
electronically calculated. 
6.11.3 
Clinical Opiate Withdrawal Scale  
The COWS assessment will be administered electronically according to the SOE in Appendix 1, 
Appendix 2, Appendix 3, Appendix 4, and Appendix 5.  The COWS is an 11-item, validated 
instrument used to assess symptoms of opiate withdrawal (Wesson 2003, Tompkins 2009).  The 
score is the sum of the response to each of the 11 items.  The COWS is sometimes used by 
clinicians treating subjects with buprenorphine.  A score of 5 to 12 is considered mild, 13 to 24 is 
moderate, 25 to 36 is moderately severe, and a score of exceeding 36 is considered severe 
withdrawal.  COWS scores will be electronically calculated.  Each subject should be assessed by 
the same qualified and trained individuals throughout the course of the study as much as 
possible.  This scale is presented in Appendix 12. 


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6.11.4 
Subjective Opiate Withdrawal Scale 
The SOWS (Handlesman 1987) will be administered electronically according to the SOE in 
Appendix 1, Appendix 2, Appendix 3, Appendix 4, and Appendix 5.  The SOWS is a 16-item 
scale completed by the subject and used to assess the subject’s perception of opiate withdrawal 
symptoms.  SOWS scores will be electronically calculated.  This scale is presented in Appendix 
13. 
6.12 Health Economics and Outcomes Assessments 
Health economics and outcomes assessments will include: EQ 5D-5L, SF-36v2, MSQ, HCRU, 
TEA, ASI-Lite, BDI-II, and BPI.  
All questionnaires will be completed at the appropriate study visits as indicated in the following 
sections. 
6.12.1 
EuroQoL-5 Dimensions-5 Levels (EQ-5D-5L) and EQ-VAS 
The EQ-5D-5L will be used to record subjects’ health-related quality of life throughout the study 
at the time points indicated in the SOEs (Appendix 1, Appendix 2, Appendix 3, Appendix 4, and 
Appendix 5).  It will be administered electronically.  
The EQ-5D-5L is a widely-used, generic health-related quality of life instrument, which consists 
of 2 sections:  the EQ-5D-5L descriptive system and the EQ visual analogue scale (EQ VAS) 
(Appendix 18).  The EQ-5D-5L is comprised of 5 questions/dimensions (mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression) each of which can take 1 of 5 
responses.  The responses record 5 levels of severity (no problems/slight problems/moderate 
problems/severe problems/extreme problems) within a particular EQ-5D dimension.  EQ-5D -5L 
health states can be converted to a single summary index (range: 0-1) by using value sets that 
attaches values to each of the levels in each dimension.  The EQ-VAS is a standard, vertical, 20 -
cm visual analogue scale and will be used for recording a subject’s rating for their current health-
related quality of life state (Herdman 2007).   
6.12.2 
Medical Outcomes Study Short Form-36 (SF-36v2) 
The SF-36v2 is a generic, subject-reported outcome instrument used to assess quality of life, 
which will be administered electronically at the time points indicated in the SOEs (Appendix 1, 
Appendix 2, Appendix 3, Appendix 4, and Appendix 5).  
The SF-36v2 is a 36-question instrument, which assesses 8 health concepts: 1) limitations in 
physical activities because of health problems; 2) limitations in social activities because of 
physical or emotional problems; 3) limitations in usual role activities because of physical health 
problems; 4) bodily pain; 5) general mental health (psychological distress and well-being); 6) 
limitations in usual role activities because of emotional problems; 7) vitality (energy and 
fatigue); and 8) general health perceptions (Appendix 19).  The scale score of each domain is 
calculated based on the summed score across items included in the domain and is rescaled to 0 to 
100 with higher scores indicating better health states. 


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The SF-36v2 provides scores for each of the eight health domains and psychometrically-based 
physical component summary (PCS) and mental component summary (MCS) scores. The 
physical functioning, role physical, bodily pain, and general health can be used to construct a 
PCS score, while the vitality, social functioning, role emotional, and mental health scales are 
used to construct the MCS Scores (Ware 2007). 
6.12.3 
Medication Satisfaction Questionnaire (MSQ) 
The MSQ is a single-item, patient-rated questionnaire (Appendix 20) that evaluates patient 
satisfaction with opioid medication. (Vernon 2010).  Medication satisfaction will be measured 
with the MSQ at the time points indicated in the SOEs (Appendix 2, Appendix 3, Appendix 4, 
and Appendix 5) electronically. 
6.12.4 
Healthcare Resource Utilization (HCRU) Questionnaire 
The Healthcare Resource Utilization questionnaire will be completed by the Investigator or 
designee at the time points indicated in the SOEs (Appendix 1, Appendix 2, Appendix 3, 
Appendix 4, and Appendix 5).  The HCRU will be used to collect current health insurance status, 
hospitalizations; residential substance abuse treatment; general practitioner, specialist, and 
counseling visits; and ED visits (Appendix 21).  It will be administered electronically. 
The outpatient services captured on this questionnaire are ones conducted outside the study.  
Visits to the study site for scheduled study visits should not be reported here. 
6.12.5 
Treatment Effectiveness Assessment (TEA) 
The TEA is a patient-reported instrument which will be measured at the time points indicated in 
the SOEs (Appendix 1, Appendix 2, Appendix 3, Appendix 4, and Appendix 5). 
 
The TEA is a 4-item scale completed by the subject and used to assess the subject’s perception 
of treatment effectiveness (Ling 2012).  Patients respond to the TEA questions providing both 
numerical responses and brief feedback about their situation on four domains: substance use 
(drugs, alcohol, tobacco), health (e.g., physical, emotional health), lifestyle (e.g., housing or 
living situation, family, employment, relationships), and community (e.g., obeying laws and 
becoming a responsible member of society).  The TEA scale is presented in Appendix 22. 
6.12.6 
Addiction Severity Index (ASI) Lite 
The ASI Lite is a patient-reported instrument that is conducted via interview by a team member 
trained in the administration of the ASI Lite. ASI Lite will be administered at the time points 
indicated in the SOEs (Appendix 2, Appendix 3, Appendix 4, and Appendix 5). Given the nature 
of the ASI Lite, this instrument can be administered before or after injection of RBP-6000.  
The ASI Lite, in an interview used to assess the subject’s addiction severity, covers 7 potential 
problem areas: medical, employment/support status, alcohol, drug, legal, family/social, and 
psychiatric problems (Strain 1996). The ASI Lite interview text is presented in Appendix 23. The 
ASI obtains lifetime information about problem behaviors, as well as problems within the 


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previous 30 days. Of note, some items of the ASI Lite are only asked once at the initial visit; at 
subsequent time points only items indicated in the questionnaire should be administered.  
Below is a brief description of each of the scales that will be included within the trial:   
The medical status section of the ASI gathers basic information about the patient's medical 
history. It addresses information about lifetime hospitalizations, long-term medical problems and 
recent physical ailments.  The employment/support status section of the ASI gathers information 
about the resources a patient can record on a job application, as well as his or her current sources 
of income. Many items will have a 30-day recall period regarding current employment. The 
drug/alcohol section of the ASI gathers information about the patient's substance abuse history. It 
addresses information about current and lifetime substance abuse, consequences of abuse, 
periods of abstinence, treatment episodes, and financial burden of substance abuse. While 
lifetime versions of these items are also available, this would only be assessed at first interview.  
The legal status section of the ASI gathers information about the patient's legal history. It 
addresses information about probation or parole, charges, convictions, incarcerations or 
detainments, and illegal activities.  The family/social relationships section is designed to 
summarize the psychiatric, alcohol and drug abuse problems of the patient's relatives in each of 
the specified categories.  The psychiatric problem section gathers information on psychiatric 
symptoms experienced by the patient. 
6.12.7 
Beck Depression Inventory II (BDI-II) 
Depression is highly prevalent in patients with opioid use disorders.  Studies have been 
conducted using buprenorphine as a treatment for major depressive disorder.  
The Beck Depression Inventory II (BDI-II) is used to measure the severity of depression in 
adults and adolescents.  The BDI-II is scored on a 4 point Likert scale, each item ranging from 0-
3; it has a 2 week recall period, can be self-administered or administered by interview and takes 
5-10 minutes to complete.  
The strengths of the BDI-II include its ease of use; also, it is widely known and the results are 
easy to score and interpret.  The BDI-II has been successfully used to discriminate and measure 
depression in chronic pain patients on opioid therapy (Geisser 1997, Farren 2002, McCauley 
2014).   
The BDI-II assessment will be administered electronically according to the SOE in Appendix 1, 
Appendix 2, Appendix 3, Appendix 4, and Appendix 5.  This scale is presented in Appendix 24. 
Roll-over subjects who did not complete the BDI-II at EOS/Day 169 will complete this 
assessment at the screening visit. 
6.12.8 
Brief Pain Inventory (BPI) Short Form 
A substantial number of patients in the US with opioid use disorder began by using prescription 
pain medications and subsequently developed dependence. Many of these patients are concerned 
at the beginning of therapy that their pain may worsen when they are no longer taking their 
opioid medication.   
The Brief Pain Inventory Short Form (BPI-SF) is used to measure the severity of pain and the 
impact of pain on daily functions in adults. The BPI-SF has a 24-hour recall period and can be 


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self-administered or administered by an interviewer. It takes approximately 5 minutes to 
complete an instrument.  
The BPI has been widely used to measure pain severity among opioid users (Rosenblum 2003).  
BPI-SF consists of a combination of yes/no questions, an item based on human figure drawing, 
open-ended questions, and items based on a numeric rating scale.  Key strengths of the BPI-SF 
are that it is easy to administer and can provide rapid assessment of pain. BPI has been translated 
in many languages and is widely used. It captures all the components of pain: structural, intensity 
and its effect on patients.   
The BPI assessment will be administered electronically according to the SOE in Appendix 1, 
Appendix 2, Appendix 3, Appendix 4, and Appendix 5.  This scale is presented in Appendix 25.  
Roll-over subjects who did not complete the BPI at EOS/Day 169 will complete this assessment 
at the screening visit. 
6.13 Concomitant Medication Assessments 
The Investigator or designee will record any concomitant therapies given for 30 days prior to the 
start of and during the course of the study on the concomitant medication page of the subject’s 
source documentation and eCRF. Any changes in concomitant therapy during the study will also 
be documented, including cessation of therapy, initiation of therapy, and dose changes. 
6.14 Removal of Subjects from the Study 
Subjects will be free to withdraw at any time for any reason, or they may be withdrawn if 
necessary, to protect their health and safety or the integrity of the study data.   
The Investigator or medically qualified sub-investigator may choose to withdraw a subject from 
the study at any time.  Reasons for removing a subject from the study may include, but are not 
limited to the following: 
• Protocol deviation that might compromise data integrity, protocol compliance, or subject 
safety, 
• An AE is reported that compromises or potentially compromises subject safety, 
• The Sponsor or Investigator terminates the study, or 
• The subject requests to be discontinued from the study (i.e., subject declines further study 
participation). 
 
If a subject withdraws prematurely from the study after receiving IMP, the primary reason for 
withdrawal will be documented as 1 of the above, lost to follow-up, or other in the source 
documentation.  
In the event a subject is lost to follow up, the site staff must make reasonable attempts to contact 
the subject.  A minimum of 2 documented telephone calls followed by a certified mailed letter is 
considered reasonable. 


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6.14.1 
Early Removal of RBP-6000 
In the event of an emergency or if a subject withdraws or is withdrawn within the first 14 days of 
receiving an injection of RBP-6000, subjects may have the option to have the depot surgically 
removed by a physician delegated to perform surgery. The medically responsible physician 
should carefully discuss this option with subjects given the use of ATRIGEL Delivery System 
and the feasibility of extracting the depot. The surgical procedure requires a small incision in the 
abdomen where the depot was placed, removal of the depot with forceps, and suturing to close 
the incision.  The subject should have the EOS assessments performed at the time of early 
removal of RBP-6000. Subjects that have had an RBP-6000 depot removed should have follow-
up telephone contact(s) within 7 to 14 days to assess status and for resolution of related AEs. In 
the event a subject cannot be contacted for the follow-up telephone contact, a minimum of 2 
documented telephone calls followed by a certified mailed letter is considered reasonable. At this 
point, the subject may be considered lost to follow-up. 
The extracted RBP-6000 depot will be disposed of into an appropriate, secure biohazard 
container per the standard operating procedures (SOPs) at the clinical site.  
Detailed RBP-6000 depot removal instructions are in Appendix 8. 
6.14.2 
Stopping Rules 
The Investigator must contact the Sponsor immediately to discuss whether to suspend dosing if 
an AE or laboratory abnormalities indicates that continued dosing of subsequent subjects would 
not be tolerated or would jeopardize the subjects’ safety.  The Sponsor alone may suspend dosing 
at any time for any reason. 
Factors that must be considered for suspension of dosing include the frequency, severity, clinical 
significance, possible causality, and anticipated reversibility of all observed AEs or laboratory 
abnormalities for each specific SC injection group.  If dosing is suspended, the IRB will be 
notified in accordance with IRB requirements. 
6.14.3 
Screen Failures 
A screen failure subject is one from whom informed consent is obtained and is documented in 
writing (i.e., the subject signs the ICF) but who did not receive study medication. 
Rescreening of a de novo subject may be permitted after consultation with the study medical 
monitor. 
6.15 Other Study Procedures 
6.15.1 
Counseling/Behavioral Therapy 
After enrollment, subjects will receive manual-guided, individual behavioral therapy once a 
week for 5 weeks, then bi-weekly (every 2 weeks) up until injection 6, at which point it will 
occur monthly to accompany the pharmacotherapy as indicated in the SOEs (Appendix 2, 


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Appendix 3, Appendix 4, and Appendix 5). Behavioral therapy will continue through the end of 
the study (EOS/ET visit). It is at the Investigator’s discretion to provide additional behavioral 
counseling above this standard frequency.The reason(s) that additional counseling was provided 
should be documented in source documentation. Behavioral therapy can be conducted by any 
appropriately trained staff member at the site. 
An Individual Drug Counseling (IDC) reference manual will be provided to each site.   
6.15.2 
Unscheduled Visits 
If unscheduled visits occur, the Investigator must record the following in the subject’s source 
documentation: 
• Any AEs 
• Reason for unscheduled visit 
• Recording of any changes or additions to concomitant medications dose or regimen 
• COWS (if deemed appropriate) 
• Any clinical assessments deemed appropriate for the clinical care of the subject 
Unscheduled visits should not alter the timing of the routine study schedule. 
6.15.3 
Additional Care of Study Subjects Following Completion of the Study 
Each subject will be evaluated on his or her final study day.  Subjects who experience SAEs at 
the EOS, or experience the onset of an SAE after the final visit, will be followed up as described 
in Section 6.10.11.  No other additional care of study subjects will take place following 
completion of the study.  
6.15.4 
Treating Toxicity 
Treatment of suspected RBP-6000 toxicity should be at the judgment of the Investigator or 
medically-qualified sub-investigator and may include an attempt to remove the depot if toxicity 
is discovered within the first 14 days post injection.  Subjects who have had RBP-6000 removed 
will be followed up according to the procedures described in the SOE (EOS/ET Visit; Appendix 
3 and Appendix 5) and Section 6.14. 
6.15.5 
Ancillary Medications 
Treatment of signs and symptoms of opioid withdrawal after enrollment can be treated with 
ancillary medications allowed by the protocol, as clinically indicated by the Investigator or 
physician Sub-Investigator.  Subjects whose symptoms are not manageable will be discontinued 
from the study and will be followed up according to the procedures described in the SOE 
(EOS/ET Visit; Appendix 3 and Appendix 5) and Section 6.14. 


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6.16 Appropriateness of Measurements 
Within the study population of opioid-dependent subjects, certain common signs and symptoms 
are displayed that must be evaluated for safety and efficacy of treatment during clinical trials.  
The instruments used (e.g., COWS, SOWS, Opioid Craving VAS, and eC-SSRS) were 
developed to measure the specific symptoms exhibited by and challenges facing opioid-
dependent individuals. 


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7 
STUDY ACTIVITIES 
This study will be conducted as a fully non-residential (outpatient) study.  An overview of the 
study is shown in Figure 2 and Figure 3.  Details on procedures/activities for this study are 
provided in Section 6 and SOEs are provided in Appendix 1, Appendix 2, Appendix 3, Appendix 
4, and Appendix 5. 


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8 
QUALITY CONTROL AND ASSURANCE 
8.1 
Quality Control 
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study centers, review of protocol procedures with the investigators 
and associated personnel before the study, periodic monitoring visits by the Sponsor, and direct 
transmission of clinical laboratory data from a central laboratory into the Sponsor’s (or 
designee’s) database.  Written instructions will be provided for study drug preparation and 
dosing, collection, preparation, and shipment of blood, plasma, and urine samples.  Guidelines 
for eCRF completion will be provided and reviewed with study personnel before the start of the 
study.  The Sponsor (or designee) will review eCRFs for accuracy and completeness during on-
site monitoring visits and after transmission to the Sponsor (or designee).  Any discrepancies will 
be resolved with the Investigator or suitably qualified designee, as appropriate. 
8.2 
Quality Assurance 
This study will be organized, performed, and reported in compliance with the protocol, Standard 
Operating Procedures (SOPs), working practice documents, and applicable regulations and 
guidelines.   
In accordance with the standards defined in Sponsor SOPs and applicable regulatory 
requirements, clinical studies sponsored by Sponsor are subject to Sponsor Quality Audits at the 
study sites that will be conducted by personnel from an appropriate unit.  Site audits will be 
made periodically by the Sponsor’s (or contractor’s) qualified compliance auditing team, which 
is an independent function from the study conduct team.  Audits will include review of, but are 
not limited to, drug supply, presence of required documents, the informed consent process, and 
comparison of eCRFs with source documents.  The investigator agrees to participate with audits 
conducted at a reasonable time in a reasonable manner.  Full consultation with the Investigator 
will be made prior to and during such an audit, which will be conducted according to the Quality 
Assurance Unit SOPs.  In addition, this study is subject to inspection by regulatory authorities.  
If such a regulatory inspection occurs, the Investigator agrees to allow the regulatory inspector 
direct access to all relevant study documents.  The investigator should contact the Sponsor 
immediately if this occurs and must fully cooperate with the inspection conducted at a reasonable 
time in a reasonable manner. 


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9 
PLANNED STATISTICAL METHODS 
9.1 
General Considerations 
A Statistical Analysis Plan (SAP) will be prepared after the protocol is approved and before 
database lock occurs.  The SAP will provide further details regarding the definition of analysis 
endpoints, data handling rules, and the statistical methodology to be used to address all study 
objectives.  The SAP will also include formats for the summary and analysis tables, listings, and 
graphical displays. 
This section describes methods for sample size determination, analysis populations, and planned 
analyses for, safety, PK, and clinical outcomes endpoints.  Additional unplanned analyses may 
be required after all planned analyses have been completed.  Any unplanned analyses will be 
clearly identified in the clinical study report.  Any deviations from the analyses described below 
will be included in the SAP, which will form Appendix 16.1.9 of the clinical study report. 
Continuous variables will be summarized using descriptive statistics such as means, standard 
deviations (SD), medians, minimums, and maximums.  Categorical variables will be reported as 
frequency counts (including number missing) and the percentage of subjects in corresponding 
categories.  Individual subject data will be presented by subject in data listings.  Data listings will 
include all data collected from the initial screening visit to the end of study for all subjects 
enrolled.   
9.2 
Determination of Sample Size 
There is no formal sample size calculation. Approximately 300 de novo subjects as well as 
approximately 300 subjects who completed the RB-US-13-0001 efficacy study will be enrolled 
into this study to ensure at least 100 subjects reach 1 year of treatment with RBP-6000. 
9.3 
Analysis Populations 
The following populations will be used for data analyses: 
9.3.1 
Safety Population 
The Safety Population comprises all subjects who received at least 1 dose of RBP-6000 during 
the open-label treatment phase of the study. This population will be used for all safety analyses.   
9.3.2 
Clinical Outcome Assessment and PK Populations 
The Clinical Outcome Assessment population will include subjects who were dosed with 
RBP-6000 and have at least 1 post-dose Clinical Outcome Assessment value.  
The PK Population will include any subject who receives a dose of RBP-6000 or at least 1 dose 
of SUBOXONE sublingual film and has at least 1 sample collected post-dose.  
   


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9.4 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics (gender, race, age, weight, height) will be summarized 
by treatment group using descriptive statistics.  Qualitative variables (gender, race) will be 
summarized using frequencies while quantitative variables (age, weight, height) will be 
summarized using mean, SD, median, minimum, and maximum. 
9.5 
Primary Analysis 
9.5.1 
Safety Endpoints 
Safety variables will include AEs, local injection site tolerability (e.g., injection site grading); 
injection site pain using a subject-reported VAS; suicidality using the eC-SSRS, concomitant 
medications; changes in clinical laboratory results (hematology, chemistry and urinalysis); vital 
sign measurements; 12-lead ECGs, physical examination results; body weight, height, BMI, and 
abdominal fat measurement (waist-to-hip ratio). Safety variables will be analyzed using the 
safety population.  
Baseline is defined as the last non-missing value prior to SC injection on Day 1.  No imputation 
of missing values will be performed. 
9.5.1.1 
Adverse Events 
All AEs will be coded using the most up-to-date version of the Medical Dictionary for 
Regulatory Activities (MedDRA) and reported to the FDA. AEs that began more than 30 days 
after the last study subject assessment day will not be included in the safety analysis. Only 
TEAEs occurring post administration of RBP-6000 will be included in the safety analysis (See 
Section 6.10.10). 
The incidence of AEs (number and percent of subjects reporting the AE at least once during the 
study) will be summarized for all AEs, by the relationship to study drug and by severity. 
9.5.1.2 
Laboratory Data 
At each visit where clinical laboratory assessments are conducted, summary statistics for the 
absolute laboratory value and the changes from baseline will be presented.   
9.5.1.3 
Vital Signs 
Vital signs measurements will be assessed for clinical relevance and be performed as deemed 
medically necessary by research personnel.  Vital signs will be taken after the subject has 
completed a minimum 3-minute rest in the supine position.  Systolic and diastolic BP 
measurements will be assessed while supine throughout the trial. 
9.5.1.4 
Other Variables Related to Safety 
Results from 12-lead ECGs will be categorized as normal, abnormal clinically significant, or 
abnormal not clinically significant and will be summarized by time point using frequency counts 


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and percentages.  ECG interval measurements as well as change from baseline will also be 
summarized by time point using descriptive statistics (mean, median, SD, minimum, maximum).  
Additional analysis of ECG parameters will be outlined in the SAP. 
Medical history will be coded using MedDRA and summarized by treatment group as described 
for AEs (Section 9.5.1.1).  Body weight, height, BMI, and abdominal fat measurement (waist-to-
hip ratio) will be summarized using descriptive statistics (mean, median, SD, minimum, 
maximum), including change from baseline. 
Total eC-SSRS scores will be summarized using descriptive statistics (mean, median, SD, 
minimum, maximum), including change from baseline.  Subjects’ self-reported illicit drug use 
from the TLFB will be summarized as descriptive statistics. 
Prior and concomitant medications will be coded using the most recent version of the World 
Health Organization (WHO) Drug dictionary.  Incidence (number and percent of subjects 
reporting the medication at least once during the study) will be summarized for all concomitant 
medications. 
Local injection site tolerability as assessed by the Injection Site Grading scale will be 
summarized by category and severity using frequency counts and percentages similar to 
summaries for AEs (Section 9.5.1.1).  Injection Site Pain VAS scores will be summarized by 
dose, injection, and time point after injection.  The burning/stinging categorical variable 
(Yes/No) will be summarized by percent of responses in each treatment. 
9.6 
Secondary Analysis 
9.6.1 
Clinical Outcomes Assessments 
COWS, SOWS and Opioid Craving VAS total scores will be summarized using descriptive 
statistics (mean, median, SD, minimum, maximum), including change from baseline. Subjects’ 
self-reported illicit drug use from the TLFB will be summarized using descriptive statistics. 
The cumulative distribution function (CDF) of the percentage of urine samples negative for 
opioids and that of the percentage of self-reports from the TLFB negative for illicit opioid use 
will be calculated. Other outcome efficacy measures will be estimated using descriptive 
statistics.  
9.7 
Other Analyses 
9.7.1 
PK/PD Modeling 
The population PK model established using the data collected in the double-blind, placebo-
controlled, efficacy study (Study RB-US-13-0001) will be refined using the sparse PK samples 
collected from the roll-over subjects in the present study to characterize the disposition of 
buprenorphine and norbuprenorphine following SC injections of RBP-6000, with the assessment 
of potential covariates affecting the PK of both compounds.  Subsequently, the relationships 
between buprenorphine plasma concentrations and clinical outcomes assessments will be 


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investigated.  These relationships will be initially assessed in a descriptive manner, and, if 
applicable, appropriate PK/PD models will be developed to describe these relationships.  A 
stand-alone modeling analysis plan will be generated, and the results will be reported in a 
standalone modeling report.  
9.7.2 
Health Economic and Outcomes Assessment 
The health economic and outcomes research endpoints for this study are: 
• EQ-5D-5L 
• SF-36v2  
• MSQ  
• HCRU  
• TEA 
• ASI Lite 
• BDI-II 
• BPI 
Summary scores for these measures will be calculated, as appropriate. Categorical variables will 
be summarized using frequencies and percentages. Continuous measures will be summarized 
using descriptive statistics (mean, standard deviation, median, minimum, maximum) as 
appropriate. An analysis of change will be conducted.  A stand-alone statistical analysis plan will 
be developed prior to database lock for health economics and outcomes research assessments.  
A separate stand-alone SAP will be developed prior to database lock with full detail regarding 
health economics and outcomes analyses. 
9.8 
Handling of Missing Data 
For dichotomous outcome measures such as UDS results (negative; non-negative) and self-
reports for illicit opioid use (negative; non-negative), any missing observation will be recorded 
as “non-negative.” For all continuous endpoints (e.g., COWS, SOWS, and VAS), the missing 
data mechanism will be assumed to be either missing completely at random (MCAR) or missing 
at random (MAR).  The missing data will not be imputed because the analysis method, mixed 
model for repeated measures (MMRM), does not require any imputation and no sensitivity 
analyses will be performed on these variables.  For time-to-event variables, if the event of 
interest is not observed prior to withdrawal or end of treatment, the observations will be censored 
at the time of withdrawal or at the end of treatment.  For example, if some subjects still have not 
had a urine sample negative for opioids combined with self-reports negative for illicit opioid use 
when the study ends or at the time of withdrawal from the study, then the time to first urine 
sample negative for opioids combined with self-reports negative for illicit opioid use will be 
censored at the last time they were assessed. 


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9.9 
Subjects Who Withdraw from the Study 
Subjects who withdraw after receiving RBP-6000 will not be replaced. 
9.10 Interim Analyses 
No interim analysis will be performed for this study.   


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10 ADMINISTRATIVE CONSIDERATIONS 
10.1 Investigators and Study Administrative Structure 
10.1.1 
Indivior Inc. 
Indivior Inc. 
10710 Midlothian Turnpike, Suite 430 
Richmond, VA 23235 
 
10.1.2 
Investigational Site(s) 
This study will be conducted at up to 50 sites in the US. 
10.1.3 
Laboratories 
The safety laboratory tests (serum chemistry, hematology, serology, and urinalysis), as well as 
the specialty laboratory tests (Bioanalytical and Pharmacokinetic) will be conducted at a central 
laboratory that is certified and accredited to perform the assigned assessments. 
Collection of safety laboratory samples is described in Section 6.6.2.  The Clinical Laboratory 
will provide normal ranges and collection, processing, and shipping instructions to the sites in a 
separate laboratory reference manual. 
10.2 Institutional Review Board or Independent Ethics Committee 
Approval 
The protocol will be reviewed by an independent, appropriately constituted, centralized IRB/ 
Independent Ethics Committee (IEC).  Study enrolment and protocol related procedures, which 
do not form part of the subject’s normal clinical treatment, will not be performed until the 
IRB/IEC of record has provided written approval of the protocol or a modification thereof.  The 
IRB/IEC must be constituted and operate in accordance with the principles and requirements of 
ICH GCP. 
Study drug can only be supplied to the Investigator after documentation on all ethical and legal 
requirements for starting the study has been received by the Sponsor.  This documentation must 
also include an IRB/IEC membership list that contains member’s occupations.  If the IRB/IEC 
will not disclose the names of the committee members, the IRB/IEC Federalwide Assurance 
Number may be accepted as a substitute for this list.  Formal approval by the IRB/IEC should 
mention the study title, study code, study site (or region or area of jurisdiction, as applicable), 
and any other documents reviewed.  It must mention the date on which the decision was made 
and must be officially signed by a committee member. 
10.3 Ethical Conduct of the Study 
The Investigator is responsible for ensuring that the clinical study is performed in accordance 
with the protocol, current ICH GCP guidelines, and applicable regulatory and country-specific 


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requirements.  GCP is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects.  
Compliance with this standard provides the public assurance that the rights, safety, and 
well-being of study subjects are protected and that the clinical study data are credible. 
10.4 Subject Information and Consent 
Prior to the subject incurring the first study related procedure, the Investigator or designated 
individual will explain to each subject the nature of the study, its purpose, procedures, expected 
duration, alternative therapies available, and the benefits and risks involved in study 
participation. It should also be mentioned that all informed consent documents and other 
documents used in the conduct of the study have been approved by an IRB/IEC. 
In the case of a non-medically qualified person conducting the consent process, he/she should 
have ready access to a medically qualified investigator to whom any questions from the study 
subject may be referred. Subjects will be given consent documents to review and the opportunity 
to ask questions. Subjects will be informed of their right to withdraw from the study at any time 
without prejudice.  
After this explanation and before any study-specific procedures have been performed, the subject 
will voluntarily sign and date the ICF to indicate he/she wishes to participate in study.  The 
Investigator or the individual designated to conduct the consent discussion for the Investigator 
will also sign and date the ICF. The time (hour and minute) the consent is signed must also be 
recorded in the subject’s source notes, by the person obtaining consent from the subject. Verbal 
informed consent followed by a signed consent short form is not acceptable to Sponsor. 
Prior to participation in the study, the subject will receive a copy of the signed and dated ICF 
along with an emergency card with contact information for the Investigator and site staff in the 
event of a medical emergency during the study. 
10.5 Subject Confidentiality 
All subject-identifying documentation generated in this study must be considered confidential 
and must not be disclosed to any persons not directly concerned with the study without written 
permission from the subject.  However, authorized regulatory officials and Sponsor personnel (or 
their representatives) will be allowed full access to inspect and copy the records.  All subject 
bodily fluids, and/or other materials collected shall be used solely in accordance with this 
protocol and the informed consent signed by the subject, unless otherwise agreed to in writing by 
the Sponsor. 
Each subject will be identified by initials and an assigned subject number when reporting study 
information to any entity outside of the study center.  Data containing subject identification will 
not be removed from the study center without subject identifiers having been redacted. 
A Certificate of Confidentiality will be obtained for this study prior to subject screening. 


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10.6 Study Monitoring 
In accordance with applicable regulations, GCP, and Sponsor procedures, the clinical monitor(s) 
will periodically contact the site, including conducting on-site visits at intervals agreed by the 
Investigator and documented in the Clinical Monitoring Plan and the Site Initiation Visit Report.   
The clinical monitor(s) will contact the site prior to the start of the study to discuss the protocol 
and data collection procedures with site personnel.  In accordance with applicable regulations 
and GCP guidelines, the Investigator shall make available for direct access all study-related 
records upon request of the Sponsor, the Sponsor’s agents, clinical monitor(s), auditors, and/or 
IRB/IEC.  The Sponsor’s monitors will visit the site during the study in addition to maintaining 
frequent telephone and written communication.  The extent, nature, and frequency of on-site 
visits will be based on such considerations as the study objectives and/or endpoints, the purpose 
of the study, study design complexity, and enrolment rate.   
The Investigator must allow the clinical monitor(s) direct access to all relevant documents and to 
allocate his/her time and the time of his/her staff to the clinical monitor(s) to discuss findings and 
any relevant issues. 
10.6.1 
Study and Site Closure 
Upon completion of the study, study closeout activities must be conducted by the Sponsor or its 
designee in conjunction with the Investigator, as appropriate. 
In addition, the Sponsor reserves the right to temporarily suspend or prematurely discontinue this 
study at any time and for any reason.  If such action is taken, the Sponsor will discuss this with 
the Investigator (including the reason[s] for taking such action) at that time.  The Sponsor will 
also inform the regulatory authorities of the suspension or termination of the study and the 
reason(s) for the action.  If required by applicable regulations, the Investigator must inform the 
IRB/IEC promptly and provide the reason(s) for the suspension or termination.  If the study is 
prematurely discontinued, all study data and study drug remaining on site must be returned to the 
Sponsor or its designee. 
10.7 Case Report Forms and Study Records 
The Investigator is responsible for the quality of the data recorded in the electronic Case Report 
Forms (eCRFs).  The data recorded should be a complete and accurate account of the subject’s 
record collected during the study.  Study data are not to be gathered directly onto the eCRF but 
must be gathered onto primary source documents at the clinical site. Completion of source 
documents will precede the completion of the eCRF.  Source documents may be electronic, hard 
copy, or a combination of both.  Source documents are defined as the results of original 
observations and activities of a clinical investigation. Source documents will include, but are not 
limited to, progress notes, electronic data, screening logs, and recorded data from automated 
instruments. All source documents pertaining to this study will be maintained by the 
investigators and made available for direct inspection by the authorized study personnel outlined 
in the ICF. The ePRO tablet will be considered the source document for individual ePRO 
elements such as study-specific scales when collected directly onto the tablet. 


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Data collection will be completed according to the guidelines provided by Sponsor or its 
designee.   
For all subjects who signed an informed consent, all required data are to be recorded using 
source documents and reported on the eCRF, except for study scales that are recorded directly on 
the ePRO tablet.  Site staff will receive training on the eCRF completion guidelines and 
requirements for source documentation. 
Completed eCRFs will be reviewed by the study monitor in line with eCRF completion 
guidelines for the study to ensure completeness and consistency.  The study monitor will review 
every subject’s eCRF with source data verification for at least all critical data points.  The source 
data verification plan for this study will define the level of source data verification required for 
non-critical data points.  Screen failure data and source documents require only source data 
verification for critical data points such as informed consent, demographics, AEs, reason for 
termination, i.e., inclusion/exclusion.  Any discrepancies found during the eCRF review will be 
clarified by the Investigator or designated individual.  This includes eCRF reviews at the site by 
Sponsor or its designee, or during quality assurance review of the data.   
An explanation must be documented for any missing data.  Any changes to information in the 
study progress notes and other source documents will be initialled and dated on the day the 
change is made by a site staff member authorized to make the change.  Changes will be made by 
striking a single line through erroneous data (so as not to obliterate the original data), and clearly 
entering the correct data (e.g., wrong data right data).  If the reason for the change is not 
apparent, a brief explanation for the change will be written in the source documentation by the 
clinician. 
The Investigator must sign and date a declaration attesting to his/her responsibility for the quality 
of all data recorded, and that the data represents a complete and accurate record of each subject’s 
participation in the study.   
All eCRF entries, corrections, and alterations must be made by the Investigator or designated 
individual.  The Investigator or designated individual must adjust the eCRF (if applicable) and 
complete the query. 
10.8 Data Monitoring Committee 
Not applicable; there will be no data monitoring committee for this study. 
10.9 Protocol Deviations 
This study is intended to be conducted as described in this protocol.  At the outset of the study, a 
process for defining and handling protocol deviations will be established.  This will include 
determining which violations will be designated “key” and require immediate notification to the 
Sponsor.  In the event of a deviation from the protocol due to an emergency, accident, or 
mistake, the Investigator or designated individual must contact the Sponsor at the earliest 
possible time by telephone.  This will allow an early joint decision regarding the subject’s 
continuation in the study.  This decision will be documented by the Investigator and the Sponsor, 


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and reviewed by the monitor.  Deviations from the protocol are to be documented.  The 
Investigator or designated individual will be responsible for identifying and reporting all 
deviations, which are defined as isolated occurrences involving a procedure that did not follow 
the study protocol or study-specific procedure.  Deviations will be reported as required to the 
IRB and in the final study report. 
10.10 Access to Source Documentation 
The Investigator must agree to complete a subject identification and enrolment log to permit easy 
identification of each subject during and after the study.  This document will be reviewed by the 
Sponsor site contact for completeness.  The subject identification and enrollment log will be 
treated as confidential and will be filed by the Investigator in the study center file.  To ensure 
subject confidentiality, no copy will be made.  All reports and communications relating to the 
study will identify subjects by initials and assigned number only.  The Investigator must also 
complete a subject-screening log, which reports on all subjects who were seen to determine 
eligibility for inclusion in the study. 
At a minimum, source documentation must be available for the following to confirm data 
collected in the eCRF: subject identification, eligibility, and study identification; study 
discussion and date of informed consent; dates of visits; results of safety and efficacy parameters 
as required by the protocol; record of all AEs; concomitant medications; study drug 
administered; date of study completion or early discontinuation, and reason for early 
discontinuation if applicable. 
10.11 Data Generation and Analysis 
10.11.1 Data Collection and Data Management 
Study specific data that has been outlined in the protocol will be entered into the clinical 
database by individual(s) designated by the Investigator in accordance with the CRF Completion 
Guidelines.  Data is verified electronically using a series of on-line programmed edit checks that 
have been created by the CDM (Clinical Data Manager) and programmed by the Clinical Data 
Programmer or Designee.  Data discrepancies will be brought to the attention of the clinical team 
and investigated by the CRA and Site Study Coordinator.  CRAs will review and verify all data 
collected in the eCRF against source documentation during scheduled monitoring visits.  The 
CRA will work closely with the Site Study Coordinator to address any discrepancies which have 
been found so that proper resolutions can be made and documented into the clinical database.  
An audit trail within the system will track all changes made to the data. 
10.11.2 Database Quality Assurance  
The clinical database will be reviewed and checked for omissions, apparent errors, and values 
requiring further clarification using computerized and manual procedures.  Data queries 
requiring clarification will be generated and addressed by the investigational site.  Only 
authorized personnel will make corrections to the clinical database, and all corrections will be 
documented in an audit trail.   


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10.12 Retention of Data 
All documents pertaining to the study, including all versions of the approved study protocol, 
copy of the informed consent document and Health Insurance Portability and Accountability Act 
documents, completed eCRFs, source documents (subject records, subject diaries, hospital 
records, laboratory records, drug accountability records, etc.), and other study-related documents 
will be retained in the permanent archives of the study site. 
The Investigator must therefore notify and obtain approval in writing from the Sponsor prior to 
destruction of any study records or provide an opportunity for the Sponsor to collect such 
records.  If the investigator withdraws from the study (e.g., relocation, retirement) all study-
related records should be transferred, in a written agreement with the Sponsor, to a mutually 
agreed upon designee within a Sponsor-specified timeframe. 
10.13 Financial Disclosure 
RBP requires, for each study, the disclosure of any financial interests from each investigator or 
sub-investigator, including financial interests of the spouse and each dependent child of the 
investigator who is directly involved in the treatment or evaluation of research subjects that 
could affect the reliability of data submitted to regulatory authorities. The collection of this 
financial interest information at the start of the study, as well as any updates should this 
information change, is required by the FDA when submitting a marketing application and is in 
line with the GCP requirement to consider any potential conflicts of interest. 
10.14 Publication and Disclosure Policy 
A clinical study report will be prepared following completion of the study.  The report will be a 
record of the total study conduct and will be subject to Sponsor approval and restrictions on 
distribution/disclosure.   
The study data will be owned by Sponsor.  Publication of any and all data will be at the 
discretion of Sponsor.  The Investigator will not disseminate, present, or publish any of the study 
data without the prior written approval of Sponsor to do so. 


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followback reports of psychoactive substance use by drug abusing patients: psychometric 
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Herdman M ,Gudex C , Lloyd A, et al (2011).  Development and preliminary testing of the new 
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ICH guidance: E9 Statistical Principles for Clinical Trials.  
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clinical-trials.html.  Accessed 14 April 2015. 
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McCauley JL, Mercer MA, Barth KS, Brady KT, Back SE (2014). Pain management perceptions 
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Nasser AF, Heidbreder C, Gomeni R, et al (2014).  A population pharmacokinetic and 
pharmacodynamic modelling approach to support the clinical development of RBP-6000, a new, 
subcutaneously injectable, long-acting, sustained-release formulation of buprenorphine, for the 
treatment of opioid dependence. Clin Pharmacokinet. DOI 10.1007/s40262-014-0155-0 
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by visual analog scales. Drug and Alcohol Dependence. 40: 235-239. 


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National Institute on Drug Abuse (NIDA).  Principles of Drug Addiction Treatment: A Research-
Based Guide. NIH Publication No. 00-4180. Rockville, MD: NIDA, 1999, reprinted 2000. 
Nielsen, S, Taylor, DA (2005).  The effect of buprenorphine and benzodiazepines on respiration 
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Posner K, Brown GK, Stanley B, et al (2011).  The Columbia-suicide severity rating scale: initial 
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Reckitt Benckiser Pharmaceuticals RBP-6000 Investigator's Brochure, Edition 4. 24 February 
2014. 
Rosenblum A, Joseph H, Fong C, Kipnis S, Cleland C, Portenoy RK (2003).  Prevalence and 
characteristics of chronic pain among chemically dependent patients in methadone maintenance 
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SUBOXONE® (buprenorphine and naloxone) sublingual film Prescribing Information. Reckitt 
Benckiser Pharmaceuticals Inc. April 2014. 
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Studies. Mortality Data From the Drug Abuse Warning Network, 2001. DAWN Series D-23, 
DHHS Pub. No. (SMA) 03-3781. Rockville, MD, 2002. 
Thomas J. Drug injectors sharing cookers and cotton increase their risk of hepatitis C (2001). 
NIDA Notes 16(3):9–11. 
Tompkins D, Bigelow G, Harrison J, Johnson R, Fudala P, Strain E (2009).  Concurrent 
validation of the Clinical Opiate Withdrawal Scale (COWS) and single-item indices against the 
Clinical Institute Narcotic Assessment (CINA) opioid withdrawal instrument.  Drug Alcohol 
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Vernon MK, Revicki DA, Awad AG, et al (2010).  Psychometric evaluation of the Medication 
Satisfaction Questionnaire (MSQ) to assess satisfaction with antipsychotic medication among 
schizophrenia patients. Schizophr Res. 118(1-3):271-278.  
Walsh SL, Preston KL, Stitzer ML, Cone EJ, Bigelow GE (1994).  Clinical pharmacology of 
buprenorphine: ceiling effects at high doses. Clin Pharmacol Ther. 55:569–580. 
Ware JE, Jr, Kosinski M, Bjorner JB, Turner-Bowker, DM, Gandek, B. and Maruish, ME 
(2007).  User's Manual for the SF-36v2TM Health Survey (2nd Ed). Lincoln, RI, QualityMetric 
Incorporated. 
White AG, Birnbaum HG, Mareva MN, et al (2005).  Direct costs of opioid abuse in an insured 
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Umbricht A, Heustis M, Cone EJ, Preston KL (2004).  Effects of High-Dose Intravenous 
Buprenorphine in Experienced Opioid Abusers.  J Clin Psychopharmacol. 24(5):479-487. 
 


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Appendix 1 
Schedule of Events – Screening and SUBOXONE Film Induction 
Evaluation 
Screening 
Visit  
(Up to 3 days after 
EOS Visit/Day169 
of RB-US-13-
0001for roll-over 
subjects) 15 
SUBOXONE sublingual film 
Run-In 
Induction  
(3 days) 
Dose Adjustment  
(1 to 11 days) 
Days  
-21 to -15 
Day  
-14  
Day  
-13 
Day 
-12 
Day 
-11 
Day 
-8 
Day 
-4 
Day 
-1 
 
 
 
 
+1 day 
±1 day 
-1 day 
Informed Consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria Reviewed 
X 
 
 
 
 
 
 
 
IWRS 
X 
X 
X 
X 
X 
X 
X 
X 
Demographics 1 
X 
 
 
 
 
 
 
 
Medical History 1 
X 
 
 
 
 
 
 
 
eC-SSRS (Baseline Version) 
X 13 
 
 
 
 
 
 
 
Physical Examination 2 
X 13 
 
 
 
 
 
 
 
Vital Signs 3 
X 13 
X 
X 
X 
X 
X 
X 
X 
Body Weight 
X 13 
 
 
 
 
 
 
 
BMI Calculation 
X 13 
 
 
 
 
 
 
 
Hip-to-Waist Ratio 
X 13 
 
 
 
 
 
 
 
12-lead ECG (supine > 10 min) 4 
X 13 
 
 
 
 
 
 
 
Urine Drug Screen (UDS) 
X 13 
 
 
 
 
 
 
 
Urine Pregnancy Test 5 
 
X 
 
 
 
 
 
 
Screening Labs / Hormone Panel 
X 13 
 
 
 
 
 
 
 
Urinalysis/ Hematology/Serum Chemistry 
X 13 
 
 
 
 
 
 
 
Opioid Craving VAS 6 
X 13 
 
 
 
X 
X 
X 
X 
Clinical Opiate Withdrawal Scale (COWS) 6 
X 13 
X 
X 
X 
X 
X 
X 
X 
Subjective Opiate Withdrawal Scale (SOWS) 6 
X 13 
X 
X 
X 
X 
X 
X 
X 


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Evaluation 
Screening 
Visit  
(Up to 3 days after 
EOS Visit/Day169 
of RB-US-13-
0001for roll-over 
subjects) 15 
SUBOXONE sublingual film 
Run-In 
Induction  
(3 days) 
Dose Adjustment  
(1 to 11 days) 
Days  
-21 to -15 
Day  
-14  
Day  
-13 
Day 
-12 
Day 
-11 
Day 
-8 
Day 
-4 
Day 
-1 
 
 
 
 
+1 day 
±1 day 
-1 day 
BDI-II 
X 13,14 
 
 
 
 
 
 
 
BPI 
X 13, 14 
 
 
 
 
 
 
 
TLFB Interview 
X 13 
 
 
 
 
 
 
 
Concomitant Medications 
X 7, 13 
X 
X 
X 
X 
X 
X 
X 
AE Assessment 8 
X 13 
X 
X 
X 
X 
X 
X 
X 
Day -1 Criteria Reviewed 
 
 
 
 
X 9 
X 9 
X 9 
X 10 
SUBOXONE SL film administration 11 
 
X 
X 
X 
X 12 
X 12 
X 12 
X 12 
EQ-5D-5L 
X 13 
 
 
 
 
 
 
 
SF-36v2 
X 13 
 
 
 
 
 
 
 
Health Insurance 
X 13 
 
 
 
 
 
 
 
HCRU 
X 13 
 
 
 
 
 
 
 
TEA 
X 
 
 
 
 
 
 
 
AE = adverse event; BDI-II = Beck Depression Inventory II; BMI = body mass index; BPI = Brief Pain Inventory Short Form; COWS = Clinical Opiate 
Withdrawal Scale; eC-SSRS =  electronic Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; EQ-5D-5L =  EuroQol EQ-5D-5L;; 
HCRU = Healthcare resource utilization; IXRS=Interactive voice/web response system; MSQ =  Medication Satisfaction Questionnaire; SF-36v2 = 36-
Item Short Form Health Survey, Version 2; SL = sublingual; SOWS = subjective opiate withdrawal scale; TEA = Treatment Effectiveness Assessment; 
TLFB = Timeline Followback; VAS = Visual Analog Scale 
 
1. A complete medical and psychiatric history, including use of tobacco, drugs of abuse, alcohol and caffeine.  Update demographics and medical history, 
including use of tobacco, drugs of abuse, alcohol, and caffeine for roll-over subjects. 
2. Complete examination (excluding pelvic, breast, and rectal), including general appearance, skin, head, eyes, ears, nose, throat, neck, thyroid, 
chest/lungs, heart, abdomen, lymph nodes, extremities, and a brief neurological assessment.   


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3. Includes blood pressure (BP; supine ≥ 3 minutes), pulse oximetry, pulse rate, respiratory rate, oral temperature, and height (screening visit only).  Vital 
signs will be assessed within < 60 minutes before administration of SUBOXONE sublingual film. 
4. 
Must be performed prior to labs 
5. Only for female subjects who are of childbearing potential (not postmenopausal or surgically sterile for at least 1 year). 
6. Assessments should be performed prior to each SUBOXONE SL film dosing and at approximately the same time each day (±2 hours).   
7. Include a review of previous (within 30 days prior to screen) and ongoing medications. 
8. A PK sample will be taken as soon as possible after any SAE is reported.  If possible, an additional sample should be collected when the SAE has been 
resolved. 
9. This visit becomes Day -1 if the following criteria are met: 
• 
No allergic reaction to SUBOXONE sublingual film 
• 
Daily dose of SUBOXONE sublingual film between 8 mg/2 mg - 24 mg/6 mg (inclusive) buprenorphine/naloxone. 
• 
COWS score of ≤ 12 
• 
Opioid Craving VAS score of ≤ 20 mm 
If Day -1 criteria are met, the subject will be scheduled the following day (Injection Visit 1/Day 1) to receive the first injection of RBP-6000 after 
enrollment criteria are met.  
10. If Day -1 criteria are not met after 14 days of SUBOXONE sublingual film treatment, and a subject still has significant withdrawal signs/symptoms and 
opioid cravings (COWS score >12 and Opioid Craving VAS >20 mm), they will not be eligible to continue in the study.  They will be provided with 
information on the options for opioid use disorder treatment. 
11. SUBOXONE SL film dosing should take place at the same time of day (± 2 hours).   
12. Subjects should not take their dose of SUBOXONE SL film until after it has been determined if they have met Day -1 criteria (footnote #10). 
13. RB-US-13-0001 roll-over subjects study procedures completed at EOS/Day 169 will serve as the screening assessments for Protocol RB-US-13-0003 
14. Roll-over subjects who did not complete the BDI-II and the BPI at EOS/Day 169 visit will complete these assessments at Screening for Protocol RB-
US-13-0003 only after consent for the RB-US-13-0003 is obtained. 
15. For roll-over subjects only and at the Investigator’s discretion: Induction can begin on the day of screening for subjects who meet study criteria. 
 


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Appendix 2 
Schedule of Events – RBP-6000 Injection 1 – 3 Visits 
Evaluation 
Inj 1 
Post Inj 1 Assessments 
 
Inj 2 
Post 
Inj 2 
24hrs 
Post 
Inj 2 
Inj 3 
Post 
Inj 3 
24hrs 
Post 
Inj 3 
Wk1 
D 
1 
Wk1 
D 
2 
Wk2 
D 
8 
Wk3 
D 
15 
Wk4 
D 
22 
Wk5 
D 
29 
Wk5 
D 
30 
Wk7 
D 
43 
Wk9 
D 
57 
Wk9 
D 
58 
W11 
D 
71 
Window  
 
+1 
±2 
±2 
±2 
±2 
+1 
±2 
±2 
+1 
±2 
IWRS 
X 
 
 
 
 
X 
 
 
X 
 
 
Enrollment 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs 1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body Weight 
X 
 
 
 
 
 
 
 
 
 
 
BMI Calculation 
X 
 
 
 
 
 
 
 
 
 
 
Hip-to-Waist Ratio 
X 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 2 
(supine > 10 min) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology/ Serum 
Chemistry 3 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
Hormone Panel 3 
X 
 
 
 
 
 
 
 
 
 
 
Urinalysis 3 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
Urine Pregnancy Test 4 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
Urine Drug Screen 5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK Sampling (Roll-over 
patients only) 6  
X 
 
 
X 
 
X 
 
X 
X 
 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE Assessment 7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
eC-SSRS (Since last-visit-
version) 7 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
TLFB Interview 7 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
Opioid Craving VAS  7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
COWS 7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SOWS 7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BDI-II 7 
X 
 
 
 
 
X 
 
 
X 
 
 
BPI  7 
X 
 
 
 
 
X 
 
 
X 
 
 
RBP-6000 Injection 
X 
 
 
 
 
X 
 
 
X 
 
 


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Evaluation 
Inj 1 
Post Inj 1 Assessments 
 
Inj 2 
Post 
Inj 2 
24hrs 
Post 
Inj 2 
Inj 3 
Post 
Inj 3 
24hrs 
Post 
Inj 3 
Wk1 
D 
1 
Wk1 
D 
2 
Wk2 
D 
8 
Wk3 
D 
15 
Wk4 
D 
22 
Wk5 
D 
29 
Wk5 
D 
30 
Wk7 
D 
43 
Wk9 
D 
57 
Wk9 
D 
58 
W11 
D 
71 
Window  
 
+1 
±2 
±2 
±2 
±2 
+1 
±2 
±2 
+1 
±2 
Injection Site Grading Scale 8 
X 
X 
 
 
 
X 
X 
 
X 
X 
 
Injection Site Pain VAS 9 
X 
 
 
 
 
X 
 
 
X 
 
 
Injection Site Evaluation 10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Behavioral Therapy 11 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
EQ-5D-5L 7 
X 
 
 
 
 
 
 
 
X 
 
 
SF-36v2 7 
X 
 
 
 
 
 
 
 
X 
 
 
MSQ 7 
 
 
 
 
 
 
 
 
X 
 
 
Health Insurance  
X 
 
 
 
 
X 
 
 
X 
 
 
HCRU  
X 
 
 
 
 
X 
 
 
X 
 
 
TEA 
X 
 
 
 
 
X 
 
 
X 
 
 
ASI Lite 
X 
 
 
 
 
 
 
 
X12 
 
 
AE = adverse event; ASI = Addiction Severity Index; BDI-II = Beck Depression Inventory II; BMI = body mass index; BPI = Brief Pain Inventory Short Form; 
COWS = Clinical Opiate Withdrawal Scale; eC-SSRS = electronic Columbia Suicide Severity Rating Scale; D = Day; ECG = electrocardiogram; EQ-5D-5L =  
EuroQol EQ-5D-5L; HCRU = Healthcare resource utilization; Inj. = injection; IXRS=Interactive voice/web response system; MSQ =  Medication Satisfaction 
Questionnaire; PK = pharmacokinetic/pharmacokinetics; SF-36v2 = 36-Item Short Form Health Survey, Version 2; SC = subcutaneous; SOWS = subjective 
opiate withdrawal scale; TEA = Treatment Effectiveness Assessment; TLFB = Timeline Followback; VAS = Visual Analog Scale 
 
1. Includes blood pressure, pulse oximetry, pulse rate, respiratory rate, and oral temperature which must be taken after subject is supine ≥ 3 minutes. On 
injection day 1, vital signs will be taken ≤ 60 minutes prior to SC injection, and then 0.5, and 2 hours post SC injection (± 15 minutes). For all 
subsequent injection days, vital signs will be taken ≤ 60 minutes prior to SC injection, and 1 hour post SC injection (± 15 minutes). For non-injection 
days, vital signs will be taken at approximately the same time of day as the Day 1 pre-injection vital signs. 
2. On Injection day 1, an ECG will be performed ≤ 60 minutes prior to SC injection, and then 0.5, and 2 hours post SC injection (± 30 minutes). For all 
subsequent injection days, an ECG will be recorded ≤ 60 minutes prior to SC injection, and 1 hour post SC injection (± 30 minutes). For non-injection 
days, an ECG will be performed at approximately the same time of day as the Day 1 pre-injection ECG. All ECGs must be performed prior to laboratory 
assessments. 
3. On injection days blood and urine samples will be taken ≤ 60 minutes prior to SC injection and after the ECG has been performed. 
4. Only for female subjects who are of childbearing potential (not postmenopausal or surgically sterile for at least 1 year). 
5. An additional urine drug screen can be done if use is suspected.  Oxycodone may not show up in all opiate assays and should be assessed separately. 


RBP-6000 
 
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Clinical Study Protocol: RB-US-13-0003 
 
11 September 2015 
 
 
Confidential 
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6. A PK sample will be taken as soon as possible after any SAE is reported regardless if the patient is de novo or roll-over.  If possible, an additional 
sample should be collected when the SAE has been resolved. Only roll-over patients will receive the regularly scheduled PK assessments detailed in this 
table. 
7. Assessments should be performed prior to RBP-6000 injection and at approximately the same time each day ±2 hours. 
8. Local injection site grading will be performed at time of SC injection (within 10 minutes), 1 hour (± 15 minutes), and 24 hours (±4 hours) post SC 
injection. 
9. Injection Site Pain VAS will be completed by the subject within 1 minute after the completion of the injection and then at 5, 10, 15, 30, and 60 minutes 
(± 5 minutes) post-completion of injection. 
10. Injection site will be evaluated for evidence of attempted removal.   
11. Additional unscheduled visits for behavioral therapy may be added at the Investigator’s discretion.  
12. Collect information for the Employment/Support Status, Alcohol, Drug, Legal, Family/Social, and Psychological section only. Follow-up version of the 
questionnaire (only circled items, no lifetime recall). 
 
 


RBP-6000 
 
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Clinical Study Protocol: RB-US-13-0003 
 
11 September 2015 
 
 
Confidential 
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Appendix 3 
Schedule of Events – RBP-6000 Injection 4 – 6 Visits for all Subjects and End of 
Study/Early Termination and Follow-Up Visits for Roll-over Subjects 
Evaluation 
Inj 4 
Post 
Inj 4 
24hrs 
Post 
Inj 4 
Inj 5 
Post 
Inj 5 
24hrs 
Post 
Inj 5 
Inj 6 
Post 
Inj 6 
24hrs 
EOS/ET/ 
Safety Follow-Up 
Wk13 
D 
85 
Wk13 
D 
86 
W15 
D 
99 
Wk17 
D 
113 
Wk17 
D 
114 
Wk19 
D 
127 
Wk21 
D 
141 
Wk21 
D 
142 
Wk25 
D 
16913 
Wk29 
D 
197 
Window  
±2 
+1 
±2 
±2 
+1 
±2 
±2 
+1 
±2 
±2 
IWRS 
X 
 
 
X 
 
 
X 
 
X14 
X 
Vital Signs 1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body Weight 
X 
 
 
 
 
 
X 
 
X 
 
BMI Calculation 
X 
 
 
 
 
 
X 
 
X 
 
Hip-to-Waist Ratio 
X 
 
 
 
 
 
X 
 
X 
 
12-lead ECG (supine > 10 min) 2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology/ Serum Chemistry 3 
X 
 
X 
X 
 
X 
X 
 
X 
X 
Hormone Panel 3 
X 
 
 
 
 
 
X 
 
X 
 
Urinalysis 3 
X 
 
X 
X 
 
X 
X 
 
X 
X 
Urine Pregnancy  
Test 3 
X 
 
X 
X 
 
X 
X 
 
X 
 
Serum Pregnancy Test 4 
 
 
 
 
 
 
 
 
 
X 
Urine Drug Screen 5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PK Sampling (Roll-over patients only) 6 
X 
 
X 
X 
 
X 
X 
 
X 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE Assessment 8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
eC-SSRS (Since last-visit-version) 8 
X 
 
X 
X 
 
X 
X 
 
X 
 
TLFB Interview 8 
X 
 
X 
X 
 
X 
X 
 
X 
 
Opioid Craving VAS  8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
COWS  8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
SOWS  8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


RBP-6000 
 
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Clinical Study Protocol: RB-US-13-0003 
 
11 September 2015 
 
 
Confidential 
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Evaluation 
Inj 4 
Post 
Inj 4 
24hrs 
Post 
Inj 4 
Inj 5 
Post 
Inj 5 
24hrs 
Post 
Inj 5 
Inj 6 
Post 
Inj 6 
24hrs 
EOS/ET/ 
Safety Follow-Up 
Wk13 
D 
85 
Wk13 
D 
86 
W15 
D 
99 
Wk17 
D 
113 
Wk17 
D 
114 
Wk19 
D 
127 
Wk21 
D 
141 
Wk21 
D 
142 
Wk25 
D 
16913 
Wk29 
D 
197 
Window  
±2 
+1 
±2 
±2 
+1 
±2 
±2 
+1 
±2 
±2 
BDI-II 8 
X 
 
 
X 
 
 
X 
 
X 
 
BPI 8 
X 
 
 
X 
 
 
X 
 
X 
 
RBP-6000 Injection 
X 
 
 
X 
 
 
X 
 
 
 
Injection Site  
Grading Scale 9 
X 
X 
 
X 
X 
 
X 
X 
 
 
Injection Site Pain VAS 10 
X 
 
 
X 
 
 
X 
 
 
 
Injection Site Evaluation 11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Behavioral Therapy 12 
X 
 
X 
X 
 
X 
X 
 
X 
 
EQ-5D-5L 8 
 
 
 
 
 
 
X 
 
X 
 
SF-36v2 8 
 
 
 
 
 
 
X 
 
X 
 
MSQ 8 
 
 
 
 
 
 
X 
 
X 
 
Health Insurance 8 
X 
 
 
X 
 
 
X 
 
X 
 
HCRU  8 
X 
 
 
X 
 
 
X 
 
X 
 
TEA 8 
X 
 
 
X 
 
 
X 
 
X 
 
ASI Lite 
 
 
 
 
 
 
X17 
 
X18 
 


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Clinical Study Protocol: RB-US-13-0003 
 
11 September 2015 
 
 
Confidential 
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Evaluation 
Inj 4 
Post 
Inj 4 
24hrs 
Post 
Inj 4 
Inj 5 
Post 
Inj 5 
24hrs 
Post 
Inj 5 
Inj 6 
Post 
Inj 6 
24hrs 
EOS/ET/ 
Safety Follow-Up 
Wk13 
D 
85 
Wk13 
D 
86 
W15 
D 
99 
Wk17 
D 
113 
Wk17 
D 
114 
Wk19 
D 
127 
Wk21 
D 
141 
Wk21 
D 
142 
Wk25 
D 
16913 
Wk29 
D 
197 
Window  
±2 
+1 
±2 
±2 
+1 
±2 
±2 
+1 
±2 
±2 
Physical Examination 15 
 
 
 
 
 
 
 
 
X 
 
Review of Treatment Options 
 
 
 
 
 
 
 
 
X 
X 
SUBOXONE SL film administration 16 
 
 
 
 
 
 
 
 
X 
 
EOS 
 
 
 
 
 
 
 
 
 
X 
AE = adverse event; ASI = Addiction Severity Index; BDI-II = Beck Depression Inventory II; BMI = body mass index; BPI = Brief Pain Inventory Short Form; 
COWS = Clinical Opiate Withdrawal Scale; eC-SSRS = electronic Columbia Suicide Severity Rating Scale; D = Day; ECG = electrocardiogram; EOS/ET = End 
of Study/Early Termination;EQ-5D-5L =  EuroQol EQ-5D-5L; HCRU = Healthcare resource utilization; Inj. = injection; IXRS=Interactive voice/web response 
system; MSQ =  Medication Satisfaction Questionnaire; PK = pharmacokinetic/pharmacokinetics; SF-36v2 = 36-Item Short Form Health Survey, Version 2; SC 
= subcutaneous; SL = sublingual; SOWS = subjective opiate withdrawal scale; TEA = Treatment Effectiveness Assessment; TLFB = Timeline Followback; 
VAS = Visual Analog Scale. 
1. Includes blood pressure, pulse oximetry, pulse rate, respiratory rate, and oral temperature which must be taken after subject is supine ≥ 3 minutes. On 
days injections 2-12 are given, vital signs will be taken ≤ 60 minutes prior to SC injection, and 1 hour post SC injection (± 15 minutes). For non-
injection days, vital signs will be taken at approximately the same time of day as the Day 1 pre-injection vital signs. 
2. On days injections 2-12 are given, an ECG will be performed ≤ 60 minutes prior to SC injection, and 1 hour post SC injection (± 30 minutes). For non-
injection days, an ECG will be performed at approximately the same time of day as the Day 1 pre-injection ECG. All ECGs must be performed prior to 
labs and PK samples. 
3. On injection days, blood and urine samples will be taken ≤ 60 minutes prior to SC injection and after the ECGs has been performed. 
4. Only for female subjects who are of childbearing potential (not postmenopausal or surgically sterile for at least 1 year). 
5. An additional urine drug screen can be done if use is suspected.  Oxycodone may not show up in all opiate assays and should be assessed separately. 
6. PK samples taken for roll-over subjects only. See PK table (Appendix 6) for exact time points  
7. A PK sample will be taken as soon as possible after any SAE is reported.  If possible, an additional sample should be collected when the SAE has been 
resolved. 
8. Assessments should be performed prior to RBP-6000 injection and at approximately the same time each day ±2 hours. 
9. Local injection site grading will be performed at time of SC injection (within 10 minutes), 1 hour (± 15 minutes), and 24 hours (±4 hours) post SC 
injection.  
10. Injection Site Pain VAS will be completed by the subject within 1 minute after completion of the injection and then at  5, 10, 15, 30, and 60 (± 5 
minutes) post-completion of injection. 
11. Injection site will be evaluated for evidence of attempted removal.   
12. Additional unscheduled visits for behavioral therapy may be added at the Investigator's discretion. 
13. For roll-over subjects, the procedures at Week 25/Day 169 will serve as the EOS assessments.  For de novo subjects who discontinued participation in 
the study after receiving RBP-6000, the procedures at Week 25/Day 169 will serve as the ET assessments. 


RBP-6000 
 
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Clinical Study Protocol: RB-US-13-0003 
 
11 September 2015 
 
 
Confidential 
Page 89 of 167 
14. IXRS contacted to confirm study completion or discontinuation status (date and reason for discontinuation). 
15. Complete examination (excluding pelvic, breast, and rectal), including general appearance, skin, head, eyes, ears, nose, throat, neck, thyroid, 
chest/lungs, heart, abdomen, lymph nodes, extremities, and a brief neurological assessment.   
16. Return to the same dose that was used on Day -1. 
17. Collect information for the Employment/Support Status, Alcohol, Drug, Legal, Family/Social, and Psychological section only. Follow-up version of the 
questionnaire (only circled items, no lifetime recall). 
18. Complete all ASI-Lite scales. Follow-up version of the questionnaire (only circled items, no lifetime recall). 
 
 
 


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Clinical Study Protocol: RB-US-13-0003 
 
11 September 2015 
 
 
Confidential 
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Appendix 4 
Schedule of Events – RBP-6000 Injection 7 – 9 Visits for de novo Subjects  
Evaluation 
Inj 7 
Post Inj 7 
24hrs 
Inj 8 
Post Inj 8 
24hrs 
Inj 9 
Post Inj 9 
24hrs 
Wk25 
D169 
Wk25 
D170 
Wk29 
D197 
Wk29 
D198 
Wk33 
D225 
Wk33 
D226 
Window  
±2 
+1 
±2 
+1 
±2 
+1 
IWRS 
X 
 
X 
 
X 
 
Vital Signs 1 
X 
X 
X 
X 
X 
X 
Body Weight 
X 
 
 
 
 
 
BMI Calculation 
X 
 
 
 
 
 
Hip-to-Waist Ratio 
X 
 
 
 
 
 
12-lead ECG 2 
(supine > 10 min)  
X 
X 
X 
X 
X 
X 
Hematology/ Serum Chemistry 3 
X 
 
X 
 
X 
 
Hormone Panel 3 
X 
 
 
 
 
 
Urinalysis  3 
X 
 
X 
 
X 
 
Urine Pregnancy Test  4 
X 
 
X 
 
X 
 
Urine Drug Screen 5 
X 
X 
X 
X 
X 
X 
Concomitant Medications  
X 
X 
X 
X 
X 
X 
AE Assessment 6 
X 
X 
X 
X 
X 
X 
eC-SSRS (Since last-visit-version) 7 
X 
 
X 
 
X 
 
TLFB Interview 7 
X 
 
X 
 
X 
 
Opioid Craving  
VAS 7 
X 
X 
X 
X 
X 
X 
COWS 7 
X 
X 
X 
X 
X 
X 
SOWS 7 
X 
X 
X 
X 
X 
X 
BDI-II 7 
X 
 
X 
 
X 
 
BPI 7 
X 
 
X 
 
X 
 
RBP-6000 Injection 
X 
 
X 
 
X 
 


RBP-6000 
 
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Clinical Study Protocol: RB-US-13-0003 
 
11 September 2015 
 
 
Confidential 
Page 91 of 167 
Evaluation 
Inj 7 
Post Inj 7 
24hrs 
Inj 8 
Post Inj 8 
24hrs 
Inj 9 
Post Inj 9 
24hrs 
Wk25 
D169 
Wk25 
D170 
Wk29 
D197 
Wk29 
D198 
Wk33 
D225 
Wk33 
D226 
Window  
±2 
+1 
±2 
+1 
±2 
+1 
Injection Site Grading Scale 8 
X 
X 
X 
X 
X 
X 
Injection Site Pain VAS 9 
X 
 
X 
 
X 
 
Injection Site Evaluation 10 
X 
X 
X 
X 
X 
X 
Behavioral Therapy 11 
X 
 
X 
 
X 
 
EQ-5D-5L 7 
 
 
 
 
X 
 
SF-36v2 7 
 
 
 
 
X 
 
MSQ 7 
 
 
 
 
X 
 
Health Insurance 7 
X 
 
X 
 
X 
 
HCRU  7 
X 
 
X 
 
X 
 
TEA 7 
X 
 
X 
 
X 
 
ASI Lite 
 
 
 
 
X12 
 
 
AE = adverse event; ASI = Addiction Severity Index; BDI-II = Beck Depression Inventory II; BMI = body mass index; BPI = Brief Pain Inventory Short 
Form; COWS = Clinical Opiate Withdrawal Scale; eC-SSRS = electronic Columbia Suicide Severity Rating Scale; D = Day; ECG = electrocardiogram; EQ-
5D-5L =  EuroQol EQ-5D-5L; HCRU = Healthcare resource utilization; Inj. = injection; IXRS=Interactive voice/web response system; MSQ =  Medication 
Satisfaction Questionnaire; PK = pharmacokinetic/pharmacokinetics; SF-36v2 = 36-Item Short Form Health Survey, Version 2; SC = subcutaneous; SOWS 
= subjective opiate withdrawal scale; TEA = Treatment Effectiveness Assessment; TLFB = Timeline Followback; VAS = Visual Analog Scale 
 
1. Includes blood pressure, pulse oximetry, pulse rate, respiratory rate, and oral temperature which must be taken after subject is supine ≥ 3 minutes. On 
days injections 2-12 are given, vital signs will be taken ≤ 60 minutes prior to SC injection, and 1 hour post SC injection (± 15 minutes). For non-
injection days, vital signs will be taken at approximately the same time of day as the Day 1 pre-injection vital signs. 
2. On days injections 2-12 are given, an ECG will be recorded ≤ 60 minutes prior to SC injection, and 1 hour post SC injection (± 30 minutes). For non-
injection days, an ECG will be performed at approximately the same time of day as the Day 1 pre-injection ECG. All ECGs must be performed prior to 
labs and PK samples. 
3. On injection days, blood and urine samples will be taken ≤ 60 minutes prior to SC injection and after the ECGs has been performed. 
4. Only for female subjects who are of childbearing potential (not postmenopausal or surgically sterile for at least 1 year). 
5. An additional urine drug screen can be done if use is suspected.  Oxycodone may not show up in all opiate assays and should be assessed separately. 
6. A PK sample will be taken as soon as possible after any SAE is reported.  If possible, an additional sample should be collected when the SAE has been 
resolved. 
7. Assessments should be performed prior to RBP-6000 injection and at approximately the same time each day ±2 hours. 


RBP-6000 
 
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Clinical Study Protocol: RB-US-13-0003 
 
11 September 2015 
 
 
Confidential 
Page 92 of 167 
8. Local injection site grading will be performed at time of SC injection (within 10 minutes), 1 hour (± 15 minutes), and 24 hours (±4 hours) post SC 
injection.  
9. Injection Site Pain VAS will be completed by the subject within 1 minute after the completion of the injection and then at 5, 10, 15, 30, and 60 minutes 
(± 5 minutes) post-completion of injection. 
10. Injection site will be evaluated for evidence of attempted removal.   
11. Additional unscheduled visits for behavioral therapy may be added at the Investigator’s discretion. 
12. Collect information for the Employment/Support Status, Alcohol, Drug, Legal, Family/Social, and Psychological section only. Follow-up version of the 
questionnaire (only circled items, no lifetime recall). 


RBP-6000 
 
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Clinical Study Protocol: RB-US-13-0003 
 
11 September 2015 
 
 
Confidential 
Page 93 of 167 
Appendix 5 
Schedule of Events – RBP-6000 Injection 10 – 12 Visits and End of Study/Early 
Termination Visit and Follow-Up for de novo Subjects  
Evaluation 
Inj 10 
Post Inj 
10 24hrs 
Inj 11 
Post Inj 
11 24hrs 
Inj 12 
Post Inj 
12 24hrs 
EOS/ET/ 
Safety Follow-Up 
Wk37 
D253 
Wk37 
D254 
Wk41 
D281 
Wk41 
D282 
Wk45 
D309 
Wk45 
D310 
Wk49 
D33712 
Wk53 
D365 
Window  
±2 
+1 
±2 
+1 
±2 
+1 
±2 
±2 
IWRS 
X 
 
X 
 
X 
 
X13 
X 
Vital Signs 1 
X 
X 
X 
X 
X 
X 
X 
X 
Body Weight 
X 
 
 
 
X 
 
X 
 
BMI Calculation 
X 
 
 
 
X 
 
X 
 
Hip-to-Waist Ratio 
X 
 
 
 
X 
 
X 
 
12-lead ECG (supine > 10 min) 2 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology/ Serum Chemistry 3  
X 
 
X 
 
X 
 
X 
X 
Hormone Panel 3 
X 
 
 
 
X 
 
X 
 
Urinalysis 3 
X 
 
X 
 
X 
 
X 
X 
Urine Pregnancy Test 4 
X 
 
X 
 
X 
 
X 
 
Serum Pregnancy Test 4 
 
 
 
 
 
 
 
X 
Urine Drug Screen 5 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
AE Assessment 6 
X 
X 
X 
X 
X 
X 
X 
X 
eC-SSRS (Since last-visit-version) 7 
X 
 
X 
 
X 
 
X 
 
TLFB Interview 7 
X 
 
X 
 
X 
 
X 
 
Opioid Craving VAS 7 
X 
X 
X 
X 
X 
X 
X 
 
COWS 7 
X 
X 
X 
X 
X 
X 
X 
 
SOWS 7 
X 
X 
X 
X 
X 
X 
X 
 
BDI-II 7 
X 
 
X 
 
X 
 
X 
 
BPI 7 
X 
 
X 
 
X 
 
X 
 


RBP-6000 
 
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Clinical Study Protocol: RB-US-13-0003 
 
11 September 2015 
 
 
Confidential 
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Evaluation 
Inj 10 
Post Inj 
10 24hrs 
Inj 11 
Post Inj 
11 24hrs 
Inj 12 
Post Inj 
12 24hrs 
EOS/ET/ 
Safety Follow-Up 
Wk37 
D253 
Wk37 
D254 
Wk41 
D281 
Wk41 
D282 
Wk45 
D309 
Wk45 
D310 
Wk49 
D33712 
Wk53 
D365 
Window  
±2 
+1 
±2 
+1 
±2 
+1 
±2 
±2 
RBP-6000 Injection 
X 
 
X 
 
X 
 
 
 
Injection Site Grading Scale 8 
X 
X 
X 
X 
X 
X 
 
 
Injection Site Pain VAS 9 
X 
 
X 
 
X 
 
 
 
Injection Site Evaluation 10 
X 
X 
X 
X 
X 
X 
X 
X 
Behavioral Therapy 11 
X 
 
X 
 
X 
 
X 
 
EQ-5D-5L 7 
 
 
 
 
X 
 
X 
 
SF-36v2  7 
 
 
 
 
X 
 
X 
 
MSQ 7 
 
 
 
 
X 
 
X 
 
Health Insurance 7 
X 
 
X 
 
X 
 
X 
 
HCRU  7 
X 
 
X 
 
X 
 
X 
 
TEA 7 
X 
 
X 
 
X 
 
X 
 
ASI Lite 
 
 
 
 
X16 
 
X17 
 
Physical Examination 14 
 
 
 
 
 
 
X 
 
Review of Treatment Options 
 
 
 
 
 
 
X 
X 
SUBOXONE SL film administration 15 
 
 
 
 
 
 
X 
 
EOS 
 
 
 
 
 
 
 
X 
 
AE = adverse event; ASI = Addiction Severity Index; BDI-II = Beck Depression Inventory II; BMI = body mass index; BPI = Brief Pain Inventory Short Form; 
COWS = Clinical Opiate Withdrawal Scale; eC-SSRS = electronic Columbia Suicide Severity Rating Scale; D = Day; ECG = electrocardiogram; EOS/ET = End 
of Study/Early Termination;EQ-5D-5L =  EuroQol EQ-5D-5L; HCRU = Healthcare resource utilization; Inj. = injection; IXRS=Interactive voice/web response 
system; MSQ =  Medication Satisfaction Questionnaire; PK = pharmacokinetic/pharmacokinetics; SF-36v2 = 36-Item Short Form Health Survey, Version 2; SC 
= subcutaneous; SL = sublingual; SOWS = subjective opiate withdrawal scale; TEA = Treatment Effectiveness Assessment; TLFB = Timeline Followback; 
VAS = Visual Analog Scale. 
 


RBP-6000 
 
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Clinical Study Protocol: RB-US-13-0003 
 
11 September 2015 
 
 
Confidential 
Page 95 of 167 
1. Includes blood pressure, pulse oximetry, pulse rate, respiratory rate, and oral temperature which must be taken after subject is supine ≥ 3 minutes. On days 
injections 2-12 are given, vital signs will be taken ≤ 60 minutes prior to SC injection, and 1 hour post SC injection (± 15 minutes). For non-injection days, 
vital signs will be taken at approximately the same time of day as the Day 1 pre-injection vital signs. 
2. On days injections 2-12 are given, an ECG will be recorded ≤ 60 minutes prior to SC injection, and 1 hour post SC injection (± 30 minutes). For non-
injection days, an ECG will be performed at approximately the same time of day as the Day 1 pre-injection ECG. All ECGs must be performed prior to labs 
and PK samples. 
3. On injection days, blood and urine samples will be taken ≤ 60 minutes prior to SC injection and after the ECGs has been performed. 
4. Only for female subjects who are of childbearing potential (not postmenopausal or surgically sterile for at least 1 year). 
5. An additional urine drug screen can be done if use is suspected.  Oxycodone may not show up in all opiate assays and should be assessed separately. 
6. A PK sample will be taken as soon as possible after any SAE is reported.  If possible, an additional sample should be collected when the SAE has been 
resolved. 
7. Assessments should be performed prior to RBP-6000 injection and at approximately the same time each day ±2 hours. 
8. Local injection site grading will be performed at time of SC injection (within 10 minutes), 1 hour (± 15 minutes), and 24 hours (±4 hours) post SC injection.  
9. Injection Site Pain VAS will be completed by the subject within 1 minute after the completion of the injection and then at  5, 10, 15, 30, and 60 minutes (± 5 
minutes) post-completion of injection. 
10. Injection site will be evaluated for evidence of attempted removal. 
11. Additional unscheduled visits for behavioral therapy may be added at the Investigator’s discretion. 
12. For de novo subjects who discontinue participation in this study after receiving RBP-6000, the procedures at Week 49/Day 337 will serve as the ET 
assessments. 
13. IXRS contacted to confirm study completion or discontinuation status (date and reason for discontinuation). 
14. Complete examination (excluding pelvic, breast, and rectal), including general appearance, skin, head, eyes, ears, nose, throat, neck, thyroid, chest/lungs, 
heart, abdomen, lymph nodes, extremities, and a brief neurological assessment.   
15. Return to the same dose that was used on Day -1. 
16. Collect information for the Employment/Support Status, Alcohol, Drug, Legal, Family/Social, and Psychological section only. Follow-up version of the 
questionnaire (only circled items, no lifetime recall). 
17. Complete all ASI-Lite scales. Follow-up version of the questionnaire (only circled items, no lifetime recall). 
 


RBP-6000 
                           Indivior Inc. 
Clinical Study Protocol: RB-US-13-0003 
 
11 September 2015 
 
Confidential 
Page 96 of 167 
 
 
Appendix 6 
Pharmacokinetic Sampling Schedule 
Sample 
Number1 
Sample 
Class 
Time 
Study Phase 
Comments 
1 
PK 
Day 1 
Treatment phase (SC) 
Within 1 hour prior to 1st SC injection  
2 
PK 
Day 15 
Treatment phase (SC) 
Post 1st SC injection 
3 
PK 
Day 29 
Treatment phase (SC) 
Within 1 hour prior to 2nd SC injection  
4 
PK 
Day 43 
Treatment phase (SC) 
Post 2nd SC injection 
5 
PK 
Day 57 
Treatment phase (SC) 
Within 1 hour prior to 3rd SC injection  
6 
PK 
Day 71 
Treatment phase (SC) 
Post 3rd SC injection 
7 
PK 
Day 85 
Treatment phase (SC) 
Within 1 hour prior to 4th SC injection  
8 
PK 
Day 99 
Treatment phase (SC) 
Post 4th SC injection 
9 
PK 
Day 113 
Treatment phase (SC) 
Within 1 hour prior to 5th SC injection 
10 
PK 
Day 127 
Treatment phase (SC) 
Post 5th SC injection 
11 
PK 
Day 141 
Treatment phase (SC) 
Within 1 hour prior to 6th SC injection 
12 
PK 
Day 169 or 
ET Visit 
Treatment phase (SC) 
Post 6th SC injection 
PK = pharmacokinetic/pharmacokinetics; SC = subcutaneous 
1   Blood samples for PK analysis will be collected from roll-over subjects only (not de novo).  
However, for all subjects (de novo and roll-over), a PK sample will be taken as soon as possible after any SAE is 
reported. If possible, an additional sample should be collected when the SAE has been resolved. 
 


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Appendix 7 
SUBOXONE® 
(Buprenorphine/Nalo
xone) Sublingual 
Film Full Prescribing 
Information 
HIGHLIGHTS OF PRESCRIBING INFORMATION 
These highlights do not include all the information needed to use 
SUBOXONE safely and effectively.  See full prescribing information for 
SUBOXONE. 
SUBOXONE® (buprenorphine and naloxone) sublingual film for sublingual 
administration CIII 
Initial U.S. Approval: 2002 
----------------------------------RECENT MAJOR CHANGES--------------------------------- 
Dosage and Administration, Induction (2.1)  
 
04/2014 
Dosage and Administration, Patients With  
     Hepatic Impairment (2.5) 
 
 
 
04/2014 
Warnings and Precautions, Use in Patients 
      With Impaired Hepatic Function (5.11) 
 
 
04/2014 
----------------------------------INDICATIONS AND USAGE--------------------------------- 
SUBOXONE sublingual film is a partial-opioid agonist indicated for treatment 
of opioid dependence.  Prescription use of this product is limited under the 
Drug Addiction Treatment Act. (1) 
------------------------------DOSAGE AND ADMINISTRATION----------------------------- 
• For patients dependent on short-acting opioid products who are in opioid 
withdrawal; on Day 1, administer up to 8 mg/ 2 mg SUBOXONE sublingual 
film (in divided doses).  On Day 2, administer up to 16 mg/4 mg of 
SUBOXONE sublingual film as a single dose. (2.1) 
• For patients dependent on methadone or long-acting opioid products, 
induction onto sublingual buprenorphine monotherapy is recommended 
on Days 1 and 2 of treatment. (2.1) 
• For maintenance treatment, the target dosage of SUBOXONE sublingual 
film is usually 16 mg/4 mg as a single daily dose. (2.2) 
• Place the SUBOXONE sublingual film under the tongue, close to the base 
on the left or right side and allow to completely dissolve.  Film should not 
be chewed, swallowed, or moved after placement. (2.3) 
-----------------------------DOSAGE FORMS AND STRENGTHS---------------------------- 
Sublingual film:  2 mg buprenorphine with 0.5 mg naloxone, 4 mg 
buprenorphine with 1 mg naloxone, 8 mg buprenorphine with 2 mg naloxone 
and 12 mg buprenorphine with 3 mg naloxone. (3)  
-------------------------------------CONTRAINDICATIONS------------------------------------ 
Hypersensitivity to buprenorphine or naloxone. (4) 
-------------------------------WARNINGS AND PRECAUTIONS----------------------------- 
• Buprenorphine can be abused in a similar manner to other opioids. 
Clinical monitoring appropriate to the patient’s level of stability is 
essential. Multiple refills should not be prescribed early in treatment or 
without appropriate patient follow-up visits. (5.1)  
• Significant respiratory depression and death have occurred in association 
with buprenorphine, particularly when taken by the intravenous (IV) 
route in combination with benzodiazepines or other CNS depressants 
(including alcohol). (5.2) 
• Consider dose reduction of CNS depressants, SUBOXONE sublingual film, 
or both in situations of concomitant prescription. (5.3) 
• Store SUBOXONE sublingual film safely out of the sight and reach of 
children. Buprenorphine can cause severe, possibly fatal, respiratory 
depression in children. (5.4)   
• Chronic administration produces opioid-type physical dependence.  
Abrupt discontinuation or rapid dose taper may result in opioid 
withdrawal syndrome. (5.5) 
• Monitor liver function tests prior to initiation and during treatment and 
evaluate suspected hepatic events. (5.6) 
• Do not administer SUBOXONE sublingual film to patients with known 
hypersensitivity to buprenorphine or naloxone. (5.7) 
• An opioid withdrawal syndrome is likely to occur with parenteral misuse 
of SUBOXONE sublingual film by individuals physically dependent on full 
opioid agonists or by sublingual administration before the agonist effects 
of other opioids have subsided. (5.8) 
• Neonatal withdrawal has been reported following use of buprenorphine 
by the mother during pregnancy. (5.9)  
• SUBOXONE sublingual film is not appropriate as an analgesic. There have 
been reported deaths of opioid naïve individuals who received a 2 mg 
sublingual dose. (5.10) 
• Buprenorphine/naloxone products are not recommended in patients 
with severe hepatic impairment and may not be appropriate for patients 
with moderate hepatic impairment (5.11) 
• Caution patients about the risk of driving or operating hazardous 
machinery. (5.12) 
-------------------------------------ADVERSE REACTIONS------------------------------------- 
Adverse events commonly observed with the sublingual administration of 
the SUBOXONE sublingual film were oral hypoesthesia, glossodynia, oral 
mucosal erythema, headache, nausea, vomiting, hyperhidrosis, constipation, 
signs and symptoms of withdrawal, insomnia, pain, and peripheral edema. 
(6.1)     
To report SUSPECTED ADVERSE REACTIONS, contact Reckitt Benckiser 
Pharmaceuticals Inc. at 1-877-782-6966 or FDA at 1-800-FDA-1088 or 
www.fda.gov/medwatch. 
--------------------------------------DRUG INTERACTIONS----------------------------------- 
• Monitor patients starting or ending CYP3A4 inhibitors or inducers for 
potential over or under dosing.  (7.1)  
• Use caution in prescribing SUBOXONE sublingual film for patients 
receiving benzodiazepines or other CNS depressants and warn patients 
against concomitant self-administration/misuse. (7.3) 
---------------------------------USE IN SPECIFIC POPULATIONS---------------------------- 
• 
Pregnancy: Based on animal data, may cause fetal harm. (8.1) 
• 
Nursing mothers: Caution should be exercised when administered to a 
nursing woman. (8.3) 
• 
Safety and effectiveness of SUBOXONE sublingual film in patients below 
the age of 16 has not been established. (8.4) 
• 
Administer SUBOXONE sublingual film with caution to elderly or 
debilitated patients. (8.5) 
• 
Buprenorphine/naloxone products are not recommended in patients 
with severe hepatic impairment and may not be appropriate for 
patients with moderate hepatic impairment.  (8.6) 
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. 
Revised:  April 2014


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FULL PRESCRIBING INFORMATION: CONTENTS* 
1 
INDICATIONS AND USAGE 
2 
DOSAGE AND ADMINISTRATION 
 
        2.1 
Induction 
 
        2.2 
Maintenance 
 
        2.3 
Method of Administration 
 
        2.4 
Clinical Supervision 
 
        2.5 
Patients With Hepatic Impairment 
 
        2.6 
Unstable Patients 
        2.7 
Stopping Treatment 
        2.8 
Switching Between Buprenorphine and 
Naloxone Sublingual Tablets and SUBOXONE 
Sublingual Film 
        2.9 
Switching Between SUBOXONE Sublingual Film 
Strengths 
3 
DOSAGE FORMS AND STRENGTHS 
4 
CONTRAINDICATIONS 
5 
WARNINGS AND PRECAUTIONS 
        5.1 
Abuse Potential 
        5.2 
Respiratory Depression  
        5.3 
CNS Depression  
        5.4 
Unintentional Pediatric Exposure 
        5.5 
Dependence 
        5.6 
Hepatitis, Hepatic Events 
        5.7 
Allergic Reactions  
        5.8 
Precipitation of Opioid Withdrawal Signs and 
Symptoms 
        5.9 
Neonatal Withdrawal 
        5.10 Use in Opioid Naïve Patients 
        5.11 Use in Patients With Impaired Hepatic Function 
        5.12 Impairment of Ability to Drive or Operate 
Machinery  
        5.13 Orthostatic Hypotension 
        5.14 Elevation of Cerebrospinal Fluid Pressure  
        5.15 Elevation of Intracholedochal Pressure 
        5.16 Effects in Acute Abdominal Conditions 
        5.17 General Precautions 
6 
ADVERSE REACTIONS 
        6.1 
Clinical Trials Experience 
        6.2 
Postmarketing Experience
 
7 
DRUG INTERACTIONS   
        7.1 
Cytochrome P-450 3A4 (CYP3A4) Inhibitors and 
Inducers 
 
        7.2 
Antiretrovirals 
 
        7.3 
Benzodiazepines 
8 
USE IN SPECIFIC POPULATIONS 
 
        8.1 
Pregnancy 
 
        8.3 
Nursing Mothers 
 
        8.4 
Pediatric Use 
 
        8.5 
Geriatric Use  
        8.6 
Hepatic Impairment 
        8.7  
Renal Impairment 
9 
DRUG ABUSE AND DEPENDENCE 
 
        9.1 
Controlled Substance 
        9.2 
Abuse 
 
        9.3 
Dependence 
10 
OVERDOSAGE 
11 
DESCRIPTION 
12 
CLINICAL PHARMACOLOGY 
 
        12.1 Mechanism of Action 
 
        12.2 Pharmacodynamics 
 
        12.3 Pharmacokinetics 
13 
NONCLINICAL TOXICOLOGY 
        13.1 Carcinogenesis, Mutagenesis, Impairment of 
Fertility 
16 
HOW SUPPLIED / STORAGE AND HANDLING 
17 
PATIENT COUNSELING INFORMATION 
        17.1 Safe Use 
        17.2 Disposal of Unused SUBOXONE Sublingual Films 
 
 
* 
Sections and subsections omitted from the full 
prescribing information are not listed. 


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FULL PRESCRIBING INFORMATION 
1 
INDICATIONS AND USAGE 
SUBOXONE sublingual film is indicated for treatment of opioid dependence and should be used as part 
of a complete treatment plan to include counseling and psychosocial support.  
Under the Drug Addiction Treatment Act (DATA) codified at 21 U.S.C. 823(g), prescription use of this 
product in the treatment of opioid dependence is limited to physicians who meet certain qualifying 
requirements, and who have notified the Secretary of Health and Human Services (HHS) of their intent 
to prescribe this product for the treatment of opioid dependence and have been assigned a unique 
identification number that must be included on every prescription.   
2 
DOSAGE AND ADMINISTRATION 
2.1 
Induction 
Prior to induction, consideration should be given to the type of opioid dependence (i.e., long- or short-
acting opioid products), the time since last opioid use, and the degree or level of opioid dependence.  To 
avoid precipitating an opioid withdrawal syndrome, the first dose of buprenorphine/naloxone should be 
started only when objective signs of moderate withdrawal appear. 
On Day 1, an induction dosage of up to 8 mg /2 mg SUBOXONE sublingual film is recommended.  
Clinicians should start with an initial dose of 2 mg/ 0.5 mg or 4 mg/1 mg buprenorphine/naloxone and 
may titrate upwards in 2 or 4 mg increments of buprenorphine, at approximately 2-hour intervals, under 
supervision, to 8 mg/2 mg buprenorphine/naloxone based on the control of acute withdrawal 
symptoms.   
On Day 2, a single daily dose of up to 16 mg/4 mg SUBOXONE sublingual film is recommended.  
Medication should be prescribed in consideration of the frequency of visits. Provision of multiple refills is 
not advised early in treatment or without appropriate patient follow-up visits. 
Patients dependent on methadone or long-acting opioid products 
Patients dependent upon methadone or long-acting opioid products may be more susceptible to 
precipitated and prolonged withdrawal during induction than those on short-acting opioid products.  
Buprenorphine/naloxone combination products have not been evaluated in adequate and well-
controlled studies for induction in patients on long-acting opioid products, and contain naloxone, which 
is absorbed in small amounts by the sublingual route and could cause worse precipitated and prolonged 
withdrawal.  For this reason, buprenorphine monotherapy is recommended in patients taking long-
acting opioids when used according to approved administration instructions.  Following induction, the 
patient may then be transitioned to once-daily SUBOXONE sublingual film. 
Patients dependent on heroin or other short-acting opioid products  
 
Patients dependent on heroin or short-acting opioid products may be inducted with either SUBOXONE 
sublingual film or with sublingual buprenorphine monotherapy.  The first dose of SUBOXONE sublingual 
film or buprenorphine should be administered when objective signs of moderate opioid withdrawal 
appear, and not less than 6 hours after the patient last used an opioid. 


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It is recommended that an adequate maintenance dose, titrated to clinical effectiveness, be achieved as 
rapidly as possible.  In some studies, a too-gradual induction over several days led to a high rate of drop-
out of buprenorphine patients during the induction period. 
  
2.2 
Maintenance  
The dosage of SUBOXONE sublingual film from Day 3 onwards should be progressively adjusted in 
increments/decrements of 2 mg/0.5 mg or 4 mg/1 mg buprenorphine/naloxone to a level that holds the 
patient in treatment and suppresses opioid withdrawal signs and symptoms. 
 
After treatment induction and stabilization, the maintenance dose of SUBOXONE sublingual film is 
generally in the range of 4 mg/1 mg buprenorphine/naloxone to 24 mg/6 mg buprenorphine/naloxone per 
day depending on the individual patient and clinical response.  The recommended target dosage of 
SUBOXONE sublingual film during maintenance is 16 mg/4 mg buprenorphine/naloxone/day as a single 
daily dose.  Dosages higher than 24 mg/6 mg daily have not been demonstrated to provide a clinical 
advantage.  
2.3 
Method of Administration 
Do not cut, chew, or swallow SUBOXONE sublingual film.  Place the SUBOXONE sublingual film under the 
tongue, close to the base on the left or right side.  If an additional sublingual film is necessary to achieve 
the prescribed dose, place the additional sublingual film sublingually on the opposite side from the first 
film.  Place the sublingual film in a manner to minimize overlapping as much as possible.  The sublingual 
film must be kept under the tongue until the film is completely dissolved.  SUBOXONE sublingual film 
should NOT be moved after placement. Proper administration technique should be demonstrated to the 
patient.  
2.4  
Clinical Supervision 
Treatment should be initiated with supervised administration, progressing to unsupervised 
administration as the patient’s clinical stability permits.  SUBOXONE sublingual film is subject to 
diversion and abuse.  When determining the prescription quantity for unsupervised administration, 
consider the patient’s level of stability, the security of his or her home situation, and other factors likely 
to affect the ability to manage supplies of take-home medication. 
 
Ideally patients should be seen at reasonable intervals (e.g., at least weekly during the first month of 
treatment) based upon the individual circumstances of the patient. Medication should be prescribed in 
consideration of the frequency of visits.  Provision of multiple refills is not advised early in treatment or 
without appropriate patient follow-up visits.  Periodic assessment is necessary to determine compliance 
with the dosing regimen, effectiveness of the treatment plan, and overall patient progress.   
 
Once a stable dosage has been achieved and patient assessment (e.g., urine drug screening) does not 
indicate illicit drug use, less frequent follow-up visits may be appropriate. A once-monthly visit schedule 
may be reasonable for patients on a stable dosage of medication who are making progress toward their 
treatment objectives. Continuation or modification of pharmacotherapy should be based on the 
physician’s evaluation of treatment outcomes and objectives such as: 
 
1.  Absence of medication toxicity. 


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2.  Absence of medical or behavioral adverse effects. 
 
3.  Responsible handling of medications by the patient. 
 
4.  Patient’s compliance with all elements of the treatment plan (including recovery-oriented activities, 
psychotherapy, and/or other psychosocial modalities). 
 
5.  Abstinence from illicit drug use (including problematic alcohol and/or benzodiazepine use).  
 
If treatment goals are not being achieved, the physician should re-evaluate the appropriateness of 
continuing the current treatment.  
2.5  
Patients With Hepatic Impairment  
Because the doses of this fixed combination product cannot be individually titrated, severe hepatic 
impairment results in a reduced clearance of naloxone to a much greater extent than buprenorphine, 
and moderate hepatic impairment also results in a reduced clearance of naloxone to a greater extent 
than buprenorphine, the combination product should generally be avoided in patients with severe 
hepatic impairment and may not be appropriate for patients with moderate hepatic impairment [see 
Warnings and Precautions (5.11)]. 
2.6 
Unstable Patients 
Physicians will need to decide when they cannot appropriately provide further management for 
particular patients.  For example, some patients may be abusing or dependent on various drugs, or 
unresponsive to psychosocial intervention such that the physician does not feel that he/she has the 
expertise to manage the patient.  In such cases, the physician may want to assess whether to refer the 
patient to a specialist or more intensive behavioral treatment environment.  Decisions should be based 
on a treatment plan established and agreed upon with the patient at the beginning of treatment. 
 
Patients who continue to misuse, abuse, or divert buprenorphine products or other opioids should be 
provided with, or referred to, more intensive and structured treatment. 
2.7 
Stopping Treatment 
The decision to discontinue therapy with SUBOXONE sublingual film after a period of maintenance 
should be made as part of a comprehensive treatment plan.  Taper patients to avoid opioid withdrawal 
signs and symptoms. 


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2.8 
Switching Between Buprenorphine or Buprenorphine and Naloxone Sublingual Tablets and 
SUBOXONE Sublingual Film 
Patients being switched between buprenorphine and naloxone or buprenorphine only sublingual tablets 
and SUBOXONE sublingual film should be started on the corresponding dosage of the previously 
administered product.  However, dosage adjustments may be necessary when switching between 
products.  Not all strengths and combinations of the SUBOXONE sublingual films are bioequivalent to 
the SUBOXONE (buprenorphine and naloxone) sublingual tablets as observed in pharmacokinetic studies 
[see Clinical Pharmacology (12.3)].  Therefore, systemic exposures of buprenorphine and naloxone may 
be different when patients are switched from tablets to film or vice-versa. Patients should be monitored 
for symptoms related to over-dosing or under-dosing. 
 
2.9 
Switching Between SUBOXONE Sublingual Film Strengths 
As indicated in Table 1, the sizes and the compositions of the four units of SUBOXONE sublingual films, 
i.e.,  
2 mg/0.5 mg, 4 mg/1 mg, 8 mg/2 mg and the 12 mg/3 mg units, are different from one another. If 
patients switch between various combinations of lower and higher strength units of SUBOXONE 
sublingual films to obtain the same total dose, (e.g., from three 4 mg/1 mg units to a single 12 mg/3 mg 
unit, or vice-versa), systemic exposures of buprenorphine and naloxone may be different and patients 
should be monitored for over-dosing or under-dosing.  For this reason, pharmacist should not substitute 
one or more film strengths for another without approval of the prescriber. 
 
Table 1.  Comparison of Available SUBOXONE Sublingual Film Strengths by Dimensions and Drug 
Concentrations. 
 
SUBOXONE sublingual film unit strength 
(buprenorphine/naloxone) 
SUBOXONE sublingual 
film unit dimensions 
Buprenorphine 
Concentration 
% (w/w) 
Naloxone 
Concentration 
% (w/w) 
2 mg/0.5 mg 
22.0 mm x 12.8 mm 
5.4 
1.53 
4 mg/1 mg  
(2 times the length of the 2 mg/0.5 mg unit) 
22.0 mm x 25.6 mm 
5.4 
1.53 
8 mg/2 mg  
22.0 mm x 12.8 mm 
17.2 
4.88 
12 mg/3 mg 
(1.5 times the length of the 8 mg/2 mg unit) 
22 mm X 19.2 mm 
17.2 
4.88 
3 
DOSAGE FORMS AND STRENGTHS 
SUBOXONE sublingual film is supplied as an orange rectangular sublingual film with a white printed logo 
in four dosage strengths: 
• 
buprenorphine/naloxone 2 mg/0.5 mg,  


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• 
buprenorphine/naloxone 4 mg/1 mg, 
• 
buprenorphine/naloxone 8 mg/2 mg and 
• 
buprenorphine/naloxone 12 mg/3 mg 
4 
CONTRAINDICATIONS 
SUBOXONE sublingual film should not be administered to patients who have been shown to be 
hypersensitive to buprenorphine or naloxone as serious adverse reactions, including anaphylactic shock, 
have been reported [see Warnings and Precautions (5.7)]. 
5 
WARNINGS AND PRECAUTIONS 
5.1 
Abuse Potential  
Buprenorphine can be abused in a manner similar to other opioids, legal or illicit. Prescribe and dispense 
buprenorphine with appropriate precautions to minimize risk of misuse, abuse, or diversion, and ensure 
appropriate protection from theft, including in the home. Clinical monitoring appropriate to the 
patient’s level of stability is essential. Multiple refills should not be prescribed early in treatment or 
without appropriate patient follow-up visits [see Drug Abuse and Dependence (9.2)]. 
5.2 
Respiratory Depression  
Buprenorphine, particularly when taken by the IV route, in combination with benzodiazepines or other 
CNS depressants (including alcohol), has been associated with significant respiratory depression and 
death.  Many, but not all, post-marketing reports regarding coma and death associated with the 
concomitant use of buprenorphine and benzodiazepines involved misuse by self-injection. Deaths have 
also been reported in association with concomitant administration of buprenorphine with other 
depressants such as alcohol or other CNS depressant drugs.  Patients should be warned of the potential 
danger of self-administration of benzodiazepines or other depressants while under treatment with 
SUBOXONE sublingual film [see Drug Interactions (7.3)]. 
In the case of overdose, the primary management should be the re-establishment of adequate 
ventilation with mechanical assistance of respiration, if required.  Naloxone may be of value for the 
management of buprenorphine overdose. Higher than normal doses and repeated administration may 
be necessary. 
SUBOXONE sublingual film should be used with caution in patients with compromised respiratory 
function (e.g., chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, 
hypoxia, hypercapnia, or pre-existing respiratory depression). 
5.3 
CNS Depression  
Patients receiving buprenorphine in the presence of opioid analgesics, general anesthetics, 
benzodiazepines, phenothiazines, other tranquilizers, sedative/hypnotics, or other CNS depressants 
(including alcohol) may exhibit increased CNS depression.  Consider dose reduction of CNS depressants, 
SUBOXONE sublingual film, or both in situations of concomitant prescription [see Drug Interactions 
(7.3)]. 
5.4 
Unintentional Pediatric Exposure 
Buprenorphine can cause severe, possibly fatal, respiratory depression in children who are accidentally 
exposed to it.  Store buprenorphine-containing medications safely out of the sight and reach of children. 


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5.5 
Dependence 
Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces 
physical dependence of the opioid type, characterized by withdrawal signs and symptoms upon abrupt 
discontinuation or rapid taper.  The withdrawal syndrome is typically milder than seen with full agonists 
and may be delayed in onset.  Buprenorphine can be abused in a manner similar to other opioids.  This 
should be considered when prescribing or dispensing buprenorphine in situations when the clinician is 
concerned about an increased risk of misuse, abuse, or diversion [see Drug Abuse and Dependence 
(9.3)]. 
5.6 
Hepatitis, Hepatic Events 
Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving 
buprenorphine in clinical trials and through post-marketing adverse event reports.  The spectrum of 
abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports 
of death, hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy.  In many 
cases, the presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C 
virus, concomitant usage of other potentially hepatotoxic drugs, and ongoing injecting drug use may 
have played a causative or contributory role.  In other cases, insufficient data were available to 
determine the etiology of the abnormality.  Withdrawal of buprenorphine has resulted in amelioration 
of acute hepatitis in some cases; however, in other cases no dose reduction was necessary.  The 
possibility exists that buprenorphine had a causative or contributory role in the development of the 
hepatic abnormality in some cases.  Liver function tests, prior to initiation of treatment are 
recommended to establish a baseline.  Periodic monitoring of liver function during treatment is also 
recommended.  A biological and etiological evaluation is recommended when a hepatic event is 
suspected.  Depending on the case, SUBOXONE sublingual film may need to be carefully discontinued to 
prevent withdrawal signs and symptoms and a return by the patient to illicit drug use, and strict 
monitoring of the patient should be initiated.  
5.7 
Allergic Reactions  
Cases of hypersensitivity to buprenorphine and naloxone containing products have been reported both 
in clinical trials and in the post-marketing experience.  Cases of bronchospasm, angioneurotic edema, 
and anaphylactic shock have been reported. The most common signs and symptoms include rashes, 
hives, and pruritus.  A history of hypersensitivity to buprenorphine or naloxone is a contraindication to 
the use of SUBOXONE sublingual film.  
5.8 
Precipitation of Opioid Withdrawal Signs and Symptoms  
Because it contains naloxone, SUBOXONE sublingual film is likely to produce withdrawal signs and 
symptoms if misused parenterally by individuals dependent on full opioid agonists such as heroin, 
morphine, or methadone.  Because of the partial agonist properties of buprenorphine, SUBOXONE 
sublingual film may precipitate opioid withdrawal signs and symptoms in such persons if administered 
sublingually before the agonist effects of the opioid have subsided.  


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5.9 
Neonatal Withdrawal 
Neonatal withdrawal has been reported in the infants of women treated with buprenorphine during 
pregnancy.  From post-marketing reports, the time to onset of neonatal withdrawal signs ranged from 
Day 1 to Day 8 of life with most cases occurring on Day 1.  Adverse events associated with the neonatal 
withdrawal syndrome included hypertonia, neonatal tremor, neonatal agitation, and myoclonus, and 
there have been reports of convulsions, apnea, respiratory depression, and bradycardia.  
5.10 
Use in Opioid Naïve Patients 
There have been reported deaths of opioid naive individuals who received a 2 mg dose of 
buprenorphine as a sublingual tablet for analgesia. SUBOXONE sublingual film is not appropriate as an 
analgesic. 
5.11 
Use in Patients With Impaired Hepatic Function 
Buprenorphine/naloxone products are not recommended in patients with severe hepatic impairment 
and may not be appropriate for patients with moderate hepatic impairment.  Because hepatic 
impairment results in a reduced clearance of naloxone to a much greater extent than buprenorphine, 
the doses of buprenorphine and naloxone in this fixed-dose combination product cannot be individually 
titrated. Therefore, patients with severe hepatic impairment will be exposed to substantially higher 
levels of naloxone than patients with normal hepatic function. This may result in an increased risk of 
precipitated withdrawal at the beginning of treatment (induction) and may interfere with 
buprenorphine’s efficacy throughout treatment.  In patients with moderate hepatic impairment, the 
differential reduction of naloxone clearance compared to buprenorphine clearance is not as great as in 
subjects with severe hepatic impairment.  Therefore, buprenorphine/naloxone products are not 
recommended for initiation of treatment (induction) in patients with moderate hepatic impairment due 
to the increased risk of precipitated withdrawal. However, buprenorphine/naloxone products may be 
used with caution for maintenance treatment in patients with moderate hepatic impairment who have 
initiated treatment on a buprenorphine product without naloxone. However, patients should be 
carefully monitored and consideration given to the possibility of naloxone interfering with 
buprenorphine’s efficacy [see Use in Specific Populations (8.6)]. 
5.12 
Impairment of Ability to Drive or Operate Machinery  
SUBOXONE sublingual film may impair the mental or physical abilities required for the performance of 
potentially dangerous tasks such as driving a car or operating machinery, especially during treatment 
induction and dose adjustment.  Patients should be cautioned about driving or operating hazardous 
machinery until they are reasonably certain that SUBOXONE sublingual film therapy does not adversely 
affect his or her ability to engage in such activities.   
5.13 
Orthostatic Hypotension 
Like other opioids, SUBOXONE sublingual film may produce orthostatic hypotension in ambulatory 
patients. 
5.14 
Elevation of Cerebrospinal Fluid Pressure  
Buprenorphine, like other opioids, may elevate cerebrospinal fluid pressure and should be used with 
caution in patients with head injury, intracranial lesions, and other circumstances when cerebrospinal 
pressure may be increased.  Buprenorphine can produce miosis and changes in the level of 
consciousness that may interfere with patient evaluation. 


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5.15 
Elevation of Intracholedochal Pressure 
Buprenorphine has been shown to increase intracholedochal pressure, as do other opioids, and thus 
should be administered with caution to patients with dysfunction of the biliary tract. 
5.16 
Effects in Acute Abdominal Conditions 
As with other opioids, buprenorphine may obscure the diagnosis or clinical course of patients with acute 
abdominal conditions. 
5.17 
General Precautions 
SUBOXONE sublingual film should be administered with caution in debilitated patients and those with 
myxedema or hypothyroidism, adrenal cortical insufficiency (e.g., Addison's disease); CNS depression or 
coma; toxic psychoses; prostatic hypertrophy or urethral stricture; acute alcoholism; delirium tremens; 
or kyphoscoliosis. 
6 
ADVERSE REACTIONS 
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 
the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and 
may not reflect the rates observed in practice.   
6.1 
Clinical Trials Experience 
The safety of SUBOXONE sublingual film is supported by clinical trials using SUBUTEX (buprenorphine) 
sublingual tablets and SUBOXONE (buprenorphine and naloxone) sublingual tablets, and other trials 
using buprenorphine sublingual solutions, as well as an open-label study in 194 patients treated with 
SUBOXONE sublingual film.  In total, safety data from clinical studies are available from over 3000 
opioid-dependent subjects exposed to buprenorphine at doses in the range used in the treatment of 
opioid dependence.  Few differences in the adverse event profile were noted among SUBOXONE 
sublingual film, SUBOXONE (buprenorphine and naloxone) sublingual tablets, SUBUTEX (buprenorphine) 
sublingual tablets and a buprenorphine ethanolic sublingual solution.   
The most common adverse event (>1%) associated with the sublingual administration of the SUBOXONE 
sublingual film was oral hypoesthesia. Other adverse events were constipation, glossodynia, oral 
mucosal erythema, vomiting, intoxication, disturbance in attention, palpitations, insomnia, withdrawal 
syndrome, hyperhidrosis, and blurred vision. 
Other adverse event data were derived from larger, controlled studies of SUBOXONE (buprenorphine 
and naloxone) and SUBUTEX (buprenorphine) tablets and of buprenorphine sublingual solution.  In a 
comparative study of SUBOXONE (buprenorphine and naloxone) and SUBUTEX (buprenorphine) 
sublingual tablets, adverse event profiles were similar for subjects treated with 16 mg/4 mg SUBOXONE 
(buprenorphine and naloxone) sublingual tablets or 16 mg SUBUTEX (buprenorphine) sublingual tablets.  
The following adverse events were reported to occur by at least 5% of patients in a 4 week study of 
SUBOXONE (buprenorphine and naloxone) sublingual tablets and SUBUTEX (buprenorphine) sublingual 
tablets. 
 


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Table 2.  Adverse Events (≥ 5%) by Body System and Treatment Group in a 4 Week Study 
Body System/ Adverse Event 
(COSTART Terminology) 
SUBOXONE 
(buprenorphine and 
naloxone) sublingual 
tablets 
16 mg/4 mg/day 
N=107 
n (%) 
SUBUTEX 
(buprenorphine) 
sublingual tablets 
16 mg/day 
N=103 
n (%) 
Placebo 
N=107 
n (%) 
Body as a Whole 
Asthenia 
7 (6.5%) 
5 (4.9%) 
7 (6.5%) 
Chills 
8 (7.5%) 
8 (7.8%) 
8 (7.5%) 
Headache 
39 (36.4%) 
30 (29.1%) 
24 (22.4%) 
Infection 
6 (5.6%) 
12 (11.7%) 
7 (6.5%) 
Pain 
24 (22.4%) 
19 (18.4%) 
20 (18.7%) 
Pain abdomen 
12 (11.2%) 
12 (11.7%) 
7 (6.5%) 
Pain back 
4 (3.7%) 
8 (7.8%) 
12 (11.2%) 
Withdrawal syndrome 
27 (25.2%) 
19 (18.4%) 
40 (37.4%) 
Cardiovascular System 
Vasodilation 
10 (9.3%) 
4 (3.9%) 
7 (6.5%) 
Digestive System 
Constipation 
13 (12.1%) 
8 (7.8%) 
3 (2.8%) 
Diarrhea 
4 (3.7%) 
5 (4.9%) 
16 (15.0%) 
Nausea 
16 (15.0%) 
14 (13.6%) 
12 (11.2%) 
Vomiting 
8 (7.5%) 
8 (7.8%) 
5 (4.7%) 
Nervous System 
Insomnia 
15 (14.0%) 
22 (21.4%) 
17 (15.9%) 
Respiratory System 
Rhinitis 
5 (4.7%) 
10 (9.7%) 
14 (13.1%) 
Skin And Appendages 
Sweating 
15 (14.0%) 
13 (12.6%) 
11 (10.3%) 
Abbreviations: COSTART = Coding Symbols for Thesaurus of Adverse Reaction Terms. 
The adverse event profile of buprenorphine was also characterized in the dose-controlled study of a 
buprenorphine ethanolic solution, over a range of doses in four months of treatment.  Table 3 shows 
adverse events reported by at least 5% of subjects in any dose group in the dose-controlled trial. 
 


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Table 3.  Adverse Events (≥5%) by Body System and Treatment Group in a 16 Week Study 
Body 
System/ 
Adverse 
Event 
(COSTART 
Terminology) 
Buprenorphine Dose 
Very 
Low* 
N=184 
n (%) 
Low* 
N=180 
n (%) 
Moderate* 
N=186 
n (%) 
High* 
N=181 
n (%) 
Total* 
N=731 
n (%) 
Body as a Whole 
Abscess 
9 (5%) 
2 (1%) 
3 (2%) 
2 (1%) 
16 (2%) 
Asthenia 
26 (14%) 
28 (16%) 
26 (14%) 
24 (13%) 
104 
(14%) 
Chills 
11 (6%) 
12 (7%) 
9 (5%) 
10 (6%) 
42 (6%) 
Fever 
7 (4%) 
2 (1%) 
2 (1%) 
10 (6%) 
21 (3%) 
Flu syndrome 4 (2%) 
13 (7%) 
19 (10%) 
8 (4%) 
44 (6%) 
Headache 
51 (28%) 
62 (34%) 
54 (29%) 
53 (29%) 
220 
(30%) 
Infection 
32 (17%) 
39 (22%) 
38 (20%) 
40 (22%) 
149 
(20%) 
Injury 
accidental 
5 (3%) 
10 (6%) 
5 (3%) 
5 (3%) 
25 (3%) 
Pain 
47 (26%) 
37 (21%) 
49 (26%) 
44 (24%) 
177 
(24%) 
Pain back 
18 (10%) 
29 (16%) 
28 (15%) 
27 (15%) 
102 
(14%) 
Withdrawal 
syndrome 
45 (24%) 
40 (22%) 
41 (22%) 
36 (20%) 
162 
(22%) 
Digestive System 
Constipation 
10 (5%) 
23 (13%) 
23 (12%) 
26 (14%) 
82 (11%) 
Diarrhea 
19 (10%) 
8 (4%) 
9 (5%) 
4 (2%) 
40 (5%) 
Dyspepsia 
6 (3%) 
10 (6%) 
4 (2%) 
4 (2%) 
24 (3%) 
Nausea 
12 (7%) 
22 (12%) 
23 (12%) 
18 (10%) 
75 (10%) 
Vomiting 
8 (4%) 
6 (3%) 
10 (5%) 
14 (8%) 
38 (5%) 
Nervous System 
Anxiety 
22 (12%) 
24 (13%) 
20 (11%) 
25 (14%) 
91 (12%) 
Depression 
24 (13%) 
16 (9%) 
25 (13%) 
18 (10%) 
83 (11%) 
Dizziness 
4 (2%) 
9 (5%) 
7 (4%) 
11 (6%) 
31 (4%) 


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Insomnia 
42 (23%) 
50 (28%) 
43 (23%) 
51 (28%) 
186 
(25%) 
Nervousness 
12 (7%) 
11 (6%) 
10 (5%) 
13 (7%) 
46 (6%) 
Somnolence 
5 (3%) 
13 (7%) 
9 (5%) 
11 (6%) 
38 (5%) 
Respiratory System 
Cough 
increase 
5 (3%) 
11 (6%) 
6 (3%) 
4 (2%) 
26 (4%) 
Pharyngitis 
6 (3%) 
7 (4%) 
6 (3%) 
9 (5%) 
28 (4%) 
Rhinitis 
27 (15%) 
16 (9%) 
15 (8%) 
21 (12%) 
79 (11%) 
Skin and Appendages 
Sweat 
23 (13%) 
21 (12%) 
20 (11%) 
23 (13%) 
87 (12%) 
Special Senses 
Runny eyes 
13 (7%) 
9 (5%) 
6 (3%) 
6 (3%) 
34 (5%) 
*Sublingual solution.  Doses in this table cannot necessarily be delivered in tablet form, but for 
comparison purposes: 
1 mg solution would be less than a tablet dose of 2 mg 
4 mg solution approximates a 6 mg tablet dose 
8 mg solution approximates a 12 mg tablet dose 
16 mg solution approximates a 24 mg tablet dose 
The safety of SUBOXONE sublingual film during treatment induction is supported by a clinical trial using 16 
patients treated with SUBOXONE sublingual film and 18 treated with a buprenorphine-only sublingual film.  
Few differences in the adverse event profiles were noted between SUBOXONE sublingual film and the 
buprenorphine-only sublingual film.   
The most common adverse event occurring during treatment induction and the 3 days following induction 
using SUBOXONE sublingual film was restlessness. Other adverse events were anxiety, piloerection, 
stomach discomfort, irritability, headache, rhinorrhea, cold sweat, arthralgia, and lacrimation increased. 
Four subjects left the study early on the first day of sublingual film administration.  However, there was 
not evidence to suggest that any of the four subjects experienced precipitated withdrawal secondary to 
the administration of buprenorphine or buprenorphine/naloxone sublingual films.  


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6.2 
Postmarketing Experience 
The following adverse reactions have been identified during post-approval use of SUBOXONE sublingual 
film. Because these reactions are reported voluntarily from a population of uncertain size, it is not 
always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 
The most frequently reported postmarketing adverse events were peripheral edema, stomatitis, 
glossitis, and tongue disorder.  
7 
DRUG INTERACTIONS 
7.1 
Cytochrome P-450 3A4 (CYP3A4) Inhibitors and Inducers 
Buprenorphine is metabolized to norbuprenorphine primarily by cytochrome CYP3A4; therefore, 
potential interactions may occur when SUBOXONE sublingual film is given concurrently with agents that 
affect CYP3A4 activity.  The concomitant use of SUBOXONE sublingual film with CYP3A4 inhibitors (e.g., 
azole antifungals such as ketoconazole, macrolide antibiotics such as erythromycin, and HIV protease 
inhibitors) should be monitored and may require dose-reduction of one or both agents. 
The interaction of buprenorphine with CYP3A4 inducers has not been studied; therefore, it is 
recommended that patients receiving SUBOXONE sublingual film be monitored for signs and symptoms 
of opioid withdrawal if inducers of CYP3A4 (e.g., efavirenz, phenobarbital, carbamazepine, phenytoin, 
rifampicin) are co-administered [see Clinical Pharmacology (12.3)]. 
7.2 
Antiretrovirals 
Three classes of antiretroviral agents have been evaluated for CYP3A4 interactions with buprenorphine.  
Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme 
pathway, thus no interactions with buprenorphine are expected.  Non-nucleoside reverse transcriptase 
inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine and etravirine are 
known CYP3A inducers whereas delaviridine is a CYP3A inhibitor. Significant pharmacokinetic 
interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in 
clinical studies, but these pharmacokinetic interactions did not result in any significant 
pharmacodynamic effects. It is recommended that patients who are on chronic buprenorphine 
treatment have their dose monitored if NNRTIs are added to their treatment regimen.  Studies have 
shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, 
lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant 
pharmacodynamic effects.  Other PIs with CYP3A4 inhibitory activity (atazanavir and 
atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine and patients in 
one study reported increased sedation. Symptoms of opioid excess have been found in post-marketing 
reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly.  
Monitoring of patients taking buprenorphine and atazanavir with and without ritonavir is 
recommended, and dose reduction of buprenorphine may be warranted. 
7.3 
Benzodiazepines 
There have been a number of post-marketing reports regarding coma and death associated with the 
concomitant use of buprenorphine and benzodiazepines.  In many, but not all, of these cases, 
buprenorphine was misused by self-injection.  Preclinical studies have shown that the combination of 
benzodiazepines and buprenorphine altered the usual ceiling effect on buprenorphine-induced 
respiratory depression, making the respiratory effects of buprenorphine appear similar to those of full 


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opioid agonists.  SUBOXONE sublingual film should be prescribed with caution to patients taking 
benzodiazepines or other drugs that act on the CNS, regardless of whether these drugs are taken on the 
advice of a physician or are being abused/misused.  Patients should be warned that it is extremely 
dangerous to self-administer non-prescribed benzodiazepines while taking SUBOXONE sublingual film, 
and should also be cautioned to use benzodiazepines concurrently with SUBOXONE sublingual film only 
as directed by their physician. 
8 
USE IN SPECIFIC POPULATIONS 
8.1 
Pregnancy 
Pregnancy Category C. 
Risk Summary  
There are no adequate and well-controlled studies of SUBOXONE sublingual film or 
buprenorphine/naloxone in pregnant women. Limited published data on use of buprenorphine, the 
active ingredient in SUBOXONE, in pregnancy, have not shown an increased risk of major malformations. 
All pregnancies, regardless of drug exposure, have a background risk of 2-4% for major birth defects, and 
15-20% for pregnancy loss. Reproductive and developmental studies in rats and rabbits identified 
adverse events at clinically relevant doses. Pre-and postnatal development studies in rats demonstrated 
dystocia, increased neonatal deaths, and developmental delays. No clear teratogenic effects were seen 
with a range of doses equivalent to or greater than the human dose. However, in a few studies, some 
events such as acephalus, omphalocele, and skeletal abnormalities were observed but these findings 
were not clearly treatment-related. Embryofetal death was also observed in both rats and rabbits. 
SUBOXONE sublingual film should be used during pregnancy only if the potential benefit justifies the 
potential risk to the fetus.  
Clinical Considerations 
Disease-associated maternal and embryo-fetal risk 
Opioid dependence in pregnancy is associated with adverse obstetrical outcomes such as low birth 
weight, preterm birth, and fetal death. 
Fetal/neonatal adverse reactions 
Neonatal abstinence syndrome may occur in newborn infants of mothers who were on buprenorphine 
maintenance treatment. Observe newborns for poor feeding, diarrhea, irritability, tremor, rigidity, and 
seizures, and manage accordingly [see Warnings and Precautions (5.9)]. 
Labor or Delivery 
As with all opioids, use of buprenorphine prior to delivery may result in respiratory depression in the 
newborn. Closely monitor neonates for signs of respiratory depression. An opioid antagonist such as 
naloxone should be available for reversal of opioid induced respiratory depression in the neonate. 
Data 
Human Data 
Studies have been conducted to evaluate neonatal outcomes in women exposed to buprenorphine 
during pregnancy. Limited published data on malformations from trials, observational studies, case 
series, and case reports on buprenorphine use in pregnancy have not shown an increased risk of major 
malformations. Based on these studies the incidence of neonatal abstinence syndrome is not clear and 
there does not appear to be a dose-response relationship. 


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Animal Data 
Effects on embryo-fetal development were studied in Sprague-Dawley rats and Russian white rabbits 
following oral (1:1) and intramuscular (IM) (3:2) administration of mixtures of buprenorphine and 
naloxone.  Following oral administration to rats and rabbits, no teratogenic effects were observed at 
buprenorphine doses up to 250 mg/kg/day and 40 mg/kg/day, respectively (estimated exposure 
approximately 150 times and 50 times, respectively, the recommended human daily sublingual dose of 
16 mg on a mg/m² basis).  No definitive drug-related teratogenic effects were observed in rats and 
rabbits at IM doses up to 30 mg/kg/day (estimated exposure approximately 20 times and 35 times, 
respectively, the recommended human daily dose of 16 mg on a mg/m² basis).  Acephalus was observed 
in one rabbit fetus from the low-dose group and omphalocele was observed in two rabbit fetuses from 
the same litter in the mid-dose group; no findings were observed in fetuses from the high-dose group.  
Following oral administration of buprenorphine to rats, dose-related post-implantation losses, 
evidenced by increases in the numbers of early resorptions with consequent reductions in the numbers 
of fetuses, were observed at doses of 10 mg/kg/day or greater (estimated exposure approximately 
6 times the recommended human daily sublingual dose of 16 mg on a mg/m² basis).  In the rabbit, 
increased post-implantation losses occurred at an oral dose of 40 mg/kg/day.  Following IM 
administration in the rat and the rabbit, post-implantation losses, as evidenced by decreases in live 
fetuses and increases in resorptions, occurred at 30 mg/kg/day.   
Buprenorphine was not teratogenic in rats or rabbits after IM or subcutaneous (SC) doses up to 5 
mg/kg/day (estimated exposure was approximately 3 and 6 times, respectively, the recommended 
human daily sublingual dose of 16 mg on a mg/m2 basis), after IV doses up to 0.8 mg/kg/day (estimated 
exposure was approximately 0.5 times and equal to, respectively, the recommended human daily 
sublingual dose of 16 mg on a mg/m2 basis), or after oral doses up to 160 mg/kg/day in rats (estimated 
exposure was approximately 95 times the recommended human daily sublingual dose of 16 mg on a 
mg/m2 basis) and 25 mg/kg/day in rabbits (estimated exposure was approximately 30 times the 
recommended human daily sublingual dose of 16 mg on a mg/m2 basis). Significant increases in skeletal 
abnormalities (e.g., extra thoracic vertebra or thoraco-lumbar ribs) were noted in rats after SC 
administration of 1 mg/kg/day and up (estimated exposure was approximately 0.6 times the 
recommended human daily sublingual dose of 16 mg on a mg/m2 basis), but were not observed at oral 
doses up to 160 mg/kg/day.  Increases in skeletal abnormalities in rabbits after IM administration of 5 
mg/kg/day (estimated exposure was approximately 6 times the recommended human daily sublingual 
dose of 16 mg on a mg/m2 basis) or oral administration of 1 mg/kg/day or greater (estimated exposure 
was approximately equal to the recommended human daily sublingual dose of 16 mg on a mg/m2 basis) 
were not statistically significant. 
In rabbits, buprenorphine produced statistically significant pre-implantation losses at oral doses of 1 
mg/kg/day or greater and post-implantation losses that were statistically significant at IV doses of 0.2 
mg/kg/day or greater (estimated exposure approximately 0.3 times the recommended human daily 
sublingual dose of 16 mg on a mg/m2 basis). 
Dystocia was noted in pregnant rats treated intramuscularly with buprenorphine 5 mg/kg/day 
(approximately 3 times the recommended human daily sublingual dose of 16 mg on a mg/m² basis).  
Fertility, peri-, and post-natal development studies with buprenorphine in rats indicated increases in 
neonatal mortality after oral doses of 0.8 mg/kg/day and up (approximately 0.5 times the recommended 
human daily sublingual dose of 16 mg on a mg/m² basis), after IM doses of 0.5 mg/kg/day and up 
(approximately 0.3 times the recommended human daily sublingual dose of 16 mg on a mg/m² basis), 
and after SC doses of 0.1 mg/kg/day and up (approximately 0.06 times the recommended human daily 
sublingual dose of 16 mg on a mg/m² basis).  An apparent lack of milk production during these studies 
likely contributed to the decreased pup viability and lactation indices.  Delays in the occurrence of 


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righting reflex and startle response were noted in rat pups at an oral dose of 80 mg/kg/day 
(approximately 50 times the recommended human daily sublingual dose of 16 mg on a mg/m² basis). 
8.3 
Nursing Mothers 
Risk Summary 
Based on two studies in 13 lactating women, buprenorphine and its metabolite norbuprenorphine are 
present in low levels in human milk and infant urine, and available data have not shown adverse 
reactions in breastfed infants. There are no data on the combination product buprenorphine/naloxone 
in breastfeeding, however oral absorption of naloxone is minimal. Caution should be exercised when 
SUBOXONE is administered to a nursing woman. The developmental and health benefits of 
breastfeeding should be considered along with the mother’s clinical need for SUBOXONE and any 
potential adverse effects on the breastfed child from the drug or from the underlying maternal 
condition. 
Clinical Considerations 
Advise the nursing mother taking SUBOXONE to monitor the infant for increased drowsiness and 
breathing difficulties. 
Data 
Based on limited data from a study of 6 lactating women who were taking a median oral dose of 
buprenorphine of 0.29 mg/kg/day 5-8 days after delivery, breast milk contained a median infant dose of 
0.42 mcg/kg/day of buprenorphine and 0.33 mcg/kg/day of norbuprenorphine, which are equal to 0.2% 
and 0.12% of the maternal weight-adjusted dose. 
Based on limited data from a study of 7 lactating women who were taking a median oral dose of 
buprenorphine of 7 mg/day an average of 1.12 months after delivery, the mean milk concentrations of 
buprenorphine and norbuprenorphine were 3.65 mcg/L and 1.94 mcg/L respectively. Based on the 
limited data from this study, and assuming milk consumption of 150 mL/kg/day, an exclusively breastfed 
infant would receive an estimated mean of 0.55 mcg/kg/day of buprenorphine and 0.29 mcg/kg/day of 
norbuprenorphine, which are 0.38% and 0.18% of the maternal weight-adjusted dose. 
No adverse reactions were observed in the infants in these two studies. 
8.4 
Pediatric Use 
The safety and effectiveness of SUBOXONE sublingual film have not been established in pediatric 
patients.  This product is not appropriate for the treatment of neonatal abstinence syndrome in 
neonates, because it contains naloxone, an opioid antagonist.  
8.5 
Geriatric Use 
Clinical studies of SUBOXONE sublingual film, SUBOXONE (buprenorphine and naloxone) sublingual 
tablets, or SUBUTEX (buprenorphine) sublingual tablets did not include sufficient numbers of subjects 
aged 65 and over to determine whether they responded differently than younger subjects.  Other 
reported clinical experience has not identified differences in responses between the elderly and younger 
patients.  In general, dose selection for an elderly patient should be cautious, usually starting at the low 
end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac 
function, and of concomitant disease or other drug therapy. 


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8.6 
Hepatic Impairment 
The effect of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone has been 
evaluated in a pharmacokinetic study. Both drugs are extensively metabolized in the liver. While no 
clinically significant changes have been observed in subjects with mild hepatic impairment; the plasma 
levels have been shown to be higher and half-life values have been shown to be longer for both 
buprenorphine and naloxone in subjects with moderate and severe hepatic impairment. The magnitude 
of the effects on naloxone are greater than that on buprenorphine in both moderately and severely 
impaired subjects. The difference in magnitude of the effects on naloxone and buprenorphine are 
greater in subjects with severe hepatic impairment than in subjects with moderate hepatic impairment, 
and therefore the clinical impact of these effects is likely to be greater in patients with severe hepatic 
impairment than in patients with moderate hepatic impairment. Buprenorphine/naloxone products 
should be avoided in patients with severe hepatic impairment and may not be appropriate for patients 
with moderate hepatic impairment [see Warnings and Precautions (5.11) and Clinical Pharmacology 
(12.3)].    
8.7 
Renal Impairment  
No differences in buprenorphine pharmacokinetics were observed between 9 dialysis-dependent and 
6 normal patients following IV administration of 0.3 mg buprenorphine.  The effects of renal failure on 
naloxone pharmacokinetics are unknown. 
9 
DRUG ABUSE AND DEPENDENCE 
9.1 
Controlled Substance 
Buprenorphine is a Schedule III narcotic under the Controlled Substances Act. 
Under the Drug Addiction Treatment Act (DATA) codified at 21 U.S.C. 823(g), prescription use of this 
product in the treatment of opioid dependence is limited to physicians who meet certain qualifying 
requirements, and who have notified the Secretary of Health and Human Services (HHS) of their intent 
to prescribe this product for the treatment of opioid dependence and have been assigned a unique 
identification number that must be included on every prescription. 
9.2 
Abuse 
• 
Buprenorphine, like morphine and other opioids, has the potential for being abused and is 
subject to criminal diversion. This should be considered when prescribing or dispensing buprenorphine 
in situations when the clinician is concerned about an increased risk of misuse, abuse, or diversion.  
Healthcare professionals should contact their state professional licensing board or state controlled 
substances authority for information on how to prevent and detect abuse or diversion of this product. 
• 
Patients who continue to misuse, abuse, or divert buprenorphine products or other opioids 
should be provided with or referred for more intensive and structured treatment.   
• 
Abuse of buprenorphine poses a risk of overdose and death.  This risk is increased with the 
abuse of buprenorphine and alcohol and other substances, especially benzodiazepines. 
• 
The physician may be able to more easily detect misuse or diversion by maintaining records of 
medication prescribed including date, dose, quantity, frequency of refills, and renewal requests of 
medication prescribed. 
• 
Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of 
therapy, and proper handling and storage of the medication are appropriate measures that help to limit 
abuse of opioid drugs. 


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9.3 
Dependence  
Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces 
physical dependence of the opioid type, characterized by moderate withdrawal signs and symptoms 
upon abrupt discontinuation or rapid taper.  The withdrawal syndrome is typically milder than seen with 
full agonists and may be delayed in onset [see Warnings and Precautions (5.5)]. 
A neonatal withdrawal syndrome has been reported in the infants of women treated with 
buprenorphine during pregnancy [see Warnings and Precautions (5.9)]. 
10 
OVERDOSAGE 
The manifestations of acute overdose include pinpoint pupils, sedation, hypotension, respiratory 
depression, and death.  
In the event of overdose, the respiratory and cardiac status of the patient should be monitored 
carefully.  When respiratory or cardiac functions are depressed, primary attention should be given to the 
re-establishment of adequate respiratory exchange through provision of a patent airway and institution 
of assisted or controlled ventilation.  Oxygen, IV fluids, vasopressors, and other supportive measures 
should be employed as indicated. 
In the case of overdose, the primary management should be the re-establishment of adequate 
ventilation with mechanical assistance of respiration, if required.  Naloxone may be of value for the 
management of buprenorphine overdose.  Higher than normal doses and repeated administration may 
be necessary.  
11 
DESCRIPTION 
SUBOXONE (buprenorphine and naloxone) sublingual film is an orange film, imprinted with a logo 
identifying the product and strength in white ink.  It contains buprenorphine HCl, a mu-opioid receptor 
partial agonist and a kappa-opioid receptor antagonist, and naloxone HCl dihydrate, an opioid receptor 
antagonist, at a ratio of 4:1 (ratio of free bases).  It is intended for sublingual administration and is 
available in four dosage strengths, 2 mg buprenorphine with 0.5 mg naloxone, 4 mg buprenorphine with 1 
mg naloxone,  8 mg buprenorphine with 2 mg naloxone and 12 mg buprenorphine with 3 mg naloxone.  
Each sublingual film also contains polyethylene oxide, hydroxypropyl methylcellulose, maltitol, acesulfame 
potassium, lime flavor, citric acid, sodium citrate, FD&C yellow #6, and white ink. 
Chemically, buprenorphine HCl is (2S)-2-[17-Cyclopropylmethyl-4,5α-epoxy-3-hydroxy-6-methoxy-
6α,14-ethano-14α-morphinan-7α-yl]-3,3-dimethylbutan-2-ol hydrochloride.  It has the following 
chemical structure: 
• HCl 
Buprenorphine HCl has the molecular formula C29 H41 NO4 • HCl and the molecular weight is 504.10.  It is 
a white or off-white crystalline powder, sparingly soluble in water, freely soluble in methanol, soluble in 
alcohol, and practically insoluble in cyclohexane. 


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Chemically, naloxone HCl dihydrate is 17-Allyl-4,5 α -epoxy-3, 14-dihydroxymorphinan-6-one 
hydrochloride dihydrate.  It has the following chemical structure:  
                                                    HCl • 2H2O 
Naloxone hydrochloride dihydrate has the molecular formula C19H21NO4 • HCl • 2H2O and the molecular 
weight is 399.87.  It is a white to slightly off-white powder and is freely soluble in water, soluble in 
alcohol, and practically insoluble in toluene and ether.   
12 
CLINICAL PHARMACOLOGY 
12.1 
Mechanism of Action 
SUBOXONE sublingual film contains buprenorphine and naloxone.  Buprenorphine is a partial agonist at 
the mu-opioid receptor and an antagonist at the kappa-opioid receptor. Naloxone is a potent antagonist 
at mu-opioid receptors and produces opioid withdrawal signs and symptoms in individuals physically 
dependent on full opioid agonists when administered parenterally.  
12.2 
Pharmacodynamics 
• 
Subjective Effects: 
Comparisons of buprenorphine to full opioid agonists such as methadone and hydromorphone suggest 
that sublingual buprenorphine produces typical opioid agonist effects which are limited by a ceiling 
effect.  
In opioid-experienced subjects who were not physically dependent, acute sublingual doses of 
buprenorphine/naloxone tablets produced opioid agonist effects which reached a maximum between 
doses of 8 mg/2 mg and 16 mg/4 mg buprenorphine/naloxone.   
Opioid agonist ceiling-effects were also observed in a double-blind, parallel group, dose-ranging 
comparison of single doses of buprenorphine sublingual solution (1, 2, 4, 8, 16, or 32 mg), placebo and a 
full agonist control at various doses.  The treatments were given in ascending dose order at intervals of 
at least one week to 16 opioid-experienced subjects who were not physically dependent.  Both active 
drugs produced typical opioid agonist effects.  For all measures for which the drugs produced an effect, 
buprenorphine produced a dose-related response.  However, in each case, there was a dose that 
produced no further effect.  In contrast, the highest dose of the full agonist control always produced the 
greatest effects.  Agonist objective rating scores remained elevated for the higher doses of 
buprenorphine (8-32 mg) longer than for the lower doses and did not return to baseline until 48 hours 
after drug administration.  The onset of effects appeared more rapidly with buprenorphine than with 
the full agonist control, with most doses nearing peak effect after 100 minutes for buprenorphine 
compared to 150 minutes for the full agonist control. 
 
 
HO
N
O
OH
O


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• 
Physiologic Effects: 
Buprenorphine in IV (2, 4, 8, 12 and 16 mg) and sublingual (12 mg) doses has been administered to 
opioid-experienced subjects who were not physically dependent to examine cardiovascular, respiratory, 
and subjective effects at doses comparable to those used for treatment of opioid dependence.  
Compared to placebo, there were no statistically significant differences among any of the treatment 
conditions for blood pressure, heart rate, respiratory rate, O2 saturation, or skin temperature across 
time.  Systolic BP was higher in the 8 mg group than placebo (3 hour AUC values).  Minimum and 
maximum effects were similar across all treatments.  Subjects remained responsive to low voice and 
responded to computer prompts. Some subjects showed irritability, but no other changes were 
observed.  
The respiratory effects of sublingual buprenorphine were compared with the effects of methadone in a 
double-blind, parallel group, dose ranging comparison of single doses of buprenorphine sublingual 
solution (1, 2, 4, 8, 16, or 32 mg) and oral methadone (15, 30, 45, or 60 mg) in non-dependent, opioid-
experienced volunteers. In this study, hypoventilation not requiring medical intervention was reported 
more frequently after buprenorphine doses of 4 mg and higher than after methadone. Both drugs 
decreased O2 saturation to the same degree. 
Effect of Naloxone: 
Physiologic and subjective effects following acute sublingual administration of buprenorphine tablets 
and buprenorphine/naloxone tablets were similar at equivalent  s of buprenorphine.  Naloxone had no 
clinically significant effect when administered by the sublingual route, although blood levels of the drug 
were measurable.  Buprenorphine/naloxone, when administered sublingually to an opioid-dependent 
cohort, was recognized as an opioid agonist, whereas when administered intramuscularly, combinations 
of buprenorphine with naloxone produced opioid antagonist actions similar to naloxone.  This finding 
suggests that the naloxone in buprenorphine/naloxone tablets may deter injection of 
buprenorphine/naloxone tablets by persons with active substantial heroin or other full mu-opioid 
dependence.  However, clinicians should be aware that some opioid-dependent persons, particularly 
those with a low level of full mu-opioid physical dependence or those whose opioid physical 
dependence is predominantly to buprenorphine, abuse buprenorphine/naloxone combinations by the 
intravenous or intranasal route.  In methadone-maintained patients and heroin-dependent subjects, IV 
administration of buprenorphine/naloxone combinations precipitated opioid withdrawal signs and 
symptoms and was perceived as unpleasant and dysphoric.  In morphine-stabilized subjects, 
intravenously administered combinations of buprenorphine with naloxone produced opioid antagonist 
and withdrawal signs and symptoms that were ratio-dependent; the most intense withdrawal signs and 
symptoms were produced by 2:1 and 4:1 ratios, less intense by an 8:1 ratio.   


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12.3 
Pharmacokinetics 
Absorption:   
In pharmacokinetic studies, the 2 mg/0.5 mg and 4 mg/1 mg doses administered as SUBOXONE 
sublingual films showed comparable relative bioavailability to the same total dose of SUBOXONE 
(buprenorphine and naloxone) sublingual tablets, whereas the 8 mg/2 mg and 12 mg/3 mg doses 
administered as SUBOXONE sublingual films showed higher relative bioavailability for both 
buprenorphine and naloxone compared to the same total dose of SUBOXONE (buprenorphine and 
naloxone) sublingual tablets.  A combination of one 8 mg/2 mg and two 2 mg/0.5 mg SUBOXONE 
sublingual films (total dose of 12 mg/ 3 mg) showed comparable relative bioavailability to the same total 
dose of SUBOXONE (buprenorphine and naloxone) sublingual tablets [see Dosage and Administration 
(2.6 and 2.7)]. 
Distribution:  
Buprenorphine is approximately 96% protein bound, primarily to alpha and beta globulin. 
Naloxone is approximately 45% protein bound, primarily to albumin. 
Metabolism: 
Buprenorphine undergoes both N-dealkylation to norbuprenorphine and glucuronidation.  The N-
dealkylation pathway is mediated primarily by the CYP3A4.  Norbuprenorphine, the major metabolite, 
can further undergo glucuronidation. Norbuprenorphine has been found to bind opioid receptors in 
vitro; however, it has not been studied clinically for opioid-like activity. Naloxone undergoes direct 
glucuronidation to naloxone-3-glucuronide as well as N-dealkylation, and reduction of the 6-oxo group. 
Elimination: 
A mass balance study of buprenorphine showed complete recovery of radiolabel in urine (30%) and 
feces (69%) collected up to 11 days after dosing.  Almost all of the dose was accounted for in terms of 
buprenorphine, norbuprenorphine, and two unidentified buprenorphine metabolites.  In urine, most of 
buprenorphine and norbuprenorphine was conjugated (buprenorphine, 1% free and 9.4% conjugated; 
norbuprenorphine, 2.7% free and 11% conjugated).  In feces, almost all of the buprenorphine and 
norbuprenorphine were free (buprenorphine, 33% free and 5% conjugated; norbuprenorphine, 21% free 
and 2% conjugated). Based on all studies performed with SUBOXONE sublingual film, buprenorphine has 
a mean elimination half-life from plasma ranging from 24 to 42 hours and naloxone has a mean 
elimination half-life from plasma ranging from 2 to 12 hours. 
• 
Drug-drug Interactions: 
CYP3A4 Inhibitors and Inducers:  Subjects receiving SUBOXONE sublingual film should be monitored if 
inhibitors of CYP3A4 such as azole antifungal agents (e.g., ketoconazole), macrolide antibiotics (e.g., 
erythromycin) or HIV protease inhibitors and may require dose-reduction of one or both agents.  The 
interaction of buprenorphine with all CYP3A4 inducers has not been studied, therefore it is 
recommended that patients receiving SUBOXONE sublingual film be monitored for signs and symptoms 
of opioid withdrawal if inducers of CYP3A4 (e.g., phenobarbital, carbamazepine, phenytoin, rifampicin) 
are co-administered [see Drug Interactions (7.1)].  
Buprenorphine has been found to be a CYP2D6 and CYP3A4 inhibitor and its major metabolite, 
norbuprenorphine, has been found to be a moderate CYP2D6 inhibitor in in vitro studies employing 
human liver microsomes. However, the relatively low plasma concentrations of buprenorphine and 
norbuprenorphine resulting from therapeutic doses are not expected to raise significant drug-drug 
interaction concerns.  
• 
Special Populations: 


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Hepatic Impairment: In a pharmacokinetic study, the disposition of buprenorphine and naloxone were 
determined after administering a SUBOXONE 2.0/0.5 mg (Buprenorphine/Naloxone) sublingual tablet in 
subjects with varied degrees of hepatic impairment as indicated by Child-Pugh criteria. The disposition 
of buprenorphine and naloxone in patients with hepatic impairment were compared to disposition in 
subjects with normal hepatic function.  
 
In subjects with mild hepatic impairment, the changes in mean Cmax, AUC0-last, and half-life values of both 
buprenorphine and naloxone were not clinically significant. No dosing adjustment is needed in patients 
with mild hepatic impairment. 
 
For subjects with moderate and severe hepatic impairment, mean Cmax, AUC0-last, and half-life values of 
both buprenorphine and naloxone were increased; the effects on naloxone are greater than that on 
buprenorphine (Table 4).  
 
Table 4.  Changes in Pharmacokinetic Parameters in Subjects With Moderate and Severe Hepatic 
Impairment 
Hepatic 
Impairment 
PK Parameters 
Increase in buprenorphine 
compared to healthy subjects 
Increase in naloxone 
compared to healthy 
subjects 
Moderate 
Cmax 
8% 
170% 
AUC0-last 
64% 
218% 
Half-life 
35% 
165% 
Severe 
Cmax 
72% 
1030% 
AUC0-last 
181% 
1302% 
Half-life 
57% 
122% 
 
The difference in magnitude of the effects on naloxone and buprenorphine are greater in subjects with 
severe hepatic impairment than subjects with moderate hepatic impairment, and therefore the clinical 
impact of these effects is likely to be greater in patients with severe hepatic impairment than in patients 
with moderate hepatic impairment. Buprenorphine/naloxone products should be avoided in patients 
with severe hepatic impairment and may not be appropriate for patients with moderate hepatic 
impairment [see Warnings and Precautions (5.11) and Use in Specific Populations (8.6)]. 
 
HCV infection: In subjects with HCV infection but no sign of hepatic impairment, the changes in the 
mean Cmax, AUC0-last, and half-life values of buprenorphine and naloxone were not clinically significant in 
comparison to healthy subjects without HCV infection.  No dosing adjustment is needed in patients with 
HCV infection. 
13 
NONCLINICAL TOXICOLOGY 
13.1 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
Carcinogenicity:   
Carcinogenicity data on SUBOXONE sublingual film are not available. 


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A carcinogenicity study of buprenorphine/naloxone (4:1 ratio of the free bases) was performed in 
Alderley Park rats.  Buprenorphine/naloxone was administered in the diet at doses of approximately 7, 
31, and 123 mg/kg/day for 104 weeks (estimated exposure was approximately 4, 18, and 44 times the 
recommended human sublingual dose of 16 mg/4 mg buprenorphine/naloxone based on buprenorphine 
AUC comparisons).  A statistically significant increase in Leydig cell adenomas was observed in all dose 
groups.  No other drug-related tumors were noted. 
Carcinogenicity studies of buprenorphine were conducted in Sprague-Dawley rats and CD-1 mice. 
Buprenorphine was administered in the diet to rats at doses of 0.6, 5.5, and 56 mg/kg/day (estimated 
exposure was approximately 0.4, 3, and 35 times the recommended human daily sublingual dose of 16 
mg on a mg/m2 basis) for 27 months.  As in the buprenorphine/naloxone carcinogenicity study in rat, 
statistically significant dose-related increases in Leydig cell tumors occurred.  In an 86-week study in 
CD-1 mice, buprenorphine was not carcinogenic at dietary doses up to 100 mg/kg/day (estimated 
exposure was approximately 30 times the recommended human daily sublingual dose of 16 mg on a 
mg/m2 basis). 
Mutagenicity:  
The 4:1 combination of buprenorphine and naloxone was not mutagenic in a bacterial mutation assay 
(Ames test) using four strains of S. typhimurium and two strains of E. coli.  The combination was not 
clastogenic in an in vitro cytogenetic assay in human lymphocytes or in an IV micronucleus test in the 
rat.  
Buprenorphine was studied in a series of tests utilizing gene, chromosome, and DNA interactions in both 
prokaryotic and eukaryotic systems.  Results were negative in yeast (S. cerevisiae) for recombinant, gene 
convertant, or forward mutations; negative in Bacillus subtilis “rec” assay, negative for clastogenicity in 
CHO cells, Chinese hamster bone marrow and spermatogonia cells, and negative in the mouse 
lymphoma L5178Y assay. 
Results were equivocal in the Ames test: negative in studies in two laboratories, but positive for frame 
shift mutation at a high dose (5mg/plate) in a third study.  Results were positive in the Green-Tweets (E. 
coli) survival test, positive in a DNA synthesis inhibition (DSI) test with testicular tissue from mice, for 
both in vivo and in vitro incorporation of [3H]thymidine, and positive in unscheduled DNA synthesis 
(UDS) test using testicular cells from mice. 
Impairment of Fertility:  
Dietary administration of buprenorphine in the rat at dose levels of 500 ppm or greater (equivalent to 
approximately 47 mg/kg/day or greater; estimated exposure approximately 28 times the recommended 
human daily sublingual dose of 16 mg on a mg/m2 basis) produced a reduction in fertility demonstrated 
by reduced female conception rates.  A dietary dose of 100 ppm (equivalent to approximately 10 
mg/kg/day; estimated exposure approximately 6 times the recommended human daily sublingual dose 
of 16 mg on a mg/m2 basis) had no adverse effect on fertility. 
16 
HOW SUPPLIED / STORAGE AND HANDLING 
SUBOXONE sublingual film is supplied as an orange rectangular sublingual film with a white printed logo 
in child-resistant polyester/foil laminated pouches: 
• 
NDC 12496-1202-3 (buprenorphine/naloxone 2 mg/0.5 mg/film; content expressed in terms of 
free base) - 30 films per carton 
• 
NDC 12496-1204-3 (buprenorphine/naloxone 4 mg/1 mg/film; content expressed in terms of 
free base) - 30 films per carton 


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• 
NDC 12496-1208-3 (buprenorphine/naloxone 8 mg/2 mg/film; content expressed in terms of 
free base) -30 films per carton 
• 
NDC 12496-1212-3 (buprenorphine/naloxone 12 mg/3 mg/film; content expressed in terms of 
free base) - 30 films per carton 
Store at 25°C (77°F), excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature] 
• 
Patients should be advised to store buprenorphine-containing medications safely and out of 
sight and reach of children.   
• 
Rx only 
17 
PATIENT COUNSELING INFORMATION 
See FDA-approved patient labeling (Medication Guide) 
Patients should be advised NOT to cut, chew or swallow SUBOXONE sublingual film. 
17.1 
Safe Use 
Before initiating treatment with SUBOXONE, explain the points listed below to caregivers and 
patients. Instruct patients to read the Medication Guide each time SUBOXONE is dispensed because 
new information may be available. 
Patients should be warned that it is extremely dangerous to self-administer non-prescribed 
benzodiazepines or other CNS depressants (including alcohol) while taking SUBOXONE sublingual 
film.  Patients prescribed benzodiazepines or other CNS depressants should be cautioned to use 
them only as directed by their physician [see Warnings and Precautions (5.2), Drug Interactions 
(7.3)]. 
Patients should be advised that SUBOXONE sublingual film contains an opioid that can be a target for 
people who abuse prescription medications or street drugs.  Patients should be cautioned to keep 
their films in a safe place, and to protect them from theft. 
Patients should be instructed to keep SUBOXONE sublingual film in a secure place, out of the sight and 
reach of children.  Accidental or deliberate ingestion by a child may cause respiratory depression 
that can result in death.  Patients should be advised that if a child is exposed to SUBOXONE 
sublingual film, medical attention should be sought immediately.   
Patients should be advised never to give SUBOXONE sublingual film to anyone else, even if he or she has 
the same signs and symptoms.  It may cause harm or death. 
Patients should be advised that selling or giving away this medication is against the law. 
Patients should be cautioned that SUBOXONE sublingual film may impair the mental or physical abilities 
required for the performance of potentially dangerous tasks such as driving or operating machinery.  
Caution should be taken especially during drug induction and dose adjustment and until individuals 
are reasonably certain that buprenorphine therapy does not adversely affect their ability to engage 
in such activities [see Warnings and Precautions (5.11)]. 
Patients should be advised not to change the dosage of SUBOXONE sublingual film without consulting 
their physician. 
Patients should be advised to take SUBOXONE sublingual film once a day. 


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Patients should be advised that if they miss a dose of SUBOXONE they should take it as soon as they 
remember. If it is almost time for the next dose, they should skip the missed dose and take the next 
dose at the regular time. 
Patients should be informed that SUBOXONE sublingual film can cause drug dependence and that 
withdrawal signs and symptoms may occur when the medication is discontinued. 
Patients seeking to discontinue treatment with buprenorphine for opioid dependence should be advised 
to work closely with their physician on a tapering schedule and should be apprised of the potential 
to relapse to illicit drug use associated with discontinuation of opioid agonist/partial agonist 
medication-assisted treatment. 
Patients should be cautioned that, like other opioids, SUBOXONE sublingual film may produce 
orthostatic hypotension in ambulatory individuals [see Warnings and Precautions (5.12)]. 
Patients should inform their physician if any other prescription medications, over-the-counter 
medications, or herbal preparations are prescribed or currently being used [see Drug Interactions 
(7.1, 7.2 and 7.3)]. 
Women of childbearing potential who become pregnant or are planning to become pregnant, should be 
advised to consult their physician regarding the possible effects of using SUBOXONE sublingual film 
during pregnancy [see Use in Specific Populations (8.1)]. 
Advise women who are breastfeeding to monitor the infant for drowsiness and difficulty breathing [see 
Use in Specific Populations (8.3)].   
Patients should inform their family members that, in the event of emergency, the treating physician or 
emergency room staff should be informed that the patient is physically dependent on an opioid and 
that the patient is being treated with SUBOXONE sublingual film. 
Refer to the Medication Guide for additional information regarding the counseling information. 
 
17.2 
Disposal of Unused SUBOXONE Sublingual Films 
 
Unused SUBOXONE sublingual films should be disposed of as soon as they are no longer needed. 
Unused films should be flushed down the toilet.  
 
Revised: April 2014 
 
Manufactured for Reckitt Benckiser 
Pharmaceuticals Inc., 
Richmond, VA 23235 by:  
MonoSol Rx, LLC,  
Warren, NJ 07059 
 
Distributed by: 
Reckitt Benckiser Pharmaceuticals Inc. 
Richmond, VA 23235 


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Appendix 8 
Study Drug Preparation, Administration, and Depot 
Removal Instructions 
RBP-6000 PREPARATION AND DOSING PROCEDURE 
• 100 MG BUPRENORPHINE 
• 300 MG BUPRENORPHINE  
 
IMPORTANT:  Only qualified study personnel can prepare the study drug.  Protective gloves 
(latex or nitrile) should be worn when preparing and dosing RBP-6000.  Remove the product 
from the refrigerator at least 15 minutes before use to allow the product to reach room 
temperature before dosing.  Product may be left at room temperature up to 8 hours prior to use.  
If product is not used that day it should be marked appropriately.   
   
FOLLOW THE INSTRUCTIONS AS DIRECTED TO ENSURE PROPER DOSING 
Preparation of the Product Prior to Administration:  
The following components will be used in the preparation of RBP-6000: 
• One sealed foil pouch containing a syringe pre-filled with RBP-6000 and an oxygen 
absorber pack.  
• One sterile 19-gauge, one-inch hypodermic safety needle 
 
1. On a clean field, open the foil pouch and remove the contents. Discard the oxygen absorber 
pack.   The pouch must be retained for accountability. 
2. Un-cap the pre-filled RBP-6000 syringe and attach the safety needle cartridge by pushing in 
and turning the needle until it is finger tight. Do not strip the threaded fitting by over-
tightening the needle. Position the sheath at 90 degrees to the needle.  Pull off the needle 
cartridge cover.   More complete documentation on the usage of the SurGuard2 safety needle 
can be found in the included instruction sheet.  
3. While holding the syringe vertically with the tip upwards, expel air bubbles by stroking the 
plunger up and down. 
4. The product is now ready for administration.  Carefully recap the needle. 
Administration Procedure: 
IMPORTANT: Once prepared (removed from foil pouch), the product must be 
administered within a maximum of 30 minutes. 
 
Choose an injection site below the waist but above the hip bone; from where the body curves at 
the side to about 2 inches from the middle of the abdomen with adequate amounts of 
subcutaneous tissue that does not have excessive pigment, nodules, lesions, or hair.  Since you 
can vary the injection site with a subcutaneous injection, choose an area that has not recently 
been used.   
 
Possible injection site locations and an injection rotation pattern are shown in Figure 4.  
Injections should be started based on where the last injection in RB-US-13-0001 was given for 
roll-over subjects. 


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Figure 4 
Injection Locations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. Cleanse the injection-site area with an alcohol swab.   
 
2. Using the thumb and forefinger of your non-dominant hand, grab and bunch the area of skin 
around the injection site. 
 
3. Using your dominant hand, insert approximately half the needle length quickly. The 
approximate angle you use will depend on the amount and fullness of the subcutaneous tissue 
and the length of the needle. 
 
4. After the needle is inserted, release the skin with your nondominant hand. 
 
5. Pull back on the plunger to check for blood.  If blood is present in the syringe, do not inject.  
Withdraw the needle and discard all components safely in an appropriate biohazard 
container.  Repeat the “Preparation of the Product Prior to Administration” procedures and 
the “Administration Procedure” using a different abdominal injection site with another 
syringe of RBP-6000 and associated components. 
 
6. Inject the product using a slow, steady push. Press down on the plunger until the syringe is 
empty. 
 
7. Withdraw the needle at the same angle used for insertion. Do not rub the injection area.  If 
there is bleeding, apply minimal pressure with a gauze pad or bandage.  Engage the safety 
sheath on the needle as per the SurGuard2 needle instructions.   
 
8. Discard all components safely in an appropriate biohazard container. 
 
Hipbones 
Waist 
1 / 5 
2 / 6 
3 
4 


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PROCEDURE FOR REMOVAL OF THE RBP-6000 DEPOT 
 
In the event of an emergency or if a subject withdraws or is withdrawn within the first 14 days of 
receiving an injection of RBP-6000, subjects may have the option to have the depot surgically 
removed by a physician delegated to perform surgery. The medically responsible physician 
should carefully discuss this option with subjects given the use of ATRIGEL Delivery System 
and the feasibility of extracting the depot. 
 
The following surgical procedure should be followed: 
 
1. 
Palpate the depot and surrounding area to confirm its exact location. 
2. 
Cleanse the area with an antiseptic solution (e.g., Betadine).   
3. 
Infiltrate the area with a local anesthesia (e.g., Lidocaine 1% or a lidocaine/adrenaline 
[epinephrine] mixture) and wait for it to take effect. 
4. 
Cover the area with a sterile drape. 
5. 
Incise the skin up to the subcutaneous tissues using a scalpel.  
6. 
Using blunt and sharp dissection, identify the plane between the depot and surrounding 
subcutaneous tissues.  Once the plane is identified, separate the superficial 25% of the 
circumference of the depot with blunt dissection.  
7. 
Gently lift the incised ellipse of skin and depot with forceps.   
8. 
Once the depot is removed, ensure hemostasis, and close the skin with non-absorbable 
sutures.   
9. 
The extracted RBP-6000 depot will be disposed of into an appropriate, secure biohazard 
container per the SOP at the clinical site. 
 


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Appendix 9 
Prohibited Cytochrome P450 Inhibitors and Inducers 
The following medications are prohibited during the study: 
Cytochrome 
P450 3A4 
Inhibitors 
Cytochrome 
P450 3A4 
Inducers 
Cytochrome 
P450 2C8 
Inhibitors 
Cytochrome 
P450 2C8 
Inducers 
Amiodarone 
Ketoconazole 
Barbiturates 
Gemifibrozil 
Rifampicin 
Amprenavir 
Metronidazole 
Carbamazepine 
Trimethoprim 
 
Aprepitant 
Mibefradil 
Dexamethasone 
Glitazones 
 
Chloramphenicol Miconazole 
Efavirenz 
Montelukast 
 
Cimetidine 
Mifepristone 
Ethosuximide 
Quercetin 
 
Ciprofloxacin 
Nefazodone 
Glucocorticoids 
 
 
Clarithromycin 
Nelfinavir 
Glutethimide 
 
 
Clotrimazole 
Nicardipine 
Modafinil 
 
 
Cyclosporine 
Norfloxacin 
Nevirapine 
 
 
Delavirdine 
Norfluoxetine 
Oxcarbazepine 
 
 
Diethyl-
dithiocarbamate 
Propofol 
Phenobarbital 
 
 
Diltiazem 
Quinine 
Phenytoin 
 
 
Ethinyl estradiol 
Ritonavir 
Pioglitazone 
 
 
Erythromycin 
Saquinavir 
Primidone 
 
 
Fluconazole 
Sertraline 
Rifabutin 
 
 
Fluoxetine 
Starfruit 
Rifampin 
 
 
Fluvoxamine 
Telithromycin 
Hypericum 
perforatum 
 
 
Gestodene 
Troleandomycin 
Sulfadimidine 
 
 
Grapefruit juice 
Verapamil 
Sulfinpyrazone 
 
 
Imatinib 
Voriconazole 
Troglitazone 
 
 
Indinavir 
Zafirlukast 
Troleandomycin 
 
 
Itraconazole 
 
 
 
 
Source:  http://medicine.iupui.edu/clinpharm/ddis/clinical-table/ 


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Appendix 10 
Columbia Suicide Severity Rating Scale (eC-SSRS) -- 
Baseline/Screening Version 
 
 


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Appendix 11 
Columbia Suicide Severity Rating Scale (eC-SSRS) -- 
Since Last Visit Version 
 


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Appendix 12 
Clinical Opiate Withdrawal Scale (COWS) 
 
0 - Pulse rate 80 or below
1 - Pulse rate 81 - 100
2 - Pulse rate 101 - 120
4 - Pulse rate greater than 120
1. Resting Pulse Rate:
Measured after patient is sitting or lying for one minute.
0 - No GI symptoms
1 - Stomach cramps
2 - Nausea or loose stool
3 - Vomiting or diarrhea
5 - Multiple episodes of diarrhea or vomiting
2. GI upset: Over last 1/2 hour.
0 - No report of chills or flushing
1 - Subjective report of chills or flushing
2 - Flushed or observable moistness on face
3 - Beads of sweat on brow or face
4 - Sweat streaming off face
3. Sweating:
Over past 1/2 hour not accounted for by room temperature or patient activity.
0 - No tremor
1 - Tremor can be felt, but not observed
2 - Slight tremor observable
4 - Gross tremor or muscle twitching
4. Tremor:
Observation of outstretched hands.
0 - Able to sit still
1 - Reports difficulty sitting still, but is able to do so
3 - Frequent shifting or extraneous movements of legs/arms
5 - Unable to sit still for more than a few seconds
5. Restlessness:
For each item, mark the choice that best describes the subject's signs or symptom. Rate on just the
apparent relationship to opiate withdrawal. For example, if heart rate is increased because the patient was
jogging just prior to assessment, the increased pulse rate would not add to the score.
beats/min
Observation during assessment.
0 - No yawning
1 - Yawning once or twice during assessment
2 - Yawning three or more times during assessment
4 - Yawning several times/minute
6. Yawning: Observation durring assessment.
CLINICAL OPIOID WITHDRAWAL SCALE (COWS)
 
 
OPIATE 


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0 - Not present
1 - Nasal stuffiness or unusually moist eyes
2 - Nose running or tearing
4 - Nose constantly running or tears streaming down cheeks
11. Runny nose or tearing:
0 - None
1 - Patient reports increasing irritability or anxiousness
2 - Patient obviously irritable or anxious
4 - Patient so irritable or anxious that participation in the assessment is difficult
8. Anxiety or Irritability:
0 - Not present
1 - Mild diffuse discomfort
2 - Patient reports severe diffuse aching of joints/muscle
4 - Patient is rubbing joints or muscles and is unable to sit still because of discomfort
9. Bone or Joint aches:
0 - Skin is smooth
3 - Piloerection of skin can be felt or hairs standing up on arms
5 - Prominent piloerection
10. Gooseflesh skin:
0 - Pupils pinned or normal size for room light
1 - Pupils possibly larger than normal for room light
2 - Pupils moderately dilated
5 - Pupils so dilated that only the rim of the iris is visible
7. Pupil Size:
If patient was having pain previously, only the additional component attributed to opiate
withdrawal is scored.
Not accounted for by cold symptoms or allergies.
TOTAL SCORE (sum of all 11 items):
Score Interpretation: 5 - 12= Mild, 13 - 24= Moderate, 25 - 36=Moderately Severe, More than 36= Severe Withdrawal


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Appendix 13 
Subjective Opiate Withdrawal Scale (SOWS) 
 
Modified from : Handelsman L, Cochrane KJ, Aronson MJ, Ness R, Rubenstein KJ, Kanof PD 
(1987). Two new rating scales for opiate withdrawal.  Am J Drug Alcohol Abuse 13:293-308. 


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Appendix 14 
Opioid Craving Visual Analog Scale (Opioid Craving VAS) 
 
No craving 
_________________________________________Strongest craving ever 
100 mm scale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 15 
Injection Site Grading Scale 
 
Injection 
Site 
Reactions 
None 
(Grade 0) 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Pain 
None 
Does not 
interfere with 
activity 
Repeated use of non-
narcotic pain reliever 
> 24 hours or 
interferes with 
activity  
Any use of narcotic 
pain reliever or 
prevents daily 
activity 
Emergency room  
(ER) visit or  
hospitalization  
Tenderness 
None 
Mild discomfort 
to touch. 
Discomfort with 
movement. 
Significant 
discomfort at rest  
ER visit or 
hospitalization 
Erythema/ 
Redness* 
(quantitative) 
None 
2.5 – 5 cm 
5.1 – 10 cm 
> 10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration ** 
None 
2.5 – 5 cm and 
does not 
interfere  
with activity  
5.1 – 10 cm or  
interferes with  
activity  
> 10 cm or  
prevents daily  
activity  
Necrosis  
Swelling ** 
(subjective) 
None 
2.5 – 5 cm and 
does not 
interfere  
with activity  
5.1 – 10 cm or  
interferes with  
activity  
> 10 cm or  
prevents daily  
activity  
Necrosis  
 
* In addition to grading the measured local reaction at the greatest single diameter, the measurement should be  
recorded as a continuous variable.  
** Induration/Swelling should be evaluated and graded using the functional scale as well as the actual measurement.  
 
Modified from:   
U.S. Department of Health and Human Services, Food and Drug Administration, Center for 
Biologics Evaluation and Research, September 2007.  Guidance for Industry: Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials. [pdf] Available at: 
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInform
ation/Guidances/Vaccines/ucm091977.pdf.  Accessed 14 April 2015. 


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Appendix 16 
Injection Site Pain Visual Analog Scale (Injection Site Pain 
VAS) 
How would you rate your injection site pain today? 
 
                  No  _________________________________________ Pain as bad  
                  Pain                                                                                  as it could be 
 
 
 
 
 
Please answer the following question by checking the box with either a “Yes” or “No”: 
Are you currently experiencing any burning or stinging at the injection site? 
 
 
 
 
YES   
 
 
 
NO 
 


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Appendix 17 
Timeline Followback (TLFB) Interview 
 
 
Ethanol 


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Appendix 18 
Euro QoL EQ-5D-5L Health Questionnaire 
 


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Appendix 19 
Short Form (36) Health Survey v2 
 


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Appendix 20 
Medication Satisfaction Questionnaire  
Overall, how satisfied are you with your current opioid dependence medication? 
 
1 = extremely dissatisfied 
2 = very dissatisfied 
3 = somewhat dissatisfied 
4 = neither satisfied nor dissatisfied 
5 = somewhat satisfied 
6 = very satisfied 
7 = extremely satisfied 
 


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Appendix 21 
Health Care Resource Utilization Questionnaire 
HEALTH INSURANCE 
Primary Health Insurance  
(Please check all  that apply) 
 Commercial (for example, Blue Cross Blue  
Shield,  Aetna, Humana, United, Cigna) 
 Medicare 
 Medicaid 
 Veterans Affairs 
 Workers compensation 
 Other insurance 
 Self-pay / Out of pocket/No insurance 
 
 
INPATIENT ADMISSIONS 
 
• 
Please list in the table below all inpatient admissions in the past 30 days.  If patient is currently 
hospitalized, please check the box in the “Ongoing” column. 
• 
If patient has had no previous hospitalizations in the past 30 days, please check the 
appropriate box below. 
 No hospitalizations since the last study visit 
Admission Date  
(dd / mmm / yyyy) 
Discharge Date 
(dd / mmm / yyyy) 
Ongoing? 
Type of Admission 
1. 
_ _ / _ _ _ / _ _ _ _ 
_ _ / _ _ _ / _ _ _ _ 
 
Medical 
Surgical 
Psychiatric 
Other 
2. 
_ _ / _ _ _ / _ _ _ _ 
_ _ / _ _ _ / _ _ _ _ 
 
 Medical 
Surgical 
Psychiatric 
Other 
3. 
_ _ / _ _ _ / _ _ _ _ 
_ _ / _ _ _ / _ _ _ _ 
 
 Medical 
Surgical 
Psychiatric 
Other 
 


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EMERGENCY ROOM VISITS  
• 
Please list how many times the patient has been to the Emergency Room in the past 30 days. 
Type of Problem 
Number of Visits 
Substance abuse-related 
visits 
Other medical problems 
visits 
 
 
OUTPATIENT SERVICES 
• 
Please list how many times the patient has seen 1 of the following health professionals in the 
past 30 days. The outpatient services captured on this questionnaire are ones conducted 
outside the study 
Health Professional 
Number of Visits 
General practitioner / Internist 
visits 
Addiction Medicine Specialist 
visits 
Therapist / Counselor 
visits 
Other: Specialist 
visits 
Other:  Non-Specialist  
visits 
 


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Appendix 22 
Treatment Effectiveness Assessment (TEA) 
 
 


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Appendix 23 
Addiction Severity Index (ASI) Lite 
 


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Appendix 24 
Beck Depression Inventory II (BDI-II) 
To be supplied by RBP.   
http://www.pearsonclinical.com/psychology/products/100000159/beck-depression-inventoryii-
bdi-ii.html?Pid=015-8018-370&Mode=summary#tab-details 


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Appendix 25 
Brief Pain Inventory (BPI) Short Form 
To be supplied by RBP.   
http://www.mdanderson.org/education-and-research/departments-programs-and-
labs/departments-and-divisions/symptom-research/symptom-assessment-
tools/BPI_UserGuide.pdf 


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Appendix 26 
Sponsor Signatures 
Study Title: 
An Open-Label, Long-Term Safety and Tolerability Study of Depot 
Buprenorphine (RBP-6000) in Treatment-Seeking Subjects With 
Opioid Use Disorder 
Study Number: 
RB-US-13-0003 
Final Date: 
11 September 2015 
 
This clinical study protocol was subject to critical review and has been approved by the Sponsor.  
The following personnel contributed to writing and/or approving this protocol: 
 
Signed: 
 
 
Date:  
 
 
Senior Fellow, Clinical Science 
Indivior Inc. 
Signed: 
 
 
Date:  
 
 
Director, Clinical Pharmacology and Translational Medicine  
Indivior Inc. 
Signed: 
 
 
Date:  
 
 
Senior Manager, Clinical Pharmacology and Translational Medicine 
Indivior Inc. 
Signed: 
 
 
Date:  
 
 
Director, Biostatistics and Statistical Programming 
Indivior Inc. 
Signed: 
 
Date:  
 
 
Global Director, Health Economics 
Indivior Inc. 
Signed: 
 
Date:  
 
 
Medical Advisor 
Indivior Inc. 


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Appendix 27 
Investigator’s Signature 
Study Title: 
An Open-Label, Long-Term Safety and Tolerability Study of Depot 
Buprenorphine (RBP-6000) in Treatment-Seeking Subjects With 
Opioid Use Disorder 
Study Number: 
RB-US-13-0003 
Final Date: 
11 September 2015 
I have read the protocol described above. I agree to comply with all applicable regulations and to 
conduct the study as described in the protocol.  [enter additional text, if applicable] 
 
 
Signed: 
 
 
Date:  
 
Printed Name and Credentials: 
Title: 
Site Name: 
Address: 
Telephone: 
 
 
 
 

Prot_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
Study Title 
An Open-Label, Long-Term Safety and Tolerability Study of Depot 
Buprenorphine (RBP-6000) in Treatment-Seeking Subjects With 
Opioid Use Disorder 
NCT Number 
NCT02510014 
Date 
August 19, 2015 
 


Clinical Study Protocol: RB-US-13-0003 
Study Title: 
An Open-Label, Long-Term Safety and Tolerability Study of Depot 
Buprenorphine (RBP-6000) in Treatment-Seeking Subjects With 
Opioid Use Disorder 
Study Number: 
RB-US-13-0003 
Study Phase: 
3 
Product Name: 
RBP-6000 
IND Number: 
107,607 
Indication: 
Treatment of Opioid Use Disorder 
Investigators: 
Multicenter 
Sponsor: 
Indivior Inc. 
 
10710 Midlothian Turnpike, Suite 430 
Richmond, VA 23235 
 
Sponsor Contact: 
 
 
 
Medical Monitor: 
 
 
 
Date 
Original Protocol: 
14 April 2015 
Amendment 1: 
19 August 2015 
 
 
 
 
 
 
 
Confidentiality Statement 
The information contained in this document is privileged and confidential. Do not copy, 
circulate, or otherwise distribute without written authorization from  
Indivior Inc. 


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SYNOPSIS 
Sponsor:  
Indivior Inc., formerly Reckitt Benckiser Pharmaceuticals Inc. (RBP) 
Name of Finished Product: 
RBP-6000, 18% buprenorphine sterile solution for subcutaneous (SC) injection 
Name of Active Ingredient: 
Buprenorphine 
Name of Inactive Ingredient:  
ATRIGEL® Delivery System 
Study Title: 
An Open-Label, Long-Term Safety and Tolerability Study of Depot Buprenorphine (RBP-6000) 
in Treatment-Seeking Subjects With Opioid Use Disorder 
Study Number: 
RB-US-13-0003 
Study Phase: Phase 3 
Primary Objective: 
To assess the long-term safety and tolerability of RBP-6000 subcutaneous (SC) injections in 
subjects with opioid use disorder. 
Secondary Objective: 
To collect clinical outcome data with RBP-6000 SC injections in subjects with opioid use 
disorder. 
Tertiary Objectives:  
To evaluate the: 
• Pharmacokinetics (PK) of RBP-6000,  
• Relationships between RBP-6000 PK and clinical outcome data, and 
• Impact of RBP-6000 on health and economic outcomes. 
Study Design: 
This is a multicenter, open-label, long-term safety study in which approximately 600 subjects 
diagnosed with opioid use disorder will be enrolled (approximately 300 subjects who did not 
participate in Study RB-US-13-0001, the double-blind, placebo-controlled efficacy study of 
RBP-6000 [hereafter referred to as “de novo” subjects], and 300 subjects who completed the RB-
US-13-0001 study [hereafter referred to as “roll-over” subjects]).  Subject participation will be 
based on the Investigator’s determination that initiation or continuation of study treatment is 
appropriate; and, for subjects who participated in RB-US-13-0001, that there have been no 
significant protocol deviations or clinically relevant adverse events (AEs) that would preclude 
inclusion of the subject in this study. All subjects will provide written informed consent before 
any protocol-related procedures commence. At the Screening Visit (which is up to 3 days after 
the End of Study [EOS] Visit [Day 169 + 3] for roll-over subjects), potential subjects will be 


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reviewed for eligibility against inclusion and exclusion criteria, and eligible subjects will be 
enrolled into the trial.  
SUBOXONE Sublingual Film Run-In:  Induction 
De novo Subjects: 
De novo subjects will initially be inducted onto SUBOXONE® (buprenorphine/naloxone) 
sublingual film for 3 days according to the SUBOXONE sublingual film prescribing 
information.  They will receive their first dose of SUBOXONE sublingual film on Induction 
Day 1 after it is confirmed that the subject meets eligibility criteria and has a Clinical Opiate 
Withdrawal Scale (COWS) score > 12.  Subjects will be started with an initial dose of 2 mg/0.5 
mg (buprenorphine/naloxone) or 4 mg/1 mg and may titrate upwards in 2 or 4 mg increments of 
buprenorphine, at approximately 2-hour intervals, under clinical supervision, to 8 mg/2 mg based 
on therapeutic response.  
On Induction Day 2, subjects with a COWS score > 12 or subjects reporting withdrawal 
signs/symptoms overnight will receive a dose of SUBOXONE sublingual film equal to the total 
dose given on Induction Day 1 plus 4 mg.  (For example, if a subject received a total dose of 8 
mg of buprenorphine on Induction Day 1, the starting dose for Induction Day 2 would be 12 mg).  
If the COWS score is still > 12 one hour later, another 4 mg dose can be given. The subject 
should not exceed a maximum dose of 16 mg buprenorphine for Induction Day 2. Subsequent 
SUBOXONE sublingual film doses must be separated by at least 1 hour from the preceding dose. 
SUBOXONE sublingual film doses may also be adjusted downward if necessary.  
On Induction Day 3, subjects will be titrated to therapeutic response based on COWS scores as 
well as physician judgment. Most subjects will only require a single dose on Induction Day 3, 
which will equal the Induction Day 2 dose or the Induction Day 2 dose plus 4 mg buprenorphine. 
Additional doses may also be administered on Induction Day 3 (up to 24 mg/6 mg). Subsequent 
SUBOXONE sublingual film doses must be separated by at least 1 hour from the preceding dose.  
Subjects should reach a daily dose of between 8 mg and 24 mg buprenorphine by Induction Day 
3 and continue on that dose through the remainder of the SUBOXONE sublingual film Run-In 
period, with additional dose adjustments if necessary.  
Roll-over Subjects: 
Following screening, roll-over subjects will be inducted onto SUBOXONE sublingual film to 
achieve daily doses between 8 mg to 24 mg buprenorphine according to the SUBOXONE 
sublingual film prescribing information.  
Subjects will receive their first induction dose on Induction Day 1. Subjects should be started 
with an initial dose of 2 mg/0.5 mg (buprenorphine/naloxone) or 4 mg/1 mg and may titrate 
upwards in 2 or 4 mg increments of buprenorphine, at approximately 2-hour intervals, under 
supervision, to a total dose of up to 8 mg/2 mg based on the control of acute withdrawal 
symptoms.  
On Induction Day 2, subjects with a score for COWS of >12, or subjects reporting opioid 
withdrawal signs/symptoms overnight, should receive a dose of study drug equal to the total dose 
given on Induction Day 1 plus 4 mg.  If the COWS score is still >12 one hour later, another 4 mg 
dose can be given.  The subject should not exceed a maximum dose of 16 mg/4 mg for Induction 
Day 2.  Subsequent SUBOXONE sublingual film doses must be separated by at least 1 hour 
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necessary.   
On Induction Day 3, subjects will be titrated to therapeutic response until a therapeutic dosage is 
reached, based on COWS scores as well as physician judgment. Most subjects will only require a 
single dose on Induction Day 3 which will equal the Induction Day 2 dose or the Induction Day 2 
dose plus 4 mg. Additional doses may also be administered on Induction Day 3 (up to 24 mg).  
Subsequent SUBOXONE sublingual film doses must be separated by at least 1 hour from the 
preceding dose.  Although subjects should reach a daily dose of between 8 mg and 24 mg by 
Induction Day 3 and continue on that dose through the remainder of the SUBOXONE sublingual 
film Run-In period, dose adjustments may be necessary during the Run-In period.  
Roll-over subjects must be titrated to a minimum dose of 8 mg SUBOXONE by the end of the 
3-day Induction period regardless of their COWS scores and/or the presence or absence of 
withdrawal symptoms.   
The SUBOXONE sublingual film(s) will be administered under the tongue, close to the base on 
the left or right side, until they are dissolved.  If an additional sublingual film is required, it 
should be placed on the opposite side from the first film.  Subjects should be instructed to hold 
the films under the tongue until they dissolve.  If a third film is required, it should be placed 
under the tongue after the first 2 films have dissolved.   
SUBOXONE Sublingual Film Run-In:  Dose Adjustment (All Subjects) 
After the daily induction visits, all subjects will begin a 1-to 11-day SUBOXONE sublingual 
film dose adjustment period.  Subjects will return to the clinic at 3- to 4-day intervals for Opioid 
Craving Visual Analog Scale (VAS), COWS, and Subjective Opiate Withdrawal Scale (SOWS) 
assessments.  SUBOXONE sublingual film will be dispensed at each visit for at home dosing.  
Beginning on the 4th day of SUBOXONE sublingual film dosing, subjects will be evaluated for 
Day -1 criteria, which are identical to the criteria required for enrollment on Day 1.  These 
criteria include the following: no allergic reaction to SUBOXONE sublingual film, a daily dose 
of SUBOXONE sublingual film between 8 mg and 24 mg (inclusive) buprenorphine, a COWS 
score of ≤ 12, and an Opioid Craving VAS score of ≤ 20 mm. 
Open-Label Treatment with RBP-6000: 
On Day 1 of the study (first dose of RBP-6000), all subjects who meet enrollment criteria will 
receive a SC injection of 300 mg of buprenorphine in RBP-6000. Subsequent doses of RBP-6000 
may be adjusted down to 100 mg and back up to 300 mg based on the medical judgment of the 
Investigator. After injection of RBP-6000, subjects will not be permitted to receive supplemental 
SUBOXONE sublingual film during the RBP-6000 treatment period. Subjects who require 
supplemental SUBOXONE sublingual film or other sublingual buprenorphine pharmacotherapy 
during the RBP-6000 treatment period will be withdrawn from the study and referred for 
appropriate treatment. 
Subjects will return to the clinic for monthly injection visits (every 28 ±2 days) for a total of up 
to 12 injections for de novo subjects or for a total of 6 injections for roll-over subjects. 
Electrocardiogram (ECG) recordings and vital signs will be collected pre and post each SC 
injection. Subject-reported injection site pain Visual Analog Scale scores (VAS) will be 
collected at various times for 1 hour after each injection. Local injection site grading will be 
collected at various time points starting immediately after injection; the injection site will 
evaluated for pain, tenderness, warmth, itching, erythema, inflammation or swelling, and 


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bruising using a 4-point severity scale. At each visit after injections begin, the injection site will 
be assessed by site staff for potential reaction and will also be evaluated for evidence of attempts 
to remove the depot. 
Subjects will return to the clinic weekly for the first 5 weeks and then biweekly (i.e., every 2 
weeks) through to injection 6. After injection 6, visits will be monthly for the rest of the study 
period for urine drug screens (UDS), Timeline Followback (TLFB) interviews, opioid craving 
VAS evaluation, COWS and subject reported outcomes (Subjective Opiate Withdrawal Scale 
[SOWS]). Subjects will continue to receive counseling (manual-guided behavioral therapy) 
during the study.  
Safety assessments will be collected at each injection visit and/or at injection follow-up visits 
and will include the following: vital signs, electronic Columbia Suicide Severity Rating Scale 
(eC-SSRS) responses, ECGs, laboratory tests (hematology, chemistry, urinalysis, and pregnancy 
test), use of concomitant medications, and the frequency of AEs.  
Sparse PK blood samples will be collected for population PK analysis from the roll-over subjects 
only. PK samples for population PK analysis are not required from the de novo subjects. ECGs 
will be performed before PK sample collection. The following health economic and outcome 
assessments will also be collected: Beck Depression Inventory (BDI-II), brief pain inventory 
(BPI), EuroQol EQ-5D-5L (EQ-5D-5L), 36-Item Short Form Health Survey, Version 2 (SF-
36v2), Medication Satisfaction Questionnaire (MSQ), healthcare resource utilization (HCRU), 
Treatment Effectiveness Assessment (TEA), and Addiction Severity Index Lite (ASI). 
 
For all subjects (de novo and roll-over), a PK sample will be taken as soon as possible after any 
SAE is reported. If possible, an additional sample should be collected when the SAE has been 
resolved. 
 
SUBOXONE Transition Period/Safety Follow-up: 
At the end of the RBP-6000 treatment period, subjects will enter a 4-week SUBOXONE 
transition period/safety follow-up where they will receive the same dose of SUBOXONE 
sublingual film that they received at Day -1, and their ongoing treatment options will be 
reviewed. 
Study Population:  
Approximately 300 de novo subjects will be enrolled into this study, as well as approximately 
300 roll-over subjects. The study population will consist of individuals diagnosed with opioid 
use disorder who are seeking treatment.  
Test Product, Dose, and Mode of Administration:  
300 mg buprenorphine in RBP-6000, subcutaneous injection 
100 mg buprenorphine in RBP-6000, subcutaneous injection 
Duration of Study Treatment:  
This will be a multiple-dose study, with the first investigational product administration 
(RBP-6000 containing 300 mg buprenorphine) on Day 1. The expected maximum duration of 
participation for de novo subjects is up to approximately 55 weeks, consisting of up to 7 days of 
screening, up to 14 days SUBOXONE sublingual film Run-In, up to a 48-week open-label 


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treatment period, and a 4-week follow-up period. The expected maximum duration of 
participation for roll-over subjects is up to approximately 31 weeks, consisting of up to a 7-day 
screening period, up to 14 days SUBOXONE sublingual film Run-In, a 24-week open-label 
treatment period, and a 4-week follow-up period. 
Safety Assessments: 
Safety objectives for this study are to evaluate the safety and tolerability of RBP-6000 (100 mg 
and 300 mg) SC injection treatment in subjects with opioid use disorder. Safety assessments will 
include the following: frequency of all AEs, serious AEs (SAEs), discontinuations from study 
due to AEs; local injection site tolerability (e.g., injection site grading); injection site pain using a 
subject-reported VAS; suicidality using the eC-SSRS, use of concomitant medications; changes 
in clinical laboratory results; vital sign measurements; 12-lead ECGs, which will be interpreted 
by a central facility; physical examination results; body weight, height, and body mass index 
(BMI), and abdominal fat measurement (waist-to-hip ratio). 
Clinical Outcome Assessments: 
Clinical outcome assessments will include the UDS for opioids and other drugs; self-reported use 
of illicit opioids, other drugs, and alcohol on the TLFB; COWS, SOWS, and Opioid Craving 
VAS. 
PK Assessments: 
Sparse plasma samples will be collected for population PK analysis from the roll-over subjects 
only. No PK samples will be collected from the de novo subjects. 
Health Economics and Outcomes Assessments:  
Health economics and outcomes assessments will include: BDI-II, BPI, EQ-5D-5L, SF-36v2, 
MSQ, HCRU, TEA, and ASI-Lite. 


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Statistical Methods:  
A Statistical Analysis Plan (SAP) will be prepared after the protocol is approved and before 
database lock occurs.  The SAP will provide further details regarding the definition of analysis 
endpoints, data handling rules, and the statistical methodology to be used to address all study 
objectives.  The SAP will also include formats for the summary and analysis tables, listings, and 
graphical displays. 
Determination of Sample Size: 
Approximately 300 de novo subjects as well as approximately 300 subjects who completed the 
RB-US-13-0001 study will be enrolled into this long-term safety study to ensure 100 subjects 
reach 1 year of treatment with RBP-6000. No power analysis will be done corresponding to the 
sample sizes, but the large numbers proposed are clinically acceptable to provide adequate and 
relevant clinical conclusions from this study. 
Safety Analyses: 
Safety variables will include AEs, local injection site tolerability (e.g., injection site grading); 
injection site pain using a subject-reported VAS; suicidality using the eC-SSRS, concomitant 
medications; changes in clinical laboratory results (hematology, chemistry and urinalysis); vital 
sign measurements; 12-lead ECGs, physical examination results; body weight, height, BMI, and 
abdominal fat measurement (waist-to-hip ratio).  Safety variables will be analyzed on the safety 
population using descriptive statistics for continuous endpoints (e.g., mean, median, SD, 
minimum and maximum) and frequency counts with percentages for discrete endpoints. 
Baseline is defined as the last non-missing value prior to SC injection on Day 1.  No imputation 
of missing values will be performed. 
Clinical Outcomes Assessments: 
COWS, SOWS and Opioid Craving VAS total scores will be summarized using descriptive 
statistics (mean, median, SD, minimum, maximum), including change from baseline.  Subjects’ 
self-reported illicit drug use from the TLFB will be summarized as descriptive statistics. 
The cumulative distribution function (CDF) of the percentage of urine samples negative for 
opioids, the CDF of the percentage of self-reports from the TLFB negative for illicit opioid use, 
and other outcome measures will be calculated. 
Population PK/PD Analysis: 
The population PK model established using the data collected in the double-blind, placebo-
controlled, efficacy study (Study RB-US-13-0001) will be refined using the sparse PK samples 
collected in the present study for the roll-over subjects to characterize the disposition of 
buprenorphine and norbuprenorphine following SC injections of RBP-6000, with the assessment 
of potential covariates affecting the PK of both compounds. Subsequently, the relationships 
between buprenorphine plasma concentrations and clinical outcomes assessments will be 
investigated. These relationships will be initially assessed in a descriptive manner, and, if 
applicable, appropriate PK/PD models will be developed to describe these relationships. A stand-
alone modeling analysis plan will be generated, and the results will be reported in a standalone 
modeling report. 


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Health Economic and Outcomes Research Analyses: 
The health economic and outcomes research endpoints for this study are: BDI-II, BPI, EQ-5D-
5L, SF-36v2, MSQ, Health Insurance, HCRU, TEA, and ASI-Lite.  
Summary scores for these measures will be calculated, as appropriate. Categorical variables will 
be summarized using frequencies and percentages. Continuous measures will be summarized 
using descriptive statistics (mean, standard deviation, median, minimum, maximum) as 
appropriate. An analysis of change will be conducted. Supplementary analyses using general 
linear, mixed, or non-parametric methods will be performed as appropriate.  
A stand-alone SAP will be developed prior to database lock with full detail regarding health 
economics and outcomes analyses. 
Date of Original Approved Protocol: 14 April 2015 
Date of Amendment 1: 19 August 2015 
 


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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................2 
LIST OF IN-TEXT TABLES ..................................................................................................13 
LIST OF IN-TEXT FIGURES.................................................................................................13 
LIST OF APPENDICES ..........................................................................................................13 
LIST OF ABBREVIATIONS ..................................................................................................15 
1 
INTRODUCTION ...........................................................................................................18 
1.1 
Opioid Use Disorder ..............................................................................................18 
1.2 
Buprenorphine........................................................................................................19 
1.3 
ATRIGEL Delivery System ...................................................................................19 
1.4 
Buprenorphine in the ATRIGEL Delivery System (RBP-6000) ...........................20 
1.4.1 
Summary of Nonclinical Data .....................................................................20 
1.4.2 
Summary of Previous Clinical Data ............................................................21 
1.4.3 
Pharmacokinetic/Pharmacodynamic Modeling of RBP-6000 .....................22 
1.5 
Rationale for Dose Selection .................................................................................23 
1.6 
Known and Potential Risks and Benefits ...............................................................26 
2 
STUDY OBJECTIVES ....................................................................................................27 
2.1 
Primary Objective ..................................................................................................27 
2.2 
Secondary Objectives.............................................................................................27 
2.3 
Tertiary Objectives.................................................................................................27 
3 
INVESTIGATIONAL PLAN ..........................................................................................28 
3.1 
Overall Study Design and Plan ..............................................................................28 
3.2 
Rationale for Study Design ....................................................................................32 
3.3 
Study Duration and Dates ......................................................................................32 
4 
STUDY POPULATION SELECTION ...........................................................................33 
4.1 
Study Population ....................................................................................................33 
4.2 
Inclusion Criteria ...................................................................................................33 
4.3 
Exclusion Criteria ..................................................................................................34 
4.4 
Day -1/Enrollment Criteria ....................................................................................36 
5 
STUDY TREATMENTS .................................................................................................37 
5.1 
Description of Treatments......................................................................................37 
5.1.1 
SUBOXONE Sublingual Film .....................................................................37 
5.1.2 
Investigational Medicinal Products..............................................................37 
5.2 
Treatments Administered .......................................................................................37 
5.2.1 
Run-In Treatment Period .............................................................................37 
5.2.1.1 
SUBOXONE Sublingual Film Induction (De novo Subjects) ...........37 
5.2.1.2 
SUBOXONE Sublingual Film Induction (Roll-over Subjects) .........38 


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5.2.2 
Dose Adjustment Period (All Subjects) .......................................................39 
5.2.3 
Active Study Treatment ...............................................................................39 
5.2.4 
SUBOXONE Transition Period/Safety Follow-up ......................................40 
5.3 
Selection and Timing of Dose for Each Subject ....................................................40 
5.4 
Method of Assigning Subjects to Treatment Groups .............................................40 
5.5 
Blinding..................................................................................................................40 
5.6 
Concomitant Therapy.............................................................................................40 
5.6.1 
Permitted Concomitant Medications ............................................................41 
5.6.2 
Prohibited Concomitant Medications ..........................................................41 
5.7 
Restrictions ............................................................................................................42 
5.7.1 
Prior Therapy ...............................................................................................42 
5.7.2 
Subject Activity Restrictions .......................................................................42 
5.8 
Protocol Compliance ..............................................................................................42 
5.9 
Packaging and Labeling .........................................................................................42 
5.10 
Storage and Accountability ....................................................................................42 
5.11 
Investigational Product Retention at Study Site ....................................................43 
6 
STUDY PROCEDURES .................................................................................................44 
6.1 
Informed Consent...................................................................................................44 
6.1.1 
General Information .....................................................................................44 
6.2 
Medical History .....................................................................................................44 
6.3 
Physical Examination.............................................................................................44 
6.4 
Vital Signs ..............................................................................................................45 
6.5 
Electrocardiograms ................................................................................................45 
6.5.1 
12-Lead Electrocardiograms ........................................................................45 
6.6 
Clinical Laboratory Tests .......................................................................................46 
6.6.1 
Laboratory Parameters .................................................................................46 
6.6.2 
Sample Collection, Storage, and Shipping ..................................................48 
6.6.3 
Reference Ranges.........................................................................................48 
6.6.4 
Laboratory Results Review ..........................................................................48 
6.6.5 
Good Laboratory Practice Compliance ........................................................48 
6.7 
Pharmacokinetic Assessments ...............................................................................48 
6.8 
Administration of Study Drug ...............................................................................49 
6.9 
Safety and Suicidality Assessments .......................................................................49 
6.9.1 
Local Injection Site Tolerability ..................................................................49 
6.9.1.1 
Injection Site Grading ........................................................................49 
6.9.1.2 
Injection Site Pain Visual Analogue Scale (VAS) .............................50 
6.9.2 
Suicidality ....................................................................................................50 
6.9.2.1 
Columbia Suicide Severity Rating Scale ...........................................50 


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6.10 
Adverse Events Assessments .................................................................................50 
6.10.1 
Definition .....................................................................................................50 
6.10.2 
Performing Adverse Events Assessments ....................................................51 
6.10.3 
Timing ..........................................................................................................51 
6.10.4 
Severity ........................................................................................................51 
6.10.5 
Relationship .................................................................................................52 
6.10.6 
Expectedness ................................................................................................52 
6.10.7 
Clinical Significance ....................................................................................52 
6.10.8 
Clinical Laboratory Adverse Events ............................................................53 
6.10.9 
Serious Adverse Events ...............................................................................53 
6.10.9.1 
Definition ...........................................................................................53 
6.10.9.2 
Reporting Serious Adverse Events ....................................................53 
6.10.10 Treatment-Emergent Adverse Events ..........................................................54 
6.10.11 Procedures and Follow-Up of Subjects with Ongoing SAEs or Experiencing 
SAEs after Completion of or Withdrawal from the Study ...........................54 
6.10.12 Pregnancy .....................................................................................................54 
6.11 
Clinical Outcome Assessments ..............................................................................55 
6.11.1 
Timeline Followback Interview ...................................................................55 
6.11.2 
Opioid Craving Visual Analog Scale ...........................................................55 
6.11.3 
Clinical Opiate Withdrawal Scale ................................................................55 
6.11.4 
Subjective Opiate Withdrawal Scale ...........................................................56 
6.12 
Health Economics and Outcomes Assessments .....................................................56 
6.12.1 
EuroQoL-5 Dimensions-5 Levels (EQ-5D-5L) and EQ-VAS.....................56 
6.12.2 
Medical Outcomes Study Short Form-36 (SF-36v2) ...................................56 
6.12.5 
Treatment Effectiveness Assessment (TEA) ...............................................57 
6.12.6 
Addiction Severity Index (ASI) Lite............................................................57 
6.12.7 
Beck Depression Inventory II (BDI-II)........................................................58 
6.12.8 
Brief Pain Inventory (BPI) Short Form .......................................................58 
6.13 
Concomitant Medication Assessments ..................................................................59 
6.14 
Removal of Subjects from the Study .....................................................................59 
6.14.1 
Early Removal of RBP-6000 .......................................................................60 
6.14.2 
Stopping Rules .............................................................................................60 
6.14.3 
Screen Failures .............................................................................................60 
6.15 
Other Study Procedures .........................................................................................60 
6.15.1 
Counseling/Behavioral Therapy ..................................................................60 
6.15.2 
Unscheduled Visits ......................................................................................61 
6.15.3 
Additional Care of Study Subjects Following Completion of the Study .....61 
6.15.4 
Treating Toxicity .........................................................................................61 


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6.15.5 
Ancillary Medications ..................................................................................61 
6.16 
Appropriateness of Measurements .........................................................................62 
7 
STUDY ACTIVITIES .....................................................................................................63 
8 
QUALITY CONTROL AND ASSURANCE .................................................................64 
8.1 
Quality Control ......................................................................................................64 
8.2 
Quality Assurance ..................................................................................................64 
9 
PLANNED STATISTICAL METHODS ........................................................................65 
9.1 
General Considerations ..........................................................................................65 
9.2 
Determination of Sample Size ...............................................................................65 
9.3 
Analysis Populations ..............................................................................................65 
9.3.1 
Safety Population .........................................................................................65 
9.3.2 
Clinical Outcome Assessment and PK Populations.....................................65 
9.4 
Demographics and Baseline Characteristics ..........................................................66 
9.5 
Primary Analysis ....................................................................................................66 
9.5.1 
Safety Endpoints ..........................................................................................66 
9.5.1.1 
Adverse Events ..................................................................................66 
9.5.1.2 
Laboratory Data .................................................................................66 
9.5.1.3 
Vital Signs ..........................................................................................66 
9.5.1.4 
Other Variables Related to Safety ......................................................66 
9.6 
Secondary Analysis ................................................................................................67 
9.6.1 
Clinical Outcomes Assessments ..................................................................67 
9.7 
Other Analyses .......................................................................................................67 
9.7.1 
PK/PD Modeling ..........................................................................................67 
9.7.2 
Health Economic and Outcomes Assessment ..............................................68 
9.8 
Handling of Missing Data ......................................................................................68 
9.9 
Subjects Who Withdraw from the Study ...............................................................69 
9.10 
Interim Analyses ....................................................................................................69 
10 ADMINISTRATIVE CONSIDERATIONS ....................................................................70 
10.1 
Investigators and Study Administrative Structure .................................................70 
10.1.1 
Indivior Inc...................................................................................................70 
10.1.2 
Investigational Site(s) ..................................................................................70 
10.1.3 
Laboratories .................................................................................................70 
10.2 
Institutional Review Board or Independent Ethics Committee Approval .............70 
10.3 
Ethical Conduct of the Study .................................................................................70 
10.4 
Subject Information and Consent...........................................................................71 
10.5 
Subject Confidentiality ..........................................................................................71 
10.6 
Study Monitoring ...................................................................................................72 
10.6.1 
Study and Site Closure .................................................................................72 


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10.7 
Case Report Forms and Study Records .................................................................72 
10.8 
Data Monitoring Committee ..................................................................................73 
10.9 
Protocol Deviations ................................................................................................73 
10.10 Access to Source Documentation ..........................................................................74 
10.11 Data Generation and Analysis ...............................................................................74 
10.11.1 Data Collection and Data Management .......................................................74 
10.11.2 Database Quality Assurance ........................................................................74 
10.12 Retention of Data ...................................................................................................75 
10.13 Financial Disclosure...............................................................................................75 
10.14 Publication and Disclosure Policy .........................................................................75 
11 REFERENCE LIST .........................................................................................................76 
 
LIST OF IN-TEXT TABLES 
Table 1 
PK Parameters of the Simulated Typical PK Profile of Buprenorphine after 
Repeated RBP-6000 Injections for the Phase 3 Efficacy Study (RB-US-13-0001) ....25 
Table 2 
List of Laboratory Tests ...............................................................................47 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Model-Predicted Buprenorphine Plasma Concentrations and Mu-Opioid 
Receptor Occupancy in Each Treatment Group on RBP-6000 Following the Proposed 
Design of the Current Study ........................................................................................24 
Figure 2 
Study Overview:  De novo Subjects ............................................................30 
Figure 3 
Study Overview:  Roll-over Subjects from RB-US-13-0001 ......................31 
Figure 4 
Injection Locations.....................................................................................124 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events – Screening and SUBOXONE Film Induction ..80 
Appendix 2 
Schedule of Events – RBP-6000 Injection 1 – 3 Visits .....................83 
Appendix 3 
Schedule of Events – RBP-6000 Injection 4 – 6 Visits for all Subjects 
and End of Study/Early Termination and Follow-Up Visits for Roll-over Subjects ...86 
Appendix 4 
Schedule of Events – RBP-6000 Injection 7 – 9 Visits for de novo 
Subjects 
90 
Appendix 5 
Schedule of Events – RBP-6000 Injection 10 – 12 Visits and End of 
Study/Early Termination Visit and Follow-Up for de novo Subjects ..........................93 
Appendix 6 
Pharmacokinetic Sampling Schedule .................................................96 
Appendix 7 
SUBOXONE® (Buprenorphine/Naloxone) Sublingual Film Full 
Prescribing Information ...............................................................................................97 


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Appendix 8 
Study Drug Preparation, Administration, and Depot Removal 
Instructions 
123 
Appendix 9 
Prohibited Cytochrome P450 Inhibitors and Inducers .....................126 
Appendix 10 
Columbia Suicide Severity Rating Scale (eC-SSRS) -- 
Baseline/Screening Version .......................................................................................127 
Appendix 11 
Columbia Suicide Severity Rating Scale (eC-SSRS) -- Since Last 
Visit Version 
129 
Appendix 12 
Clinical Opiate Withdrawal Scale (COWS) ....................................131 
Appendix 13 
Subjective Opiate Withdrawal Scale (SOWS) .................................133 
Appendix 14 
Opioid Craving Visual Analog Scale (Opioid Craving VAS) .........134 
Appendix 15 
Injection Site Grading Scale ............................................................135 
Appendix 16 
Injection Site Pain Visual Analog Scale (Injection Site Pain VAS) 136 
Appendix 17 
Timeline Followback (TLFB) Interview .........................................137 
Appendix 18 
Euro QoL EQ-5D-5L Health Questionnaire ....................................138 
Appendix 19 
Short Form (36) Health Survey v2...................................................140 
Appendix 20 
Medication Satisfaction Questionnaire ............................................144 
Appendix 21 
Health Care Resource Utilization Questionnaire .............................145 
Appendix 22 
Treatment Effectiveness Assessment (TEA) ...................................147 
Appendix 23 
Addiction Severity Index (ASI) Lite................................................148 
Appendix 24 
Beck Depression Inventory II (BDI-II)............................................164 
Appendix 25 
Brief Pain Inventory (BPI) Short Form ...........................................165 
Appendix 26 
Sponsor Signatures...........................................................................166 
Appendix 27 
Investigator’s Signature ...................................................................167 
 


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LIST OF ABBREVIATIONS 
AE 
adverse event 
AIDS 
acquired immunodeficiency syndrome 
ANOVA 
analysis of variance 
ASI-Lite 
Addiction Severity Index - Lite 
AUC 
area under the plasma concentration-time curve 
BDI-II 
Beck Depression Inventory - II 
BMI 
body mass index 
BP 
blood pressure 
BPI 
Brief Pain Inventory Short Form 
Cavg 
average plasma concentration 
Cmax 
maximum plasma concentration 
Ctrough 
plasma concentration at trough, i.e. before the next injection  
CDF 
cumulative distribution function 
CNS 
central nervous system 
COWS 
Clinical Opiate Withdrawal Scale 
CRA 
clinical research associate 
DAWN 
Drug Abuse Warning Network 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
EC50 
concentration yielding 50% of the maximal effect 
eCRF 
electronic case report form 
e C-SSRS 
Electronic Columbia Suicide Severity Rating Scale 
Emax 
maximum effect 
ECG 
electrocardiogram 
ED 
emergency department 
EOS 
end of study 
ET 
early termination 
EQ-5D 
EuroQol EQ-5D (standard instrument) 
EQ-5D-5L 
EuroQol EQ-5D-5L (self-complete version) 


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EQ-VAS 
EQ-5D using visual analog scale 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HbA1c 
hemoglobin A1c 
HBsAg 
hepatitis B surface antigen  
hCG 
urine human chorionic gonadotropin 
HCl 
hydrochloride 
HCRU 
healthcare resource utilization  
HEOR 
health economics and outcomes research 
HIV 
human immunodeficiency virus 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation  
IEC 
independent ethics committee 
IM 
intramuscular 
IMP 
investigational medicinal product 
IND 
investigational new drug application (i.e., Notice of Claimed 
Investigational Exemption for a New Drug) 
INR 
international normalized ratio 
IRB 
institutional review board 
IV 
intravenous 
IWRS 
interactive web response system 
MAR 
missing at random  
MCAR 
missing completely at random  
MMRM 
mixed model repeated measures 
MSQ 
Medication Satisfaction Questionnaire 
NMP 
N-methyl pyrrolidone 
NOAEL 
no observable adverse effect level 
OTC 
over-the-counter 


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PD 
pharmacodynamic or pharmacodynamics 
PE 
physical examination 
PK 
pharmacokinetic or pharmacokinetics 
PLG or PLGH 
poly (DL-lactide-co-glycolide)  
PET 
positron emission tomography  
PI 
Principal Investigator 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
RBP 
Reckitt Benckiser Pharmaceuticals Inc. 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SD 
standard deviation 
SF-36v2 
36-Item Short Form Health Survey, Version 2 
SL 
sublingual 
SOE 
schedule of events 
SOP 
standard operating procedure 
SOWS 
Subjective Opiate Withdrawal Scale 
tmax 
time to maximum plasma concentration 
TEA 
Treatment Effectiveness Assessment  
TEAE 
treatment-emergent adverse event 
TLFB 
timeline followback 
UDS 
urine drug screen 
ULN 
upper limit of normal 
US/USA 
United States/United States of America 
VAS 
visual analog scale 


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1 
INTRODUCTION 
1.1 
Opioid Use Disorder 
Opioid use disorder, as defined in the Diagnostic and Statistical Manual of Mental Disorders, 
Fifth Edition (DSM-5; American Psychiatric Association 2013), is a neurobehavioral syndrome 
characterized by the repeated, compulsive seeking or use of an opioid despite adverse social, 
psychological, and/or physical consequences.  Opioid use disorder is a medical illness with high 
costs to individuals, families, and society.  Direct and indirect costs attributable to illicit drug use 
are estimated in 3 principal areas: crime, productivity, and health (US Department of Justice, 
Economic Impact of Illicit Drug Use on American Society, 2011).  Approximately one-third of 
all acquired immunodeficiency syndrome (AIDS) cases diagnosed in the United States (US) 
through 2009 (Centers for Disease Control and Prevention: HIV/AIDS Surveillance Report, 
2009) and many cases of hepatitis C (National Institute on Drug Abuse 2000; Thomas 2001) 
were associated with injection drug use.   
The increasing abuse of and addiction to prescription opioids is another major concern.  
According to the Substance Abuse and Mental Health Services Administration’s Office of 
Applied Studies, the incidence of abuse of prescription opioid pain medications (narcotic 
analgesics) such as hydrocodone, oxycodone, meperidine, and propoxyphene has risen markedly 
in recent years (Crane 2003).  The incidence of emergency department (ED) visits related to 
these medications has been increasing since the 1990s and has more than doubled between 1994 
and 2001 (Crane 2003).  The most recently published data from the Drug Abuse Warning 
Network (Drug Abuse Warning Network, 2009: National Estimates of Drug-Related Emergency 
Department Visits, 2011) estimated that about 2.1 million ED visits resulted from drug misuse or 
abuse, which was the equivalent of 674.4 ED visits per year per 100,000 population.  Although 
the overall number of ED visits attributable to drug misuse or abuse was stable from 2004 to 
2009, increases were seen in ED visits involving nonmedical use of pharmaceuticals with no 
other drug involvement (117% increase).  An estimated 1,079,683 ED visits in 2009 involved the 
nonmedical use of prescription drugs, over-the-counter (OTC) medicines, or other types of 
pharmaceuticals, representing about a quarter of all drug-related ED visits and over half of ED 
visits for drug abuse or misuse.  Pain relievers were the most common type of drugs reported in 
the nonmedical use category of ED visits (47.8%).  Among specific types of pain relievers, 
narcotic pain relievers such as oxycodone, hydrocodone, and methadone (13.7%, 8.0%, and 
5.8%, respectively) were most prevalent (Drug Abuse Warning Network, 2009: National 
Estimates of Drug-Related Emergency Department Visits, 2011). 
The economic burden of prescription opioid abuse is very high.  Total US societal costs of 
prescription opioid abuse were estimated at $55.7 billion in 2007 (US dollars in 2009).  
Workplace costs accounted for $25.6 billion (46%), health care costs accounted for $25.0 billion 
(45%), and criminal justice costs accounted for $5.1 billion (9%) (Birnbaum 2011).  Mean 
annual direct health care costs for opioid abusers were more than 8 times higher than for 
nonabusers.  Hospital inpatient and physician outpatient costs accounted for 46% and 31% 
respectively, of opioid abusers' health care costs.  The high costs of opioid abuse are driven 
primarily by high comorbidity rates and high utilization rates of medical services and 
prescription drugs (White 2005).  It was also found that opioid use results in lower quality of life, 


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including significantly worse physical and psychological health, compared with the general 
population (Ryan 1996). 
Given the high costs of opioid addiction to individuals, families, and society, treatments for this 
disease therefore aim to reduce the use of prescription or illicit opioids as well as the risks 
associated with injection, including transmission of human immunodeficiency virus (HIV) and 
hepatitis C virus.  Implantable formulations of opioid receptor partial agonists and antagonists 
represent an innovative alternative to daily dosing regimens, and several delivery systems are 
currently in clinical trials (Ling 2010, Rosenthal 2013).  The goal of this study is to determine 
whether RBP-6000, which is a sustained release formulation of buprenorphine in the ATRIGEL® 
delivery system, is a safe and effective treatment for opioid use disorder. 
1.2 
Buprenorphine 
In the central nervous system (CNS), opioid receptors are found in high concentrations in the 
limbic system and the spinal cord. The natural ligands for these receptors are a group of 
neuropeptides known as endorphins. Opioid analgesics mimic the action of endorphins but have 
a more prolonged action because the analgesics are not subject to rapid local metabolism. 
Three major opioid receptor subclasses have been identified: mu, kappa, and delta.  These 
subclasses mediate distinct actions with natural endorphins and opioid analgesics.  Different 
endorphin and opioid analgesic ligands demonstrate different binding affinities for the various 
subclasses of receptors.   
Buprenorphine is a member of the large family of opioid analgesics used in the treatment of 
moderate and severe acute and chronic pain. Opioid receptors are found in both the CNS and the 
periphery. Buprenorphine is a partial agonist at the mu receptor, producing a sub-maximal 
response compared to that of a full agonist. Hence, buprenorphine provides a greater margin of 
safety regarding respiratory depression in comparison to full agonist opioids. Buprenorphine is 
also an antagonist at the kappa receptor (Cowan 1977, Jasinski 1978). 
Buprenorphine has been reported to have a lower physical dependence liability than pure agonist 
analgesics such as morphine, and at a sufficient dose, it can suppress opioid withdrawal signs 
and symptoms for at least 24 hours.  Limited euphoric and respiratory depressant effects have led 
to its therapeutic use as a pharmacotherapy for opioid use disorder. 
Selected pharmacokinetic (PK) parameters for buprenorphine when administered sublingually as 
buprenorphine/naloxone films are in the SUBOXONE sublingual film prescribing information 
(Appendix 7).  Further details on the PK of buprenorphine in the ATRIGEL delivery system are 
described in Section 1.4.2. 
1.3 
ATRIGEL Delivery System 
The ATRIGEL Delivery System is a sterile, polymeric solution of a biodegradable 
poly DL-lactide-co-glycolide (PLGH) copolymer, dissolved in the water-miscible, biocompatible 
solvent N-methyl pyrrolidone (NMP).  The polymers belong to a family of poly α-hydroxy acids 
that are used in medical devices such as resorbable sutures and degradable drug delivery 


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systems.  Polymerization, which is initiated with glycolic acid, leads to a linear polymer 
containing a carboxylic acid end group.  The ATRIGEL Delivery System can be formulated to 
deliver different active ingredients for various lengths of time. 
The ATRIGEL Delivery System is well characterized.  It is currently used in 7 approved 
products worldwide, including 4 ELIGARD® products (subcutaneous [SC] depot formulations of 
leuprolide acetate), ATRIDOX® (doxycycline hyclate applied to the periodontal pocket), the 
ATRISORB® Bioabsorbable Guided Tissue Regeneration Barrier for periodontal application, and 
the ATRISORB-D Barrier (ATRISORB with doxycycline) for periodontal guided tissue 
regeneration. 
Clinical studies with these products demonstrated that the ATRIGEL Delivery System was well 
tolerated and provided consistent sustained release of the incorporated drug over the designated 
dosing interval.  Injection site reactions are expected to be mild and appear early in treatment, as 
observed in previous local irritation ATRIGEL studies (RBP-6000 Investigator’s Brochure [IB], 
Edition 4, 24 February 2014). 
1.4 
Buprenorphine in the ATRIGEL Delivery System (RBP-6000) 
RBP-6000 is a subcutaneously injected depot product under development for the treatment of 
opioid addiction. It contains buprenorphine in the ATRIGEL Delivery System and provides 
sustained plasma levels of buprenorphine over a minimum of 28 days. There is no currently 
approved, parenterally administered, sustained-release buprenorphine formulation for the 
treatment of opioid use disorder. Such a formulation could offer advantages over existing 
buprenorphine products by improving subject compliance and reducing diversion, abuse, and 
unintended exposure (e.g., in pediatric exposure), and reduce chances of swallowing drug. 
The safety profile and clinical efficacy of RBP-6000 are expected to be similar to and 
comparable with that of buprenorphine or SUBOXONE sublingual treatment.  
1.4.1 
Summary of Nonclinical Data 
Nonclinical data suggest that toxicity from RBP-6000 is unlikely at the doses planned for this 
clinical study.  The no observable adverse effect levels (NOAELs) were determined to be 250 
mg/kg (rat) and 40 mg/kg (dog) following single SC injections of RBP-6000 in 4-week toxicity 
studies.  These levels are equivalent to human buprenorphine doses of 2419 mg and 1333 mg, 
respectively (based on 60 kg body weight and calculated according US Food and Drug 
Administration guidance [FDA 2005]).  These levels provide approximately 8.1x (rat) and 4.4x 
(dog) safety margins when compared to the 300-mg buprenorphine dose in humans (based on 
60 kg body weight and calculated according US Food and Drug Administration guidance 
[FDA 2005]).  Systemic effects seen in the rat and dog 4-week toxicity studies were related to 
the pharmacology of buprenorphine or local tolerance effects of the formulation as a result of 
high dose and volume, so the safety margins are considered acceptable. 
Chronic repeated-dose studies were conducted in rats and dogs dosed with RBP-6000 once every 
4 weeks for 6 or 9 months, respectively.  These studies demonstrated systemic effects consistent 
with buprenorphine administration, such as stained fur, aggressive behavior, decreased activity, 


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reduced food consumption and body weight gain, and abnormal feces.  Minimal to mild lung 
alveolar macrophage infiltration and pancreatic acinar cell apoptosis were seen with increased 
incidence in rats, but not dogs, treated with RBP-6000.  Injection site findings were seen in both 
species, characterized microscopically by minimal to moderate granuloma formation.  Injection 
volumes were high, being 2.73 mL/m2 in rats and 3.64 mL/ m2 in dogs, compared with a volume 
of 0.62 mL/ m2 at the highest proposed clinical dose, contributing to these local findings.  
Systemic chronic NOAELs were considered to be 10 mg/kg in rats and 40 mg/kg in dogs.   
Overall, the extensive preclinical data on both the buprenorphine and SUBOXONE products and 
nonclinical PK and toxicity studies in rats and dogs support the clinical development of 
RBP-6000.  Systemic exposure to buprenorphine is not considered to pose any significant safety 
concerns following SC administration of RBP-6000.  Additionally, this clinical study will be 
conducted in subjects who have a current diagnosis of opioid use disorder and who would thus 
be expected to have a certain degree of cross-tolerance to the opioid agonist effects of 
buprenorphine.  Minimal to moderate irritation at the injection site, seen in both rats and dogs, 
may warrant attention to ensure local tolerability (RBP-6000 IB, Edition 4, 24 February 2014). 
1.4.2 
Summary of Previous Clinical Data 
In the first-in-human trial to evaluate the safety, tolerability, and PK of RBP-6000, 12 subjects 
received a single SC injection of RBP-6000 containing 20 mg of buprenorphine.  Of these 
12 subjects, 6 subjects completed the study through Day 85.  The majority (94%) of 
treatment-emergent adverse events (TEAEs) were mild, 5.4% were moderate, and 1 was severe 
in intensity.  TEAEs considered related to the study drug included injection site pain, injection 
site warmth, and injection site bruising, erythema, and edema.  All subjects experienced mild to 
moderate symptoms of withdrawal at study entry, prior to study drug injection, and after study 
drug injection.  One serious adverse event (SAE) was reported.  The SAE was notably identified 
psychosocial stressors and intermittent withdrawal, for which the subject had prolonged 
hospitalization for treatment.  This SAE was not considered to be related to the study drug.  No 
respiratory depression, temperature elevations, clinically significant lowering of oxygen 
saturation, or electrocardiogram (ECG) abnormalities were observed.  There was 1 clinically 
significant laboratory adverse event (AE; elevated hepatic enzymes), which resolved.  No 
unexpected side effects occurred in the RBP-6000 depot formulation of buprenorphine 
(RBP-6000 IB, Edition 4, 24 February 2014).  Buprenorphine was rapidly absorbed over the first 
day and peaked on the second day, with a slow decrease in plasma concentrations thereafter that 
is consistent with the slow release of buprenorphine from the ATRIGEL Delivery System.   
The PK of 50, 100, and 200 mg buprenorphine (as RBP-6000) was also evaluated in a single-
ascending-dose study in 51 subjects (RB-US-11-0020).  In this study, median buprenorphine 
time to peak concentration (tmax) in the initial burst period was observed at 24 hours for all 3 
dosages.  Buprenorphine mean plasma terminal half-life increased slightly with the increase in 
dose from 50 mg to 200 mg (1078 hours [44.9 days] at 50 mg, 1376 hours at 100 mg, and 1573 
hours at 200 mg).  Buprenorphine exhibited overall geometric mean average concentration 
values of 0.356, 0.624, and 1.108 ng/mL, respectively with 50, 100 and 200 mg buprenorphine 
while overall geometric mean Cmax values of 0.999, 1.518, and 2.381 ng/mL were observed for 
buprenorphine doses of 50, 100, and 200 mg, respectively.  With an increase in dose of RBP-


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6000 from 50 to 200 mg, mean buprenorphine exposure parameters increased less than 
proportionally to dose (RBP-6000 IB, Edition 4, 24 February 2014).  A single SC injection of 
RBP-6000 was generally safe and well tolerated.  A total of 46 of 51 subjects (90.2%) had at 
least 1 TEAE.  A total of 30 of 51 subjects (58.8%) had TEAEs that were related to treatment 
with RBP-6000.  The majority of AEs were qualified as moderate in severity (68.6%).  
Two subjects reported TEAEs that were considered to be severe but unrelated to RBP-6000.  No 
subjects withdrew from the study because of an AE. 
The safety profile of multiple-dose SC injections of RBP-6000 containing 50 mg, 100 mg, 
200 mg, and 300 mg of buprenorphine in treatment-seeking, opioid-dependent subjects in an 
open-label, multiple-dose study has recently been examined.  The results suggest that all doses 
were safe and well-tolerated following a 13-day induction and stabilization on SUBUTEX.  In 
addition, a study investigating the blockade of subjective opioid effects demonstrated that RBP-
6000 was safe and well tolerated after the SC administration of 2 monthly 300-mg doses of 
buprenorphine in RBP-6000, following a 14-day induction and stabilization period on 
SUBOXONE Film. 
1.4.3 
Pharmacokinetic/Pharmacodynamic Modeling of RBP-6000 
A population PK model was developed to characterize the disposition of buprenorphine and 
norbuprenorphine following SC injection of RBP-6000 (Nasser 2014).  This model was built 
using plasma concentration data collected in 36 opioid-dependent subjects who received single 
doses (50 mg, 100 mg, and 200 mg) of RBP-6000 in the single-ascending-dose study (RB-US-
11-0020).  Analysis of the PK profiles of RBP-6000 revealed a complex and multi-phase 
absorption profile, presenting double peaks and a prolonged plasma terminal half-life.  These 
distinguishing features of the PK of RBP-6000 required the development of a complex structural 
PK model accounting for this dual absorption process: a first absorption process that was 
associated with an initial, rapid delivery from the SC injection site, and a second absorption 
process that was associated with the slow release of buprenorphine from the ATRIGEL Delivery 
System into the systemic circulation.  The population PK model accurately predicted the PK data 
after repeated doses of RBP-6000 in the multiple ascending dose study (RB-US-12-0005) and in 
the opioid blockade study (RB-US-13-0002).  
Another population PK/PD model was developed to characterize the link between buprenorphine 
plasma concentration and mu opioid receptor occupancy (Nasser 2014).  Individual data from 15 
heroin-dependent subjects were taken from two published clinical trials (Greenwald 2003; 
Greenwald 2007).  A saturable maximum effect (Emax) model with 0.67 ng/mL effective 
concentration at 50% of maximum (EC50) and 91% Emax best described mu opioid receptor 
occupancy versus buprenorphine plasma concentrations.  At buprenorphine concentrations 
greater than 2 ng/mL, saturation occurred on mu opioid receptor occupancy where a 4.5-fold 
increase in observed buprenorphine concentrations resulted in observed mu opioid receptor 
occupancy between 70% and 90%. 
Positron emission tomography (PET) scan data were obtained in 2 subjects participating in the 
multiple-ascending dose study RB-US-12-0005 (PET scan sub-study) and receiving either 200 or 
300 mg of RBP-6000.  The PET scans were conducted at 7 days and 28 days post-dose following 


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the 12th SC injection for the first subject receiving 200 mg, and following the 6th SC injection for 
the second subject receiving 300 mg.  Both subjects were considered to be at steady-state for 
buprenorphine at the time of the PET scan measurements.  The mu opioid receptor availabilities 
of four different regions in the brain were measured, and the mu opioid receptor occupancy in 
the whole brain was calculated as described in Greenwald et al. (2003). 
The subject receiving 200 mg of RBP-6000 in the PET scan sub-study showed 79% and 75% mu 
opioid receptor occupancy on Day 7 and Day 28, respectively, following the 12th SC injection of 
RBP-6000.  The subject receiving 300 mg of RBP-6000 in the PET scan sub-study showed 92% 
and 81% mu opioid receptor occupancy on Day 7 and Day 28, respectively, following the 6th SC 
injection of RBP-6000.  These values and the corresponding PK concentrations were in 
agreement with the model predictions and the previous individual observations used to build the 
population PK/PD model. 
Linear relationships were found between mu opioid receptor occupancy and opioid withdrawal 
symptoms, and between mu opioid receptor occupancy and hydromorphone agonist blockade, 
based on the data from 15 heroin-dependent subjects (Nasser 2014).  These data suggest that a 
mean buprenorphine plasma concentration of 2 ng/mL is able to provide 70 % mu opioid 
receptor occupancy associated with low reported agonist drug effects and withdrawal symptoms 
(scores ≤2). 
Model simulations indicated that the desired 70% mu opioid receptor occupancy may be 
achieved after multiple doses of 200 mg of RBP-6000 (Nasser 2014).  The 300 mg dose was 
considered to be a full opioid blockade dose. 
1.5 
Rationale for Dose Selection 
The results of the opioid blockade study (RB-US-13-0002) showed that 300 mg was a full opioid 
blocking dose (i.e., for the “drug liking” VAS scores the upper bound of the 95% confidence 
interval ≤11), which is consistent with PK/PD modeling and simulation results. The least means 
“drug liking” VAS scores in the opioid blockade study showed that the blockade was achieved 
from the first SC injection and was maintained after the second SC injection until week 12 (i.e., 2 
months after the second injection). 
The population PK and PK/PD models presented in Section 1.4.3 were used to simulate the 
double-blind efficacy study (RB-US-13-0001).  The results of these simulations are displayed in 
Figure 1 for the two treatment arms on RBP-6000 receiving either 6 SC injections of 300 mg 
(300 mg × 2 + 300  mg × 4), or 2 SC injections of 300 mg followed by 4 SC injections of 100 mg 
(300  mg ×2  + 100  mg × 4).  
 


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Figure 1 
Model-Predicted Buprenorphine Plasma Concentrations and Mu-
Opioid Receptor Occupancy in Each Treatment Group on RBP-
6000 Following the Proposed Design of the Current Study 
 
The blue line represents the median model prediction; the yellow areas represent the 5th and the 95th 
percentiles of the predictions; µ-ORO: mu opioid receptor occupancy; wks: weeks. 
The PK parameters calculated from the simulated typical PK profile of buprenorphine are listed 
in Table 1.  Average buprenorphine plasma concentration (Cavg) over the monthly dosing interval 
was 1.9 ng/mL after the first SC injection at 300 mg, and 3.1 ng/mL after the second SC 
injection at 300 mg.  
For the subjects receiving 6 monthly SC injections of RBP-6000 at 300 mg, the predicted Cavg 
value after the 4th SC injection was 5.1 ng/mL, which is close to mean value of 4.8 ng/mL 
observed in the multiple-ascending dose study.  The predicted Cavg value after the 6th SC 
injection was 6.0 ng/mL.  For the patients receiving 2 monthly SC injections at 300 mg followed 
by 4 monthly SC injections at 100 mg, the predicted Cavg after the 6th SC injection was 
2.6 ng/mL.  All these values were above the 2 ng/mL threshold for achieving the desired 
efficacy. 
Overall, the modeling and simulation work and the opioid blockade study have shown that the 
300 mg SC dose is an appropriate dose to assess for efficacy. The current study will therefore 
evaluate the long-term safety and tolerability of this dose. It is recognized, however, that some 
individuals may need lower doses based on genetic variations, abuse behavior, etc. Accordingly, 
subsequent doses of RBP-6000 may be adjusted down to 100 mg and back up to 300 mg based 
on the medical judgment of the Investigator. 
 


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Table 1 
PK Parameters of the Simulated Typical PK Profile of Buprenorphine after Repeated RBP-6000 
Injections for the Phase 3 Efficacy Study (RB-US-13-0001) 
Buprenorphine 
(ng/mL) 
SC Injection Number 
1 
2 
3 
4 
5 
6 
 
Cmax 
Cavg 
Cmax Ctrough Cavg 
Cmax 
Ctrough 
Cavg 
Cmax 
Ctrough 
Cavg 
Cmax 
Ctrough 
Cavg 
Cmax 
Ctrough 
Cavg 
300mgx2 + 
100mgx4 
2.9 
1.9 
4.2 
1.3 
3.1 
3.5 
2.5 
3.0 
3.6 
2.6 
3.0 
3.5 
2.5 
2.8 
3.2 
2.3 
2.6 
300mgx2 + 
300mgx4 
2.9 
1.9 
4.2 
1.3 
3.1 
5.4 
2.5 
4.3 
6.4 
3.5 
5.1 
7.1 
4.2 
5.7 
7.5 
4.6 
6.0 
Cmax: maximum plasma concentration; Cavg : average plasma concentration; Ctrough: plasma concentration at trough (ie, before the next injection). 
 
 


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1.6 
Known and Potential Risks and Benefits 
The AE profile of buprenorphine is well-characterized; commonly reported effects include 
constipation, nausea, vomiting, and headache.  Buprenorphine is approved for use by various 
routes of administration (e.g., SL, intramuscular [IM], intravenous [IV], transdermal, and rectal). 
Studies of buprenorphine receptor binding in human subjects have consistently and reproducibly 
established that buprenorphine is a highly lipophilic, mu-opioid receptor partial agonist with 
slow receptor association and dissociation kinetics.  Buprenorphine has an improved safety 
profile relative to mu-opioid receptor full agonists due to its partial agonist properties.  These 
attributes of buprenorphine allow it to perform well as substitution therapy for opioid-dependent 
individuals over short-term and long-term durations.  The experiments used to establish the 
binding profile of buprenorphine were consistent across differing parenteral routes of 
administration (IV, IM, and SL); therefore, RBP-6000 is expected to perform similarly when 
administered as a SC depot in the ATRIGEL Delivery System. 
The efficacy of buprenorphine in the treatment of opioid dependence has been well established 
(see for example, New Drug Applications 20-732; 20-733; 22-410).  Buprenorphine has been 
used for medically-supervised taper (i.e., detoxification) medication and as a long-term 
medication assisted therapy (i.e., maintenance).  A recent Cochrane Review meta-analysis 
revealed that buprenorphine is statistically significantly superior to placebo in the retention of 
subjects and reduction of opioid-positive urine tests, and that buprenorphine and methadone may 
be equally efficacious at adequate dose levels of both medications (Mattick 2008). 
A sustained-release formulation of buprenorphine using the ATRIGEL Delivery System offers a 
number of potential benefits relative to shorter-acting formulations, including improved subject 
compliance, reduced diversion and misuse, as well as a reduced risk to subjects, their families, 
and the community.  


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2 
STUDY OBJECTIVES 
Indivior Inc., formerly Reckitt Benckiser Pharmaceuticals Inc. (RBP), is developing RBP-6000, 
a long-acting formulation of buprenorphine for monthly SC administration, for the treatment of 
opioid use disorder.   
2.1 
Primary Objective 
To assess the long-term safety and tolerability of RBP-6000 subcutaneous (SC) injections in 
subjects with opioid use disorder. 
2.2 
Secondary Objectives 
To collect clinical outcome data with RBP-6000 SC injections in subjects with opioid use 
disorder. 
2.3 
Tertiary Objectives 
To evaluate the: 
• PK of RBP-6000,  
• Relationship between RBP-6000 PK and clinical outcome data, and 
• Impact of RBP-6000 on health and economic outcomes. 


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a multicenter, open-label, long-term safety study in which approximately 600 subjects 
diagnosed with opioid use disorder will be enrolled (approximately 300 subjects who did not 
participate in the RB-US-13-0001 study [hereafter referred to as “de novo” subjects] and 
approximately 300 subjects that completed the RB-US-13-0001 study [hereafter referred to as 
“roll-over subjects”]).  Subject participation will be based on the Investigator’s determination 
that initiation or continuation of study treatment is appropriate; and, that among subjects who are 
continuing from the RB-US-13-0001 study, there have been no significant protocol deviations or 
clinically relevant AEs that would preclude inclusion of the subject in this study. All subjects 
will need to provide written informed consent before any protocol-related procedures commence. 
At the Screening Visit (which is up to 3 days after the End of Study [EOS] Visit (Day 169 + 3]), 
for roll-over subjects), potential subjects will be reviewed for eligibility against inclusion and 
exclusion criteria, and eligible subjects will be enrolled into the trial.  
Before receiving the first injection of RBP-6000 in this safety study, all subjects will undergo a 
Run-In period with SUBOXONE® (buprenorphine/naloxone) sublingual film to avoid 
precipitating a withdrawal syndrome and to preserve the blind in subjects treated with placebo in 
the RB-US-13-0001 study. Subjects will be inducted onto SUBOXONE sublingual film 
consistent with the SUBOXONE sublingual film label; they will then complete a 1 to 11 day 
SUBOXONE sublingual film Dose Adjustment period (Section 5.2.1). SUBOXONE dose 
adjustments will be made based on COWS scores as well as physician judgment (Section 5.2.2).   
Once subjects meet the criteria (on Day -11 to Day -1) of no significant opioid craving (≤20 mm 
on the Opioid Craving Visual Analog Scale [VAS] and no significant withdrawal (≤ 12 on the 
Clinical Opiate Withdrawal Scale [COWS]) they may receive the first SC injection of RBP-6000 
(containing 300 mg buprenorphine). Subjects with significant withdrawal signs/symptoms 
(defined as >12 on the COWS) or significant cravings for opioids (defined as >20 mm on the 
Opioid Craving VAS) after the end of the 2-week SUBOXONE sublingual film Run-In period 
will not be eligible to continue in the study and will be referred for treatment.   
On Day 1 of the study (initiation of study drug injections), all subjects will receive a SC injection 
of 300 mg of buprenorphine in RBP-6000. Subsequent doses of RBP-6000 may be adjusted 
down to 100 mg and back up to 300 mg based on the medical judgment of the Investigator. After 
injection of RBP-6000, subjects will not be permitted to receive supplemental SUBOXONE 
sublingual film during the RBP-6000 treatment period. Subjects who require supplemental 
SUBOXONE sublingual film or other sublingual buprenorphine pharmacotherapy during the 
RBP-6000 treatment period will be withdrawn from the study and referred for appropriate 
treatment. 
Subjects will return to the clinic for monthly injection visits (every 28 ±2 days) for a total of up 
to 12 injections for de novo subjects or for a total of 6 injections for roll-over subjects. ECG 
recordings and vital signs will be collected pre and post each SC injection. All ECGs will be 
interpreted by a central monitoring facility.  Subject-reported injection site pain Visual Analog 


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Scale scores (VAS) will be collected at various times up to 1 hour after each injection. Local 
injection site grading will be collected at various time points starting immediately after injection 
and will be evaluated for pain, tenderness, warmth, itching, erythema, inflammation or swelling, 
and bruising using a 4-point severity scale. At each visit after injections begin, the injection site 
will be assessed by site staff and will also be evaluated for evidence of attempts to remove the 
depot.  
Subjects will need to return to the clinic weekly for the first 5 weeks and biweekly (i.e., every 2 
weeks) until injection 6, and monthly for the rest of the study period for urine drug screens 
(UDS), Timeline Followback (TLFB) interviews, opioid craving VAS evaluation, COWS and 
subject reported outcomes (Subjective Opiate Withdrawal Scale [SOWS]). Subjects will 
continue to receive counseling (manual-guided behavioral therapy) during the study.  
Safety assessments will be collected at each injection visit and/or at injection follow-up visits 
and will include the following:  vital signs, electronic Columbia Suicide Severity Rating Scale 
(eC-SSRS) responses, ECGs, laboratory tests (hematology, chemistry, urinalysis, and pregnancy 
test), concomitant medications, and AEs.   
Sparse PK blood samples will be collected for population PK analysis for the roll-over subjects 
only. PK samples will not be collected for the de novo subjects. ECGs will be performed before 
PK sample collection. The following depression, pain, and health economic outcome 
assessments will also be collected: Beck Depression Inventory (BDI-II), brief pain inventory 
(BPI), EuroQol EQ-5D-5L (EQ-5D-5L), 36-Item Short Form Health Survey, Version 2 (SF-
36v2), Medication Satisfaction Questionnaire (MSQ), healthcare resource utilization (HCRU), 
Treatment Effectiveness Assessment (TEA) and Addiction Severity Index Lite (ASI-Lite). 
At the end of the RBP-6000 treatment period, subjects will enter a 4-week SUBOXONE 
transition period/safety follow-up where they will receive the same dose of SUBOXONE that 
they received at Day -1 and their ongoing treatment options will be reviewed. 
A schematic depicting the study design for de novo subjects is in Figure 2 and a schematic for 
roll-over subjects is in Figure 3.  A complete list of procedures and assessments for subjects is in 
the Schedule of Events (SOE) in Appendix 1, Appendix 2, Appendix 3, Appendix 4, and 
Appendix 5. 


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Figure 2 
Study Overview:  De novo Subjects 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Injection No. 7 (Week 25/Day 169) 
Injection No. 8 (Week 29/Day 197)  
Injection No. 9 (Week 33/Day 225)  
 
Injection No. 10 (Week 37/Day 253)  
Injection No. 11 (Week 41/Day 281)  
Injection No. 12 (Week 45/Day 309)  
SUBOXONE - Sublingual Film Transition (Day 337) 
End of Study Visit (Day 365)/Early Termination (Up to Day 365) 
Subjects return to clinic for this visit 
Injection No. 1 (Week 1/Day 1)  
 Followed by weekly assessment visits 
Injection No. 2 (Week 5/Day 29)  
Followed by biweekly assessment visits 
Injection No. 3 (Week 9/Day 57)  
Followed by biweekly assessment visits 
Injection No. 4 (Week 13/Day 85)  
Followed by biweekly assessment visits
Injection No. 5 (Week 17/Day 113)  
Followed by biweekly assessment visits 
Injection No. 6 (Week 21/Day 141)  
SUBOXONE Sublingual Film Run-In 
• 
Induction (3 days) 
Subjects complete daily visits on Day -14 to Day -12  
• 
Dose Adjustment (1-11 days) 
Subjects complete visits on Day -11, Day -8, Day -4, and Day -1 (all visits not required) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Early 
Termin
ation 
Subjects 
return 
to clinic 
for this 
visit 
Screening  
Screening (Day -21 to Day -15)  
study 


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Figure 3 
Study Overview:  Roll-over Subjects from RB-US-13-0001 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Injection No. 1 (Week 1/Day 1) 
 Followed by weekly assessment visits 
Injection No. 2 (Week 5/Day 29)  
Followed by biweekly assessment visits 
Injection No. 3 (Week 9/Day 57)  
Followed by biweekly assessment visits 
Injection No. 4 (Week 13/Day 85)  
Followed by biweekly assessment visits 
Injection No. 5 (Week 17/Day 113)  
Followed by biweekly assessment visits 
Injection No. 6 (Week 21/Day 141)  
SUBOXONE Sublingual Film Run-In 
• 
Induction (3 days) 
Subjects complete daily visits on Day -14 to Day -12  
• 
Dose Adjustment (1-11 days) 
Subjects complete visits on Day -11, Day -8, Day -4, and Day -1 (all visits not required) 
SUBOXONE 
Sublingual Film 
Transition 
(Day 169) 
End of Study Visit (Day 197)/Early Termination (Up to Day 197) 
Subjects return to clinic for this visit 
 
 
 
 
 
 
 
Early 
Termin
ation 
Subjects 
return to 
clinic 
for this 
visit 
Screening  
(Days -21 to -15 [Up to 3 days after EOS Visit/Day169 + 3 for Subject’s Completing  
Study RB-US-13-0001])  
Note: RB-US-13-0001 assessments completed at EOS/Day 169 will serve as screening 
assessments  


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3.2 
Rationale for Study Design 
This study is designed to assess the long-term safety, tolerability, and clinical outcomes of  
RBP-6000 SC injections in subjects with opioid use disorder.  The planned number of subjects 
was designed to ensure at least 100 subjects reach 1 year of treatment with RBP-6000 (as advised 
in the ICH-E1A Guideline - The Extent of Population Exposure to Assess Clinical Safety: For 
Drugs Intended for Long-term Treatment of Non-Life-Threatening Conditions).  The safety 
assessments used include evaluations of AEs, serious AEs (SAEs), discontinuations from study 
due to AEs; local injection site tolerability (e.g., injection site grading); injection site pain using a 
subject-reported VAS; suicidality using the eC-SSRS, concomitant medications; changes in 
clinical laboratory results; vital sign measurements; 12-lead ECGs, and physical examination 
results.  The instruments used to measure clinical outcomes (e.g., COWS, SOWS, Opioid 
Craving VAS, and eC-SSRS) were developed to measure the specific symptoms exhibited by 
and the challenges facing opioid-dependent individuals.   
3.3 
Study Duration and Dates 
The expected maximum duration of participation for de novo subjects is up to approximately 55 
weeks consisting of up to a 7-day screening period, up to a 14-day SUBOXONE sublingual film 
Run-In, up to a 48-week open-label treatment period, and a 4-week follow-up and transition 
period when subjects will receive the same dose of SUBOXONE that they received at Day -1 
and their ongoing treatment options will be reviewed. 
The expected maximum duration of participation for roll-over subjects is up to approximately 31 
weeks, consisting of up to a 7-day screening period, up to a 14-day SUBOXONE sublingual film 
Run-In, a 24-week open-label treatment period, and a 4-week follow-up and transition period 
when they will receive the same dose of SUBOXONE that they received at Day -1 and their 
ongoing treatment options will be reviewed. 
If a sufficient number of subjects reach 1 year of exposure to RBP-6000, the study may be 
stopped early, and all remaining subjects will complete EOS procedures and enter the 
SUBOXONE Transition Period/Safety Follow-up. 
Subjects who receive at least 1 dose of RBP-6000 and discontinue the trial for any reason will be 
required to complete the Early Termination (ET) visit. 


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4 
STUDY POPULATION SELECTION 
4.1 
Study Population 
Approximately 300 de novo subjects will be enrolled into this study as well as approximately 
300 roll-over subjects. The study population will consist of individuals diagnosed with opioid 
use disorder who are seeking treatment.  
4.2 
Inclusion Criteria 
A. De novo Subjects: Subjects who have not participated in Study RB-US-13-0001 must meet 
the following criteria to be enrolled in this study: 
1. Subjects seeking treatment for opioid use disorder who currently, and by medical history 
over the previous 3 months, meet the DSM-5 criteria for moderate or severe opioid use 
disorder.  
2. Subjects who provide written informed consent to participate in this study. 
3. Subjects who are an appropriate candidate for opioid partial-agonist treatment in the 
opinion of the Investigator or medically responsible physician. 
4. Either male or female. 
5. Age ≥ 18 to ≤ 65 years. 
6. Have a body mass index (BMI) of ≥ 18.0 to ≤ 35.0 kg/m2. 
7. Females: Women of childbearing potential (defined as all women who are not surgically 
sterile or postmenopausal for at least 1 year prior to informed consent), must have a 
negative pregnancy test prior to enrollment and must agree to use a medically acceptable 
means of contraception from screening through at least 6 months after the last dose of 
investigational medicinal product (IMP). 
Males: Subjects with female partners of child-bearing potential must agree to use 
medically acceptable contraception after signing the informed consent form (ICF) 
through at least 6 months after the last dose of IMP. Male subjects must also agree not to 
donate sperm during the study and for 6 months after receiving the last dose of IMP. 
The following methods of contraception are considered to be medically acceptable: 
established use of oral, injected or implanted hormonal contraception; placement of an 
intrauterine device or intrauterine system; use of a double-barrier method of 
contraception (condom or occlusive cap with use of a spermicide) or male sterilization.   
8. Subjects must agree not to take any buprenorphine products other than those administered 
during the current study throughout participation in the study. 
9. Subjects must be willing to adhere to study procedures. 
 
B. Roll-Over Subjects: Subjects who have successfully completed Study RB-US-13-0001 in its 
entirety must complete EOS/Day 169 assessments, which will serve as screening for this 
study. In addition, only the following criteria must be met to be enrolled in this study: 
1. Provide written consent to participate in this study. 
2. Be considered eligible in the medical judgment of the Investigator. 


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3. Females: Women of childbearing potential (defined as all women who are not surgically 
sterile or postmenopausal for at least 1 year prior to informed consent) must have a negative 
pregnancy test prior to enrollment and must agree to use a medically acceptable means of 
contraception from screening through at least 6 months after the last dose of IMP. 
Males: Subjects with female partners of child-bearing potential must agree to use medically 
acceptable contraception after signing the ICF through at least 6 months after the last dose of 
IMP. Male subjects must also agree not to donate sperm during the study and for 6 months 
after receiving the last dose of IMP. 
The following methods of contraception are considered to be medically acceptable:  
established use of oral, injected or implanted hormonal contraception; placement of an 
intrauterine device or intrauterine system; use of a double-barrier method of contraception 
(condom or occlusive cap with use of a spermicide) or male sterilization.   
4. Subjects must agree not to take any buprenorphine products other than those administered 
during the current study throughout participation in the study. 
5. Subjects must be willing to adhere to study procedures. 
 
4.3 
Exclusion Criteria 
A. De novo Subjects who meet any of the following criteria will be excluded from the study: 
1. Current diagnosis, other than opioid use disorder, requiring chronic opioid treatment. 
2. Current substance use disorder, as defined by DSM-5 criteria, with regard to any 
substances other than opioids, cocaine, cannabis, tobacco, or alcohol. 
3. Positive UDS result at screening for cocaine or cannabis AND meets DSM-5 criteria for 
either moderate or severe cocaine or cannabis use disorder, respectively. 
4. Meets DSM-5 criteria for moderate or severe alcohol use disorder. 
5. Treatment for opioid use disorder required by court order.   
6. Current incarceration or pending incarceration/legal action that could interfere with a 
subject’s ability to participate in the study. 
7. Pregnant or lactating females. 
8. Current use of prescription or OTC medications that are clinically relevant cytochrome 
P450 3A4 or cytochrome P450 2C8 inducers or inhibitors (e.g., rifampicin, azole 
antifungals [e.g., ketoconazole], macrolide antibiotics [e.g., erythromycin]) with the 
exception of marijuana.  More examples are provided in the excluded medications list 
(Appendix 9). 
9. History of suicidal ideation within 30 days prior to providing written informed consent as 
evidenced by answering “yes’ to questions 4 or 5 on the suicidal ideation portion of the 
eC-SSRS completed at the screening visit or history of a suicide attempt (per the eC-
SSRS) in the 6 months prior to informed consent. 
10. Current or history (within the 6 months prior to providing written informed consent) of 
chest pain or palpitation with either exertion or drug use, peripheral or generalized 
edema, clinically significant cardiovascular disease, including myocardial infarction, 
heart failure, uncontrolled hypertension, clinically significant orthostatic hypotension, 
endocarditis, or myocarditis.  
11. Clinically significant abnormal systolic blood pressure (BP) or diastolic BP, in the 
opinion of the Investigator. 


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12. Uncontrolled medical or psychiatric illness that, in the opinion of the Investigator or 
Sponsor, may place the subject at risk or interfere with outcome measures or a subject’s 
ability to participate in the study. 
13. Clinically significant abnormality (e.g., severe respiratory insufficiency) in past medical 
history or at the screening physical examination that, in the opinion of the Investigator or 
Sponsor, may place the subject at risk or interfere with outcome variables.   
14. History or presence of allergic or adverse response (including rash or anaphylaxis) to 
buprenorphine, naloxone, or the ATRIGEL Delivery System. 
15. Total bilirubin ≥ 1.5x the upper limit of normal (ULN), alanine aminotransferase (ALT) 
≥3xULN, aspartate aminotransferase (AST) ≥ 3xULN, serum creatinine > 2xULN, 
international normalized ratio (INR) >1.5xULN, lipase >3xULN, amylase >3xULN, or 
any abnormal pancreatic enzyme value above ULN that is associated with clinically 
significant, active pancreatic disorder. 
16. Congenital long QT syndrome, history of prolonged QT in the 3 months prior to 
screening, or a corrected QT interval (Fridericia’s – QTcF) >450 msec (male) or >470 
msec (female) or history of risk factors for Torsades de Pointes. 
17. Diagnosis of acquired immunodeficiency syndrome (AIDS). 
18. Affiliated with, or a family member of, site staff directly involved in the study. 
19. Unable, in the opinion of the Investigator or the medically responsible physician, to 
comply fully with the study requirements.   
20. Clinically significant anemia or low hemoglobin (levels < 9 g/dL) at Screening.  
21. Donation of > 250 mL of blood or plasma within the 30 days prior to providing written 
informed consent  
22. Participation in any other clinical trial within 30 days prior to informed consent  
23. Received medication-assisted treatment for opioid use disorder (e.g., methadone, 
buprenorphine) in the 90 days prior to providing written informed consent  
24. Previously received RBP-6000. 
25. Use of (within the past 30 days prior to providing written informed consent) or positive 
UDS result at screening for barbiturates, benzodiazepines, or  methadone.. 
 
B. Roll-Over Subjects who meet any of the following criteria will be excluded from the study: 
1. Discontinued early from Study RB-US-13-0001 
2. Experienced any major protocol deviations or adverse events during the RB-US-13-0001 
study which, in the opinion of the Investigator, could potentially compromise subject 
safety. 
3. Women of childbearing potential who have a positive pregnancy test at EOS/Day 169, 
who are pregnant or breastfeeding, seeking pregnancy, or failing to use adequate 
contraceptive methods during the study. 
 


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4.4 
Day -1/Enrollment Criteria 
Beginning on the 4th day of SUBOXONE sublingual film dosing (Study Day -11) through the 
14th day of dosing, subjects will be evaluated for Day -1 criteria.  Subjects must meet the 
following criteria in order to be enrolled: 
1. No allergic reaction to SUBOXONE sublingual film. 
2. Daily dose of SUBOXONE sublingual film between 8 mg/2 mg - 24 mg/6 mg (inclusive) 
buprenorphine/naloxone. 
3. COWS score of ≤ 12. 
4. Opioid Craving VAS score of ≤ 20 mm. 
 


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5 
STUDY TREATMENTS 
5.1 
Description of Treatments 
5.1.1 
SUBOXONE Sublingual Film 
SUBOXONE sublingual film is supplied as an orange rectangular sublingual film with a white 
printed logo.  Each SUBOXONE sublingual film contains buprenorphine HCl and naloxone HCl 
dihydrate at a 4:1 ratio expressed as the free bases.  Films are intended for SL administration and 
are available in 4 dosage strengths (2 mg/0.5 mg; 4 mg/1 mg; 8 mg/2 mg; and 12 mg/3 mg).   
5.1.2 
Investigational Medicinal Products 
RBP-6000 uses buprenorphine base in the ATRIGEL Delivery System, which is currently used 
in a number of approved commercial products.  RBP-6000 will be supplied as a single-syringe 
system, which is prefilled with RBP-6000.  The entire contents of the prefilled syringe will be 
administered.  (See Appendix 8: Study Drug Preparation and Dispensing Procedures for detailed 
dosage instructions).   
RBP-6000 is manufactured by Indivior Inc. according to Good Manufacturing Practice 
standards. 
All used syringes components will be disposed of in accordance with the site’s standard 
operating procedures (SOP) or pharmacy destruction policy. The site’s clinical research associate 
(CRA) will review the site’s SOP and/or pharmacy destruction policy.  All IMP packaging will 
be retained for CRA verification. 
5.2 
Treatments Administered 
5.2.1 
Run-In Treatment Period 
5.2.1.1 
SUBOXONE Sublingual Film Induction (De novo Subjects) 
De novo subjects will receive their first dose of SUBOXONE sublingual film on Induction 
Day 1.  Subjects will be started with an initial dose of 2 mg/0.5 mg or 4 mg/1 mg and may titrate 
upwards in 2 or 4 mg increments of buprenorphine, at approximately 2-hour intervals, under 
clinical supervision, to 8 mg/2 mg based on therapeutic response.  
On Induction Day 2, subjects with a COWS score > 12, or subjects reporting withdrawal 
signs/symptoms overnight, will receive a dose of SUBOXONE sublingual film equal to the total 
dose given on Induction Day 1 plus 4 mg. (For example, if a subject received a total dose of 8 
mg on Induction Day 1, the starting dose of buprenorphine for Induction Day 2 would be 12 mg).  
If the COWS score is still > 12 one hour later, another 4 mg dose can be given. The subject 
should not exceed a maximum dose of 16 mg/4 mg for Induction Day 2. Subsequent 
SUBOXONE sublingual film doses must be separated by at least 1 hour from the preceding dose. 
SUBOXONE sublingual film doses may also be adjusted downward if necessary.  


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On Induction Day 3, subjects will be titrated to therapeutic response based on COWS scores as 
well as physician judgment. Most subjects will only require a single dose on Induction Day 3 
which will equal the Induction Day 2 dose or the Induction Day 2 dose plus 4 mg buprenorphine. 
Additional doses may also be administered on Induction Day 3 (up to 24 mg). Subsequent 
SUBOXONE sublingual film doses must be separated by at least 1 hour from the preceding dose.  
Subjects should reach a daily dose of between 8 mg/2 mg and 24 mg/6 mg by Induction Day 3 
and continue on that dose through the remainder of the SUBOXONE sublingual film Run-In 
period, with additional dose adjustments if necessary.  
The SUBOXONE sublingual film(s) will be administered under the tongue, close to the base on 
the left or right side, until they are dissolved.  If an additional sublingual film is required, it 
should be placed on the opposite side from the first film.  Subjects should be instructed to hold 
the films under the tongue until they dissolve.  If a third film is required, it should be placed 
under the tongue after the first 2 films have dissolved.   
For more information about SUBOXONE sublingual film administration, please refer to the 
SUBOXONE Full Prescribing Information (See Appendix 7). 
5.2.1.2 
SUBOXONE Sublingual Film Induction (Roll-over Subjects) 
Following screening, roll-over subjects will be inducted on SUBOXONE sublingual film to 
achieve daily doses between 8 mg to 24 mg buprenorphine according to the SUBOXONE 
sublingual film prescribing instructions. Subjects must be titrated to a minimum dose of 8 mg 
SUBOXONE by the end of the 3-day Induction period regardless of their COWS scores and/or 
the presence or absence of withdrawal symptoms.   
Subjects will receive their first induction dose on Induction Day 1. Subjects should be started 
with an initial dose of 2 mg/0.5 mg or 4 mg/1 mg buprenorphine/naloxone and may titrate 
upwards in 2 or 4 mg increments of buprenorphine, at approximately 2-hour intervals, under 
supervision, to a total dose of up to 8 mg/2 mg buprenorphine/naloxone based on the control of 
acute withdrawal symptoms.  
On Induction Day 2, subjects with a score for COWS of > 12, or subjects reporting opioid 
withdrawal signs/symptoms overnight, should receive a dose of study drug equal to the total dose 
given on Induction Day 1 plus 4 mg.  If the COWS score is still > 12 one hour later, another 4 
mg dose can be given.  The subject should not exceed a maximum dose of 16 mg/4 mg 
buprenorphine/naloxone for Induction Day 2.  Subsequent SUBOXONE sublingual film doses 
must be separated by at least 1 hour from the preceding dose.  SUBOXONE sublingual film 
doses may also be adjusted downward if necessary.   
 
On Induction Day 3, subjects will be titrated to therapeutic response until a therapeutic dosage is 
reached, based on COWS scores as well as physician judgment. Most subjects will only require a 
single dose on Induction Day 3 which will equal the Induction Day 2 dose or the Induction Day 2 
dose plus 4 mg. Additional doses may also be administered on Induction Day 3 (up to 24 mg).  
Subsequent SUBOXONE sublingual film doses must be separated by at least 1 hour from the 
preceding dose.  Although subjects should reach a daily dose of between 8 mg and 24 mg by 


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Induction Day 3 and continue on that dose through the remainder of the SUBOXONE sublingual 
film Run-In period, dose adjustments may be necessary during the Run-In period.  
The SUBOXONE sublingual film(s) will be administered under the tongue, close to the base on 
the left or right side, until they are dissolved.  If an additional sublingual film is required, it 
should be placed on the opposite side from the first film.  Subjects should be instructed to hold 
the films under the tongue until they dissolve.  If a third film is required, it should be placed 
under the tongue after the first 2 films have dissolved.   
For more information about SUBOXONE sublingual film administration, please refer to the 
SUBOXONE Full Prescribing Information (See Appendix 7). 
5.2.2 
Dose Adjustment Period (All Subjects) 
Beginning at Day -11, subjects will be assessed to determine whether they meet Day -1 
/enrollment criteria as defined in Section 4.4.  Once subjects meet the enrollment criteria (no 
significant opioid craving (≤20 mm on the Opioid Craving Visual Analog Scale [VAS] and no 
significant withdrawal (≤ 12 on the Clinical Opiate Withdrawal Scale [COWS]), they are eligible 
to receive the first SC injection of RBP-6000 (containing 300 mg buprenorphine). Subjects with 
significant withdrawal signs/symptoms (defined as >12 on the COWS) or significant cravings for 
opioids (defined as >20 mm on the Opioid Craving VAS) after the end of the 2-week 
SUBOXONE sublingual film Run-In period will not be eligible to continue in the study and will 
be referred for treatment.   
5.2.3 Active Study Treatment 
On Day 1 of the study (initiation of study drug injections), all subjects will receive a SC injection 
of 300 mg of buprenorphine in RBP-6000. Subsequent doses of RBP-6000 may be adjusted 
down to 100 mg and back up to 300 mg based on the medical judgment of the Investigator.   All 
subjects will receive injections of RBP-6000 separated by 28 (± 2) days.   
After injection of RBP-6000, subjects will not be permitted to receive supplemental 
SUBOXONE sublingual film during the RBP-6000 treatment period. Subjects who require 
supplemental SUBOXONE sublingual film or other sublingual buprenorphine pharmacotherapy 
during the RBP-6000 treatment period will be withdrawn from the study and referred for 
appropriate treatment. 
A single SC dose will be injected by an individual who is medically qualified to perform the 
procedure and delegated by the Principal Investigator to perform the task.  Injections of 
RBP-6000 will be administered in the abdominal area below the waist but above the hip bone; 
more specifically, injection should occur in the region where the body curves at the side to about 
2 inches from the middle of the abdomen with adequate amounts of subcutaneous tissue that 
does not have excessive pigment, nodules, lesions, or hair.  RBP-6000 will form a solid polymer 
depot that contains the buprenorphine.  As the depot degrades, buprenorphine will be released 
into the systemic circulation at a consistent rate over an approximately 28-day period.  For 
detailed instructions on use, see Appendix 8. 


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5.2.4 
SUBOXONE Transition Period/Safety Follow-up 
At the end of the RBP-6000 open-label treatment period, subjects will enter a 4-week 
SUBOXONE transition period/safety follow-up where they will receive the same dose of 
SUBOXONE that they received at Day -1, and their ongoing treatment options will be reviewed. 
5.3 
Selection and Timing of Dose for Each Subject 
The study schedule is designed so that each of the injections will be separated by a maximum of 
30 days (28 days ± 2 days) and will be given on alternate sides of the subject’s abdomen (see 
Appendix 8 and the Pharmacy Manual for detailed information on administration).   
5.4 
Method of Assigning Subjects to Treatment Groups 
When a de novo or roll-over subject signs the ICF, she/he will be assigned a unique subject 
number in numerical sequence, which will be used for the duration of the study. Roll-over 
subjects will retain the subject number assigned to them in the RB-US-13-0001 study. De novo 
subjects will be assigned a unique subject number, consisting of the site number followed by 9 
and a 3 digit number in numerical sequence (e.g., the first de novo subject screened at site # 001 
will be assigned the number 0019001).  The subject number will be recorded in the source 
document and electronic case report form (eCRF). 
All subjects will be assigned to receive the 300 mg RBP-6000 dose. Subsequent doses of 
RBP-6000 may be adjusted down to 100 mg and back up to 300 mg based on the medical 
judgment of the Investigator 
5.5 
Blinding 
Not applicable; this is an open-label study  
 
5.6 
Concomitant Therapy 
Concomitant therapies are defined as prescribed medications and OTC preparations, including 
herbal preparations and vitamins, other than study medication and supplementary medication that 
the subject receives within 30 days of screening and for the during the course of the study.  Any 
medication taken by the subject is to be reported by the subject and noted on the subject’s source 
document and concomitant medication page.  Any changes in concomitant therapy during the 
study will be documented, including cessation of therapy, initiation of therapy, and dose 
changes. 
Roll-over subjects who started on a benzodiazepine during the RB-US-13-0001 study will be 
evaluated on a case-by-case basis for inclusion in the RB-US-13-0003 study.  The investigator 
will discuss these subjects with the medical monitor before enrolling into the RB-US-13-0003 
study. 
The Investigator or designee will also record any medications given for the treatment of AEs on 
the concomitant medication page.   


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5.6.1 
Permitted Concomitant Medications 
Following screening and enrollment, ancillary medications (ibuprofen, acetaminophen, 
methocarbamol, hydroxyzine, and loperamide) may be administered to subjects to help alleviate 
signs and symptoms of opioid withdrawal as deemed necessary by the Investigator or medically 
qualified sub-investigator.  Details on acceptable administration of these medications and 
preparations are provided below: 
• Ibuprofen (400 mg orally) may be given every 4 to 6 hours as needed for pain up to a 
maximum of 2400 mg per day.  Subjects for whom ibuprofen is contraindicated or not 
tolerated may be given acetaminophen (325 to 1000 mg every 4 to 6 hours) as needed up 
to a maximum of 3000 mg per day.  Caution should be exercised when using 
acetaminophen concomitantly with other medications that have potential hepatotoxic 
effects.  Methocarbamol may also be given as needed for relief of muscle pain in 
clinically appropriate doses based on physician assessment. 
• Hydroxyzine (50 to 100 mg orally) may be given every 6 hours as needed for anxiety, 
nausea, or vomiting.  Additionally, hydroxyzine (50 to 100 mg orally) may be given at 
bedtime as needed for sleep.  The hydroxyzine daily dose should not exceed a maximum 
of 600 mg per day. 
• Loperamide (2 to 4 mg orally) may be given as needed for diarrhea up to a maximum of 
16 mg per day. 
5.6.2 
Prohibited Concomitant Medications 
Concomitant therapies subject to the restrictions indicated under Prohibited Concomitant 
Medications may be used only following approval by the Sponsor unless an immediate medical 
need necessitates their use.  These are listed below:   
• Use of buprenorphine. 
• Ongoing prescription that are clinically relevant P450 3A4 inducers or inhibitors, such as 
azole antifungals (e.g., ketoconazole) and macrolide antibiotics (e.g., erythromycin). 
• Herbal supplements that have the potential to cause prolongation of the QTc interval.   
• Over-the-counter medications that have the potential to cause prolongation of the QTc 
interval.  This does not apply to over-the-counter medications listed under Concomitant 
Therapies above that are prescribed by the Investigator, or over-the counter medications 
that may be used by the Investigator for an immediate medical need that necessitates their 
use. The medical monitor should be consulted for any questions. 
• Medications, in the addition to those listed above, which may be expected to significantly 
interfere with the metabolism or excretion of buprenorphine that may be associated with 
a significant drug interaction with buprenorphine, or may pose a significant risk to 
subjects’ participation in the study. 
Other concomitant medications, OTC preparations, or therapies that are not allowed during study 
participation are listed in Appendix 9. 


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5.7 
Restrictions 
5.7.1 
Prior Therapy 
All prior medications including OTC, dietary supplements, and herbal preparations taken by the 
subject within the 30 days prior to screening will be recorded. 
5.7.2 
Subject Activity Restrictions 
Subjects should be advised to avoid strenuous exercise. 
5.8 
Protocol Compliance 
This study involves the SC injection of multiple doses of RBP-6000 containing 100 or 300 mg of 
buprenorphine (see the SOE, Appendix 2).  The Investigator may terminate a subject based on 
the subject’s inability or willingness to comply with the protocol requirements. 
IMP will be administered by designated and qualified study personnel at the site.  The time and 
duration, the dose delivered, and any dosing observations will be recorded in source 
documentation.  The Investigator or designated individual will maintain a log of all study drugs 
dispensed and returned (if applicable).  Drug supplies will be inventoried and accounted 
throughout the study. 
5.9 
Packaging and Labeling 
RBP-6000 will be packaged and labeled in a manner consistent with the study design and 
applicable regulations.  The study medication will be provided to the investigator(s) by the 
Sponsor or contractor.   
The SUBOXONE sublingual film will be supplied as bulk films in the following buprenorphine 
dosage strengths: 2mg /0.5 mg; 4 mg/1 mg; 8 mg/2 mg; and 12 mg/3 mg.  Containers will be 
labeled with a single panel disclosing the product name, lot number, contents, Sponsor name and 
address, route of administration, and appropriate precautionary statements. 
The study drug, RBP-6000, will be identified as an investigational compound. 
The following components will be used in the preparation of RBP-6000: 
• One sealed foil pouch containing a syringe prefilled with RBP-6000 and an oxygen 
absorber pack. 
• One sterile 19-gauge, 1-inch hypodermic safety needle. 
5.10 Storage and Accountability 
RBP-6000 should be stored under refrigerated conditions between 2-8ºC (36-46°F).  
SUBOXONE sublingual films should be stored at 25°C (77°F) with excursions permitted 


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between 15-30°C (59-86°F).  Temperature excursions outside of these ranges should be reported 
to the Sponsor immediately and approval for use should be obtained. 
 
The PI or designee is responsible for ensuring that all study drug received at the site is 
inventoried and accounted for throughout the study. Drug accountability is the responsibility of 
the PI or designee, with verification by the CRA. Study drug must be handled strictly in 
accordance with the protocol, handling guidelines and the label, and must be stored in a locked, 
limited access area under appropriate environmental conditions. The PI must ensure that proper 
conditions exist for storage of study treatments. The dispensing of study drug to the subject must 
be documented on the drug dispensing form. 
 
Unused study drug must be available for verification by the Sponsor’s site monitor during on-site 
monitoring visits. The return to the Sponsor of unused study drug will be documented on the 
Study Drug Return Form. 
 
The Investigator agrees not to supply RBP-6000 to any person except study personnel for SC 
injection of subjects in this study.   
5.11 Investigational Product Retention at Study Site 
The PI or medically-qualified designee agrees to conduct a study drug supply inventory for  
RBP-6000, to record results of this inventory, and to return all unused study drug to the Sponsor 
at times specified by RBP. RBP will arrange for the appropriate and timely destruction of all 
returned, unused RBP-6000. All used needles and syringes from RBP-6000 will be disposed of 
into an appropriate secure biohazard container per the standard operating procedures (SOPs) at 
the clinical site.  
All used IMP packaging (e.g. carton, foil pouch) will be retained at the study site until 
reconciliation is performed by the CRA.  After reconciliation is completed, the used IMP 
packaging may be disposed of per the SOPs at the study site. 


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6 
STUDY PROCEDURES 
The schedule of events for this study is provided in Appendix 1, Appendix 2, Appendix 3, 
Appendix 4, and Appendix 5. 
For roll-over subjects, study procedures completed at EOS/Day 169 will serve as screening 
assessments for the open-label study.   
6.1 
Informed Consent 
6.1.1 
General Information 
Prior to entering the study, the Investigator or designated individual will explain to each subject 
the nature of the study, its purpose, procedures, expected duration, alternative therapies 
available, and the benefits and risks involved in study participation. Subjects will be given the 
Institutional Review Board (IRB)-approved ICF to review and the opportunity to ask questions.  
Subjects will be informed of their right to withdraw from the study at any time without prejudice.  
The potential subjects should be able to answer simple questions about the study after the ICF 
has been reviewed and explained.  After this explanation and before any study-specific 
procedures have been performed, the subject will voluntarily sign and date the ICF to indicate 
the desire to participate in the study.  Prior to participation in the study, the subject will receive a 
copy of the signed and dated ICF.   
Roll-over subjects will complete all Day 169/EOS procedures prior to signing the ICF 
6.2 
Medical History 
For de novo subjects, a detailed medical history will be obtained by the PI or medically qualified 
designee during the screening visit (Visit 1). This will include information regarding the 
subject’s full history of medical and psychiatric conditions, diagnoses, procedures, treatments, 
concomitant medications, demographic information, and use of tobacco, drugs of abuse, alcohol, 
and caffeine, and any other noteworthy medical information, including suicidality measured 
using the eC-SSRS. Any updates to medical history information that the PI or medically 
qualified designee becomes aware of will be captured throughout the study.  All prior 
medications, OTC health, and dietary supplements taken by the subject within 30 days will be 
recorded.  In addition, hospitalizations in the past 3 months and the reason for admission 
(medical/surgical/psychiatric/other) will be recorded.   
For roll-over subjects medical history will not be re-obtained, except for new information. 
6.3 
Physical Examination 
A complete physical examination (PE) will be performed by the Investigator or medically 
qualified designee.  The physical examination will consist of an examination of the following:  
general appearance, skin, head, eyes, ears, nose, throat, neck (including thyroid), lymph nodes, 
chest and lungs, heart, abdomen, extremities, body weight, and a brief neurological assessment.  
The examination will not include a pelvic, breast, or rectal examination.  If any clinically 


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significant abnormal findings started before the date that informed consent was given, these 
findings should be recorded on the Medical History case report form (eCRF).   
If any clinically significant change from screening (Visit 1 for de novo subjects; Study RB-US-
13-0001 EOS visit (Day 169) for roll-over subjects) is noted, it will be reported as an AE and 
followed up to resolution or until reaching a stable end point. 
Weight (kg) will be assessed (in ordinary indoor clothing with shoes off) and will be recorded at 
screening as well as periodically throughout the study.  Height (cm) will be recorded at screening 
only.  BMI will be calculated at screening as well as periodically throughout the study.  BMI is 
defined as the subject’s weight in kg divided by the square of the subject’s height in meters 
(kg/m2).  The amount of abdominal fat will be measured using the waist-to-hip ratio and will be 
recorded at screening as well as periodically throughout the study.   
Procedures performed at Day 169/EOS in the RB-US-13-0001 study will not be repeated at the 
screening visit for roll-over subjects. 
Assessments are performed at the time points detailed in the SOEs (Appendix 1, Appendix 2, 
Appendix 3, Appendix 4, and Appendix 5). 
6.4 
Vital Signs 
Evaluation of vital signs will be performed after the subject has been supine for ≥ 3 minutes and 
will include a measurement of systolic and diastolic BP, pulse rate, pulse oximetry, respiratory 
rate, and oral temperature.   
If clinically significant findings, as determined by the Investigator or medically qualified sub-
investigator, occur in any vital sign measurement, that measurement will be captured as an AE 
and repeated at medically appropriate intervals until the value returns to an acceptable range, a 
specific diagnosis is established, or the condition is otherwise explained. 
Assessments will be recorded in the source documents and eCRF and will be performed at the 
time points detailed in the SOE (Appendix 1, Appendix 2, Appendix 3, Appendix 4, and 
Appendix 5). 
6.5 
Electrocardiograms 
6.5.1 
12-Lead Electrocardiograms 
Resting 12-lead ECGs will be recorded with the subject in supine position following a 10-minute 
rest period. For roll-over subjects, ECGs will be recorded prior to the PK blood sampling. 
(Appendix 6). 
Resting 12-lead ECGs will be recorded as indicated in the SOEs (Appendix 1, Appendix 2, 
Appendix 3, Appendix 4, and Appendix 5). ECGs recorded at screening will be recorded in 
triplicate, at approximately 2 - 5 minute intervals.  


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ECG intervals including HR, QT, QTcF, QTcB, RR, PR, QRS and T wave changes will be 
recorded.  ECGs will be reviewed by the Investigator during the visits for any immediate 
abnormalities. ECGs will also be reviewed by a central facility.   
The findings of the ECGs as determined by the central facility will be assessed by the 
Investigator and marked as normal, abnormal-not clinically significant, or abnormal-clinically 
significant.  All clinically significant abnormalities will be captured as AEs.  In the event that a 
clinically significant AE related to an ECG assessment occurs during the study, the Investigator 
should contact the Indivior Medical Monitor. 
6.6 
Clinical Laboratory Tests 
6.6.1 
Laboratory Parameters 
All clinical laboratory assessments will be performed by a clinical laboratory accredited by the 
College of American Pathologists or with a certificate of compliance (or certificate of waiver for 
CLIA-waived tests) issued by the Center for Medicare & Medicaid Services or Clinical 
Laboratory Improvement Amendments.  The laboratory assessments will include routine and 
screening laboratory tests.   
See the SOEs in Appendix 1, Appendix 2, Appendix 3, Appendix 4, and Appendix 5 for the 
timing of the specific required laboratory tests which are listed in Table 2.  
Any abnormal hematology, chemistry, or urinalysis test result deemed clinically significant by 
the Investigator will be repeated, including test results obtained on the final study day.  For any 
test abnormality deemed clinically significant, an AE will be recorded (unless the result was 
considered erroneous) and repeat analysis will be performed until resolution or until the 
Investigator determines that resolution of the laboratory abnormality is not expected.   
Subjects will be in a seated or supine position during blood collection.  Clinical laboratory panels 
are listed in Table 2. 


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Table 2 
List of Laboratory Tests 
Hematology: 
Hematocrit 
Hemoglobin  
Mean corpuscular hemoglobin  
Mean corpuscular hemoglobin concentration  
Mean corpuscular volume  
Platelet count 
Pancreatic enzymes 
Red blood cell count 
White blood cell count with differential 
 
Urinalysis: 
Appearance 
Bilirubin 
Color 
Glucose 
Ketones 
Leucocyte esterase 
Microscopic examination of sedimenta 
Nitrite 
Occult blood 
pH 
Protein 
Specific gravity 
Urobilinogen 
 
Hormone Panel: 
Adrenocorticotropic hormone (ACTH) Follicle Stimulating 
Hormone 
Testosterone (total and free) 
 
Pregnancy: 
Urine Pregnancy (only for females not postmenopausal or 
surgically sterile for at least 1 year) 
Serum Pregnancy 
 
Screening:    
Hemoglobin A1c  
HIV-1 and -2 antibodies 
PTT 
PT with INR 
Serum pregnancy 
 
Serum Chemistry: 
Albumin 
Alkaline phosphatase 
Alanine aminotransferase (ALT) 
Amylase 
Aspartate aminotransferase (AST) 
Blood urea nitrogen 
Calcium 
Calculated creatinine clearance 
Carbon dioxide 
Chloride 
Creatinine 
Creatine kinase and subtypes 
Gamma-glutamyl transferase 
Globulin 
Glucose (non-fasting) 
High-density lipoprotein (HDL) 
Immunoreactive trypsinogen 
Lactate dehydrogenase 
Lipase 
Low-density lipoprotein (LDL) 
Magnesium 
Phosphorus 
Potassium 
Sodium 
Total bilirubin 
Direct bilirubin 
Total cholesterol 
Total protein 
Triglycerides 
Uric acid 
 
Urine Drug Screen (UDS): 
Opioidsb 
Cocaine 
Amphetamines 
Methadone 
Cannabinoids 
Barbiturates 
Benzodiazepines 
Methamphetamine 
Phencyclidine 
Anti-HIV = human immunodeficiency virus antibodies; hCG = human chorionic gonadotropin; INR = 
international normalized ratio; IRT = immunoreactive trypsinogen; PT = prothrombin time; and PTT = 
partial thromboplastin time. 
a 
Microscopic examination of sediment will be performed only if the results of the urinalysis evaluation are 
positive (microscopic examination may include but is not limited to WBC count, RBC count, casts, and crystals). 
b 
Oxycodone may not show up in all opiate assays and should be assessed separately. 
   
 


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6.6.2 
Sample Collection, Storage, and Shipping 
All blood sampling will be by individual venipuncture or with the use of a saline lock.  Blood 
and urine sample collection and processing procedures will be outlined in a separate reference 
manual to be provided to the site. 
6.6.3 
Reference Ranges 
Up-to-date reference ranges for the above investigations must be obtained for the laboratory 
performing analyses prior to the start of the study and be updated as appropriate during the 
course of the study. 
6.6.4 
Laboratory Results Review 
The Investigator will review the results and comment on the laboratory results sheet for all 
abnormal values, identifying those that are abnormal but not clinically significant as well as 
those that are significantly abnormal.  The Investigator will sign and date the laboratory results 
sheet to indicate that the review has taken place. 
Clinical Laboratory Changes:  It is the Investigator’s responsibility to review the results of all 
laboratory tests as they become available.  This review will be documented by the Investigator 
on the laboratory report.  For each abnormal laboratory test result, the Investigator needs to 
ascertain if this is a clinically significant abnormal change from baseline for that individual 
subject.  
6.6.5 
Good Laboratory Practice Compliance 
Confirmation of compliance with Good Laboratory Practice (GLP) will be obtained from the 
designated Bioanalytical Laboratory prior to the start of the study. 
6.7 
Pharmacokinetic Assessments 
Blood samples for population PK analysis will be collected from roll-over subjects only at the 
time points indicated in the PK sampling schedule (Appendix 6). The plasma concentrations of 
buprenorphine and norbuprenorphine will be quantified using specific and validated liquid 
chromatography tandem mass spectrometry methods. A laboratory manual for PK sample 
collection, processing, storage, and shipping will be supplied. 
For all subjects (de novo and roll-over), a PK sample will be taken as soon as possible after any 
SAE is reported.  If possible, an additional sample should be collected when the SAE has been 
resolved. 
The exact times (to the minute) of PK blood sampling as well as the exact times of drug 
administration will be recorded in the source and eCRF.   


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6.8 
Administration of Study Drug 
The study drug will be assigned by an IWRS system. Injections will be administered by a 
physician or suitably-qualified designee (e.g., physician, nurse, nurse practitioner, PA) who has 
been delegated to perform the task.  Study drug will be supplied only to subjects participating in 
the study. The Investigator agrees not to allow the study drug to be administered from, nor stored 
at, any site other than the study site agreed upon with the Sponsor. 
See Appendix 7 for detailed descriptions of dosing for the SUBOXONE sublingual film. 
Detailed instructions for the preparation and administration of RBP-6000 are in Appendix 8. 
If at an injection visit there is a safety concern with administration of RBP-6000 or placebo, after 
discussion with the medical monitor or sponsor, dosing can be delayed up to one week.  In the 
event this occurs, the subsequent doses will be delayed.  There must be at least 26 days between 
injections of study medication. 
All used syringe components will be disposed of into an appropriate secure biohazard container 
or per the SOPs at the study site. 
All used IMP packaging (e.g., carton, foil pouch) will be retained at the study site until the CRA 
conducts a visit to perform reconciliation.  After the reconciliation is completed, the used IMP 
packaging may then be disposed of per the SOPs at the study site. 
Unused IMP and returned SUBOXONE sublingual film must be available for verification by the 
Sponsor’s site monitor during on-site monitoring visits.  The return of unused or used returned 
IMP for destruction will be documented on the drug return form. 
6.9 
Safety and Suicidality Assessments 
Safety will be assessed by AEs, vital signs,  ECGs, clinical laboratory assessments, local 
injection site grading scale, injection site pain VAS, and eC-SSRS responses. See the SOE for 
specific timing of assessments (Appendix 1, Appendix 2, Appendix 3, Appendix 4, and 
Appendix 5). 
6.9.1 
Local Injection Site Tolerability 
6.9.1.1 
Injection Site Grading 
Local injection site grading will be performed by the Investigator or a trained and qualified 
health care professional, according to the SOE in Appendix 2, Appendix 3, Appendix 4, and 
Appendix 5.  Injection sites will be assessed for pain, tenderness, erythema/redness, induration, 
or swelling.  Local injection site tolerability will be assigned a severity grade, including none 
(grade 0), mild (grade 1), moderate (grade 2), severe (grade 3), or potentially life threatening 
(grade 4) utilizing the Injection Site Grading Scale in Appendix 15.  The local injection site 
grading assessment will be completed electronically on injection days immediately after each 
injection (within 10 minutes) and at 1 hour (± 15 minutes) and 24 hours (± 4 hours) after each 
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6.9.1.2 
Injection Site Pain Visual Analogue Scale (VAS)  
Injection site pain will be assessed by the subject at each injection visit electronically with a 
100mm VAS scale, where 0 represents no pain and 10 represents maximum pain (Appendix 16).  
The injection site-pain VAS scores will be obtained (after the completion of the injection) within 
1 minute and then at 5, 10, 15, 30, and 60 minutes (±5 minutes).  The timing of the Injection Site 
Pain VAS should be measured from the end of the injection.  In addition to rating pain levels by 
marking on the line the point they feel best represents their perception of their current state, the 
subject will also answer the following question with either a Yes or No: Are you currently 
experiencing any burning or stinging at the injection site? 
6.9.2 
Suicidality 
6.9.2.1 
Columbia Suicide Severity Rating Scale 
The eC-SSRS will be administered according to the SOE in Appendix 1, Appendix 2, Appendix 
3, Appendix 4, and Appendix 5.  The eC-SSRS is a questionnaire designed for assessment of 
suicidal ideation and behavior in adolescents and adults (Posner 2011).  The questionnaire will 
be administered as an electronic, self-rated version (eC-SSRS).  Clinical trial versions of the 
questionnaire are available for trial screening and follow up visits.  A sample section from the 
Baseline/Screening eC-SSRS and the follow up eC-SSRS are presented in Appendix 10 and 
Appendix 11, respectively.   
If a subject becomes suicidal during the study, the investigator should provide the appropriate 
treatment to the subject.  If the suicidality is deemed to be related to IMP and it is within 14 days 
of an injection, the depot may be removed (Section 6.14.1).  
The eC-SSRS should be completed prior to SUBOXONE and RBP-6000 injection and at 
approximately the same time each day ±2 hours. 
If, there is a positive on the eC-SSRS after screening the subject will be evaluated by the 
investigator for continuation in the study.  If needed, the investigator can consult with the 
medical monitor on continuation in the study of subjects with a positive eC-SSRS. 
6.10 Adverse Events Assessments 
6.10.1 
Definition 
In accordance with ICH and US FDA guidance, any untoward medical occurrence incurred by a 
subject that occurs after the first study-related procedure to the completion of the protocol-
defined safety surveillance period and is associated with the use of the drug, regardless of the 
presence of causal relationship, is a reportable AE.   
Abnormal results of diagnostic procedures, including laboratory test abnormalities, are 
considered AEs if they: 
• Result in discontinuation from the study, 


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• Require treatment or any other therapeutic intervention, 
• Require further diagnostic evaluation (excluding a repetition of the same procedure to 
confirm the abnormality), or 
• Are associated with clinical signs or symptoms that would have a significant clinical 
impact, as determined by the Investigator. 
6.10.2 
Performing Adverse Events Assessments 
The Investigator is ultimately responsible for assessing and reporting all AEs as outlined in the 
protocol.  The assessment of AEs may be delegated to a medically qualified sub-investigator, 
trained on this study protocol, who is listed on the FDA Form 1572 or equivalent document, and 
on the delegation of authority form. 
AEs should be volunteered by the subject or solicited from the subject using a standard 
statement, obtained from examination of the subject at a clinic visit, or from observations of 
clinically significant laboratory values or special examination abnormal values.  If an event 
assessed by one of the study scales requires intervention, or if in the opinion of the Investigator, 
it is clinically significant, then it will be reported as an AE. 
All AEs are to be assessed and recorded in a timely manner and followed to resolution or until 
the Investigator determines that there is not an anticipated resolution.  Each AE is to be 
documented with reference to severity, date of occurrence, duration, treatment, and outcome.  
Furthermore, each AE is to be classified as being serious or non-serious.  In addition, the 
Investigator must assess whether the AE is drug-related or not.  Changes in severity of AEs 
should be documented as one event at the maximum severity that occurred during the study. 
6.10.3 
Timing 
AEs will be captured from the time the subject gives informed consent until the subject 
completes the study. 
Surgical procedures, planned before enrollment of the subject in the study, are not considered 
AEs if the condition was known before study inclusion.  In this case the medical condition 
should be reported in the subject’s medical history.   
If a subject experiences the onset of an SAE within 30 days following study completion and in 
the opinion of the Investigator, that SAE is associated with the study, it will be followed and 
reported as described in Section 6.10.9.2. 
If a SAE occurs a PK sample will be taken as soon as possible after the event is reported.  If 
possible, an additional sample should be collected when the SAE has been resolved. 
6.10.4 
Severity 
Adverse events with changes in severity should be documented as one event at the maximum 
severity. 


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Intensity 
Definition 
Mild 
Causes transient or mild discomfort ; no limitation of usual activities; no 
medical intervention required 
Moderate 
Causes mild to moderate limitation in activity; some limitation of usual 
activities: no or minimal medical intervention or therapy is required. 
Severe 
Causes marked limitation in activity; some assistance is usually required; 
medical intervention or therapy is required; hospitalization is probable.   
 
The term “severe” is used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe); the event itself, however, may be of relatively minor medical significance 
(such as a severe headache). This is not the same as “serious,” which is based on subject/event 
outcome or action criteria usually associated with events that pose a threat to a subject’s life or 
functioning. Seriousness (not severity) serves as a guide for defining regulatory reporting 
obligations. 
6.10.5 
Relationship 
The Investigator or a medically qualified sub-investigator, trained on this study protocol, listed 
on the 1572 form or equivalent document and on the delegation of authority form is responsible 
for determining the AE relationship to the investigational product. 
The following categories will be used to define the relationship of an AE to the administration of 
the investigational product: 
 
Not Related: 
Data are available to identify a clear alternative cause for the AE other than 
the investigational product. 
Related: 
The cause of the AE is related to the investigational product and cannot be 
reasonably explained by other factors (e.g., the subject’s clinical state, 
concomitant therapy, and/or other interventions). 
 
6.10.6 
Expectedness 
An unexpected AE is any AE, the nature and severity of which is not consistent with the 
applicable product information (e.g., Investigator’s Brochure for an investigational product or 
product label/summary of product characteristics for an approved product). 
6.10.7 
Clinical Significance 
The Investigator or medically qualified sub-investigator, trained on this study protocol, listed on 
the 1572 form or equivalent document and on the delegation of authority form is responsible for 
determining clinical significance of abnormal assessment results (e.g., laboratory or ECG results) 
for the subject. 


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6.10.8 
Clinical Laboratory Adverse Events 
Changes in laboratory values or vital signs, or other safety parameters (e.g., ECG, neurological 
and clinical symptom assessments) as noted in the protocol are a subset of AEs and are 
reportable only if considered to be clinically significant by the investigator or medically qualified 
sub-investigator except that: 
• Baseline assessments are differentiated from AE/symptoms that are incurred post 
informed consent.  These baseline lab assessments, if determined to be clinically 
significant abnormal values, reflect the status of the subject prior to study participation.  
These clinically significant pre-dose abnormal assessments without clinical symptoms 
will not be reported as AEs.  
6.10.9 
Serious Adverse Events 
6.10.9.1 
Definition 
A SAE is defined as any AE occurring at any dose that results in any of the following outcomes:  
• death,  
• life-threatening AE, 
• hospitalization or prolongation of existing hospitalization,  
• a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or 
• a congenital anomaly or birth defect. 
“Important medical events may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.”  
6.10.9.2 
Reporting Serious Adverse Events 
All SAEs will be reported to the Sponsor by the Investigator or designee by email or fax within 
24 hours of discovery, using the form provided by the Sponsor.  The SAE report should also be 
emailed to the Sponsor Medical Monitor. 
In the event of an SAE, the Investigator or designee will notify Indivior Pharmacovigilance: 
Email: PatientSafetyNA@indivior.com  
Fax: (804) 423-8951 
Indivior Inc. 
10710 Midlothian Turnpike, Suite 430 
Richmond, VA 23235 
 
In the event that medical discussion is required for an SAE, the Sponsor Medical Monitor should 
be contacted: 


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The Investigator or designee must inform the IRB immediately regarding any AE (does not have 
to be causally related) that is both serious and unexpected; or that represents a series of AEs that 
on analysis is unanticipated, or occurs at an unanticipated frequency, or otherwise represents an 
unanticipated safety risk to the study subject. The IRB may subsequently choose to modify the 
informed consent or request changes to the protocol or Investigator’s Brochure.  A PK sample 
will be taken as soon as possible after any SAE is reported. If possible, an additional sample 
should be collected when the SAE has been resolved. 
6.10.10 Treatment-Emergent Adverse Events 
A TEAE is an AE that either commenced following initiation of study drug or was present prior 
to the initiation of study drug, but increased in frequency or severity following initiation of 
treatment, regardless of causality. 
6.10.11 Procedures and Follow-Up of Subjects with Ongoing SAEs or Experiencing 
SAEs after Completion of or Withdrawal from the Study 
Subjects with SAEs ongoing at the end of the study or after ET will be followed by the 
Investigator until stabilization or resolution.  If a subject experiences the onset of an SAE within 
a period of 30 days following study completion or withdrawal and, in the opinion of the 
Investigator or medically qualified sub-investigator, it is associated with the study, it will be 
followed up and reported as described for other SAEs. 
6.10.12 Pregnancy 
If a female subject believes she is pregnant (e.g., missed period, self-administered pregnancy 
test) the subject will be instructed to return to the clinical unit within 48 hours to undergo a 
serum pregnancy test.  If a pregnancy in a subject is confirmed at any time during the study 
through a serum pregnancy performed by the study laboratory, the subject will be discontinued 
from the study and will undergo all final study visit procedures (with the exception of a urine 
pregnancy test).  If the partner of a study subject becomes pregnant, the pregnancy will be 
reported to the clinical unit within 48 hours of the subject’s knowledge of the pregnancy.   
All confirmed pregnancies that occur within this study will be followed until resolution (i.e., 
termination [voluntary or spontaneous] or birth).   
Pregnancy ([study subject or the partner of a study subject] [without associated unexpected or 
adverse sequelae]) is not a reportable AE but must be reported to the Sponsor within 24 hours of 
the Investigator or study staff first being aware of the subject’s condition. 


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6.11 Clinical Outcome Assessments 
Clinical outcome assessments will include the UDS for opioids and other drugs; self-reported use 
of illicit opioids, other drugs, and alcohol on the TLFB; COWS, SOWS, and Opioid Craving 
VAS. 
6.11.1 
Timeline Followback Interview 
The TLFB Interview will be administered according to the SOE in Appendix 1, Appendix 2, 
Appendix 3, Appendix 4, and Appendix 5. The TLFB Interview is a method to assess recent drug 
use and will be administered electronically.  The questionnaire should be administered by an 
interviewer.  The interview instrument asks subjects to retrospectively estimate their drug use in 
the 30 days prior to screen at the screening visit and since the last visit at all subsequent visits.  
Only occurrence of use is captured (i.e., used or did not use) (Fals-Stewart 2000). The interview 
takes approximately 10-30 minutes to complete and is appropriate for males and females 14 
years of age and older.  Drugs to be assessed in this study include opioids, methadone, 
buprenorphine, cocaine, barbiturates, benzodiazepines, amphetamines/methamphetamine, 
phencyclidine, and ethanol (Appendix 17). 
The timeline followback interview should be completed prior to SUBOXONE and RBP-6000 
injection and at approximately the same time each day ± 2 hours. 
6.11.2 
Opioid Craving Visual Analog Scale  
The Opioid Craving VAS will be administered electronically according to the SOE in Appendix 
1, Appendix 2, Appendix 3, Appendix 4, and Appendix 5.  A VAS is an instrument that 
measures a characteristic or attitude that is believed to range across a continuum of values and 
cannot easily be directly measured.  The amount of opioid craving that a subject feels for illicit 
opioids (not the buprenorphine used for treatment of opioid use disorder) can be recorded along a 
continuum from “no craving at all” to “strongest craving ever” (McMillan and Gilmore-Thomas 
1996).  Operationally, the VAS is a horizontal line, 100 millimeters (mm) in length, anchored by 
word descriptors at each end, as illustrated in Appendix 14.  The subject indicates the point on 
the line that he/she feels represents his/her perception of their current state.  The VAS score is 
the difference from the left hand end of the line to the point that the subject marks and will be 
electronically calculated. 
6.11.3 
Clinical Opiate Withdrawal Scale  
The COWS assessment will be administered electronically according to the SOE in Appendix 1, 
Appendix 2, Appendix 3, Appendix 4, and Appendix 5.  The COWS is an 11-item, validated 
instrument used to assess symptoms of opiate withdrawal (Wesson 2003, Tompkins 2009).  The 
score is the sum of the response to each of the 11 items.  The COWS is sometimes used by 
clinicians treating subjects with buprenorphine.  A score of 5 to 12 is considered mild, 13 to 24 is 
moderate, 25 to 36 is moderately severe, and a score of exceeding 36 is considered severe 
withdrawal.  COWS scores will be electronically calculated.  Each subject should be assessed by 
the same qualified and trained individuals throughout the course of the study as much as 
possible.  This scale is presented in Appendix 12. 


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6.11.4 
Subjective Opiate Withdrawal Scale 
The SOWS (Handlesman 1987) will be administered electronically according to the SOE in 
Appendix 1, Appendix 2, Appendix 3, Appendix 4, and Appendix 5.  The SOWS is a 16-item 
scale completed by the subject and used to assess the subject’s perception of opiate withdrawal 
symptoms.  SOWS scores will be electronically calculated.  This scale is presented in Appendix 
13. 
6.12 Health Economics and Outcomes Assessments 
Health economics and outcomes assessments will include: EQ 5D-5L, SF-36v2, MSQ, HCRU, 
TEA, ASI-Lite, BDI-II, and BPI.  
All questionnaires will be completed at the appropriate study visits as indicated in the following 
sections. 
6.12.1 
EuroQoL-5 Dimensions-5 Levels (EQ-5D-5L) and EQ-VAS 
The EQ-5D-5L will be used to record subjects’ health-related quality of life throughout the study 
at the time points indicated in the SOEs (Appendix 1, Appendix 2, Appendix 3, Appendix 4, and 
Appendix 5).  It will be administered electronically.  
The EQ-5D-5L is a widely-used, generic health-related quality of life instrument, which consists 
of 2 sections:  the EQ-5D-5L descriptive system and the EQ visual analogue scale (EQ VAS) 
(Appendix 18).  The EQ-5D-5L is comprised of 5 questions/dimensions (mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression) each of which can take 1 of 5 
responses.  The responses record 5 levels of severity (no problems/slight problems/moderate 
problems/severe problems/extreme problems) within a particular EQ-5D dimension.  EQ-5D -5L 
health states can be converted to a single summary index (range: 0-1) by using value sets that 
attaches values to each of the levels in each dimension.  The EQ-VAS is a standard, vertical, 20 -
cm visual analogue scale and will be used for recording a subject’s rating for their current health-
related quality of life state (Herdman 2007).   
6.12.2 
Medical Outcomes Study Short Form-36 (SF-36v2) 
The SF-36v2 is a generic, subject-reported outcome instrument used to assess quality of life, 
which will be administered electronically at the time points indicated in the SOEs (Appendix 1, 
Appendix 2, Appendix 3, Appendix 4, and Appendix 5).  
The SF-36v2 is a 36-question instrument, which assesses 8 health concepts: 1) limitations in 
physical activities because of health problems; 2) limitations in social activities because of 
physical or emotional problems; 3) limitations in usual role activities because of physical health 
problems; 4) bodily pain; 5) general mental health (psychological distress and well-being); 6) 
limitations in usual role activities because of emotional problems; 7) vitality (energy and 
fatigue); and 8) general health perceptions (Appendix 19).  The scale score of each domain is 
calculated based on the summed score across items included in the domain and is rescaled to 0 to 
100 with higher scores indicating better health states. 


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The SF-36v2 provides scores for each of the eight health domains and psychometrically-based 
physical component summary (PCS) and mental component summary (MCS) scores. The 
physical functioning, role physical, bodily pain, and general health can be used to construct a 
PCS score, while the vitality, social functioning, role emotional, and mental health scales are 
used to construct the MCS Scores (Ware 2007). 
6.12.3 
Medication Satisfaction Questionnaire (MSQ) 
The MSQ is a single-item, patient-rated questionnaire (Appendix 20) that evaluates patient 
satisfaction with opioid medication. (Vernon 2010).  Medication satisfaction will be measured 
with the MSQ at the time points indicated in the SOEs (Appendix 2, Appendix 3, Appendix 4, 
and Appendix 5) electronically. 
6.12.4 
Healthcare Resource Utilization (HCRU) Questionnaire 
The Healthcare Resource Utilization questionnaire will be completed by the Investigator or 
designee at the time points indicated in the SOEs (Appendix 1, Appendix 2, Appendix 3, 
Appendix 4, and Appendix 5).  The HCRU will be used to collect current health insurance status, 
hospitalizations; residential substance abuse treatment; general practitioner, specialist, and 
counseling visits; and ED visits (Appendix 21).  It will be administered electronically. 
The outpatient services captured on this questionnaire are ones conducted outside the study.  
Visits to the study site for scheduled study visits should not be reported here. 
6.12.5 
Treatment Effectiveness Assessment (TEA) 
The TEA is a patient-reported instrument which will be measured at the time points indicated in 
the SOEs (Appendix 1, Appendix 2, Appendix 3, Appendix 4, and Appendix 5). 
 
The TEA is a 4-item scale completed by the subject and used to assess the subject’s perception 
of treatment effectiveness (Ling 2012).  Patients respond to the TEA questions providing both 
numerical responses and brief feedback about their situation on four domains: substance use 
(drugs, alcohol, tobacco), health (e.g., physical, emotional health), lifestyle (e.g., housing or 
living situation, family, employment, relationships), and community (e.g., obeying laws and 
becoming a responsible member of society).  The TEA scale is presented in Appendix 22. 
6.12.6 
Addiction Severity Index (ASI) Lite 
The ASI Lite is a patient-reported instrument that is conducted via interview by a team member 
trained in the administration of the ASI Lite. ASI Lite will be administered at the time points 
indicated in the SOEs (Appendix 2, Appendix 3, Appendix 4, and Appendix 5). Given the nature 
of the ASI Lite, this instrument can be administered before or after injection of RBP-6000.  
The ASI Lite, in an interview used to assess the subject’s addiction severity, covers 7 potential 
problem areas: medical, employment/support status, alcohol, drug, legal, family/social, and 
psychiatric problems (Strain 1996). The ASI Lite interview text is presented in Appendix 23. The 
ASI obtains lifetime information about problem behaviors, as well as problems within the 


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previous 30 days. Of note, some items of the ASI Lite are only asked once at the initial visit; at 
subsequent time points only items indicated in the questionnaire should be administered.  
Below is a brief description of each of the scales that will be included within the trial:   
The medical status section of the ASI gathers basic information about the patient's medical 
history. It addresses information about lifetime hospitalizations, long-term medical problems and 
recent physical ailments.  The employment/support status section of the ASI gathers information 
about the resources a patient can record on a job application, as well as his or her current sources 
of income. Many items will have a 30-day recall period regarding current employment. The 
drug/alcohol section of the ASI gathers information about the patient's substance abuse history. It 
addresses information about current and lifetime substance abuse, consequences of abuse, 
periods of abstinence, treatment episodes, and financial burden of substance abuse. While 
lifetime versions of these items are also available, this would only be assessed at first interview.  
The legal status section of the ASI gathers information about the patient's legal history. It 
addresses information about probation or parole, charges, convictions, incarcerations or 
detainments, and illegal activities.  The family/social relationships section is designed to 
summarize the psychiatric, alcohol and drug abuse problems of the patient's relatives in each of 
the specified categories.  The psychiatric problem section gathers information on psychiatric 
symptoms experienced by the patient. 
6.12.7 
Beck Depression Inventory II (BDI-II) 
Depression is highly prevalent in patients with opioid use disorders.  Studies have been 
conducted using buprenorphine as a treatment for major depressive disorder.  
The Beck Depression Inventory II (BDI-II) is used to measure the severity of depression in 
adults and adolescents.  The BDI-II is scored on a 4 point Likert scale, each item ranging from 0-
3; it has a 2 week recall period, can be self-administered or administered by interview and takes 
5-10 minutes to complete.  
The strengths of the BDI-II include its ease of use; also, it is widely known and the results are 
easy to score and interpret.  The BDI-II has been successfully used to discriminate and measure 
depression in chronic pain patients on opioid therapy (Geisser 1997, Farren 2002, McCauley 
2014).   
The BDI-II assessment will be administered electronically according to the SOE in Appendix 1, 
Appendix 2, Appendix 3, Appendix 4, and Appendix 5.  This scale is presented in Appendix 24. 
Roll-over subjects who did not complete the BDI-II at EOS/Day 169 will complete this 
assessment at the screening visit. 
6.12.8 
Brief Pain Inventory (BPI) Short Form 
A substantial number of patients in the US with opioid use disorder began by using prescription 
pain medications and subsequently developed dependence. Many of these patients are concerned 
at the beginning of therapy that their pain may worsen when they are no longer taking their 
opioid medication.   
The Brief Pain Inventory Short Form (BPI-SF) is used to measure the severity of pain and the 
impact of pain on daily functions in adults. The BPI-SF has a 24-hour recall period and can be 


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self-administered or administered by an interviewer. It takes approximately 5 minutes to 
complete an instrument.  
The BPI has been widely used to measure pain severity among opioid users (Rosenblum 2003).  
BPI-SF consists of a combination of yes/no questions, an item based on human figure drawing, 
open-ended questions, and items based on a numeric rating scale.  Key strengths of the BPI-SF 
are that it is easy to administer and can provide rapid assessment of pain. BPI has been translated 
in many languages and is widely used. It captures all the components of pain: structural, intensity 
and its effect on patients.   
The BPI assessment will be administered electronically according to the SOE in Appendix 1, 
Appendix 2, Appendix 3, Appendix 4, and Appendix 5.  This scale is presented in Appendix 25.  
Roll-over subjects who did not complete the BPI at EOS/Day 169 will complete this assessment 
at the screening visit. 
6.13 Concomitant Medication Assessments 
The Investigator or designee will record any concomitant therapies given for 30 days prior to the 
start of and during the course of the study on the concomitant medication page of the subject’s 
source documentation and eCRF. Any changes in concomitant therapy during the study will also 
be documented, including cessation of therapy, initiation of therapy, and dose changes. 
6.14 Removal of Subjects from the Study 
Subjects will be free to withdraw at any time for any reason, or they may be withdrawn if 
necessary, to protect their health and safety or the integrity of the study data.   
The Investigator or medically qualified sub-investigator may choose to withdraw a subject from 
the study at any time.  Reasons for removing a subject from the study may include, but are not 
limited to the following: 
• Protocol deviation that might compromise data integrity, protocol compliance, or subject 
safety, 
• An AE is reported that compromises or potentially compromises subject safety, 
• The Sponsor or Investigator terminates the study, or 
• The subject requests to be discontinued from the study (i.e., subject declines further study 
participation). 
 
If a subject withdraws prematurely from the study after receiving IMP, the primary reason for 
withdrawal will be documented as 1 of the above, lost to follow-up, or other in the source 
documentation.  
In the event a subject is lost to follow up, the site staff must make reasonable attempts to contact 
the subject.  A minimum of 2 documented telephone calls followed by a certified mailed letter is 
considered reasonable. 


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6.14.1 
Early Removal of RBP-6000 
In the event of an emergency or if a subject withdraws or is withdrawn within the first 14 days of 
receiving an injection of RBP-6000, subjects may have the option to have the depot surgically 
removed by a physician delegated to perform surgery. The medically responsible physician 
should carefully discuss this option with subjects given the use of ATRIGEL Delivery System 
and the feasibility of extracting the depot. The surgical procedure requires a small incision in the 
abdomen where the depot was placed, removal of the depot with forceps, and suturing to close 
the incision.  The subject should have the EOS assessments performed at the time of early 
removal of RBP-6000. Subjects that have had an RBP-6000 depot removed should have follow-
up telephone contact(s) within 7 to 14 days to assess status and for resolution of related AEs. In 
the event a subject cannot be contacted for the follow-up telephone contact, a minimum of 2 
documented telephone calls followed by a certified mailed letter is considered reasonable. At this 
point, the subject may be considered lost to follow-up. 
The extracted RBP-6000 depot will be disposed of into an appropriate, secure biohazard 
container per the standard operating procedures (SOPs) at the clinical site.  
Detailed RBP-6000 depot removal instructions are in Appendix 8. 
6.14.2 
Stopping Rules 
The Investigator must contact the Sponsor immediately to discuss whether to suspend dosing if 
an AE or laboratory abnormalities indicates that continued dosing of subsequent subjects would 
not be tolerated or would jeopardize the subjects’ safety.  The Sponsor alone may suspend dosing 
at any time for any reason. 
Factors that must be considered for suspension of dosing include the frequency, severity, clinical 
significance, possible causality, and anticipated reversibility of all observed AEs or laboratory 
abnormalities for each specific SC injection group.  If dosing is suspended, the IRB will be 
notified in accordance with IRB requirements. 
6.14.3 
Screen Failures 
A screen failure subject is one from whom informed consent is obtained and is documented in 
writing (i.e., the subject signs the ICF) but who did not receive study medication. 
Rescreening of a de novo subject may be permitted after consultation with the study medical 
monitor. 
6.15 Other Study Procedures 
6.15.1 
Counseling/Behavioral Therapy 
After enrollment, subjects will receive manual-guided, individual behavioral therapy once a 
week for 5 weeks, then bi-weekly (every 2 weeks) up until injection 6, at which point it will 
occur monthly to accompany the pharmacotherapy as indicated in the SOEs (Appendix 2, 


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Appendix 3, Appendix 4, and Appendix 5). Behavioral therapy will continue through the end of 
the study (EOS/ET visit). It is at the Investigator’s discretion to provide additional behavioral 
counseling above this standard frequency.The reason(s) that additional counseling was provided 
should be documented in source documentation. Behavioral therapy can be conducted by any 
appropriately trained staff member at the site. 
An Individual Drug Counseling (IDC) reference manual will be provided to each site.   
6.15.2 
Unscheduled Visits 
If unscheduled visits occur, the Investigator must record the following in the subject’s source 
documentation: 
• Any AEs 
• Reason for unscheduled visit 
• Recording of any changes or additions to concomitant medications dose or regimen 
• COWS (if deemed appropriate) 
• Any clinical assessments deemed appropriate for the clinical care of the subject 
Unscheduled visits should not alter the timing of the routine study schedule. 
6.15.3 
Additional Care of Study Subjects Following Completion of the Study 
Each subject will be evaluated on his or her final study day.  Subjects who experience SAEs at 
the EOS, or experience the onset of an SAE after the final visit, will be followed up as described 
in Section 6.10.11.  No other additional care of study subjects will take place following 
completion of the study.  
6.15.4 
Treating Toxicity 
Treatment of suspected RBP-6000 toxicity should be at the judgment of the Investigator or 
medically-qualified sub-investigator and may include an attempt to remove the depot if toxicity 
is discovered within the first 14 days post injection.  Subjects who have had RBP-6000 removed 
will be followed up according to the procedures described in the SOE (EOS/ET Visit; Appendix 
3 and Appendix 5) and Section 6.14. 
6.15.5 
Ancillary Medications 
Treatment of signs and symptoms of opioid withdrawal after enrollment can be treated with 
ancillary medications allowed by the protocol, as clinically indicated by the Investigator or 
physician Sub-Investigator.  Subjects whose symptoms are not manageable will be discontinued 
from the study and will be followed up according to the procedures described in the SOE 
(EOS/ET Visit; Appendix 3 and Appendix 5) and Section 6.14. 


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6.16 Appropriateness of Measurements 
Within the study population of opioid-dependent subjects, certain common signs and symptoms 
are displayed that must be evaluated for safety and efficacy of treatment during clinical trials.  
The instruments used (e.g., COWS, SOWS, Opioid Craving VAS, and eC-SSRS) were 
developed to measure the specific symptoms exhibited by and challenges facing opioid-
dependent individuals. 


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7 
STUDY ACTIVITIES 
This study will be conducted as a fully non-residential (outpatient) study.  An overview of the 
study is shown in Figure 2 and Figure 3.  Details on procedures/activities for this study are 
provided in Section 6 and SOEs are provided in Appendix 1, Appendix 2, Appendix 3, Appendix 
4, and Appendix 5. 


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8 
QUALITY CONTROL AND ASSURANCE 
8.1 
Quality Control 
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study centers, review of protocol procedures with the investigators 
and associated personnel before the study, periodic monitoring visits by the Sponsor, and direct 
transmission of clinical laboratory data from a central laboratory into the Sponsor’s (or 
designee’s) database.  Written instructions will be provided for study drug preparation and 
dosing, collection, preparation, and shipment of blood, plasma, and urine samples.  Guidelines 
for eCRF completion will be provided and reviewed with study personnel before the start of the 
study.  The Sponsor (or designee) will review eCRFs for accuracy and completeness during on-
site monitoring visits and after transmission to the Sponsor (or designee).  Any discrepancies will 
be resolved with the Investigator or suitably qualified designee, as appropriate. 
8.2 
Quality Assurance 
This study will be organized, performed, and reported in compliance with the protocol, Standard 
Operating Procedures (SOPs), working practice documents, and applicable regulations and 
guidelines.   
In accordance with the standards defined in Sponsor SOPs and applicable regulatory 
requirements, clinical studies sponsored by Sponsor are subject to Sponsor Quality Audits at the 
study sites that will be conducted by personnel from an appropriate unit.  Site audits will be 
made periodically by the Sponsor’s (or contractor’s) qualified compliance auditing team, which 
is an independent function from the study conduct team.  Audits will include review of, but are 
not limited to, drug supply, presence of required documents, the informed consent process, and 
comparison of eCRFs with source documents.  The investigator agrees to participate with audits 
conducted at a reasonable time in a reasonable manner.  Full consultation with the Investigator 
will be made prior to and during such an audit, which will be conducted according to the Quality 
Assurance Unit SOPs.  In addition, this study is subject to inspection by regulatory authorities.  
If such a regulatory inspection occurs, the Investigator agrees to allow the regulatory inspector 
direct access to all relevant study documents.  The investigator should contact the Sponsor 
immediately if this occurs and must fully cooperate with the inspection conducted at a reasonable 
time in a reasonable manner. 


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9 
PLANNED STATISTICAL METHODS 
9.1 
General Considerations 
A Statistical Analysis Plan (SAP) will be prepared after the protocol is approved and before 
database lock occurs.  The SAP will provide further details regarding the definition of analysis 
endpoints, data handling rules, and the statistical methodology to be used to address all study 
objectives.  The SAP will also include formats for the summary and analysis tables, listings, and 
graphical displays. 
This section describes methods for sample size determination, analysis populations, and planned 
analyses for, safety, PK, and clinical outcomes endpoints.  Additional unplanned analyses may 
be required after all planned analyses have been completed.  Any unplanned analyses will be 
clearly identified in the clinical study report.  Any deviations from the analyses described below 
will be included in the SAP, which will form Appendix 16.1.9 of the clinical study report. 
Continuous variables will be summarized using descriptive statistics such as means, standard 
deviations (SD), medians, minimums, and maximums.  Categorical variables will be reported as 
frequency counts (including number missing) and the percentage of subjects in corresponding 
categories.  Individual subject data will be presented by subject in data listings.  Data listings will 
include all data collected from the initial screening visit to the end of study for all subjects 
enrolled.   
9.2 
Determination of Sample Size 
There is no formal sample size calculation. Approximately 300 de novo subjects as well as 
approximately 300 subjects who completed the RB-US-13-0001 efficacy study will be enrolled 
into this study to ensure at least 100 subjects reach 1 year of treatment with RBP-6000. 
9.3 
Analysis Populations 
The following populations will be used for data analyses: 
9.3.1 
Safety Population 
The Safety Population comprises all subjects who received at least 1 dose of RBP-6000 during 
the open-label treatment phase of the study. This population will be used for all safety analyses.   
9.3.2 
Clinical Outcome Assessment and PK Populations 
The Clinical Outcome Assessment population will include subjects who were dosed with 
RBP-6000 and have at least 1 post-dose Clinical Outcome Assessment value.  
The PK Population will include any subject who receives a dose of RBP-6000 or at least 1 dose 
of SUBOXONE sublingual film and has at least 1 sample collected post-dose.  
   


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9.4 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics (gender, race, age, weight, height) will be summarized 
by treatment group using descriptive statistics.  Qualitative variables (gender, race) will be 
summarized using frequencies while quantitative variables (age, weight, height) will be 
summarized using mean, SD, median, minimum, and maximum. 
9.5 
Primary Analysis 
9.5.1 
Safety Endpoints 
Safety variables will include AEs, local injection site tolerability (e.g., injection site grading); 
injection site pain using a subject-reported VAS; suicidality using the eC-SSRS, concomitant 
medications; changes in clinical laboratory results (hematology, chemistry and urinalysis); vital 
sign measurements; 12-lead ECGs, physical examination results; body weight, height, BMI, and 
abdominal fat measurement (waist-to-hip ratio). Safety variables will be analyzed using the 
safety population.  
Baseline is defined as the last non-missing value prior to SC injection on Day 1.  No imputation 
of missing values will be performed. 
9.5.1.1 
Adverse Events 
All AEs will be coded using the most up-to-date version of the Medical Dictionary for 
Regulatory Activities (MedDRA) and reported to the FDA. AEs that began more than 30 days 
after the last study subject assessment day will not be included in the safety analysis. Only 
TEAEs occurring post administration of RBP-6000 will be included in the safety analysis (See 
Section 6.10.10). 
The incidence of AEs (number and percent of subjects reporting the AE at least once during the 
study) will be summarized for all AEs, by the relationship to study drug and by severity. 
9.5.1.2 
Laboratory Data 
At each visit where clinical laboratory assessments are conducted, summary statistics for the 
absolute laboratory value and the changes from baseline will be presented.   
9.5.1.3 
Vital Signs 
Vital signs measurements will be assessed for clinical relevance and be performed as deemed 
medically necessary by research personnel.  Vital signs will be taken after the subject has 
completed a minimum 3-minute rest in the supine position.  Systolic and diastolic BP 
measurements will be assessed while supine throughout the trial. 
9.5.1.4 
Other Variables Related to Safety 
Results from 12-lead ECGs will be categorized as normal, abnormal clinically significant, or 
abnormal not clinically significant and will be summarized by time point using frequency counts 


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and percentages.  ECG interval measurements as well as change from baseline will also be 
summarized by time point using descriptive statistics (mean, median, SD, minimum, maximum).  
Additional analysis of ECG parameters will be outlined in the SAP. 
Medical history will be coded using MedDRA and summarized by treatment group as described 
for AEs (Section 9.5.1.1).  Body weight, height, BMI, and abdominal fat measurement (waist-to-
hip ratio) will be summarized using descriptive statistics (mean, median, SD, minimum, 
maximum), including change from baseline. 
Total eC-SSRS scores will be summarized using descriptive statistics (mean, median, SD, 
minimum, maximum), including change from baseline.  Subjects’ self-reported illicit drug use 
from the TLFB will be summarized as descriptive statistics. 
Prior and concomitant medications will be coded using the most recent version of the World 
Health Organization (WHO) Drug dictionary.  Incidence (number and percent of subjects 
reporting the medication at least once during the study) will be summarized for all concomitant 
medications. 
Local injection site tolerability as assessed by the Injection Site Grading scale will be 
summarized by category and severity using frequency counts and percentages similar to 
summaries for AEs (Section 9.5.1.1).  Injection Site Pain VAS scores will be summarized by 
dose, injection, and time point after injection.  The burning/stinging categorical variable 
(Yes/No) will be summarized by percent of responses in each treatment. 
9.6 
Secondary Analysis 
9.6.1 
Clinical Outcomes Assessments 
COWS, SOWS and Opioid Craving VAS total scores will be summarized using descriptive 
statistics (mean, median, SD, minimum, maximum), including change from baseline. Subjects’ 
self-reported illicit drug use from the TLFB will be summarized using descriptive statistics. 
The cumulative distribution function (CDF) of the percentage of urine samples negative for 
opioids and that of the percentage of self-reports from the TLFB negative for illicit opioid use 
will be calculated. Other outcome efficacy measures will be estimated using descriptive 
statistics.  
9.7 
Other Analyses 
9.7.1 
PK/PD Modeling 
The population PK model established using the data collected in the double-blind, placebo-
controlled, efficacy study (Study RB-US-13-0001) will be refined using the sparse PK samples 
collected from the roll-over subjects in the present study to characterize the disposition of 
buprenorphine and norbuprenorphine following SC injections of RBP-6000, with the assessment 
of potential covariates affecting the PK of both compounds.  Subsequently, the relationships 
between buprenorphine plasma concentrations and clinical outcomes assessments will be 


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investigated.  These relationships will be initially assessed in a descriptive manner, and, if 
applicable, appropriate PK/PD models will be developed to describe these relationships.  A 
stand-alone modeling analysis plan will be generated, and the results will be reported in a 
standalone modeling report.  
9.7.2 
Health Economic and Outcomes Assessment 
The health economic and outcomes research endpoints for this study are: 
• EQ-5D-5L 
• SF-36v2  
• MSQ  
• HCRU  
• TEA 
• ASI Lite 
• BDI-II 
• BPI 
Summary scores for these measures will be calculated, as appropriate. Categorical variables will 
be summarized using frequencies and percentages. Continuous measures will be summarized 
using descriptive statistics (mean, standard deviation, median, minimum, maximum) as 
appropriate. An analysis of change will be conducted.  A stand-alone statistical analysis plan will 
be developed prior to database lock for health economics and outcomes research assessments.  
A separate stand-alone SAP will be developed prior to database lock with full detail regarding 
health economics and outcomes analyses. 
9.8 
Handling of Missing Data 
For dichotomous outcome measures such as UDS results (negative; non-negative) and self-
reports for illicit opioid use (negative; non-negative), any missing observation will be recorded 
as “non-negative.” For all continuous endpoints (e.g., COWS, SOWS, and VAS), the missing 
data mechanism will be assumed to be either missing completely at random (MCAR) or missing 
at random (MAR).  The missing data will not be imputed because the analysis method, mixed 
model for repeated measures (MMRM), does not require any imputation and no sensitivity 
analyses will be performed on these variables.  For time-to-event variables, if the event of 
interest is not observed prior to withdrawal or end of treatment, the observations will be censored 
at the time of withdrawal or at the end of treatment.  For example, if some subjects still have not 
had a urine sample negative for opioids combined with self-reports negative for illicit opioid use 
when the study ends or at the time of withdrawal from the study, then the time to first urine 
sample negative for opioids combined with self-reports negative for illicit opioid use will be 
censored at the last time they were assessed. 


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9.9 
Subjects Who Withdraw from the Study 
Subjects who withdraw after receiving RBP-6000 will not be replaced. 
9.10 Interim Analyses 
No interim analysis will be performed for this study.   


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10 ADMINISTRATIVE CONSIDERATIONS 
10.1 Investigators and Study Administrative Structure 
10.1.1 
Indivior Inc. 
Indivior Inc. 
10710 Midlothian Turnpike, Suite 430 
Richmond, VA 23235 
 
10.1.2 
Investigational Site(s) 
This study will be conducted at up to 50 sites in the US. 
10.1.3 
Laboratories 
The safety laboratory tests (serum chemistry, hematology, serology, and urinalysis), as well as 
the specialty laboratory tests (Bioanalytical and Pharmacokinetic) will be conducted at a central 
laboratory that is certified and accredited to perform the assigned assessments. 
Collection of safety laboratory samples is described in Section 6.6.2.  The Clinical Laboratory 
will provide normal ranges and collection, processing, and shipping instructions to the sites in a 
separate laboratory reference manual. 
10.2 Institutional Review Board or Independent Ethics Committee 
Approval 
The protocol will be reviewed by an independent, appropriately constituted, centralized IRB/ 
Independent Ethics Committee (IEC).  Study enrolment and protocol related procedures, which 
do not form part of the subject’s normal clinical treatment, will not be performed until the 
IRB/IEC of record has provided written approval of the protocol or a modification thereof.  The 
IRB/IEC must be constituted and operate in accordance with the principles and requirements of 
ICH GCP. 
Study drug can only be supplied to the Investigator after documentation on all ethical and legal 
requirements for starting the study has been received by the Sponsor.  This documentation must 
also include an IRB/IEC membership list that contains member’s occupations.  If the IRB/IEC 
will not disclose the names of the committee members, the IRB/IEC Federalwide Assurance 
Number may be accepted as a substitute for this list.  Formal approval by the IRB/IEC should 
mention the study title, study code, study site (or region or area of jurisdiction, as applicable), 
and any other documents reviewed.  It must mention the date on which the decision was made 
and must be officially signed by a committee member. 
10.3 Ethical Conduct of the Study 
The Investigator is responsible for ensuring that the clinical study is performed in accordance 
with the protocol, current ICH GCP guidelines, and applicable regulatory and country-specific 


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requirements.  GCP is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects.  
Compliance with this standard provides the public assurance that the rights, safety, and 
well-being of study subjects are protected and that the clinical study data are credible. 
10.4 Subject Information and Consent 
Prior to the subject incurring the first study related procedure, the Investigator or designated 
individual will explain to each subject the nature of the study, its purpose, procedures, expected 
duration, alternative therapies available, and the benefits and risks involved in study 
participation. It should also be mentioned that all informed consent documents and other 
documents used in the conduct of the study have been approved by an IRB/IEC. 
In the case of a non-medically qualified person conducting the consent process, he/she should 
have ready access to a medically qualified investigator to whom any questions from the study 
subject may be referred. Subjects will be given consent documents to review and the opportunity 
to ask questions. Subjects will be informed of their right to withdraw from the study at any time 
without prejudice.  
After this explanation and before any study-specific procedures have been performed, the subject 
will voluntarily sign and date the ICF to indicate he/she wishes to participate in study.  The 
Investigator or the individual designated to conduct the consent discussion for the Investigator 
will also sign and date the ICF. The time (hour and minute) the consent is signed must also be 
recorded in the subject’s source notes, by the person obtaining consent from the subject. Verbal 
informed consent followed by a signed consent short form is not acceptable to Sponsor. 
Prior to participation in the study, the subject will receive a copy of the signed and dated ICF 
along with an emergency card with contact information for the Investigator and site staff in the 
event of a medical emergency during the study. 
10.5 Subject Confidentiality 
All subject-identifying documentation generated in this study must be considered confidential 
and must not be disclosed to any persons not directly concerned with the study without written 
permission from the subject.  However, authorized regulatory officials and Sponsor personnel (or 
their representatives) will be allowed full access to inspect and copy the records.  All subject 
bodily fluids, and/or other materials collected shall be used solely in accordance with this 
protocol and the informed consent signed by the subject, unless otherwise agreed to in writing by 
the Sponsor. 
Each subject will be identified by initials and an assigned subject number when reporting study 
information to any entity outside of the study center.  Data containing subject identification will 
not be removed from the study center without subject identifiers having been redacted. 
A Certificate of Confidentiality will be obtained for this study prior to subject screening. 


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10.6 Study Monitoring 
In accordance with applicable regulations, GCP, and Sponsor procedures, the clinical monitor(s) 
will periodically contact the site, including conducting on-site visits at intervals agreed by the 
Investigator and documented in the Clinical Monitoring Plan and the Site Initiation Visit Report.   
The clinical monitor(s) will contact the site prior to the start of the study to discuss the protocol 
and data collection procedures with site personnel.  In accordance with applicable regulations 
and GCP guidelines, the Investigator shall make available for direct access all study-related 
records upon request of the Sponsor, the Sponsor’s agents, clinical monitor(s), auditors, and/or 
IRB/IEC.  The Sponsor’s monitors will visit the site during the study in addition to maintaining 
frequent telephone and written communication.  The extent, nature, and frequency of on-site 
visits will be based on such considerations as the study objectives and/or endpoints, the purpose 
of the study, study design complexity, and enrolment rate.   
The Investigator must allow the clinical monitor(s) direct access to all relevant documents and to 
allocate his/her time and the time of his/her staff to the clinical monitor(s) to discuss findings and 
any relevant issues. 
10.6.1 
Study and Site Closure 
Upon completion of the study, study closeout activities must be conducted by the Sponsor or its 
designee in conjunction with the Investigator, as appropriate. 
In addition, the Sponsor reserves the right to temporarily suspend or prematurely discontinue this 
study at any time and for any reason.  If such action is taken, the Sponsor will discuss this with 
the Investigator (including the reason[s] for taking such action) at that time.  The Sponsor will 
also inform the regulatory authorities of the suspension or termination of the study and the 
reason(s) for the action.  If required by applicable regulations, the Investigator must inform the 
IRB/IEC promptly and provide the reason(s) for the suspension or termination.  If the study is 
prematurely discontinued, all study data and study drug remaining on site must be returned to the 
Sponsor or its designee. 
10.7 Case Report Forms and Study Records 
The Investigator is responsible for the quality of the data recorded in the electronic Case Report 
Forms (eCRFs).  The data recorded should be a complete and accurate account of the subject’s 
record collected during the study.  Study data are not to be gathered directly onto the eCRF but 
must be gathered onto primary source documents at the clinical site. Completion of source 
documents will precede the completion of the eCRF.  Source documents may be electronic, hard 
copy, or a combination of both.  Source documents are defined as the results of original 
observations and activities of a clinical investigation. Source documents will include, but are not 
limited to, progress notes, electronic data, screening logs, and recorded data from automated 
instruments. All source documents pertaining to this study will be maintained by the 
investigators and made available for direct inspection by the authorized study personnel outlined 
in the ICF. The ePRO tablet will be considered the source document for individual ePRO 
elements such as study-specific scales when collected directly onto the tablet. 


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Data collection will be completed according to the guidelines provided by Sponsor or its 
designee.   
For all subjects who signed an informed consent, all required data are to be recorded using 
source documents and reported on the eCRF, except for study scales that are recorded directly on 
the ePRO tablet.  Site staff will receive training on the eCRF completion guidelines and 
requirements for source documentation. 
Completed eCRFs will be reviewed by the study monitor in line with eCRF completion 
guidelines for the study to ensure completeness and consistency.  The study monitor will review 
every subject’s eCRF with source data verification for at least all critical data points.  The source 
data verification plan for this study will define the level of source data verification required for 
non-critical data points.  Screen failure data and source documents require only source data 
verification for critical data points such as informed consent, demographics, AEs, reason for 
termination, i.e., inclusion/exclusion.  Any discrepancies found during the eCRF review will be 
clarified by the Investigator or designated individual.  This includes eCRF reviews at the site by 
Sponsor or its designee, or during quality assurance review of the data.   
An explanation must be documented for any missing data.  Any changes to information in the 
study progress notes and other source documents will be initialled and dated on the day the 
change is made by a site staff member authorized to make the change.  Changes will be made by 
striking a single line through erroneous data (so as not to obliterate the original data), and clearly 
entering the correct data (e.g., wrong data right data).  If the reason for the change is not 
apparent, a brief explanation for the change will be written in the source documentation by the 
clinician. 
The Investigator must sign and date a declaration attesting to his/her responsibility for the quality 
of all data recorded, and that the data represents a complete and accurate record of each subject’s 
participation in the study.   
All eCRF entries, corrections, and alterations must be made by the Investigator or designated 
individual.  The Investigator or designated individual must adjust the eCRF (if applicable) and 
complete the query. 
10.8 Data Monitoring Committee 
Not applicable; there will be no data monitoring committee for this study. 
10.9 Protocol Deviations 
This study is intended to be conducted as described in this protocol.  At the outset of the study, a 
process for defining and handling protocol deviations will be established.  This will include 
determining which violations will be designated “key” and require immediate notification to the 
Sponsor.  In the event of a deviation from the protocol due to an emergency, accident, or 
mistake, the Investigator or designated individual must contact the Sponsor at the earliest 
possible time by telephone.  This will allow an early joint decision regarding the subject’s 
continuation in the study.  This decision will be documented by the Investigator and the Sponsor, 


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and reviewed by the monitor.  Deviations from the protocol are to be documented.  The 
Investigator or designated individual will be responsible for identifying and reporting all 
deviations, which are defined as isolated occurrences involving a procedure that did not follow 
the study protocol or study-specific procedure.  Deviations will be reported as required to the 
IRB and in the final study report. 
10.10 Access to Source Documentation 
The Investigator must agree to complete a subject identification and enrolment log to permit easy 
identification of each subject during and after the study.  This document will be reviewed by the 
Sponsor site contact for completeness.  The subject identification and enrollment log will be 
treated as confidential and will be filed by the Investigator in the study center file.  To ensure 
subject confidentiality, no copy will be made.  All reports and communications relating to the 
study will identify subjects by initials and assigned number only.  The Investigator must also 
complete a subject-screening log, which reports on all subjects who were seen to determine 
eligibility for inclusion in the study. 
At a minimum, source documentation must be available for the following to confirm data 
collected in the eCRF: subject identification, eligibility, and study identification; study 
discussion and date of informed consent; dates of visits; results of safety and efficacy parameters 
as required by the protocol; record of all AEs; concomitant medications; study drug 
administered; date of study completion or early discontinuation, and reason for early 
discontinuation if applicable. 
10.11 Data Generation and Analysis 
10.11.1 Data Collection and Data Management 
Study specific data that has been outlined in the protocol will be entered into the clinical 
database by individual(s) designated by the Investigator in accordance with the CRF Completion 
Guidelines.  Data is verified electronically using a series of on-line programmed edit checks that 
have been created by the CDM (Clinical Data Manager) and programmed by the Clinical Data 
Programmer or Designee.  Data discrepancies will be brought to the attention of the clinical team 
and investigated by the CRA and Site Study Coordinator.  CRAs will review and verify all data 
collected in the eCRF against source documentation during scheduled monitoring visits.  The 
CRA will work closely with the Site Study Coordinator to address any discrepancies which have 
been found so that proper resolutions can be made and documented into the clinical database.  
An audit trail within the system will track all changes made to the data. 
10.11.2 Database Quality Assurance  
The clinical database will be reviewed and checked for omissions, apparent errors, and values 
requiring further clarification using computerized and manual procedures.  Data queries 
requiring clarification will be generated and addressed by the investigational site.  Only 
authorized personnel will make corrections to the clinical database, and all corrections will be 
documented in an audit trail.   


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10.12 Retention of Data 
All documents pertaining to the study, including all versions of the approved study protocol, 
copy of the informed consent document and Health Insurance Portability and Accountability Act 
documents, completed eCRFs, source documents (subject records, subject diaries, hospital 
records, laboratory records, drug accountability records, etc.), and other study-related documents 
will be retained in the permanent archives of the study site. 
The Investigator must therefore notify and obtain approval in writing from the Sponsor prior to 
destruction of any study records or provide an opportunity for the Sponsor to collect such 
records.  If the investigator withdraws from the study (e.g., relocation, retirement) all study-
related records should be transferred, in a written agreement with the Sponsor, to a mutually 
agreed upon designee within a Sponsor-specified timeframe. 
10.13 Financial Disclosure 
RBP requires, for each study, the disclosure of any financial interests from each investigator or 
sub-investigator, including financial interests of the spouse and each dependent child of the 
investigator who is directly involved in the treatment or evaluation of research subjects that 
could affect the reliability of data submitted to regulatory authorities. The collection of this 
financial interest information at the start of the study, as well as any updates should this 
information change, is required by the FDA when submitting a marketing application and is in 
line with the GCP requirement to consider any potential conflicts of interest. 
10.14 Publication and Disclosure Policy 
A clinical study report will be prepared following completion of the study.  The report will be a 
record of the total study conduct and will be subject to Sponsor approval and restrictions on 
distribution/disclosure.   
The study data will be owned by Sponsor.  Publication of any and all data will be at the 
discretion of Sponsor.  The Investigator will not disseminate, present, or publish any of the study 
data without the prior written approval of Sponsor to do so. 


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Appendix 1 
Schedule of Events – Screening and SUBOXONE Film Induction 
Evaluation 
Screening 
Visit  
(Up to 3 days after 
EOS Visit/Day169 
of RB-US-13-
0001for roll-over 
subjects) 
SUBOXONE sublingual film 
Run-In 
Induction  
(3 days) 
Dose Adjustment  
(1 to 11 days) 
Days  
-21 to -15 
Day  
-14  
Day  
-13 
Day 
-12 
Day 
-11 
Day 
-8 
Day 
-4 
Day 
-1 
 
 
 
 
+1 day 
±1 day 
-1 day 
Informed Consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria Reviewed 
X 
 
 
 
 
 
 
 
IWRS 
X 
X 
X 
X 
X 
X 
X 
X 
Demographics 1 
X 
 
 
 
 
 
 
 
Medical History 1 
X 
 
 
 
 
 
 
 
eC-SSRS (Baseline Version) 
X 13 
 
 
 
 
 
 
 
Physical Examination 2 
X 13 
 
 
 
 
 
 
 
Vital Signs 3 
X 13 
X 
X 
X 
X 
X 
X 
X 
Body Weight 
X 13 
 
 
 
 
 
 
 
BMI Calculation 
X 13 
 
 
 
 
 
 
 
Hip-to-Waist Ratio 
X 13 
 
 
 
 
 
 
 
12-lead ECG (supine > 10 min) 4 
X 13 
 
 
 
 
 
 
 
Urine Drug Screen (UDS) 
X 13 
 
 
 
 
 
 
 
Urine Pregnancy Test 5 
 
X 
 
 
 
 
 
 
Screening Labs / Hormone Panel 
X 13 
 
 
 
 
 
 
 
Urinalysis/ Hematology/Serum Chemistry 
X 13 
 
 
 
 
 
 
 
Opioid Craving VAS 6 
X 13 
 
 
 
X 
X 
X 
X 
Clinical Opiate Withdrawal Scale (COWS) 6 
X 13 
X 
X 
X 
X 
X 
X 
X 
Subjective Opiate Withdrawal Scale (SOWS) 6 
X 13 
X 
X 
X 
X 
X 
X 
X 


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Page 81 of 167 
Evaluation 
Screening 
Visit  
(Up to 3 days after 
EOS Visit/Day169 
of RB-US-13-
0001for roll-over 
subjects) 
SUBOXONE sublingual film 
Run-In 
Induction  
(3 days) 
Dose Adjustment  
(1 to 11 days) 
Days  
-21 to -15 
Day  
-14  
Day  
-13 
Day 
-12 
Day 
-11 
Day 
-8 
Day 
-4 
Day 
-1 
 
 
 
 
+1 day 
±1 day 
-1 day 
BDI-II 
X 13,14 
 
 
 
 
 
 
 
BPI 
X 13, 14 
 
 
 
 
 
 
 
TLFB Interview 
X 13 
 
 
 
 
 
 
 
Concomitant Medications 
X 7, 13 
X 
X 
X 
X 
X 
X 
X 
AE Assessment 8 
X 13 
X 
X 
X 
X 
X 
X 
X 
Day -1 Criteria Reviewed 
 
 
 
 
X 9 
X 9 
X 9 
X 10 
SUBOXONE SL film administration 11 
 
X 
X 
X 
X 12 
X 12 
X 12 
X 12 
EQ-5D-5L 
X 13 
 
 
 
 
 
 
 
SF-36v2 
X 13 
 
 
 
 
 
 
 
Health Insurance 
X 13 
 
 
 
 
 
 
 
HCRU 
X 13 
 
 
 
 
 
 
 
TEA 
X 
 
 
 
 
 
 
 
AE = adverse event; BDI-II = Beck Depression Inventory II; BMI = body mass index; BPI = Brief Pain Inventory Short Form; COWS = Clinical Opiate 
Withdrawal Scale; eC-SSRS =  electronic Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; EQ-5D-5L =  EuroQol EQ-5D-5L;; 
HCRU = Healthcare resource utilization; IXRS=Interactive voice/web response system; MSQ =  Medication Satisfaction Questionnaire; SF-36v2 = 36-
Item Short Form Health Survey, Version 2; SL = sublingual; SOWS = subjective opiate withdrawal scale; TEA = Treatment Effectiveness Assessment; 
TLFB = Timeline Followback; VAS = Visual Analog Scale 
 
1. A complete medical and psychiatric history, including use of tobacco, drugs of abuse, alcohol and caffeine.  Update demographics and medical history, 
including use of tobacco, drugs of abuse, alcohol, and caffeine for roll-over subjects. 
2. Complete examination (excluding pelvic, breast, and rectal), including general appearance, skin, head, eyes, ears, nose, throat, neck, thyroid, 
chest/lungs, heart, abdomen, lymph nodes, extremities, and a brief neurological assessment.   


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3. Includes blood pressure (BP; supine ≥ 3 minutes), pulse oximetry, pulse rate, respiratory rate, oral temperature, and height (screening visit only).  Vital 
signs will be assessed within < 60 minutes before administration of SUBOXONE sublingual film. 
4. 
Must be performed prior to labs 
5. Only for female subjects who are of childbearing potential (not postmenopausal or surgically sterile for at least 1 year). 
6. Assessments should be performed prior to each SUBOXONE SL film dosing and at approximately the same time each day (±2 hours).   
7. Include a review of previous (within 30 days prior to screen) and ongoing medications. 
8. A PK sample will be taken as soon as possible after any SAE is reported.  If possible, an additional sample should be collected when the SAE has been 
resolved. 
9. This visit becomes Day -1 if the following criteria are met: 
• 
No allergic reaction to SUBOXONE sublingual film 
• 
Daily dose of SUBOXONE sublingual film between 8 mg/2 mg - 24 mg/6 mg (inclusive) buprenorphine/naloxone. 
• 
COWS score of ≤ 12 
• 
Opioid Craving VAS score of ≤ 20 mm 
If Day -1 criteria are met, the subject will be scheduled the following day (Injection Visit 1/Day 1) to receive the first injection of RBP-6000 after 
enrollment criteria are met.  
10. If Day -1 criteria are not met after 14 days of SUBOXONE sublingual film treatment, and a subject still has significant withdrawal signs/symptoms and 
opioid cravings (COWS score >12 and Opioid Craving VAS >20 mm), they will not be eligible to continue in the study.  They will be provided with 
information on the options for opioid use disorder treatment. 
11. SUBOXONE SL film dosing should take place at the same time of day (± 2 hours).   
12. Subjects should not take their dose of SUBOXONE SL film until after it has been determined if they have met Day -1 criteria (footnote #10). 
13. RB-US-13-0001 roll-over subjects study procedures completed at EOS/Day 169 will serve as the screening assessments for Protocol RB-US-13-0003 
14. Roll-over subjects who did not complete the BDI-II and the BPI at EOS/Day 169 visit will complete these assessments at Screening for Protocol RB-
US-13-0003 only after consent for the RB-US-13-0003 is obtained. 
 


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Appendix 2 
Schedule of Events – RBP-6000 Injection 1 – 3 Visits 
Evaluation 
Inj 
1 
Post Inj 1 Assessments 
 
Inj 2 
Post 
Inj 2 
24hrs 
Post 
Inj 2 
Inj 3 
Post 
Inj 3 
24hrs 
Post 
Inj 3 
Wk
1 
D 
1 
Wk1 
D 
2 
Wk2 
D 
8 
Wk3 
D 
15 
Wk4 
D 
22 
Wk5 
D 
29 
Wk5 
D 
30 
Wk7 
D 
43 
Wk9 
D 
57 
Wk9 
D 
58 
W11 
D 
71 
Window  
 
+1 
±2 
±2 
±2 
±2 
+1 
±2 
±2 
+1 
±2 
IWRS 
X 
 
 
 
 
X 
 
 
X 
 
 
Enrollment 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs 1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body Weight 
X 
 
 
 
 
 
 
 
 
 
 
BMI Calculation 
X 
 
 
 
 
 
 
 
 
 
 
Hip-to-Waist Ratio 
X 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 2 
(supine > 10 min) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology/ Serum Chemistry 3 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
Hormone Panel 3 
X 
 
 
 
 
 
 
 
 
 
 
Urinalysis 3 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
Urine Pregnancy Test 4 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
Urine Drug Screen 5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK Sampling (Roll-over patients 
only) 6  
X 
 
 
X 
 
X 
 
X 
X 
 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE Assessment 7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
eC-SSRS (Since last-visit-
version) 7 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
TLFB Interview 7 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
Opioid Craving VAS  7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
COWS 7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SOWS 7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Evaluation 
Inj 
1 
Post Inj 1 Assessments 
 
Inj 2 
Post 
Inj 2 
24hrs 
Post 
Inj 2 
Inj 3 
Post 
Inj 3 
24hrs 
Post 
Inj 3 
Wk
1 
D 
1 
Wk1 
D 
2 
Wk2 
D 
8 
Wk3 
D 
15 
Wk4 
D 
22 
Wk5 
D 
29 
Wk5 
D 
30 
Wk7 
D 
43 
Wk9 
D 
57 
Wk9 
D 
58 
W11 
D 
71 
Window  
 
+1 
±2 
±2 
±2 
±2 
+1 
±2 
±2 
+1 
±2 
BDI-II 7 
X 
 
 
 
 
X 
 
 
X 
 
 
BPI  7 
X 
 
 
 
 
X 
 
 
X 
 
 
RBP-6000 Injection 
X 
 
 
 
 
X 
 
 
X 
 
 
Injection Site Grading Scale 8 
X 
X 
 
 
 
X 
X 
 
X 
X 
 
Injection Site Pain VAS 9 
X 
 
 
 
 
X 
 
 
X 
 
 
Injection Site Evaluation 10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Behavioral Therapy 11 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
EQ-5D-5L 7 
X 
 
 
 
 
 
 
 
X 
 
 
SF-36v2 7 
X 
 
 
 
 
 
 
 
X 
 
 
MSQ 7 
 
 
 
 
 
 
 
 
X 
 
 
Health Insurance  
X 
 
 
 
 
X 
 
 
X 
 
 
HCRU  
X 
 
 
 
 
X 
 
 
X 
 
 
TEA 
X 
 
 
 
 
X 
 
 
X 
 
 
ASI Lite 
X 
 
 
 
 
 
 
 
X 
 
 
AE = adverse event; ASI = Addiction Severity Index; BDI-II = Beck Depression Inventory II; BMI = body mass index; BPI = Brief Pain Inventory Short Form; 
COWS = Clinical Opiate Withdrawal Scale; eC-SSRS = electronic Columbia Suicide Severity Rating Scale; D = Day; ECG = electrocardiogram; EQ-5D-5L =  
EuroQol EQ-5D-5L; HCRU = Healthcare resource utilization; Inj. = injection; IXRS=Interactive voice/web response system; MSQ =  Medication Satisfaction 
Questionnaire; PK = pharmacokinetic/pharmacokinetics; SF-36v2 = 36-Item Short Form Health Survey, Version 2; SC = subcutaneous; SOWS = subjective 
opiate withdrawal scale; TEA = Treatment Effectiveness Assessment; TLFB = Timeline Followback; VAS = Visual Analog Scale 
 
1. Includes blood pressure, pulse oximetry, pulse rate, respiratory rate, and oral temperature which must be taken after subject is supine ≥ 3 minutes. On 
injection day 1, vital signs will be taken ≤ 60 minutes prior to SC injection, and then 0.5, and 2 hours post SC injection (± 15 minutes). For all 
subsequent injection days, vital signs will be taken ≤ 60 minutes prior to SC injection, and 1 hour post SC injection (± 15 minutes). For non-injection 
days, vital signs will be taken at approximately the same time of day as the Day 1 pre-injection vital signs. 
2. On Injection day 1, an ECG will be performed ≤ 60 minutes prior to SC injection, and then 0.5, and 2 hours post SC injection (± 30 minutes). For all 
subsequent injection days, an ECG will be recorded ≤ 60 minutes prior to SC injection, and 1 hour post SC injection (± 30 minutes). For non-injection 


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days, an ECG will be performed at approximately the same time of day as the Day 1 pre-injection ECG. All ECGs must be performed prior to laboratory 
assessments. 
3. On injection days blood and urine samples will be taken ≤ 60 minutes prior to SC injection and after the ECG has been performed. 
4. Only for female subjects who are of childbearing potential (not postmenopausal or surgically sterile for at least 1 year). 
5. An additional urine drug screen can be done if use is suspected.  Oxycodone may not show up in all opiate assays and should be assessed separately. 
6. A PK sample will be taken as soon as possible after any SAE is reported regardless if the patient is de novo or roll-over.  If possible, an additional 
sample should be collected when the SAE has been resolved. Only roll-over patients will receive the regularly scheduled PK assessments detailed in this 
table. 
7. Assessments should be performed prior to RBP-6000 injection and at approximately the same time each day ±2 hours. 
8. Local injection site grading will be performed at time of SC injection (within 10 minutes), 1 hour (± 15 minutes), and 24 hours (±4 hours) post SC 
injection. 
9. Injection Site Pain VAS will be completed by the subject within 1 minute after the completion of the injection and then at 5, 10, 15, 30, and 60 minutes 
(± 5 minutes) post-completion of injection. 
10. Injection site will be evaluated for evidence of attempted removal.   
11. Additional unscheduled visits for behavioral therapy may be added at the Investigator’s discretion.  
 
 


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Appendix 3 
Schedule of Events – RBP-6000 Injection 4 – 6 Visits for all Subjects and End of 
Study/Early Termination and Follow-Up Visits for Roll-over Subjects 
 
Evaluation 
Inj 4 
Post 
Inj 4 
24hrs 
Post 
Inj 4 
Inj 5 
Post 
Inj 5 
24hrs 
Post 
Inj 5 
Inj 6 
Post 
Inj 6 
24hrs 
EOS/ET/ 
Safety Follow-Up 
Wk13 
D 
85 
Wk13 
D 
86 
W15 
D 
99 
Wk17 
D 
113 
Wk17 
D 
114 
Wk19 
D 
127 
Wk21 
D 
141 
Wk21 
D 
142 
Wk25 
D 
16913 
Wk29 
D 
197 
Window  
±2 
+1 
±2 
±2 
+1 
±2 
±2 
+1 
±2 
±2 
IWRS 
X 
 
 
X 
 
 
X 
 
X14 
X 
Vital Signs 1 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
Body Weight 
X 
 
 
 
 
 
X 
 
X 
 
BMI Calculation 
X 
 
 
 
 
 
X 
 
X 
 
Hip-to-Waist Ratio 
X 
 
 
 
 
 
X 
 
X 
 
12-lead ECG (supine > 10 min) 2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology/ Serum Chemistry 3 
X 
 
X 
X 
 
X 
X 
 
X 
X 
Hormone Panel 3 
X 
 
 
 
 
 
X 
 
X 
 
Urinalysis 3 
X 
 
X 
X 
 
X 
X 
 
X 
X 
Urine Pregnancy  
Test 3 
X 
 
X 
X 
 
X 
X 
 
X 
 
Serum Pregnancy Test 4 
 
 
 
 
 
 
 
 
 
X 
Urine Drug Screen 5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PK Sampling (Roll-over patients only) 6 
X 
 
X 
X 
 
X 
X 
 
X 
 
Concomitant Medications 
X 
 
X 
X 
 
X 
X 
 
X 
X 
AE Assessment 8 
X 
 
X 
X 
 
X 
X 
 
X 
X 
eC-SSRS (Since last-visit-version) 8 
X 
 
X 
X 
 
X 
X 
 
X 
 
TLFB Interview 8 
X 
 
X 
X 
 
X 
X 
 
X 
 


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Evaluation 
Inj 4 
Post 
Inj 4 
24hrs 
Post 
Inj 4 
Inj 5 
Post 
Inj 5 
24hrs 
Post 
Inj 5 
Inj 6 
Post 
Inj 6 
24hrs 
EOS/ET/ 
Safety Follow-Up 
Wk13 
D 
85 
Wk13 
D 
86 
W15 
D 
99 
Wk17 
D 
113 
Wk17 
D 
114 
Wk19 
D 
127 
Wk21 
D 
141 
Wk21 
D 
142 
Wk25 
D 
16913 
Wk29 
D 
197 
Window  
±2 
+1 
±2 
±2 
+1 
±2 
±2 
+1 
±2 
±2 
Opioid Craving VAS  8 
X 
 
X 
X 
 
X 
X 
 
X 
 
COWS  8 
X 
 
X 
X 
 
X 
X 
 
X 
 
SOWS  8 
X 
 
X 
X 
 
X 
X 
 
X 
 
BDI-II 8 
X 
 
 
X 
 
 
X 
 
 
X 
BPI 8 
X 
 
 
X 
 
 
X 
 
 
X 
RBP-6000 Injection 
X 
 
 
X 
 
 
X 
 
 
 
Injection Site  
Grading Scale 9 
X 
 
 
X 
 
 
X 
 
 
 
Injection Site Pain VAS 10 
X 
 
 
X 
 
 
X 
 
 
 
Injection Site Evaluation 11 
X 
 
X 
X 
 
X 
X 
 
X 
X 
Behavioral Therapy 12 
X 
 
X 
X 
 
X 
X 
 
X 
 
EQ-5D-5L 8 
 
 
 
 
 
 
X 
 
X 
 
SF-36v2 8 
 
 
 
 
 
 
X 
 
X 
 
MSQ 8 
 
 
 
 
 
 
X 
 
X 
 
Health Insurance 8 
X 
 
 
X 
 
 
X 
 
X 
 
HCRU  8 
X 
 
 
X 
 
 
X 
 
X 
 
TEA 8 
X 
 
 
X 
 
 
X 
 
X 
 
ASI Lite 
 
 
 
 
 
 
X 
 
X 
 


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Evaluation 
Inj 4 
Post 
Inj 4 
24hrs 
Post 
Inj 4 
Inj 5 
Post 
Inj 5 
24hrs 
Post 
Inj 5 
Inj 6 
Post 
Inj 6 
24hrs 
EOS/ET/ 
Safety Follow-Up 
Wk13 
D 
85 
Wk13 
D 
86 
W15 
D 
99 
Wk17 
D 
113 
Wk17 
D 
114 
Wk19 
D 
127 
Wk21 
D 
141 
Wk21 
D 
142 
Wk25 
D 
16913 
Wk29 
D 
197 
Window  
±2 
+1 
±2 
±2 
+1 
±2 
±2 
+1 
±2 
±2 
Physical Examination 15 
 
 
 
 
 
 
 
 
X 
 
Review of Treatment Options 
 
 
 
 
 
 
 
 
X 
X 
SUBOXONE SL film administration 16 
 
 
 
 
 
 
 
 
X 
 
EOS 
 
 
 
 
 
 
 
 
 
X 
 
AE = adverse event; ASI = Addiction Severity Index; BDI-II = Beck Depression Inventory II; BMI = body mass index; BPI = Brief Pain Inventory Short Form; 
COWS = Clinical Opiate Withdrawal Scale; eC-SSRS = electronic Columbia Suicide Severity Rating Scale; D = Day; ECG = electrocardiogram; EOS/ET = End 
of Study/Early Termination;EQ-5D-5L =  EuroQol EQ-5D-5L; HCRU = Healthcare resource utilization; Inj. = injection; IXRS=Interactive voice/web response 
system; MSQ =  Medication Satisfaction Questionnaire; PK = pharmacokinetic/pharmacokinetics; SF-36v2 = 36-Item Short Form Health Survey, Version 2; SC 
= subcutaneous; SL = sublingual; SOWS = subjective opiate withdrawal scale; TEA = Treatment Effectiveness Assessment; TLFB = Timeline Followback; 
VAS = Visual Analog Scale. 
1. Includes blood pressure, pulse oximetry, pulse rate, respiratory rate, and oral temperature which must be taken after subject is supine ≥ 3 minutes. On 
days injections 2-12 are given, vital signs will be taken ≤ 60 minutes prior to SC injection, and 1 hour post SC injection (± 15 minutes). For non-
injection days, vital signs will be taken at approximately the same time of day as the Day 1 pre-injection vital signs. 
2. On days injections 2-12 are given, an ECG will be performed ≤ 60 minutes prior to SC injection, and 1 hour post SC injection (± 30 minutes). For non-
injection days, an ECG will be performed at approximately the same time of day as the Day 1 pre-injection ECG. All ECGs must be performed prior to 
labs and PK samples. 
3. On injection days, blood and urine samples will be taken ≤ 60 minutes prior to SC injection and after the ECGs has been performed. 
4. Only for female subjects who are of childbearing potential (not postmenopausal or surgically sterile for at least 1 year). 
5. An additional urine drug screen can be done if use is suspected.  Oxycodone may not show up in all opiate assays and should be assessed separately. 
6. PK samples taken for roll-over subjects only. See PK table (Appendix 6) for exact time points  
7. A PK sample will be taken as soon as possible after any SAE is reported.  If possible, an additional sample should be collected when the SAE has been 
resolved. 
8. Assessments should be performed prior to RBP-6000 injection and at approximately the same time each day ±2 hours. 
9. Local injection site grading will be performed at time of SC injection (within 10 minutes), 1 hour (± 15 minutes), and 24 hours (±4 hours) post SC 
injection.  
10. Injection Site Pain VAS will be completed by the subject within 1 minute after completion of the injection and then at  5, 10, 15, 30, and 60 (± 5 
minutes) post-completion of injection. 
11. Injection site will be evaluated for evidence of attempted removal.   
12. Additional unscheduled visits for behavioral therapy may be added at the Investigator's discretion. 


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13. For roll-over subjects, the procedures at Week 25/Day 169 will serve as the EOS assessments.  For de novo subjects who discontinued participation in 
the study after receiving RBP-6000, the procedures at Week 25/Day 169 will serve as the ET assessments. 
14. IXRS contacted to confirm study completion or discontinuation status (date and reason for discontinuation). 
15. Complete examination (excluding pelvic, breast, and rectal), including general appearance, skin, head, eyes, ears, nose, throat, neck, thyroid, 
chest/lungs, heart, abdomen, lymph nodes, extremities, and a brief neurological assessment.   
16. Return to the same dose that was used on Day -1. 
 
 
 


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Appendix 4 
Schedule of Events – RBP-6000 Injection 7 – 9 Visits for de novo Subjects  
Evaluation 
Inj 7 
Post Inj 7 
24hrs 
Inj 8 
Post Inj 8 
24hrs 
Inj 9 
Post Inj 9 
24hrs 
Wk25 
D169 
Wk25 
D170 
Wk29 
D197 
Wk29 
D198 
Wk33 
D225 
Wk33 
D226 
Window  
±2 
+1 
±2 
+1 
±2 
+1 
IWRS 
X 
 
X 
 
X 
 
Vital Signs 1 
X 
X 
X 
X 
X 
X 
Body Weight 
X 
 
 
 
 
 
BMI Calculation 
X 
 
 
 
 
 
Hip-to-Waist Ratio 
X 
 
 
 
 
 
12-lead ECG 2 
(supine > 10 min)  
X 
X 
X 
X 
X 
X 
Hematology/ Serum Chemistry 3 
X 
 
X 
 
X 
 
Hormone Panel 3 
X 
 
 
 
 
 
Urinalysis  3 
X 
 
X 
 
X 
 
Urine Pregnancy Test  4 
X 
 
X 
 
X 
 
Urine Drug Screen 5 
X 
 
X 
 
X 
 
Concomitant Medications  
X 
 
X 
 
X 
 
AE Assessment 6 
X 
 
X 
 
X 
 
eC-SSRS (Since last-visit-version) 7 
X 
 
X 
 
X 
 
TLFB Interview 7 
X 
 
X 
 
X 
 
Opioid Craving  
VAS 7 
X 
X 
X 
X 
X 
X 
COWS 7 
X 
X 
X 
X 
X 
X 
SOWS 7 
X 
X 
X 
X 
X 
X 
BDI-II 7 
X 
 
X 
 
X 
 
BPI 7 
X 
 
X 
 
X 
 
RBP-6000 Injection 
X 
 
X 
 
X 
 


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Evaluation 
Inj 7 
Post Inj 7 
24hrs 
Inj 8 
Post Inj 8 
24hrs 
Inj 9 
Post Inj 9 
24hrs 
Wk25 
D169 
Wk25 
D170 
Wk29 
D197 
Wk29 
D198 
Wk33 
D225 
Wk33 
D226 
Window  
±2 
+1 
±2 
+1 
±2 
+1 
Injection Site Grading Scale 8 
X 
X 
X 
X 
X 
X 
Injection Site Pain VAS 9 
X 
 
X 
 
X 
 
Injection Site Evaluation 10 
X 
X 
X 
X 
X 
X 
Behavioral Therapy 11 
X 
 
X 
 
X 
 
EQ-5D-5L 7 
 
 
 
 
X 
 
SF-36v2 7 
 
 
 
 
X 
 
MSQ 7 
 
 
 
 
X 
 
Health Insurance 7 
X 
 
X 
 
X 
 
HCRU  7 
X 
 
X 
 
X 
 
TEA 7 
X 
 
X 
 
X 
 
ASI Lite 
 
 
 
 
X 
 
 
AE = adverse event; ASI = Addiction Severity Index; BDI-II = Beck Depression Inventory II; BMI = body mass index; BPI = Brief Pain Inventory Short 
Form; COWS = Clinical Opiate Withdrawal Scale; eC-SSRS = electronic Columbia Suicide Severity Rating Scale; D = Day; ECG = electrocardiogram; EQ-
5D-5L =  EuroQol EQ-5D-5L; HCRU = Healthcare resource utilization; Inj. = injection; IXRS=Interactive voice/web response system; MSQ =  Medication 
Satisfaction Questionnaire; PK = pharmacokinetic/pharmacokinetics; SF-36v2 = 36-Item Short Form Health Survey, Version 2; SC = subcutaneous; SOWS 
= subjective opiate withdrawal scale; TEA = Treatment Effectiveness Assessment; TLFB = Timeline Followback; VAS = Visual Analog Scale 
 
1. Includes blood pressure, pulse oximetry, pulse rate, respiratory rate, and oral temperature which must be taken after subject is supine ≥ 3 minutes. On 
days injections 2-12 are given, vital signs will be taken ≤ 60 minutes prior to SC injection, and 1 hour post SC injection (± 15 minutes). For non-
injection days, vital signs will be taken at approximately the same time of day as the Day 1 pre-injection vital signs. 
2. On days injections 2-12 are given, an ECG will be recorded ≤ 60 minutes prior to SC injection, and 1 hour post SC injection (± 30 minutes). For non-
injection days, an ECG will be performed at approximately the same time of day as the Day 1 pre-injection ECG. All ECGs must be performed prior to 
labs and PK samples. 
3. On injection days, blood and urine samples will be taken ≤ 60 minutes prior to SC injection and after the ECGs has been performed. 
4. Only for female subjects who are of childbearing potential (not postmenopausal or surgically sterile for at least 1 year). 
5. An additional urine drug screen can be done if use is suspected.  Oxycodone may not show up in all opiate assays and should be assessed separately. 
6. A PK sample will be taken as soon as possible after any SAE is reported.  If possible, an additional sample should be collected when the SAE has been 
resolved. 
7. Assessments should be performed prior to RBP-6000 injection and at approximately the same time each day ±2 hours. 


RBP-6000 
 
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Clinical Study Protocol: RB-US-13-0003 
 
19 August 2015 
 
 
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8. Local injection site grading will be performed at time of SC injection (within 10 minutes), 1 hour (± 15 minutes), and 24 hours (±4 hours) post SC 
injection.  
9. Injection Site Pain VAS will be completed by the subject within 1 minute after the completion of the injection and then at 5, 10, 15, 30, and 60 minutes 
(± 5 minutes) post-completion of injection. 
10. Injection site will be evaluated for evidence of attempted removal.   
11. Additional unscheduled visits for behavioral therapy may be added at the Investigator’s discretion. 


RBP-6000 
 
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Clinical Study Protocol: RB-US-13-0003 
 
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Appendix 5 
Schedule of Events – RBP-6000 Injection 10 – 12 Visits and End of Study/Early 
Termination Visit and Follow-Up for de novo Subjects  
Evaluation 
Inj 10 
Post Inj 
10 24hrs 
Inj 11 
Post Inj 
11 24hrs 
Inj 12 
Post Inj 
12 24hrs 
EOS/ET/ 
Safety Follow-Up 
Wk37 
D253 
Wk37 
D254 
Wk41 
D281 
Wk41 
D282 
Wk45 
D309 
Wk45 
D310 
Wk49 
D33712 
Wk53 
D365 
Window  
±2 
+1 
±2 
+1 
±2 
+1 
±2 
±2 
IWRS 
X 
 
X 
 
X 
 
X13 
X 
Vital Signs 1 
X 
X 
X 
X 
X 
X 
X 
X 
Body Weight 
X 
 
 
 
X 
 
X 
 
BMI Calculation 
X 
 
 
 
X 
 
X 
 
Hip-to-Waist Ratio 
X 
 
 
 
X 
 
X 
 
12-lead ECG (supine > 10 min) 2 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology/ Serum Chemistry 3  
X 
 
X 
 
X 
 
X 
X 
Hormone Panel 3 
X 
 
 
 
X 
 
X 
 
Urinalysis 3 
X 
 
X 
 
X 
 
X 
X 
Urine Pregnancy Test 4 
X 
 
X 
 
X 
 
X 
 
Serum Pregnancy Test 4 
 
 
 
 
 
 
 
X 
Urine Drug Screen 5 
X 
 
X 
 
X 
 
X 
 
Concomitant Medications 
X 
 
X 
 
X 
 
X 
X 
AE Assessment 6 
X 
 
X 
 
X 
 
X 
X 
eC-SSRS (Since last-visit-version) 7 
X 
 
X 
 
X 
 
X 
 
TLFB Interview 7 
X 
 
X 
 
X 
 
X 
 
Opioid Craving VAS 7 
X 
X 
X 
X 
X 
X 
X 
 
COWS 7 
X 
X 
X 
X 
X 
X 
X 
 
SOWS 7 
X 
X 
X 
X 
X 
X 
X 
 
BDI-II 7 
X 
 
X 
 
X 
 
 
X 
BPI 7 
X 
 
 
 
X 
 
 
X 


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Evaluation 
Inj 10 
Post Inj 
10 24hrs 
Inj 11 
Post Inj 
11 24hrs 
Inj 12 
Post Inj 
12 24hrs 
EOS/ET/ 
Safety Follow-Up 
Wk37 
D253 
Wk37 
D254 
Wk41 
D281 
Wk41 
D282 
Wk45 
D309 
Wk45 
D310 
Wk49 
D33712 
Wk53 
D365 
Window  
±2 
+1 
±2 
+1 
±2 
+1 
±2 
±2 
RBP-6000 Injection 
X 
 
X 
 
X 
 
 
 
Injection Site Grading Scale 8 
X 
X 
X 
X 
X 
X 
 
 
Injection Site Pain VAS 9 
X 
 
X 
 
X 
 
 
 
Injection Site Evaluation 10 
X 
X 
X 
X 
X 
X 
X 
X 
Behavioral Therapy 11 
X 
 
X 
 
X 
 
X 
 
EQ-5D-5L 7 
 
 
 
 
X 
 
X 
 
SF-36v2  7 
 
 
 
 
X 
 
X 
 
MSQ 7 
 
 
 
 
X 
 
X 
 
Health Insurance 7 
X 
 
X 
 
X 
 
X 
 
HCRU  7 
X 
 
X 
 
X 
 
X 
 
TEA 7 
X 
 
X 
 
X 
 
X 
 
ASI Lite 
 
 
 
 
X 
 
X 
 
Physical Examination 14 
 
 
 
 
 
 
X 
 
Review of Treatment Options 
 
 
 
 
 
 
X 
X 
SUBOXONE SL film administration 15 
 
 
 
 
 
 
X 
 
EOS 
 
 
 
 
 
 
 
X 
 
AE = adverse event; ASI = Addiction Severity Index; BDI-II = Beck Depression Inventory II; BMI = body mass index; BPI = Brief Pain Inventory Short Form; 
COWS = Clinical Opiate Withdrawal Scale; eC-SSRS = electronic Columbia Suicide Severity Rating Scale; D = Day; ECG = electrocardiogram; EOS/ET = End 
of Study/Early Termination;EQ-5D-5L =  EuroQol EQ-5D-5L; HCRU = Healthcare resource utilization; Inj. = injection; IXRS=Interactive voice/web response 
system; MSQ =  Medication Satisfaction Questionnaire; PK = pharmacokinetic/pharmacokinetics; SF-36v2 = 36-Item Short Form Health Survey, Version 2; SC 
= subcutaneous; SL = sublingual; SOWS = subjective opiate withdrawal scale; TEA = Treatment Effectiveness Assessment; TLFB = Timeline Followback; 
VAS = Visual Analog Scale. 
 


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1. Includes blood pressure, pulse oximetry, pulse rate, respiratory rate, and oral temperature which must be taken after subject is supine ≥ 3 minutes. On days 
injections 2-12 are given, vital signs will be taken ≤ 60 minutes prior to SC injection, and 1 hour post SC injection (± 15 minutes). For non-injection days, 
vital signs will be taken at approximately the same time of day as the Day 1 pre-injection vital signs. 
2. On days injections 2-12 are given, an ECG will be recorded ≤ 60 minutes prior to SC injection, and 1 hour post SC injection (± 30 minutes). For non-
injection days, an ECG will be performed at approximately the same time of day as the Day 1 pre-injection ECG. All ECGs must be performed prior to labs 
and PK samples. 
3. On injection days, blood and urine samples will be taken ≤ 60 minutes prior to SC injection and after the ECGs has been performed. 
4. Only for female subjects who are of childbearing potential (not postmenopausal or surgically sterile for at least 1 year). 
5. An additional urine drug screen can be done if use is suspected.  Oxycodone may not show up in all opiate assays and should be assessed separately. 
6. A PK sample will be taken as soon as possible after any SAE is reported.  If possible, an additional sample should be collected when the SAE has been 
resolved. 
7. Assessments should be performed prior to RBP-6000 injection and at approximately the same time each day ±2 hours. 
8. Local injection site grading will be performed at time of SC injection (within 10 minutes), 1 hour (± 15 minutes), and 24 hours (±4 hours) post SC injection.  
9. Injection Site Pain VAS will be completed by the subject within 1 minute after the completion of the injection and then at  5, 10, 15, 30, and 60 minutes (± 5 
minutes) post-completion of injection. 
10. Injection site will be evaluated for evidence of attempted removal. 
11. Additional unscheduled visits for behavioral therapy may be added at the Investigator’s discretion. 
12. For de novo subjects who discontinue participation in this study after receiving RBP-6000, the procedures at Week 49/Day 337 will serve as the ET 
assessments. 
13. IXRS contacted to confirm study completion or discontinuation status (date and reason for discontinuation). 
14. Complete examination (excluding pelvic, breast, and rectal), including general appearance, skin, head, eyes, ears, nose, throat, neck, thyroid, chest/lungs, 
heart, abdomen, lymph nodes, extremities, and a brief neurological assessment.   
15. Return to the same dose that was used on Day -1. 
 


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Appendix 6 
Pharmacokinetic Sampling Schedule 
Sample 
Number1 
Sample 
Class 
Time 
Study Phase 
Comments 
1 
PK 
Day 1 
Treatment phase (SC) 
Within 1 hour prior to 1st SC injection  
2 
PK 
Day 15 
Treatment phase (SC) 
Post 1st SC injection 
3 
PK 
Day 29 
Treatment phase (SC) 
Within 1 hour prior to 2nd SC injection  
4 
PK 
Day 43 
Treatment phase (SC) 
Post 2nd SC injection 
5 
PK 
Day 57 
Treatment phase (SC) 
Within 1 hour prior to 3rd SC injection  
6 
PK 
Day 71 
Treatment phase (SC) 
Post 3rd SC injection 
7 
PK 
Day 85 
Treatment phase (SC) 
Within 1 hour prior to 4th SC injection  
8 
PK 
Day 99 
Treatment phase (SC) 
Post 4th SC injection 
9 
PK 
Day 113 
Treatment phase (SC) 
Within 1 hour prior to 5th SC injection 
10 
PK 
Day 127 
Treatment phase (SC) 
Post 5th SC injection 
11 
PK 
Day 141 
Treatment phase (SC) 
Within 1 hour prior to 6th SC injection 
12 
PK 
Day 169 or 
ET Visit 
Treatment phase (SC) 
Post 6th SC injection 
PK = pharmacokinetic/pharmacokinetics; SC = subcutaneous 
1   Blood samples for PK analysis will be collected from roll-over subjects only (not de novo).  
However, for all subjects (de novo and roll-over), a PK sample will be taken as soon as possible after any SAE is 
reported. If possible, an additional sample should be collected when the SAE has been resolved. 
 


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Appendix 7 
SUBOXONE® 
(Buprenorphine/Nalo
xone) Sublingual 
Film Full Prescribing 
Information 
HIGHLIGHTS OF PRESCRIBING INFORMATION 
These highlights do not include all the information needed to use 
SUBOXONE safely and effectively.  See full prescribing information for 
SUBOXONE. 
SUBOXONE® (buprenorphine and naloxone) sublingual film for sublingual 
administration CIII 
Initial U.S. Approval: 2002 
----------------------------------RECENT MAJOR CHANGES--------------------------------- 
Dosage and Administration, Induction (2.1)  
 
04/2014 
Dosage and Administration, Patients With  
     Hepatic Impairment (2.5) 
 
 
 
04/2014 
Warnings and Precautions, Use in Patients 
      With Impaired Hepatic Function (5.11) 
 
 
04/2014 
----------------------------------INDICATIONS AND USAGE--------------------------------- 
SUBOXONE sublingual film is a partial-opioid agonist indicated for treatment 
of opioid dependence.  Prescription use of this product is limited under the 
Drug Addiction Treatment Act. (1) 
------------------------------DOSAGE AND ADMINISTRATION----------------------------- 
• For patients dependent on short-acting opioid products who are in opioid 
withdrawal; on Day 1, administer up to 8 mg/ 2 mg SUBOXONE sublingual 
film (in divided doses).  On Day 2, administer up to 16 mg/4 mg of 
SUBOXONE sublingual film as a single dose. (2.1) 
• For patients dependent on methadone or long-acting opioid products, 
induction onto sublingual buprenorphine monotherapy is recommended 
on Days 1 and 2 of treatment. (2.1) 
• For maintenance treatment, the target dosage of SUBOXONE sublingual 
film is usually 16 mg/4 mg as a single daily dose. (2.2) 
• Place the SUBOXONE sublingual film under the tongue, close to the base 
on the left or right side and allow to completely dissolve.  Film should not 
be chewed, swallowed, or moved after placement. (2.3) 
-----------------------------DOSAGE FORMS AND STRENGTHS---------------------------- 
Sublingual film:  2 mg buprenorphine with 0.5 mg naloxone, 4 mg 
buprenorphine with 1 mg naloxone, 8 mg buprenorphine with 2 mg naloxone 
and 12 mg buprenorphine with 3 mg naloxone. (3)  
-------------------------------------CONTRAINDICATIONS------------------------------------ 
Hypersensitivity to buprenorphine or naloxone. (4) 
-------------------------------WARNINGS AND PRECAUTIONS----------------------------- 
• Buprenorphine can be abused in a similar manner to other opioids. 
Clinical monitoring appropriate to the patient’s level of stability is 
essential. Multiple refills should not be prescribed early in treatment or 
without appropriate patient follow-up visits. (5.1)  
• Significant respiratory depression and death have occurred in association 
with buprenorphine, particularly when taken by the intravenous (IV) 
route in combination with benzodiazepines or other CNS depressants 
(including alcohol). (5.2) 
• Consider dose reduction of CNS depressants, SUBOXONE sublingual film, 
or both in situations of concomitant prescription. (5.3) 
• Store SUBOXONE sublingual film safely out of the sight and reach of 
children. Buprenorphine can cause severe, possibly fatal, respiratory 
depression in children. (5.4)   
• Chronic administration produces opioid-type physical dependence.  
Abrupt discontinuation or rapid dose taper may result in opioid 
withdrawal syndrome. (5.5) 
• Monitor liver function tests prior to initiation and during treatment and 
evaluate suspected hepatic events. (5.6) 
• Do not administer SUBOXONE sublingual film to patients with known 
hypersensitivity to buprenorphine or naloxone. (5.7) 
• An opioid withdrawal syndrome is likely to occur with parenteral misuse 
of SUBOXONE sublingual film by individuals physically dependent on full 
opioid agonists or by sublingual administration before the agonist effects 
of other opioids have subsided. (5.8) 
• Neonatal withdrawal has been reported following use of buprenorphine 
by the mother during pregnancy. (5.9)  
• SUBOXONE sublingual film is not appropriate as an analgesic. There have 
been reported deaths of opioid naïve individuals who received a 2 mg 
sublingual dose. (5.10) 
• Buprenorphine/naloxone products are not recommended in patients 
with severe hepatic impairment and may not be appropriate for patients 
with moderate hepatic impairment (5.11) 
• Caution patients about the risk of driving or operating hazardous 
machinery. (5.12) 
-------------------------------------ADVERSE REACTIONS------------------------------------- 
Adverse events commonly observed with the sublingual administration of 
the SUBOXONE sublingual film were oral hypoesthesia, glossodynia, oral 
mucosal erythema, headache, nausea, vomiting, hyperhidrosis, constipation, 
signs and symptoms of withdrawal, insomnia, pain, and peripheral edema. 
(6.1)     
To report SUSPECTED ADVERSE REACTIONS, contact Reckitt Benckiser 
Pharmaceuticals Inc. at 1-877-782-6966 or FDA at 1-800-FDA-1088 or 
www.fda.gov/medwatch. 
--------------------------------------DRUG INTERACTIONS----------------------------------- 
• Monitor patients starting or ending CYP3A4 inhibitors or inducers for 
potential over or under dosing.  (7.1)  
• Use caution in prescribing SUBOXONE sublingual film for patients 
receiving benzodiazepines or other CNS depressants and warn patients 
against concomitant self-administration/misuse. (7.3) 
---------------------------------USE IN SPECIFIC POPULATIONS---------------------------- 
• 
Pregnancy: Based on animal data, may cause fetal harm. (8.1) 
• 
Nursing mothers: Caution should be exercised when administered to a 
nursing woman. (8.3) 
• 
Safety and effectiveness of SUBOXONE sublingual film in patients below 
the age of 16 has not been established. (8.4) 
• 
Administer SUBOXONE sublingual film with caution to elderly or 
debilitated patients. (8.5) 
• 
Buprenorphine/naloxone products are not recommended in patients 
with severe hepatic impairment and may not be appropriate for 
patients with moderate hepatic impairment.  (8.6) 
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. 
Revised:  April 2014


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FULL PRESCRIBING INFORMATION: CONTENTS* 
1 
INDICATIONS AND USAGE 
2 
DOSAGE AND ADMINISTRATION 
 
        2.1 
Induction 
 
        2.2 
Maintenance 
 
        2.3 
Method of Administration 
 
        2.4 
Clinical Supervision 
 
        2.5 
Patients With Hepatic Impairment 
 
        2.6 
Unstable Patients 
        2.7 
Stopping Treatment 
        2.8 
Switching Between Buprenorphine and 
Naloxone Sublingual Tablets and SUBOXONE 
Sublingual Film 
        2.9 
Switching Between SUBOXONE Sublingual Film 
Strengths 
3 
DOSAGE FORMS AND STRENGTHS 
4 
CONTRAINDICATIONS 
5 
WARNINGS AND PRECAUTIONS 
        5.1 
Abuse Potential 
        5.2 
Respiratory Depression  
        5.3 
CNS Depression  
        5.4 
Unintentional Pediatric Exposure 
        5.5 
Dependence 
        5.6 
Hepatitis, Hepatic Events 
        5.7 
Allergic Reactions  
        5.8 
Precipitation of Opioid Withdrawal Signs and 
Symptoms 
        5.9 
Neonatal Withdrawal 
        5.10 Use in Opioid Naïve Patients 
        5.11 Use in Patients With Impaired Hepatic Function 
        5.12 Impairment of Ability to Drive or Operate 
Machinery  
        5.13 Orthostatic Hypotension 
        5.14 Elevation of Cerebrospinal Fluid Pressure  
        5.15 Elevation of Intracholedochal Pressure 
        5.16 Effects in Acute Abdominal Conditions 
        5.17 General Precautions 
6 
ADVERSE REACTIONS 
        6.1 
Clinical Trials Experience 
        6.2 
Postmarketing Experience
 
7 
DRUG INTERACTIONS   
        7.1 
Cytochrome P-450 3A4 (CYP3A4) Inhibitors and 
Inducers 
 
        7.2 
Antiretrovirals 
 
        7.3 
Benzodiazepines 
8 
USE IN SPECIFIC POPULATIONS 
 
        8.1 
Pregnancy 
 
        8.3 
Nursing Mothers 
 
        8.4 
Pediatric Use 
 
        8.5 
Geriatric Use  
        8.6 
Hepatic Impairment 
        8.7  
Renal Impairment 
9 
DRUG ABUSE AND DEPENDENCE 
 
        9.1 
Controlled Substance 
        9.2 
Abuse 
 
        9.3 
Dependence 
10 
OVERDOSAGE 
11 
DESCRIPTION 
12 
CLINICAL PHARMACOLOGY 
 
        12.1 Mechanism of Action 
 
        12.2 Pharmacodynamics 
 
        12.3 Pharmacokinetics 
13 
NONCLINICAL TOXICOLOGY 
        13.1 Carcinogenesis, Mutagenesis, Impairment of 
Fertility 
16 
HOW SUPPLIED / STORAGE AND HANDLING 
17 
PATIENT COUNSELING INFORMATION 
        17.1 Safe Use 
        17.2 Disposal of Unused SUBOXONE Sublingual Films 
 
 
* 
Sections and subsections omitted from the full 
prescribing information are not listed. 


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FULL PRESCRIBING INFORMATION 
1 
INDICATIONS AND USAGE 
SUBOXONE sublingual film is indicated for treatment of opioid dependence and should be used as part 
of a complete treatment plan to include counseling and psychosocial support.  
Under the Drug Addiction Treatment Act (DATA) codified at 21 U.S.C. 823(g), prescription use of this 
product in the treatment of opioid dependence is limited to physicians who meet certain qualifying 
requirements, and who have notified the Secretary of Health and Human Services (HHS) of their intent 
to prescribe this product for the treatment of opioid dependence and have been assigned a unique 
identification number that must be included on every prescription.   
2 
DOSAGE AND ADMINISTRATION 
2.1 
Induction 
Prior to induction, consideration should be given to the type of opioid dependence (i.e., long- or short-
acting opioid products), the time since last opioid use, and the degree or level of opioid dependence.  To 
avoid precipitating an opioid withdrawal syndrome, the first dose of buprenorphine/naloxone should be 
started only when objective signs of moderate withdrawal appear. 
On Day 1, an induction dosage of up to 8 mg /2 mg SUBOXONE sublingual film is recommended.  
Clinicians should start with an initial dose of 2 mg/ 0.5 mg or 4 mg/1 mg buprenorphine/naloxone and 
may titrate upwards in 2 or 4 mg increments of buprenorphine, at approximately 2-hour intervals, under 
supervision, to 8 mg/2 mg buprenorphine/naloxone based on the control of acute withdrawal 
symptoms.   
On Day 2, a single daily dose of up to 16 mg/4 mg SUBOXONE sublingual film is recommended.  
Medication should be prescribed in consideration of the frequency of visits. Provision of multiple refills is 
not advised early in treatment or without appropriate patient follow-up visits. 
Patients dependent on methadone or long-acting opioid products 
Patients dependent upon methadone or long-acting opioid products may be more susceptible to 
precipitated and prolonged withdrawal during induction than those on short-acting opioid products.  
Buprenorphine/naloxone combination products have not been evaluated in adequate and well-
controlled studies for induction in patients on long-acting opioid products, and contain naloxone, which 
is absorbed in small amounts by the sublingual route and could cause worse precipitated and prolonged 
withdrawal.  For this reason, buprenorphine monotherapy is recommended in patients taking long-
acting opioids when used according to approved administration instructions.  Following induction, the 
patient may then be transitioned to once-daily SUBOXONE sublingual film. 
Patients dependent on heroin or other short-acting opioid products  
 
Patients dependent on heroin or short-acting opioid products may be inducted with either SUBOXONE 
sublingual film or with sublingual buprenorphine monotherapy.  The first dose of SUBOXONE sublingual 
film or buprenorphine should be administered when objective signs of moderate opioid withdrawal 
appear, and not less than 6 hours after the patient last used an opioid. 


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It is recommended that an adequate maintenance dose, titrated to clinical effectiveness, be achieved as 
rapidly as possible.  In some studies, a too-gradual induction over several days led to a high rate of drop-
out of buprenorphine patients during the induction period. 
  
2.2 
Maintenance  
The dosage of SUBOXONE sublingual film from Day 3 onwards should be progressively adjusted in 
increments/decrements of 2 mg/0.5 mg or 4 mg/1 mg buprenorphine/naloxone to a level that holds the 
patient in treatment and suppresses opioid withdrawal signs and symptoms. 
 
After treatment induction and stabilization, the maintenance dose of SUBOXONE sublingual film is 
generally in the range of 4 mg/1 mg buprenorphine/naloxone to 24 mg/6 mg buprenorphine/naloxone per 
day depending on the individual patient and clinical response.  The recommended target dosage of 
SUBOXONE sublingual film during maintenance is 16 mg/4 mg buprenorphine/naloxone/day as a single 
daily dose.  Dosages higher than 24 mg/6 mg daily have not been demonstrated to provide a clinical 
advantage.  
2.3 
Method of Administration 
Do not cut, chew, or swallow SUBOXONE sublingual film.  Place the SUBOXONE sublingual film under the 
tongue, close to the base on the left or right side.  If an additional sublingual film is necessary to achieve 
the prescribed dose, place the additional sublingual film sublingually on the opposite side from the first 
film.  Place the sublingual film in a manner to minimize overlapping as much as possible.  The sublingual 
film must be kept under the tongue until the film is completely dissolved.  SUBOXONE sublingual film 
should NOT be moved after placement. Proper administration technique should be demonstrated to the 
patient.  
2.4  
Clinical Supervision 
Treatment should be initiated with supervised administration, progressing to unsupervised 
administration as the patient’s clinical stability permits.  SUBOXONE sublingual film is subject to 
diversion and abuse.  When determining the prescription quantity for unsupervised administration, 
consider the patient’s level of stability, the security of his or her home situation, and other factors likely 
to affect the ability to manage supplies of take-home medication. 
 
Ideally patients should be seen at reasonable intervals (e.g., at least weekly during the first month of 
treatment) based upon the individual circumstances of the patient. Medication should be prescribed in 
consideration of the frequency of visits.  Provision of multiple refills is not advised early in treatment or 
without appropriate patient follow-up visits.  Periodic assessment is necessary to determine compliance 
with the dosing regimen, effectiveness of the treatment plan, and overall patient progress.   
 
Once a stable dosage has been achieved and patient assessment (e.g., urine drug screening) does not 
indicate illicit drug use, less frequent follow-up visits may be appropriate. A once-monthly visit schedule 
may be reasonable for patients on a stable dosage of medication who are making progress toward their 
treatment objectives. Continuation or modification of pharmacotherapy should be based on the 
physician’s evaluation of treatment outcomes and objectives such as: 
 
1.  Absence of medication toxicity. 


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2.  Absence of medical or behavioral adverse effects. 
 
3.  Responsible handling of medications by the patient. 
 
4.  Patient’s compliance with all elements of the treatment plan (including recovery-oriented activities, 
psychotherapy, and/or other psychosocial modalities). 
 
5.  Abstinence from illicit drug use (including problematic alcohol and/or benzodiazepine use).  
 
If treatment goals are not being achieved, the physician should re-evaluate the appropriateness of 
continuing the current treatment.  
2.5  
Patients With Hepatic Impairment  
Because the doses of this fixed combination product cannot be individually titrated, severe hepatic 
impairment results in a reduced clearance of naloxone to a much greater extent than buprenorphine, 
and moderate hepatic impairment also results in a reduced clearance of naloxone to a greater extent 
than buprenorphine, the combination product should generally be avoided in patients with severe 
hepatic impairment and may not be appropriate for patients with moderate hepatic impairment [see 
Warnings and Precautions (5.11)]. 
2.6 
Unstable Patients 
Physicians will need to decide when they cannot appropriately provide further management for 
particular patients.  For example, some patients may be abusing or dependent on various drugs, or 
unresponsive to psychosocial intervention such that the physician does not feel that he/she has the 
expertise to manage the patient.  In such cases, the physician may want to assess whether to refer the 
patient to a specialist or more intensive behavioral treatment environment.  Decisions should be based 
on a treatment plan established and agreed upon with the patient at the beginning of treatment. 
 
Patients who continue to misuse, abuse, or divert buprenorphine products or other opioids should be 
provided with, or referred to, more intensive and structured treatment. 
2.7 
Stopping Treatment 
The decision to discontinue therapy with SUBOXONE sublingual film after a period of maintenance 
should be made as part of a comprehensive treatment plan.  Taper patients to avoid opioid withdrawal 
signs and symptoms. 


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2.8 
Switching Between Buprenorphine or Buprenorphine and Naloxone Sublingual Tablets and 
SUBOXONE Sublingual Film 
Patients being switched between buprenorphine and naloxone or buprenorphine only sublingual tablets 
and SUBOXONE sublingual film should be started on the corresponding dosage of the previously 
administered product.  However, dosage adjustments may be necessary when switching between 
products.  Not all strengths and combinations of the SUBOXONE sublingual films are bioequivalent to 
the SUBOXONE (buprenorphine and naloxone) sublingual tablets as observed in pharmacokinetic studies 
[see Clinical Pharmacology (12.3)].  Therefore, systemic exposures of buprenorphine and naloxone may 
be different when patients are switched from tablets to film or vice-versa. Patients should be monitored 
for symptoms related to over-dosing or under-dosing. 
 
2.9 
Switching Between SUBOXONE Sublingual Film Strengths 
As indicated in Table 1, the sizes and the compositions of the four units of SUBOXONE sublingual films, 
i.e.,  
2 mg/0.5 mg, 4 mg/1 mg, 8 mg/2 mg and the 12 mg/3 mg units, are different from one another. If 
patients switch between various combinations of lower and higher strength units of SUBOXONE 
sublingual films to obtain the same total dose, (e.g., from three 4 mg/1 mg units to a single 12 mg/3 mg 
unit, or vice-versa), systemic exposures of buprenorphine and naloxone may be different and patients 
should be monitored for over-dosing or under-dosing.  For this reason, pharmacist should not substitute 
one or more film strengths for another without approval of the prescriber. 
 
Table 1.  Comparison of Available SUBOXONE Sublingual Film Strengths by Dimensions and Drug 
Concentrations. 
 
SUBOXONE sublingual film unit strength 
(buprenorphine/naloxone) 
SUBOXONE sublingual 
film unit dimensions 
Buprenorphine 
Concentration 
% (w/w) 
Naloxone 
Concentration 
% (w/w) 
2 mg/0.5 mg 
22.0 mm x 12.8 mm 
5.4 
1.53 
4 mg/1 mg  
(2 times the length of the 2 mg/0.5 mg unit) 
22.0 mm x 25.6 mm 
5.4 
1.53 
8 mg/2 mg  
22.0 mm x 12.8 mm 
17.2 
4.88 
12 mg/3 mg 
(1.5 times the length of the 8 mg/2 mg unit) 
22 mm X 19.2 mm 
17.2 
4.88 
3 
DOSAGE FORMS AND STRENGTHS 
SUBOXONE sublingual film is supplied as an orange rectangular sublingual film with a white printed logo 
in four dosage strengths: 
• 
buprenorphine/naloxone 2 mg/0.5 mg,  


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• 
buprenorphine/naloxone 4 mg/1 mg, 
• 
buprenorphine/naloxone 8 mg/2 mg and 
• 
buprenorphine/naloxone 12 mg/3 mg 
4 
CONTRAINDICATIONS 
SUBOXONE sublingual film should not be administered to patients who have been shown to be 
hypersensitive to buprenorphine or naloxone as serious adverse reactions, including anaphylactic shock, 
have been reported [see Warnings and Precautions (5.7)]. 
5 
WARNINGS AND PRECAUTIONS 
5.1 
Abuse Potential  
Buprenorphine can be abused in a manner similar to other opioids, legal or illicit. Prescribe and dispense 
buprenorphine with appropriate precautions to minimize risk of misuse, abuse, or diversion, and ensure 
appropriate protection from theft, including in the home. Clinical monitoring appropriate to the 
patient’s level of stability is essential. Multiple refills should not be prescribed early in treatment or 
without appropriate patient follow-up visits [see Drug Abuse and Dependence (9.2)]. 
5.2 
Respiratory Depression  
Buprenorphine, particularly when taken by the IV route, in combination with benzodiazepines or other 
CNS depressants (including alcohol), has been associated with significant respiratory depression and 
death.  Many, but not all, post-marketing reports regarding coma and death associated with the 
concomitant use of buprenorphine and benzodiazepines involved misuse by self-injection. Deaths have 
also been reported in association with concomitant administration of buprenorphine with other 
depressants such as alcohol or other CNS depressant drugs.  Patients should be warned of the potential 
danger of self-administration of benzodiazepines or other depressants while under treatment with 
SUBOXONE sublingual film [see Drug Interactions (7.3)]. 
In the case of overdose, the primary management should be the re-establishment of adequate 
ventilation with mechanical assistance of respiration, if required.  Naloxone may be of value for the 
management of buprenorphine overdose. Higher than normal doses and repeated administration may 
be necessary. 
SUBOXONE sublingual film should be used with caution in patients with compromised respiratory 
function (e.g., chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, 
hypoxia, hypercapnia, or pre-existing respiratory depression). 
5.3 
CNS Depression  
Patients receiving buprenorphine in the presence of opioid analgesics, general anesthetics, 
benzodiazepines, phenothiazines, other tranquilizers, sedative/hypnotics, or other CNS depressants 
(including alcohol) may exhibit increased CNS depression.  Consider dose reduction of CNS depressants, 
SUBOXONE sublingual film, or both in situations of concomitant prescription [see Drug Interactions 
(7.3)]. 
5.4 
Unintentional Pediatric Exposure 
Buprenorphine can cause severe, possibly fatal, respiratory depression in children who are accidentally 
exposed to it.  Store buprenorphine-containing medications safely out of the sight and reach of children. 


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5.5 
Dependence 
Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces 
physical dependence of the opioid type, characterized by withdrawal signs and symptoms upon abrupt 
discontinuation or rapid taper.  The withdrawal syndrome is typically milder than seen with full agonists 
and may be delayed in onset.  Buprenorphine can be abused in a manner similar to other opioids.  This 
should be considered when prescribing or dispensing buprenorphine in situations when the clinician is 
concerned about an increased risk of misuse, abuse, or diversion [see Drug Abuse and Dependence 
(9.3)]. 
5.6 
Hepatitis, Hepatic Events 
Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving 
buprenorphine in clinical trials and through post-marketing adverse event reports.  The spectrum of 
abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports 
of death, hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy.  In many 
cases, the presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C 
virus, concomitant usage of other potentially hepatotoxic drugs, and ongoing injecting drug use may 
have played a causative or contributory role.  In other cases, insufficient data were available to 
determine the etiology of the abnormality.  Withdrawal of buprenorphine has resulted in amelioration 
of acute hepatitis in some cases; however, in other cases no dose reduction was necessary.  The 
possibility exists that buprenorphine had a causative or contributory role in the development of the 
hepatic abnormality in some cases.  Liver function tests, prior to initiation of treatment are 
recommended to establish a baseline.  Periodic monitoring of liver function during treatment is also 
recommended.  A biological and etiological evaluation is recommended when a hepatic event is 
suspected.  Depending on the case, SUBOXONE sublingual film may need to be carefully discontinued to 
prevent withdrawal signs and symptoms and a return by the patient to illicit drug use, and strict 
monitoring of the patient should be initiated.  
5.7 
Allergic Reactions  
Cases of hypersensitivity to buprenorphine and naloxone containing products have been reported both 
in clinical trials and in the post-marketing experience.  Cases of bronchospasm, angioneurotic edema, 
and anaphylactic shock have been reported. The most common signs and symptoms include rashes, 
hives, and pruritus.  A history of hypersensitivity to buprenorphine or naloxone is a contraindication to 
the use of SUBOXONE sublingual film.  
5.8 
Precipitation of Opioid Withdrawal Signs and Symptoms  
Because it contains naloxone, SUBOXONE sublingual film is likely to produce withdrawal signs and 
symptoms if misused parenterally by individuals dependent on full opioid agonists such as heroin, 
morphine, or methadone.  Because of the partial agonist properties of buprenorphine, SUBOXONE 
sublingual film may precipitate opioid withdrawal signs and symptoms in such persons if administered 
sublingually before the agonist effects of the opioid have subsided.  


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5.9 
Neonatal Withdrawal 
Neonatal withdrawal has been reported in the infants of women treated with buprenorphine during 
pregnancy.  From post-marketing reports, the time to onset of neonatal withdrawal signs ranged from 
Day 1 to Day 8 of life with most cases occurring on Day 1.  Adverse events associated with the neonatal 
withdrawal syndrome included hypertonia, neonatal tremor, neonatal agitation, and myoclonus, and 
there have been reports of convulsions, apnea, respiratory depression, and bradycardia.  
5.10 
Use in Opioid Naïve Patients 
There have been reported deaths of opioid naive individuals who received a 2 mg dose of 
buprenorphine as a sublingual tablet for analgesia. SUBOXONE sublingual film is not appropriate as an 
analgesic. 
5.11 
Use in Patients With Impaired Hepatic Function 
Buprenorphine/naloxone products are not recommended in patients with severe hepatic impairment 
and may not be appropriate for patients with moderate hepatic impairment.  Because hepatic 
impairment results in a reduced clearance of naloxone to a much greater extent than buprenorphine, 
the doses of buprenorphine and naloxone in this fixed-dose combination product cannot be individually 
titrated. Therefore, patients with severe hepatic impairment will be exposed to substantially higher 
levels of naloxone than patients with normal hepatic function. This may result in an increased risk of 
precipitated withdrawal at the beginning of treatment (induction) and may interfere with 
buprenorphine’s efficacy throughout treatment.  In patients with moderate hepatic impairment, the 
differential reduction of naloxone clearance compared to buprenorphine clearance is not as great as in 
subjects with severe hepatic impairment.  Therefore, buprenorphine/naloxone products are not 
recommended for initiation of treatment (induction) in patients with moderate hepatic impairment due 
to the increased risk of precipitated withdrawal. However, buprenorphine/naloxone products may be 
used with caution for maintenance treatment in patients with moderate hepatic impairment who have 
initiated treatment on a buprenorphine product without naloxone. However, patients should be 
carefully monitored and consideration given to the possibility of naloxone interfering with 
buprenorphine’s efficacy [see Use in Specific Populations (8.6)]. 
5.12 
Impairment of Ability to Drive or Operate Machinery  
SUBOXONE sublingual film may impair the mental or physical abilities required for the performance of 
potentially dangerous tasks such as driving a car or operating machinery, especially during treatment 
induction and dose adjustment.  Patients should be cautioned about driving or operating hazardous 
machinery until they are reasonably certain that SUBOXONE sublingual film therapy does not adversely 
affect his or her ability to engage in such activities.   
5.13 
Orthostatic Hypotension 
Like other opioids, SUBOXONE sublingual film may produce orthostatic hypotension in ambulatory 
patients. 
5.14 
Elevation of Cerebrospinal Fluid Pressure  
Buprenorphine, like other opioids, may elevate cerebrospinal fluid pressure and should be used with 
caution in patients with head injury, intracranial lesions, and other circumstances when cerebrospinal 
pressure may be increased.  Buprenorphine can produce miosis and changes in the level of 
consciousness that may interfere with patient evaluation. 


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5.15 
Elevation of Intracholedochal Pressure 
Buprenorphine has been shown to increase intracholedochal pressure, as do other opioids, and thus 
should be administered with caution to patients with dysfunction of the biliary tract. 
5.16 
Effects in Acute Abdominal Conditions 
As with other opioids, buprenorphine may obscure the diagnosis or clinical course of patients with acute 
abdominal conditions. 
5.17 
General Precautions 
SUBOXONE sublingual film should be administered with caution in debilitated patients and those with 
myxedema or hypothyroidism, adrenal cortical insufficiency (e.g., Addison's disease); CNS depression or 
coma; toxic psychoses; prostatic hypertrophy or urethral stricture; acute alcoholism; delirium tremens; 
or kyphoscoliosis. 
6 
ADVERSE REACTIONS 
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 
the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and 
may not reflect the rates observed in practice.   
6.1 
Clinical Trials Experience 
The safety of SUBOXONE sublingual film is supported by clinical trials using SUBUTEX (buprenorphine) 
sublingual tablets and SUBOXONE (buprenorphine and naloxone) sublingual tablets, and other trials 
using buprenorphine sublingual solutions, as well as an open-label study in 194 patients treated with 
SUBOXONE sublingual film.  In total, safety data from clinical studies are available from over 3000 
opioid-dependent subjects exposed to buprenorphine at doses in the range used in the treatment of 
opioid dependence.  Few differences in the adverse event profile were noted among SUBOXONE 
sublingual film, SUBOXONE (buprenorphine and naloxone) sublingual tablets, SUBUTEX (buprenorphine) 
sublingual tablets and a buprenorphine ethanolic sublingual solution.   
The most common adverse event (>1%) associated with the sublingual administration of the SUBOXONE 
sublingual film was oral hypoesthesia. Other adverse events were constipation, glossodynia, oral 
mucosal erythema, vomiting, intoxication, disturbance in attention, palpitations, insomnia, withdrawal 
syndrome, hyperhidrosis, and blurred vision. 
Other adverse event data were derived from larger, controlled studies of SUBOXONE (buprenorphine 
and naloxone) and SUBUTEX (buprenorphine) tablets and of buprenorphine sublingual solution.  In a 
comparative study of SUBOXONE (buprenorphine and naloxone) and SUBUTEX (buprenorphine) 
sublingual tablets, adverse event profiles were similar for subjects treated with 16 mg/4 mg SUBOXONE 
(buprenorphine and naloxone) sublingual tablets or 16 mg SUBUTEX (buprenorphine) sublingual tablets.  
The following adverse events were reported to occur by at least 5% of patients in a 4 week study of 
SUBOXONE (buprenorphine and naloxone) sublingual tablets and SUBUTEX (buprenorphine) sublingual 
tablets. 
 


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Table 2.  Adverse Events (≥ 5%) by Body System and Treatment Group in a 4 Week Study 
Body System/ Adverse Event 
(COSTART Terminology) 
SUBOXONE 
(buprenorphine and 
naloxone) sublingual 
tablets 
16 mg/4 mg/day 
N=107 
n (%) 
SUBUTEX 
(buprenorphine) 
sublingual tablets 
16 mg/day 
N=103 
n (%) 
Placebo 
N=107 
n (%) 
Body as a Whole 
Asthenia 
7 (6.5%) 
5 (4.9%) 
7 (6.5%) 
Chills 
8 (7.5%) 
8 (7.8%) 
8 (7.5%) 
Headache 
39 (36.4%) 
30 (29.1%) 
24 (22.4%) 
Infection 
6 (5.6%) 
12 (11.7%) 
7 (6.5%) 
Pain 
24 (22.4%) 
19 (18.4%) 
20 (18.7%) 
Pain abdomen 
12 (11.2%) 
12 (11.7%) 
7 (6.5%) 
Pain back 
4 (3.7%) 
8 (7.8%) 
12 (11.2%) 
Withdrawal syndrome 
27 (25.2%) 
19 (18.4%) 
40 (37.4%) 
Cardiovascular System 
Vasodilation 
10 (9.3%) 
4 (3.9%) 
7 (6.5%) 
Digestive System 
Constipation 
13 (12.1%) 
8 (7.8%) 
3 (2.8%) 
Diarrhea 
4 (3.7%) 
5 (4.9%) 
16 (15.0%) 
Nausea 
16 (15.0%) 
14 (13.6%) 
12 (11.2%) 
Vomiting 
8 (7.5%) 
8 (7.8%) 
5 (4.7%) 
Nervous System 
Insomnia 
15 (14.0%) 
22 (21.4%) 
17 (15.9%) 
Respiratory System 
Rhinitis 
5 (4.7%) 
10 (9.7%) 
14 (13.1%) 
Skin And Appendages 
Sweating 
15 (14.0%) 
13 (12.6%) 
11 (10.3%) 
Abbreviations: COSTART = Coding Symbols for Thesaurus of Adverse Reaction Terms. 
The adverse event profile of buprenorphine was also characterized in the dose-controlled study of a 
buprenorphine ethanolic solution, over a range of doses in four months of treatment.  Table 3 shows 
adverse events reported by at least 5% of subjects in any dose group in the dose-controlled trial. 
 


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Table 3.  Adverse Events (≥5%) by Body System and Treatment Group in a 16 Week Study 
Body 
System/ 
Adverse 
Event 
(COSTART 
Terminology) 
Buprenorphine Dose 
Very 
Low* 
N=184 
n (%) 
Low* 
N=180 
n (%) 
Moderate* 
N=186 
n (%) 
High* 
N=181 
n (%) 
Total* 
N=731 
n (%) 
Body as a Whole 
Abscess 
9 (5%) 
2 (1%) 
3 (2%) 
2 (1%) 
16 (2%) 
Asthenia 
26 (14%) 
28 (16%) 
26 (14%) 
24 (13%) 
104 
(14%) 
Chills 
11 (6%) 
12 (7%) 
9 (5%) 
10 (6%) 
42 (6%) 
Fever 
7 (4%) 
2 (1%) 
2 (1%) 
10 (6%) 
21 (3%) 
Flu syndrome 4 (2%) 
13 (7%) 
19 (10%) 
8 (4%) 
44 (6%) 
Headache 
51 (28%) 
62 (34%) 
54 (29%) 
53 (29%) 
220 
(30%) 
Infection 
32 (17%) 
39 (22%) 
38 (20%) 
40 (22%) 
149 
(20%) 
Injury 
accidental 
5 (3%) 
10 (6%) 
5 (3%) 
5 (3%) 
25 (3%) 
Pain 
47 (26%) 
37 (21%) 
49 (26%) 
44 (24%) 
177 
(24%) 
Pain back 
18 (10%) 
29 (16%) 
28 (15%) 
27 (15%) 
102 
(14%) 
Withdrawal 
syndrome 
45 (24%) 
40 (22%) 
41 (22%) 
36 (20%) 
162 
(22%) 
Digestive System 
Constipation 
10 (5%) 
23 (13%) 
23 (12%) 
26 (14%) 
82 (11%) 
Diarrhea 
19 (10%) 
8 (4%) 
9 (5%) 
4 (2%) 
40 (5%) 
Dyspepsia 
6 (3%) 
10 (6%) 
4 (2%) 
4 (2%) 
24 (3%) 
Nausea 
12 (7%) 
22 (12%) 
23 (12%) 
18 (10%) 
75 (10%) 
Vomiting 
8 (4%) 
6 (3%) 
10 (5%) 
14 (8%) 
38 (5%) 
Nervous System 
Anxiety 
22 (12%) 
24 (13%) 
20 (11%) 
25 (14%) 
91 (12%) 
Depression 
24 (13%) 
16 (9%) 
25 (13%) 
18 (10%) 
83 (11%) 
Dizziness 
4 (2%) 
9 (5%) 
7 (4%) 
11 (6%) 
31 (4%) 


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Insomnia 
42 (23%) 
50 (28%) 
43 (23%) 
51 (28%) 
186 
(25%) 
Nervousness 
12 (7%) 
11 (6%) 
10 (5%) 
13 (7%) 
46 (6%) 
Somnolence 
5 (3%) 
13 (7%) 
9 (5%) 
11 (6%) 
38 (5%) 
Respiratory System 
Cough 
increase 
5 (3%) 
11 (6%) 
6 (3%) 
4 (2%) 
26 (4%) 
Pharyngitis 
6 (3%) 
7 (4%) 
6 (3%) 
9 (5%) 
28 (4%) 
Rhinitis 
27 (15%) 
16 (9%) 
15 (8%) 
21 (12%) 
79 (11%) 
Skin and Appendages 
Sweat 
23 (13%) 
21 (12%) 
20 (11%) 
23 (13%) 
87 (12%) 
Special Senses 
Runny eyes 
13 (7%) 
9 (5%) 
6 (3%) 
6 (3%) 
34 (5%) 
*Sublingual solution.  Doses in this table cannot necessarily be delivered in tablet form, but for 
comparison purposes: 
1 mg solution would be less than a tablet dose of 2 mg 
4 mg solution approximates a 6 mg tablet dose 
8 mg solution approximates a 12 mg tablet dose 
16 mg solution approximates a 24 mg tablet dose 
The safety of SUBOXONE sublingual film during treatment induction is supported by a clinical trial using 16 
patients treated with SUBOXONE sublingual film and 18 treated with a buprenorphine-only sublingual film.  
Few differences in the adverse event profiles were noted between SUBOXONE sublingual film and the 
buprenorphine-only sublingual film.   
The most common adverse event occurring during treatment induction and the 3 days following induction 
using SUBOXONE sublingual film was restlessness. Other adverse events were anxiety, piloerection, 
stomach discomfort, irritability, headache, rhinorrhea, cold sweat, arthralgia, and lacrimation increased. 
Four subjects left the study early on the first day of sublingual film administration.  However, there was 
not evidence to suggest that any of the four subjects experienced precipitated withdrawal secondary to 
the administration of buprenorphine or buprenorphine/naloxone sublingual films.  


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6.2 
Postmarketing Experience 
The following adverse reactions have been identified during post-approval use of SUBOXONE sublingual 
film. Because these reactions are reported voluntarily from a population of uncertain size, it is not 
always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 
The most frequently reported postmarketing adverse events were peripheral edema, stomatitis, 
glossitis, and tongue disorder.  
7 
DRUG INTERACTIONS 
7.1 
Cytochrome P-450 3A4 (CYP3A4) Inhibitors and Inducers 
Buprenorphine is metabolized to norbuprenorphine primarily by cytochrome CYP3A4; therefore, 
potential interactions may occur when SUBOXONE sublingual film is given concurrently with agents that 
affect CYP3A4 activity.  The concomitant use of SUBOXONE sublingual film with CYP3A4 inhibitors (e.g., 
azole antifungals such as ketoconazole, macrolide antibiotics such as erythromycin, and HIV protease 
inhibitors) should be monitored and may require dose-reduction of one or both agents. 
The interaction of buprenorphine with CYP3A4 inducers has not been studied; therefore, it is 
recommended that patients receiving SUBOXONE sublingual film be monitored for signs and symptoms 
of opioid withdrawal if inducers of CYP3A4 (e.g., efavirenz, phenobarbital, carbamazepine, phenytoin, 
rifampicin) are co-administered [see Clinical Pharmacology (12.3)]. 
7.2 
Antiretrovirals 
Three classes of antiretroviral agents have been evaluated for CYP3A4 interactions with buprenorphine.  
Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme 
pathway, thus no interactions with buprenorphine are expected.  Non-nucleoside reverse transcriptase 
inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine and etravirine are 
known CYP3A inducers whereas delaviridine is a CYP3A inhibitor. Significant pharmacokinetic 
interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in 
clinical studies, but these pharmacokinetic interactions did not result in any significant 
pharmacodynamic effects. It is recommended that patients who are on chronic buprenorphine 
treatment have their dose monitored if NNRTIs are added to their treatment regimen.  Studies have 
shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, 
lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant 
pharmacodynamic effects.  Other PIs with CYP3A4 inhibitory activity (atazanavir and 
atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine and patients in 
one study reported increased sedation. Symptoms of opioid excess have been found in post-marketing 
reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly.  
Monitoring of patients taking buprenorphine and atazanavir with and without ritonavir is 
recommended, and dose reduction of buprenorphine may be warranted. 
7.3 
Benzodiazepines 
There have been a number of post-marketing reports regarding coma and death associated with the 
concomitant use of buprenorphine and benzodiazepines.  In many, but not all, of these cases, 
buprenorphine was misused by self-injection.  Preclinical studies have shown that the combination of 
benzodiazepines and buprenorphine altered the usual ceiling effect on buprenorphine-induced 
respiratory depression, making the respiratory effects of buprenorphine appear similar to those of full 


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opioid agonists.  SUBOXONE sublingual film should be prescribed with caution to patients taking 
benzodiazepines or other drugs that act on the CNS, regardless of whether these drugs are taken on the 
advice of a physician or are being abused/misused.  Patients should be warned that it is extremely 
dangerous to self-administer non-prescribed benzodiazepines while taking SUBOXONE sublingual film, 
and should also be cautioned to use benzodiazepines concurrently with SUBOXONE sublingual film only 
as directed by their physician. 
8 
USE IN SPECIFIC POPULATIONS 
8.1 
Pregnancy 
Pregnancy Category C. 
Risk Summary  
There are no adequate and well-controlled studies of SUBOXONE sublingual film or 
buprenorphine/naloxone in pregnant women. Limited published data on use of buprenorphine, the 
active ingredient in SUBOXONE, in pregnancy, have not shown an increased risk of major malformations. 
All pregnancies, regardless of drug exposure, have a background risk of 2-4% for major birth defects, and 
15-20% for pregnancy loss. Reproductive and developmental studies in rats and rabbits identified 
adverse events at clinically relevant doses. Pre-and postnatal development studies in rats demonstrated 
dystocia, increased neonatal deaths, and developmental delays. No clear teratogenic effects were seen 
with a range of doses equivalent to or greater than the human dose. However, in a few studies, some 
events such as acephalus, omphalocele, and skeletal abnormalities were observed but these findings 
were not clearly treatment-related. Embryofetal death was also observed in both rats and rabbits. 
SUBOXONE sublingual film should be used during pregnancy only if the potential benefit justifies the 
potential risk to the fetus.  
Clinical Considerations 
Disease-associated maternal and embryo-fetal risk 
Opioid dependence in pregnancy is associated with adverse obstetrical outcomes such as low birth 
weight, preterm birth, and fetal death. 
Fetal/neonatal adverse reactions 
Neonatal abstinence syndrome may occur in newborn infants of mothers who were on buprenorphine 
maintenance treatment. Observe newborns for poor feeding, diarrhea, irritability, tremor, rigidity, and 
seizures, and manage accordingly [see Warnings and Precautions (5.9)]. 
Labor or Delivery 
As with all opioids, use of buprenorphine prior to delivery may result in respiratory depression in the 
newborn. Closely monitor neonates for signs of respiratory depression. An opioid antagonist such as 
naloxone should be available for reversal of opioid induced respiratory depression in the neonate. 
Data 
Human Data 
Studies have been conducted to evaluate neonatal outcomes in women exposed to buprenorphine 
during pregnancy. Limited published data on malformations from trials, observational studies, case 
series, and case reports on buprenorphine use in pregnancy have not shown an increased risk of major 
malformations. Based on these studies the incidence of neonatal abstinence syndrome is not clear and 
there does not appear to be a dose-response relationship. 


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Animal Data 
Effects on embryo-fetal development were studied in Sprague-Dawley rats and Russian white rabbits 
following oral (1:1) and intramuscular (IM) (3:2) administration of mixtures of buprenorphine and 
naloxone.  Following oral administration to rats and rabbits, no teratogenic effects were observed at 
buprenorphine doses up to 250 mg/kg/day and 40 mg/kg/day, respectively (estimated exposure 
approximately 150 times and 50 times, respectively, the recommended human daily sublingual dose of 
16 mg on a mg/m² basis).  No definitive drug-related teratogenic effects were observed in rats and 
rabbits at IM doses up to 30 mg/kg/day (estimated exposure approximately 20 times and 35 times, 
respectively, the recommended human daily dose of 16 mg on a mg/m² basis).  Acephalus was observed 
in one rabbit fetus from the low-dose group and omphalocele was observed in two rabbit fetuses from 
the same litter in the mid-dose group; no findings were observed in fetuses from the high-dose group.  
Following oral administration of buprenorphine to rats, dose-related post-implantation losses, 
evidenced by increases in the numbers of early resorptions with consequent reductions in the numbers 
of fetuses, were observed at doses of 10 mg/kg/day or greater (estimated exposure approximately 
6 times the recommended human daily sublingual dose of 16 mg on a mg/m² basis).  In the rabbit, 
increased post-implantation losses occurred at an oral dose of 40 mg/kg/day.  Following IM 
administration in the rat and the rabbit, post-implantation losses, as evidenced by decreases in live 
fetuses and increases in resorptions, occurred at 30 mg/kg/day.   
Buprenorphine was not teratogenic in rats or rabbits after IM or subcutaneous (SC) doses up to 5 
mg/kg/day (estimated exposure was approximately 3 and 6 times, respectively, the recommended 
human daily sublingual dose of 16 mg on a mg/m2 basis), after IV doses up to 0.8 mg/kg/day (estimated 
exposure was approximately 0.5 times and equal to, respectively, the recommended human daily 
sublingual dose of 16 mg on a mg/m2 basis), or after oral doses up to 160 mg/kg/day in rats (estimated 
exposure was approximately 95 times the recommended human daily sublingual dose of 16 mg on a 
mg/m2 basis) and 25 mg/kg/day in rabbits (estimated exposure was approximately 30 times the 
recommended human daily sublingual dose of 16 mg on a mg/m2 basis). Significant increases in skeletal 
abnormalities (e.g., extra thoracic vertebra or thoraco-lumbar ribs) were noted in rats after SC 
administration of 1 mg/kg/day and up (estimated exposure was approximately 0.6 times the 
recommended human daily sublingual dose of 16 mg on a mg/m2 basis), but were not observed at oral 
doses up to 160 mg/kg/day.  Increases in skeletal abnormalities in rabbits after IM administration of 5 
mg/kg/day (estimated exposure was approximately 6 times the recommended human daily sublingual 
dose of 16 mg on a mg/m2 basis) or oral administration of 1 mg/kg/day or greater (estimated exposure 
was approximately equal to the recommended human daily sublingual dose of 16 mg on a mg/m2 basis) 
were not statistically significant. 
In rabbits, buprenorphine produced statistically significant pre-implantation losses at oral doses of 1 
mg/kg/day or greater and post-implantation losses that were statistically significant at IV doses of 0.2 
mg/kg/day or greater (estimated exposure approximately 0.3 times the recommended human daily 
sublingual dose of 16 mg on a mg/m2 basis). 
Dystocia was noted in pregnant rats treated intramuscularly with buprenorphine 5 mg/kg/day 
(approximately 3 times the recommended human daily sublingual dose of 16 mg on a mg/m² basis).  
Fertility, peri-, and post-natal development studies with buprenorphine in rats indicated increases in 
neonatal mortality after oral doses of 0.8 mg/kg/day and up (approximately 0.5 times the recommended 
human daily sublingual dose of 16 mg on a mg/m² basis), after IM doses of 0.5 mg/kg/day and up 
(approximately 0.3 times the recommended human daily sublingual dose of 16 mg on a mg/m² basis), 
and after SC doses of 0.1 mg/kg/day and up (approximately 0.06 times the recommended human daily 
sublingual dose of 16 mg on a mg/m² basis).  An apparent lack of milk production during these studies 
likely contributed to the decreased pup viability and lactation indices.  Delays in the occurrence of 


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righting reflex and startle response were noted in rat pups at an oral dose of 80 mg/kg/day 
(approximately 50 times the recommended human daily sublingual dose of 16 mg on a mg/m² basis). 
8.3 
Nursing Mothers 
Risk Summary 
Based on two studies in 13 lactating women, buprenorphine and its metabolite norbuprenorphine are 
present in low levels in human milk and infant urine, and available data have not shown adverse 
reactions in breastfed infants. There are no data on the combination product buprenorphine/naloxone 
in breastfeeding, however oral absorption of naloxone is minimal. Caution should be exercised when 
SUBOXONE is administered to a nursing woman. The developmental and health benefits of 
breastfeeding should be considered along with the mother’s clinical need for SUBOXONE and any 
potential adverse effects on the breastfed child from the drug or from the underlying maternal 
condition. 
Clinical Considerations 
Advise the nursing mother taking SUBOXONE to monitor the infant for increased drowsiness and 
breathing difficulties. 
Data 
Based on limited data from a study of 6 lactating women who were taking a median oral dose of 
buprenorphine of 0.29 mg/kg/day 5-8 days after delivery, breast milk contained a median infant dose of 
0.42 mcg/kg/day of buprenorphine and 0.33 mcg/kg/day of norbuprenorphine, which are equal to 0.2% 
and 0.12% of the maternal weight-adjusted dose. 
Based on limited data from a study of 7 lactating women who were taking a median oral dose of 
buprenorphine of 7 mg/day an average of 1.12 months after delivery, the mean milk concentrations of 
buprenorphine and norbuprenorphine were 3.65 mcg/L and 1.94 mcg/L respectively. Based on the 
limited data from this study, and assuming milk consumption of 150 mL/kg/day, an exclusively breastfed 
infant would receive an estimated mean of 0.55 mcg/kg/day of buprenorphine and 0.29 mcg/kg/day of 
norbuprenorphine, which are 0.38% and 0.18% of the maternal weight-adjusted dose. 
No adverse reactions were observed in the infants in these two studies. 
8.4 
Pediatric Use 
The safety and effectiveness of SUBOXONE sublingual film have not been established in pediatric 
patients.  This product is not appropriate for the treatment of neonatal abstinence syndrome in 
neonates, because it contains naloxone, an opioid antagonist.  
8.5 
Geriatric Use 
Clinical studies of SUBOXONE sublingual film, SUBOXONE (buprenorphine and naloxone) sublingual 
tablets, or SUBUTEX (buprenorphine) sublingual tablets did not include sufficient numbers of subjects 
aged 65 and over to determine whether they responded differently than younger subjects.  Other 
reported clinical experience has not identified differences in responses between the elderly and younger 
patients.  In general, dose selection for an elderly patient should be cautious, usually starting at the low 
end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac 
function, and of concomitant disease or other drug therapy. 


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8.6 
Hepatic Impairment 
The effect of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone has been 
evaluated in a pharmacokinetic study. Both drugs are extensively metabolized in the liver. While no 
clinically significant changes have been observed in subjects with mild hepatic impairment; the plasma 
levels have been shown to be higher and half-life values have been shown to be longer for both 
buprenorphine and naloxone in subjects with moderate and severe hepatic impairment. The magnitude 
of the effects on naloxone are greater than that on buprenorphine in both moderately and severely 
impaired subjects. The difference in magnitude of the effects on naloxone and buprenorphine are 
greater in subjects with severe hepatic impairment than in subjects with moderate hepatic impairment, 
and therefore the clinical impact of these effects is likely to be greater in patients with severe hepatic 
impairment than in patients with moderate hepatic impairment. Buprenorphine/naloxone products 
should be avoided in patients with severe hepatic impairment and may not be appropriate for patients 
with moderate hepatic impairment [see Warnings and Precautions (5.11) and Clinical Pharmacology 
(12.3)].    
8.7 
Renal Impairment  
No differences in buprenorphine pharmacokinetics were observed between 9 dialysis-dependent and 
6 normal patients following IV administration of 0.3 mg buprenorphine.  The effects of renal failure on 
naloxone pharmacokinetics are unknown. 
9 
DRUG ABUSE AND DEPENDENCE 
9.1 
Controlled Substance 
Buprenorphine is a Schedule III narcotic under the Controlled Substances Act. 
Under the Drug Addiction Treatment Act (DATA) codified at 21 U.S.C. 823(g), prescription use of this 
product in the treatment of opioid dependence is limited to physicians who meet certain qualifying 
requirements, and who have notified the Secretary of Health and Human Services (HHS) of their intent 
to prescribe this product for the treatment of opioid dependence and have been assigned a unique 
identification number that must be included on every prescription. 
9.2 
Abuse 
• 
Buprenorphine, like morphine and other opioids, has the potential for being abused and is 
subject to criminal diversion. This should be considered when prescribing or dispensing buprenorphine 
in situations when the clinician is concerned about an increased risk of misuse, abuse, or diversion.  
Healthcare professionals should contact their state professional licensing board or state controlled 
substances authority for information on how to prevent and detect abuse or diversion of this product. 
• 
Patients who continue to misuse, abuse, or divert buprenorphine products or other opioids 
should be provided with or referred for more intensive and structured treatment.   
• 
Abuse of buprenorphine poses a risk of overdose and death.  This risk is increased with the 
abuse of buprenorphine and alcohol and other substances, especially benzodiazepines. 
• 
The physician may be able to more easily detect misuse or diversion by maintaining records of 
medication prescribed including date, dose, quantity, frequency of refills, and renewal requests of 
medication prescribed. 
• 
Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of 
therapy, and proper handling and storage of the medication are appropriate measures that help to limit 
abuse of opioid drugs. 


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9.3 
Dependence  
Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces 
physical dependence of the opioid type, characterized by moderate withdrawal signs and symptoms 
upon abrupt discontinuation or rapid taper.  The withdrawal syndrome is typically milder than seen with 
full agonists and may be delayed in onset [see Warnings and Precautions (5.5)]. 
A neonatal withdrawal syndrome has been reported in the infants of women treated with 
buprenorphine during pregnancy [see Warnings and Precautions (5.9)]. 
10 
OVERDOSAGE 
The manifestations of acute overdose include pinpoint pupils, sedation, hypotension, respiratory 
depression, and death.  
In the event of overdose, the respiratory and cardiac status of the patient should be monitored 
carefully.  When respiratory or cardiac functions are depressed, primary attention should be given to the 
re-establishment of adequate respiratory exchange through provision of a patent airway and institution 
of assisted or controlled ventilation.  Oxygen, IV fluids, vasopressors, and other supportive measures 
should be employed as indicated. 
In the case of overdose, the primary management should be the re-establishment of adequate 
ventilation with mechanical assistance of respiration, if required.  Naloxone may be of value for the 
management of buprenorphine overdose.  Higher than normal doses and repeated administration may 
be necessary.  
11 
DESCRIPTION 
SUBOXONE (buprenorphine and naloxone) sublingual film is an orange film, imprinted with a logo 
identifying the product and strength in white ink.  It contains buprenorphine HCl, a mu-opioid receptor 
partial agonist and a kappa-opioid receptor antagonist, and naloxone HCl dihydrate, an opioid receptor 
antagonist, at a ratio of 4:1 (ratio of free bases).  It is intended for sublingual administration and is 
available in four dosage strengths, 2 mg buprenorphine with 0.5 mg naloxone, 4 mg buprenorphine with 1 
mg naloxone,  8 mg buprenorphine with 2 mg naloxone and 12 mg buprenorphine with 3 mg naloxone.  
Each sublingual film also contains polyethylene oxide, hydroxypropyl methylcellulose, maltitol, acesulfame 
potassium, lime flavor, citric acid, sodium citrate, FD&C yellow #6, and white ink. 
Chemically, buprenorphine HCl is (2S)-2-[17-Cyclopropylmethyl-4,5α-epoxy-3-hydroxy-6-methoxy-
6α,14-ethano-14α-morphinan-7α-yl]-3,3-dimethylbutan-2-ol hydrochloride.  It has the following 
chemical structure: 
• HCl 
Buprenorphine HCl has the molecular formula C29 H41 NO4 • HCl and the molecular weight is 504.10.  It is 
a white or off-white crystalline powder, sparingly soluble in water, freely soluble in methanol, soluble in 
alcohol, and practically insoluble in cyclohexane. 


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Chemically, naloxone HCl dihydrate is 17-Allyl-4,5 α -epoxy-3, 14-dihydroxymorphinan-6-one 
hydrochloride dihydrate.  It has the following chemical structure:  
                                                    HCl • 2H2O 
Naloxone hydrochloride dihydrate has the molecular formula C19H21NO4 • HCl • 2H2O and the molecular 
weight is 399.87.  It is a white to slightly off-white powder and is freely soluble in water, soluble in 
alcohol, and practically insoluble in toluene and ether.   
12 
CLINICAL PHARMACOLOGY 
12.1 
Mechanism of Action 
SUBOXONE sublingual film contains buprenorphine and naloxone.  Buprenorphine is a partial agonist at 
the mu-opioid receptor and an antagonist at the kappa-opioid receptor. Naloxone is a potent antagonist 
at mu-opioid receptors and produces opioid withdrawal signs and symptoms in individuals physically 
dependent on full opioid agonists when administered parenterally.  
12.2 
Pharmacodynamics 
• 
Subjective Effects: 
Comparisons of buprenorphine to full opioid agonists such as methadone and hydromorphone suggest 
that sublingual buprenorphine produces typical opioid agonist effects which are limited by a ceiling 
effect.  
In opioid-experienced subjects who were not physically dependent, acute sublingual doses of 
buprenorphine/naloxone tablets produced opioid agonist effects which reached a maximum between 
doses of 8 mg/2 mg and 16 mg/4 mg buprenorphine/naloxone.   
Opioid agonist ceiling-effects were also observed in a double-blind, parallel group, dose-ranging 
comparison of single doses of buprenorphine sublingual solution (1, 2, 4, 8, 16, or 32 mg), placebo and a 
full agonist control at various doses.  The treatments were given in ascending dose order at intervals of 
at least one week to 16 opioid-experienced subjects who were not physically dependent.  Both active 
drugs produced typical opioid agonist effects.  For all measures for which the drugs produced an effect, 
buprenorphine produced a dose-related response.  However, in each case, there was a dose that 
produced no further effect.  In contrast, the highest dose of the full agonist control always produced the 
greatest effects.  Agonist objective rating scores remained elevated for the higher doses of 
buprenorphine (8-32 mg) longer than for the lower doses and did not return to baseline until 48 hours 
after drug administration.  The onset of effects appeared more rapidly with buprenorphine than with 
the full agonist control, with most doses nearing peak effect after 100 minutes for buprenorphine 
compared to 150 minutes for the full agonist control. 
 
 
HO
N
O
OH
O


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• 
Physiologic Effects: 
Buprenorphine in IV (2, 4, 8, 12 and 16 mg) and sublingual (12 mg) doses has been administered to 
opioid-experienced subjects who were not physically dependent to examine cardiovascular, respiratory, 
and subjective effects at doses comparable to those used for treatment of opioid dependence.  
Compared to placebo, there were no statistically significant differences among any of the treatment 
conditions for blood pressure, heart rate, respiratory rate, O2 saturation, or skin temperature across 
time.  Systolic BP was higher in the 8 mg group than placebo (3 hour AUC values).  Minimum and 
maximum effects were similar across all treatments.  Subjects remained responsive to low voice and 
responded to computer prompts. Some subjects showed irritability, but no other changes were 
observed.  
The respiratory effects of sublingual buprenorphine were compared with the effects of methadone in a 
double-blind, parallel group, dose ranging comparison of single doses of buprenorphine sublingual 
solution (1, 2, 4, 8, 16, or 32 mg) and oral methadone (15, 30, 45, or 60 mg) in non-dependent, opioid-
experienced volunteers. In this study, hypoventilation not requiring medical intervention was reported 
more frequently after buprenorphine doses of 4 mg and higher than after methadone. Both drugs 
decreased O2 saturation to the same degree. 
Effect of Naloxone: 
Physiologic and subjective effects following acute sublingual administration of buprenorphine tablets 
and buprenorphine/naloxone tablets were similar at equivalent  s of buprenorphine.  Naloxone had no 
clinically significant effect when administered by the sublingual route, although blood levels of the drug 
were measurable.  Buprenorphine/naloxone, when administered sublingually to an opioid-dependent 
cohort, was recognized as an opioid agonist, whereas when administered intramuscularly, combinations 
of buprenorphine with naloxone produced opioid antagonist actions similar to naloxone.  This finding 
suggests that the naloxone in buprenorphine/naloxone tablets may deter injection of 
buprenorphine/naloxone tablets by persons with active substantial heroin or other full mu-opioid 
dependence.  However, clinicians should be aware that some opioid-dependent persons, particularly 
those with a low level of full mu-opioid physical dependence or those whose opioid physical 
dependence is predominantly to buprenorphine, abuse buprenorphine/naloxone combinations by the 
intravenous or intranasal route.  In methadone-maintained patients and heroin-dependent subjects, IV 
administration of buprenorphine/naloxone combinations precipitated opioid withdrawal signs and 
symptoms and was perceived as unpleasant and dysphoric.  In morphine-stabilized subjects, 
intravenously administered combinations of buprenorphine with naloxone produced opioid antagonist 
and withdrawal signs and symptoms that were ratio-dependent; the most intense withdrawal signs and 
symptoms were produced by 2:1 and 4:1 ratios, less intense by an 8:1 ratio.   


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12.3 
Pharmacokinetics 
Absorption:   
In pharmacokinetic studies, the 2 mg/0.5 mg and 4 mg/1 mg doses administered as SUBOXONE 
sublingual films showed comparable relative bioavailability to the same total dose of SUBOXONE 
(buprenorphine and naloxone) sublingual tablets, whereas the 8 mg/2 mg and 12 mg/3 mg doses 
administered as SUBOXONE sublingual films showed higher relative bioavailability for both 
buprenorphine and naloxone compared to the same total dose of SUBOXONE (buprenorphine and 
naloxone) sublingual tablets.  A combination of one 8 mg/2 mg and two 2 mg/0.5 mg SUBOXONE 
sublingual films (total dose of 12 mg/ 3 mg) showed comparable relative bioavailability to the same total 
dose of SUBOXONE (buprenorphine and naloxone) sublingual tablets [see Dosage and Administration 
(2.6 and 2.7)]. 
Distribution:  
Buprenorphine is approximately 96% protein bound, primarily to alpha and beta globulin. 
Naloxone is approximately 45% protein bound, primarily to albumin. 
Metabolism: 
Buprenorphine undergoes both N-dealkylation to norbuprenorphine and glucuronidation.  The N-
dealkylation pathway is mediated primarily by the CYP3A4.  Norbuprenorphine, the major metabolite, 
can further undergo glucuronidation. Norbuprenorphine has been found to bind opioid receptors in 
vitro; however, it has not been studied clinically for opioid-like activity. Naloxone undergoes direct 
glucuronidation to naloxone-3-glucuronide as well as N-dealkylation, and reduction of the 6-oxo group. 
Elimination: 
A mass balance study of buprenorphine showed complete recovery of radiolabel in urine (30%) and 
feces (69%) collected up to 11 days after dosing.  Almost all of the dose was accounted for in terms of 
buprenorphine, norbuprenorphine, and two unidentified buprenorphine metabolites.  In urine, most of 
buprenorphine and norbuprenorphine was conjugated (buprenorphine, 1% free and 9.4% conjugated; 
norbuprenorphine, 2.7% free and 11% conjugated).  In feces, almost all of the buprenorphine and 
norbuprenorphine were free (buprenorphine, 33% free and 5% conjugated; norbuprenorphine, 21% free 
and 2% conjugated). Based on all studies performed with SUBOXONE sublingual film, buprenorphine has 
a mean elimination half-life from plasma ranging from 24 to 42 hours and naloxone has a mean 
elimination half-life from plasma ranging from 2 to 12 hours. 
• 
Drug-drug Interactions: 
CYP3A4 Inhibitors and Inducers:  Subjects receiving SUBOXONE sublingual film should be monitored if 
inhibitors of CYP3A4 such as azole antifungal agents (e.g., ketoconazole), macrolide antibiotics (e.g., 
erythromycin) or HIV protease inhibitors and may require dose-reduction of one or both agents.  The 
interaction of buprenorphine with all CYP3A4 inducers has not been studied, therefore it is 
recommended that patients receiving SUBOXONE sublingual film be monitored for signs and symptoms 
of opioid withdrawal if inducers of CYP3A4 (e.g., phenobarbital, carbamazepine, phenytoin, rifampicin) 
are co-administered [see Drug Interactions (7.1)].  
Buprenorphine has been found to be a CYP2D6 and CYP3A4 inhibitor and its major metabolite, 
norbuprenorphine, has been found to be a moderate CYP2D6 inhibitor in in vitro studies employing 
human liver microsomes. However, the relatively low plasma concentrations of buprenorphine and 
norbuprenorphine resulting from therapeutic doses are not expected to raise significant drug-drug 
interaction concerns.  
• 
Special Populations: 


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Hepatic Impairment: In a pharmacokinetic study, the disposition of buprenorphine and naloxone were 
determined after administering a SUBOXONE 2.0/0.5 mg (Buprenorphine/Naloxone) sublingual tablet in 
subjects with varied degrees of hepatic impairment as indicated by Child-Pugh criteria. The disposition 
of buprenorphine and naloxone in patients with hepatic impairment were compared to disposition in 
subjects with normal hepatic function.  
 
In subjects with mild hepatic impairment, the changes in mean Cmax, AUC0-last, and half-life values of both 
buprenorphine and naloxone were not clinically significant. No dosing adjustment is needed in patients 
with mild hepatic impairment. 
 
For subjects with moderate and severe hepatic impairment, mean Cmax, AUC0-last, and half-life values of 
both buprenorphine and naloxone were increased; the effects on naloxone are greater than that on 
buprenorphine (Table 4).  
 
Table 4.  Changes in Pharmacokinetic Parameters in Subjects With Moderate and Severe Hepatic 
Impairment 
Hepatic 
Impairment 
PK Parameters 
Increase in buprenorphine 
compared to healthy subjects 
Increase in naloxone 
compared to healthy 
subjects 
Moderate 
Cmax 
8% 
170% 
AUC0-last 
64% 
218% 
Half-life 
35% 
165% 
Severe 
Cmax 
72% 
1030% 
AUC0-last 
181% 
1302% 
Half-life 
57% 
122% 
 
The difference in magnitude of the effects on naloxone and buprenorphine are greater in subjects with 
severe hepatic impairment than subjects with moderate hepatic impairment, and therefore the clinical 
impact of these effects is likely to be greater in patients with severe hepatic impairment than in patients 
with moderate hepatic impairment. Buprenorphine/naloxone products should be avoided in patients 
with severe hepatic impairment and may not be appropriate for patients with moderate hepatic 
impairment [see Warnings and Precautions (5.11) and Use in Specific Populations (8.6)]. 
 
HCV infection: In subjects with HCV infection but no sign of hepatic impairment, the changes in the 
mean Cmax, AUC0-last, and half-life values of buprenorphine and naloxone were not clinically significant in 
comparison to healthy subjects without HCV infection.  No dosing adjustment is needed in patients with 
HCV infection. 
13 
NONCLINICAL TOXICOLOGY 
13.1 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
Carcinogenicity:   
Carcinogenicity data on SUBOXONE sublingual film are not available. 


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A carcinogenicity study of buprenorphine/naloxone (4:1 ratio of the free bases) was performed in 
Alderley Park rats.  Buprenorphine/naloxone was administered in the diet at doses of approximately 7, 
31, and 123 mg/kg/day for 104 weeks (estimated exposure was approximately 4, 18, and 44 times the 
recommended human sublingual dose of 16 mg/4 mg buprenorphine/naloxone based on buprenorphine 
AUC comparisons).  A statistically significant increase in Leydig cell adenomas was observed in all dose 
groups.  No other drug-related tumors were noted. 
Carcinogenicity studies of buprenorphine were conducted in Sprague-Dawley rats and CD-1 mice. 
Buprenorphine was administered in the diet to rats at doses of 0.6, 5.5, and 56 mg/kg/day (estimated 
exposure was approximately 0.4, 3, and 35 times the recommended human daily sublingual dose of 16 
mg on a mg/m2 basis) for 27 months.  As in the buprenorphine/naloxone carcinogenicity study in rat, 
statistically significant dose-related increases in Leydig cell tumors occurred.  In an 86-week study in 
CD-1 mice, buprenorphine was not carcinogenic at dietary doses up to 100 mg/kg/day (estimated 
exposure was approximately 30 times the recommended human daily sublingual dose of 16 mg on a 
mg/m2 basis). 
Mutagenicity:  
The 4:1 combination of buprenorphine and naloxone was not mutagenic in a bacterial mutation assay 
(Ames test) using four strains of S. typhimurium and two strains of E. coli.  The combination was not 
clastogenic in an in vitro cytogenetic assay in human lymphocytes or in an IV micronucleus test in the 
rat.  
Buprenorphine was studied in a series of tests utilizing gene, chromosome, and DNA interactions in both 
prokaryotic and eukaryotic systems.  Results were negative in yeast (S. cerevisiae) for recombinant, gene 
convertant, or forward mutations; negative in Bacillus subtilis “rec” assay, negative for clastogenicity in 
CHO cells, Chinese hamster bone marrow and spermatogonia cells, and negative in the mouse 
lymphoma L5178Y assay. 
Results were equivocal in the Ames test: negative in studies in two laboratories, but positive for frame 
shift mutation at a high dose (5mg/plate) in a third study.  Results were positive in the Green-Tweets (E. 
coli) survival test, positive in a DNA synthesis inhibition (DSI) test with testicular tissue from mice, for 
both in vivo and in vitro incorporation of [3H]thymidine, and positive in unscheduled DNA synthesis 
(UDS) test using testicular cells from mice. 
Impairment of Fertility:  
Dietary administration of buprenorphine in the rat at dose levels of 500 ppm or greater (equivalent to 
approximately 47 mg/kg/day or greater; estimated exposure approximately 28 times the recommended 
human daily sublingual dose of 16 mg on a mg/m2 basis) produced a reduction in fertility demonstrated 
by reduced female conception rates.  A dietary dose of 100 ppm (equivalent to approximately 10 
mg/kg/day; estimated exposure approximately 6 times the recommended human daily sublingual dose 
of 16 mg on a mg/m2 basis) had no adverse effect on fertility. 
16 
HOW SUPPLIED / STORAGE AND HANDLING 
SUBOXONE sublingual film is supplied as an orange rectangular sublingual film with a white printed logo 
in child-resistant polyester/foil laminated pouches: 
• 
NDC 12496-1202-3 (buprenorphine/naloxone 2 mg/0.5 mg/film; content expressed in terms of 
free base) - 30 films per carton 
• 
NDC 12496-1204-3 (buprenorphine/naloxone 4 mg/1 mg/film; content expressed in terms of 
free base) - 30 films per carton 


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• 
NDC 12496-1208-3 (buprenorphine/naloxone 8 mg/2 mg/film; content expressed in terms of 
free base) -30 films per carton 
• 
NDC 12496-1212-3 (buprenorphine/naloxone 12 mg/3 mg/film; content expressed in terms of 
free base) - 30 films per carton 
Store at 25°C (77°F), excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature] 
• 
Patients should be advised to store buprenorphine-containing medications safely and out of 
sight and reach of children.   
• 
Rx only 
17 
PATIENT COUNSELING INFORMATION 
See FDA-approved patient labeling (Medication Guide) 
Patients should be advised NOT to cut, chew or swallow SUBOXONE sublingual film. 
17.1 
Safe Use 
Before initiating treatment with SUBOXONE, explain the points listed below to caregivers and 
patients. Instruct patients to read the Medication Guide each time SUBOXONE is dispensed because 
new information may be available. 
Patients should be warned that it is extremely dangerous to self-administer non-prescribed 
benzodiazepines or other CNS depressants (including alcohol) while taking SUBOXONE sublingual 
film.  Patients prescribed benzodiazepines or other CNS depressants should be cautioned to use 
them only as directed by their physician [see Warnings and Precautions (5.2), Drug Interactions 
(7.3)]. 
Patients should be advised that SUBOXONE sublingual film contains an opioid that can be a target for 
people who abuse prescription medications or street drugs.  Patients should be cautioned to keep 
their films in a safe place, and to protect them from theft. 
Patients should be instructed to keep SUBOXONE sublingual film in a secure place, out of the sight and 
reach of children.  Accidental or deliberate ingestion by a child may cause respiratory depression 
that can result in death.  Patients should be advised that if a child is exposed to SUBOXONE 
sublingual film, medical attention should be sought immediately.   
Patients should be advised never to give SUBOXONE sublingual film to anyone else, even if he or she has 
the same signs and symptoms.  It may cause harm or death. 
Patients should be advised that selling or giving away this medication is against the law. 
Patients should be cautioned that SUBOXONE sublingual film may impair the mental or physical abilities 
required for the performance of potentially dangerous tasks such as driving or operating machinery.  
Caution should be taken especially during drug induction and dose adjustment and until individuals 
are reasonably certain that buprenorphine therapy does not adversely affect their ability to engage 
in such activities [see Warnings and Precautions (5.11)]. 
Patients should be advised not to change the dosage of SUBOXONE sublingual film without consulting 
their physician. 
Patients should be advised to take SUBOXONE sublingual film once a day. 


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Patients should be advised that if they miss a dose of SUBOXONE they should take it as soon as they 
remember. If it is almost time for the next dose, they should skip the missed dose and take the next 
dose at the regular time. 
Patients should be informed that SUBOXONE sublingual film can cause drug dependence and that 
withdrawal signs and symptoms may occur when the medication is discontinued. 
Patients seeking to discontinue treatment with buprenorphine for opioid dependence should be advised 
to work closely with their physician on a tapering schedule and should be apprised of the potential 
to relapse to illicit drug use associated with discontinuation of opioid agonist/partial agonist 
medication-assisted treatment. 
Patients should be cautioned that, like other opioids, SUBOXONE sublingual film may produce 
orthostatic hypotension in ambulatory individuals [see Warnings and Precautions (5.12)]. 
Patients should inform their physician if any other prescription medications, over-the-counter 
medications, or herbal preparations are prescribed or currently being used [see Drug Interactions 
(7.1, 7.2 and 7.3)]. 
Women of childbearing potential who become pregnant or are planning to become pregnant, should be 
advised to consult their physician regarding the possible effects of using SUBOXONE sublingual film 
during pregnancy [see Use in Specific Populations (8.1)]. 
Advise women who are breastfeeding to monitor the infant for drowsiness and difficulty breathing [see 
Use in Specific Populations (8.3)].   
Patients should inform their family members that, in the event of emergency, the treating physician or 
emergency room staff should be informed that the patient is physically dependent on an opioid and 
that the patient is being treated with SUBOXONE sublingual film. 
Refer to the Medication Guide for additional information regarding the counseling information. 
 
17.2 
Disposal of Unused SUBOXONE Sublingual Films 
 
Unused SUBOXONE sublingual films should be disposed of as soon as they are no longer needed. 
Unused films should be flushed down the toilet.  
 
Revised: April 2014 
 
Manufactured for Reckitt Benckiser 
Pharmaceuticals Inc., 
Richmond, VA 23235 by:  
MonoSol Rx, LLC,  
Warren, NJ 07059 
 
Distributed by: 
Reckitt Benckiser Pharmaceuticals Inc. 
Richmond, VA 23235 


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Appendix 8 
Study Drug Preparation, Administration, and Depot 
Removal Instructions 
RBP-6000 PREPARATION AND DOSING PROCEDURE 
• 100 MG BUPRENORPHINE 
• 300 MG BUPRENORPHINE  
 
IMPORTANT:  Only qualified study personnel can prepare the study drug.  Protective gloves 
(latex or nitrile) should be worn when preparing and dosing RBP-6000.  Remove the product 
from the refrigerator at least 15 minutes before use to allow the product to reach room 
temperature before dosing.  Product may be left at room temperature up to 8 hours prior to use.  
If product is not used that day it should be marked appropriately.   
   
FOLLOW THE INSTRUCTIONS AS DIRECTED TO ENSURE PROPER DOSING 
Preparation of the Product Prior to Administration:  
The following components will be used in the preparation of RBP-6000: 
• One sealed foil pouch containing a syringe pre-filled with RBP-6000 and an oxygen 
absorber pack.  
• One sterile 19-gauge, one-inch hypodermic safety needle 
 
1. On a clean field, open the foil pouch and remove the contents. Discard the oxygen absorber 
pack.   The pouch must be retained for accountability. 
2. Un-cap the pre-filled RBP-6000 syringe and attach the safety needle cartridge by pushing in 
and turning the needle until it is finger tight. Do not strip the threaded fitting by over-
tightening the needle. Position the sheath at 90 degrees to the needle.  Pull off the needle 
cartridge cover.   More complete documentation on the usage of the SurGuard2 safety needle 
can be found in the included instruction sheet.  
3. While holding the syringe vertically with the tip upwards, expel air bubbles by stroking the 
plunger up and down. 
4. The product is now ready for administration.  Carefully recap the needle. 
Administration Procedure: 
IMPORTANT: Once prepared (removed from foil pouch), the product must be 
administered within a maximum of 30 minutes. 
 
Choose an injection site below the waist but above the hip bone; from where the body curves at 
the side to about 2 inches from the middle of the abdomen with adequate amounts of 
subcutaneous tissue that does not have excessive pigment, nodules, lesions, or hair.  Since you 
can vary the injection site with a subcutaneous injection, choose an area that has not recently 
been used.   
 
Possible injection site locations and an injection rotation pattern are shown in Figure 4. 


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Figure 4 
Injection Locations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. Cleanse the injection-site area with an alcohol swab.   
 
2. Using the thumb and forefinger of your non-dominant hand, grab and bunch the area of skin 
around the injection site. 
 
3. Using your dominant hand, insert approximately half the needle length quickly. The 
approximate angle you use will depend on the amount and fullness of the subcutaneous tissue 
and the length of the needle. 
 
4. After the needle is inserted, release the skin with your nondominant hand. 
 
5. Pull back on the plunger to check for blood.  If blood is present in the syringe, do not inject.  
Withdraw the needle and discard all components safely in an appropriate biohazard 
container.  Repeat the “Preparation of the Product Prior to Administration” procedures and 
the “Administration Procedure” using a different abdominal injection site with another 
syringe of RBP-6000 and associated components. 
 
6. Inject the product using a slow, steady push. Press down on the plunger until the syringe is 
empty. 
 
7. Withdraw the needle at the same angle used for insertion. Do not rub the injection area.  If 
there is bleeding, apply minimal pressure with a gauze pad or bandage.  Engage the safety 
sheath on the needle as per the SurGuard2 needle instructions.   
 
8. Discard all components safely in an appropriate biohazard container. 
 
Hipbones 
Waist 
1 / 5 
2 / 6 
3 
4 


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PROCEDURE FOR REMOVAL OF THE RBP-6000 DEPOT 
 
In the event of an emergency or if a subject withdraws or is withdrawn within the first 14 days of 
receiving an injection of RBP-6000, subjects may have the option to have the depot surgically 
removed by a physician delegated to perform surgery. The medically responsible physician 
should carefully discuss this option with subjects given the use of ATRIGEL Delivery System 
and the feasibility of extracting the depot. 
 
The following surgical procedure should be followed: 
 
1. 
Palpate the depot and surrounding area to confirm its exact location. 
2. 
Cleanse the area with an antiseptic solution (e.g., Betadine).   
3. 
Infiltrate the area with a local anesthesia (e.g., Lidocaine 1% or a lidocaine/adrenaline 
[epinephrine] mixture) and wait for it to take effect. 
4. 
Cover the area with a sterile drape. 
5. 
Incise the skin up to the subcutaneous tissues using a scalpel.  
6. 
Using blunt and sharp dissection, identify the plane between the depot and surrounding 
subcutaneous tissues.  Once the plane is identified, separate the superficial 25% of the 
circumference of the depot with blunt dissection.  
7. 
Gently lift the incised ellipse of skin and depot with forceps.   
8. 
Once the depot is removed, ensure hemostasis, and close the skin with non-absorbable 
sutures.   
9. 
The extracted RBP-6000 depot will be disposed of into an appropriate, secure biohazard 
container per the SOP at the clinical site. 
 


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Appendix 9 
Prohibited Cytochrome P450 Inhibitors and Inducers 
The following medications are prohibited during the study: 
Cytochrome 
P450 3A4 
Inhibitors 
Cytochrome 
P450 3A4 
Inducers 
Cytochrome 
P450 2C8 
Inhibitors 
Cytochrome 
P450 2C8 
Inducers 
Amiodarone 
Ketoconazole 
Barbiturates 
Gemifibrozil 
Rifampicin 
Amprenavir 
Metronidazole 
Carbamazepine 
Trimethoprim 
 
Aprepitant 
Mibefradil 
Dexamethasone 
Glitazones 
 
Chloramphenicol Miconazole 
Efavirenz 
Montelukast 
 
Cimetidine 
Mifepristone 
Ethosuximide 
Quercetin 
 
Ciprofloxacin 
Nefazodone 
Glucocorticoids 
 
 
Clarithromycin 
Nelfinavir 
Glutethimide 
 
 
Clotrimazole 
Nicardipine 
Modafinil 
 
 
Cyclosporine 
Norfloxacin 
Nevirapine 
 
 
Delavirdine 
Norfluoxetine 
Oxcarbazepine 
 
 
Diethyl-
dithiocarbamate 
Propofol 
Phenobarbital 
 
 
Diltiazem 
Quinine 
Phenytoin 
 
 
Ethinyl estradiol 
Ritonavir 
Pioglitazone 
 
 
Erythromycin 
Saquinavir 
Primidone 
 
 
Fluconazole 
Sertraline 
Rifabutin 
 
 
Fluoxetine 
Starfruit 
Rifampin 
 
 
Fluvoxamine 
Telithromycin 
Hypericum 
perforatum 
 
 
Gestodene 
Troleandomycin 
Sulfadimidine 
 
 
Grapefruit juice 
Verapamil 
Sulfinpyrazone 
 
 
Imatinib 
Voriconazole 
Troglitazone 
 
 
Indinavir 
Zafirlukast 
Troleandomycin 
 
 
Itraconazole 
 
 
 
 
Source:  http://medicine.iupui.edu/clinpharm/ddis/clinical-table/ 


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Appendix 10 
Columbia Suicide Severity Rating Scale (eC-SSRS) -- 
Baseline/Screening Version 
 
 


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Appendix 11 
Columbia Suicide Severity Rating Scale (eC-SSRS) -- 
Since Last Visit Version 
 


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Appendix 12 
Clinical Opiate Withdrawal Scale (COWS) 
 
0 - Pulse rate 80 or below
1 - Pulse rate 81 - 100
2 - Pulse rate 101 - 120
4 - Pulse rate greater than 120
1. Resting Pulse Rate:
Measured after patient is sitting or lying for one minute.
0 - No GI symptoms
1 - Stomach cramps
2 - Nausea or loose stool
3 - Vomiting or diarrhea
5 - Multiple episodes of diarrhea or vomiting
2. GI upset: Over last 1/2 hour.
0 - No report of chills or flushing
1 - Subjective report of chills or flushing
2 - Flushed or observable moistness on face
3 - Beads of sweat on brow or face
4 - Sweat streaming off face
3. Sweating:
Over past 1/2 hour not accounted for by room temperature or patient activity.
0 - No tremor
1 - Tremor can be felt, but not observed
2 - Slight tremor observable
4 - Gross tremor or muscle twitching
4. Tremor:
Observation of outstretched hands.
0 - Able to sit still
1 - Reports difficulty sitting still, but is able to do so
3 - Frequent shifting or extraneous movements of legs/arms
5 - Unable to sit still for more than a few seconds
5. Restlessness:
For each item, mark the choice that best describes the subject's signs or symptom. Rate on just the
apparent relationship to opiate withdrawal. For example, if heart rate is increased because the patient was
jogging just prior to assessment, the increased pulse rate would not add to the score.
beats/min
Observation during assessment.
0 - No yawning
1 - Yawning once or twice during assessment
2 - Yawning three or more times during assessment
4 - Yawning several times/minute
6. Yawning: Observation durring assessment.
CLINICAL 
 WITHDRAWAL SCALE (COWS)
 
 
OPIATE 


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0 - Not present
1 - Nasal stuffiness or unusually moist eyes
2 - Nose running or tearing
4 - Nose constantly running or tears streaming down cheeks
11. Runny nose or tearing:
0 - None
1 - Patient reports increasing irritability or anxiousness
2 - Patient obviously irritable or anxious
4 - Patient so irritable or anxious that participation in the assessment is difficult
8. Anxiety or Irritability:
0 - Not present
1 - Mild diffuse discomfort
2 - Patient reports severe diffuse aching of joints/muscle
4 - Patient is rubbing joints or muscles and is unable to sit still because of discomfort
9. Bone or Joint aches:
0 - Skin is smooth
3 - Piloerection of skin can be felt or hairs standing up on arms
5 - Prominent piloerection
10. Gooseflesh skin:
0 - Pupils pinned or normal size for room light
1 - Pupils possibly larger than normal for room light
2 - Pupils moderately dilated
5 - Pupils so dilated that only the rim of the iris is visible
7. Pupil Size:
If patient was having pain previously, only the additional component attributed to opiate
withdrawal is scored.
Not accounted for by cold symptoms or allergies.
TOTAL SCORE (sum of all 11 items):
Score Interpretation: 5 - 12= Mild, 13 - 24= Moderate, 25 - 36=Moderately Severe, More than 36= Severe Withdrawal


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Appendix 13 
Subjective Opiate Withdrawal Scale (SOWS) 
 
Modified from : Handelsman L, Cochrane KJ, Aronson MJ, Ness R, Rubenstein KJ, Kanof PD 
(1987). Two new rating scales for opiate withdrawal.  Am J Drug Alcohol Abuse 13:293-308. 


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Appendix 14 
Opioid Craving Visual Analog Scale (Opioid Craving VAS) 
 
No craving 
_________________________________________Strongest craving ever 
100 mm scale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 15 
Injection Site Grading Scale 
 
Injection 
Site 
Reactions 
None 
(Grade 0) 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Pain 
None 
Does not 
interfere with 
activity 
Repeated use of non-
narcotic pain reliever 
> 24 hours or 
interferes with 
activity  
Any use of narcotic 
pain reliever or 
prevents daily 
activity 
Emergency room  
(ER) visit or  
hospitalization  
Tenderness 
None 
Mild discomfort 
to touch. 
Discomfort with 
movement. 
Significant 
discomfort at rest  
ER visit or 
hospitalization 
Erythema/ 
Redness* 
(quantitative) 
None 
2.5 – 5 cm 
5.1 – 10 cm 
> 10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration ** 
None 
2.5 – 5 cm and 
does not 
interfere  
with activity  
5.1 – 10 cm or  
interferes with  
activity  
> 10 cm or  
prevents daily  
activity  
Necrosis  
Swelling ** 
(subjective) 
None 
2.5 – 5 cm and 
does not 
interfere  
with activity  
5.1 – 10 cm or  
interferes with  
activity  
> 10 cm or  
prevents daily  
activity  
Necrosis  
 
* In addition to grading the measured local reaction at the greatest single diameter, the measurement should be  
recorded as a continuous variable.  
** Induration/Swelling should be evaluated and graded using the functional scale as well as the actual measurement.  
 
Modified from:   
U.S. Department of Health and Human Services, Food and Drug Administration, Center for 
Biologics Evaluation and Research, September 2007.  Guidance for Industry: Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials. [pdf] Available at: 
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInform
ation/Guidances/Vaccines/ucm091977.pdf.  Accessed 14 April 2015. 


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Appendix 16 
Injection Site Pain Visual Analog Scale (Injection Site Pain 
VAS) 
How would you rate your injection site pain today? 
 
                  No  _________________________________________ Pain as bad  
                  Pain                                                                                  as it could be 
 
 
 
 
 
Please answer the following question by checking the box with either a “Yes” or “No”: 
Are you currently experiencing any burning or stinging at the injection site? 
 
 
 
 
YES   
 
 
 
NO 
 


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Appendix 17 
Timeline Followback (TLFB) Interview 
 
 
Ethanol 


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Appendix 18 
Euro QoL EQ-5D-5L Health Questionnaire 
 


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Appendix 19 
Short Form (36) Health Survey v2 
 


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Appendix 20 
Medication Satisfaction Questionnaire  
Overall, how satisfied are you with your current opioid dependence medication? 
 
1 = extremely dissatisfied 
2 = very dissatisfied 
3 = somewhat dissatisfied 
4 = neither satisfied nor dissatisfied 
5 = somewhat satisfied 
6 = very satisfied 
7 = extremely satisfied 
 


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Appendix 21 
Health Care Resource Utilization Questionnaire 
HEALTH INSURANCE 
Primary Health Insurance  
(Please check all  that apply) 
 Commercial (for example, Blue Cross Blue  
Shield,  Aetna, Humana, United, Cigna) 
 Medicare 
 Medicaid 
 Veterans Affairs 
 Workers compensation 
 Other insurance 
 Self-pay / Out of pocket/No insurance 
 
 
INPATIENT ADMISSIONS 
 
• 
Please list in the table below all inpatient admissions in the past 30 days.  If patient is currently 
hospitalized, please check the box in the “Ongoing” column. 
• 
If patient has had no previous hospitalizations in the past 30 days, please check the 
appropriate box below. 
 No hospitalizations since the last study visit 
Admission Date  
(dd / mmm / yyyy) 
Discharge Date 
(dd / mmm / yyyy) 
Ongoing? 
Type of Admission 
1. 
_ _ / _ _ _ / _ _ _ _ 
_ _ / _ _ _ / _ _ _ _ 
 
Medical 
Surgical 
Psychiatric 
Other 
2. 
_ _ / _ _ _ / _ _ _ _ 
_ _ / _ _ _ / _ _ _ _ 
 
 Medical 
Surgical 
Psychiatric 
Other 
3. 
_ _ / _ _ _ / _ _ _ _ 
_ _ / _ _ _ / _ _ _ _ 
 
 Medical 
Surgical 
Psychiatric 
Other 
 


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EMERGENCY ROOM VISITS  
• 
Please list how many times the patient has been to the Emergency Room in the past 30 days. 
Type of Problem 
Number of Visits 
Substance abuse-related 
visits 
Other medical problems 
visits 
 
 
OUTPATIENT SERVICES 
• 
Please list how many times the patient has seen 1 of the following health professionals in the 
past 30 days. The outpatient services captured on this questionnaire are ones conducted 
outside the study 
Health Professional 
Number of Visits 
General practitioner / Internist 
visits 
Addiction Medicine Specialist 
visits 
Therapist / Counselor 
visits 
Other: Specialist 
visits 
Other:  Non-Specialist  
visits 
 


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Appendix 22 
Treatment Effectiveness Assessment (TEA) 
 
 


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Appendix 23 
Addiction Severity Index (ASI) Lite 
 


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Appendix 24 
Beck Depression Inventory II (BDI-II) 
To be supplied by RBP.   
http://www.pearsonclinical.com/psychology/products/100000159/beck-depression-inventoryii-
bdi-ii.html?Pid=015-8018-370&Mode=summary#tab-details 


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Appendix 25 
Brief Pain Inventory (BPI) Short Form 
To be supplied by RBP.   
http://www.mdanderson.org/education-and-research/departments-programs-and-
labs/departments-and-divisions/symptom-research/symptom-assessment-
tools/BPI_UserGuide.pdf 


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Appendix 26 
Sponsor Signatures 
Study Title: 
An Open-Label, Long-Term Safety and Tolerability Study of Depot 
Buprenorphine (RBP-6000) in Treatment-Seeking Subjects With 
Opioid Use Disorder 
Study Number: 
RB-US-13-0003 
Final Date: 
19 August 2015 
 
This clinical study protocol was subject to critical review and has been approved by the Sponsor.  
The following personnel contributed to writing and/or approving this protocol: 
 
Signed: 
 
 
Date:  
 
 
Senior Fellow, Clinical Science 
Indivior Inc. 
Signed: 
 
 
Date:  
 
 
Director, Clinical Pharmacology and Translational Medicine  
Indivior Inc. 
Signed: 
 
 
Date:  
 
 
Senior Manager, Clinical Pharmacology and Translational Medicine 
Indivior Inc. 
Signed: 
 
 
Date:  
 
 
Director, Biostatistics and Statistical Programming 
Indivior Inc. 
Signed: 
 
Date:  
 
 
Global Director, Health Economics 
Indivior Inc. 
Signed: 
 
Date:  
 
 
Medical Advisor 
Indivior Inc. 


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Appendix 27 
Investigator’s Signature 
Study Title: 
An Open-Label, Long-Term Safety and Tolerability Study of Depot 
Buprenorphine (RBP-6000) in Treatment-Seeking Subjects With 
Opioid Use Disorder 
Study Number: 
RB-US-13-0003 
Final Date: 
19 August 2015 
I have read the protocol described above. I agree to comply with all applicable regulations and to 
conduct the study as described in the protocol.  [enter additional text, if applicable] 
 
 
Signed: 
 
 
Date:  
 
Printed Name and Credentials: 
Title: 
Site Name: 
Address: 
Telephone: 
 
 
 
 

Prot_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
Study Title 
An Open-Label, Long-Term Safety and Tolerability Study of Depot 
Buprenorphine (RBP-6000) in Treatment-Seeking Subjects With 
Opioid Use Disorder 
NCT Number 
NCT02510014 
Date 
April 14, 2015 
 


Clinical Study Protocol: RB-US-13-0003
Study Title:
An Open-Label, Long-Term Safety and Tolerability Study of Depot 
Buprenorphine (RBP-6000) in Treatment-Seeking Subjects With 
Opioid Use Disorder
Study Number:
RB-US-13-0003
Study Phase:
3
Product Name:
RBP-6000
IND Number:
107,607
Indication:
Treatment of Opioid Use Disorder
Investigators:
Multicenter
Sponsor:
Reckitt Benckiser Pharmaceuticals Inc.
A Subsidiary of Indivior PLC
10710 Midlothian Turnpike, Suite 430
Richmond, VA 23235
Sponsor Contact:
Medical Monitor:
Date
Original Protocol:
14 April 2015
Confidentiality Statement
The information contained in this document is privileged and confidential.  Do not copy, 
circulate, or otherwise distribute without written authorization from 
Reckitt Benckiser Pharmaceuticals Inc.


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SYNOPSIS
Sponsor: 
Reckitt Benckiser Pharmaceuticals Inc. (RBP)
Name of Finished Product:
RBP-6000, 18% buprenorphine sterile solution for subcutaneous (SC) injection
Name of Active Ingredient:
Buprenorphine
Name of Inactive Ingredient: 
ATRIGEL® Delivery System
Study Title:
An Open-Label, Long-Term Safety and Tolerability Study of Depot Buprenorphine (RBP-6000) 
in Treatment-Seeking Subjects With Opioid Use Disorder
Study Number:
RB-US-13-0003
Study Phase: Phase 3
Primary Objective:
To assess the long-term safety and tolerability of RBP-6000 subcutaneous (SC) injections in 
subjects with opioid use disorder.
Secondary Objective:
To collect clinical outcome data with RBP-6000 SC injections in subjects with opioid use 
disorder.
Tertiary Objectives: 
To evaluate the:

Pharmacokinetics (PK) of RBP-6000, 

Relationships between RBP-6000 PK and clinical outcome data, and

Impact of RBP-6000 on health and economic outcomes.
Study Design:
This is a multicenter, open-label, long-term safety study in which approximately 600 subjects 
diagnosed with opioid use disorder will be enrolled (approximately 300 subjects who did not 
participate in Study RB-US-13-0001, the double-blind, placebo-controlled efficacy study of 
RBP-6000 [hereafter referred to as “de novo” subjects], and 300 subjects who completed the RB-
US-13-0001 study [hereafter referred to as “roll-over” subjects]).  Subject participation will be 
based on the Investigator’s determination that initiation or continuation of study treatment is 
appropriate; and, for subjects who participated in RB-US-13-0001, that there have been no 
significant protocol deviations or clinically relevant adverse events (AEs) that would preclude 
inclusion of the subject in this study. All subjects will provide written informed consent before 
any protocol-related procedures commence. At the Screening Visit (which is up to 3 days after 
the End of Study [EOS] Visit [Day 169 + 3] for roll-over subjects), potential subjects will be 


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reviewed for eligibility against inclusion and exclusion criteria, and eligible subjects will be 
enrolled into the trial. 
SUBOXONE Sublingual Film Run-In:  Induction
De novo Subjects:
De novo subjects will initially be inducted onto SUBOXONE® (buprenorphine/naloxone) 
sublingual film for 3 days according to the SUBOXONE sublingual film prescribing 
information.  They will receive their first dose of SUBOXONE sublingual film on Induction 
Day 1 after it is confirmed that the subject meets eligibility criteria and has a Clinical Opiate 
Withdrawal Scale (COWS) score > 12.  Subjects will be started with an initial dose of 2 mg/0.5 
mg (buprenorphine/naloxone) or 4 mg/1 mg and may titrate upwards in 2 or 4 mg increments of 
buprenorphine, at approximately 2-hour intervals, under clinical supervision, to 8 mg/2 mg based 
on therapeutic response. 
On Induction Day 2, subjects with a COWS score > 12 or subjects reporting withdrawal 
signs/symptoms overnight will receive a dose of SUBOXONE sublingual film equal to the total 
dose given on Induction Day 1 plus 4 mg. (For example, if a subject received a total dose of 8 
mg of buprenorphine on Induction Day 1, the starting dose for Induction Day 2 would be 12 mg).  
If the COWS score is still > 12 one hour later, another 4 mg dose can be given. The subject 
should not exceed a maximum dose of 16 mg buprenorphine for Induction Day 2. Subsequent 
SUBOXONE sublingual film doses must be separated by at least 1 hour from the preceding dose. 
SUBOXONE sublingual film doses may also be adjusted downward if necessary. 
On Induction Day 3, subjects will be titrated to therapeutic response based on COWS scores as 
well as physician judgment. Most subjects will only require a single dose on Induction Day 3,
which will equal the Induction Day 2 dose or the Induction Day 2 dose plus 4 mg buprenorphine. 
Additional doses may also be administered on Induction Day 3 (up to 24 mg/6 mg). Subsequent 
SUBOXONE sublingual film doses must be separated by at least 1 hour from the preceding dose.  
Subjects should reach a daily dose of between 8 mg and 24 mg buprenorphine by Induction Day 
3 and continue on that dose through the remainder of the SUBOXONE sublingual film Run-In 
period, with additional dose adjustments if necessary. 
Roll-over Subjects:
Following screening, roll-over subjects will be inducted onto SUBOXONE sublingual film to 
achieve daily doses between 8 mg to 24 mg buprenorphine according to the SUBOXONE 
sublingual film prescribing information. 
Subjects will receive their first induction dose on Induction Day 1. Subjects should be started 
with an initial dose of 2 mg/0.5 mg (buprenorphine/naloxone) or 4 mg/1 mg and may titrate 
upwards in 2 or 4 mg increments of buprenorphine, at approximately 2-hour intervals, under 
supervision, to a total dose of up to 8 mg/2 mg based on the control of acute withdrawal 
symptoms. 
On Induction Day 2, subjects with a score for COWS of >12, or subjects reporting opioid 
withdrawal signs/symptoms overnight, should receive a dose of study drug equal to the total dose 
given on Induction Day 1 plus 4 mg.  If the COWS score is still >12 one hour later, another 4 mg 
dose can be given.  The subject should not exceed a maximum dose of 16 mg/4 mg for Induction 
Day 2.  Subsequent SUBOXONE sublingual film doses must be separated by at least 1 hour 
from the preceding dose.  SUBOXONE sublingual film doses may also be adjusted downward if 


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necessary.  
On Induction Day 3, subjects will be titrated to therapeutic response until a therapeutic dosage is 
reached, based on COWS scores as well as physician judgment. Most subjects will only require a 
single dose on Induction Day 3 which will equal the Induction Day 2 dose or the Induction Day 2 
dose plus 4 mg. Additional doses may also be administered on Induction Day 3 (up to 24 mg).  
Subsequent SUBOXONE sublingual film doses must be separated by at least 1 hour from the 
preceding dose.  Although subjects should reach a daily dose of between 8 mg and 24 mg by 
Induction Day 3 and continue on that dose through the remainder of the SUBOXONE sublingual 
film Run-In period, dose adjustments may be necessary during the Run-In period. 
Roll-over subjects must be titrated to a minimum dose of 8 mg SUBOXONE by the end of the 
3-day Induction period regardless of their COWS scores and/or the presence or absence of 
withdrawal symptoms.  
The SUBOXONE sublingual film(s) will be administered under the tongue, close to the base on 
the left or right side, until they are dissolved.  If an additional sublingual film is required, it 
should be placed on the opposite side from the first film.  Subjects should be instructed to hold 
the films under the tongue until they dissolve.  If a third film is required, it should be placed 
under the tongue after the first 2 films have dissolved.
SUBOXONE Sublingual Film Run-In:  Dose Adjustment (All Subjects)
After the daily induction visits, all subjects will begin a 1-to 11-day SUBOXONE sublingual 
film dose adjustment period.  Subjects will return to the clinic at 3- to 4-day intervals for Opioid 
Craving Visual Analog Scale (VAS), COWS, and Subjective Opiate Withdrawal Scale (SOWS) 
assessments.  SUBOXONE sublingual film will be dispensed at each visit for at home dosing.  
Beginning on the 4th day of SUBOXONE sublingual film dosing, subjects will be evaluated for 
Day -1 criteria, which are identical to the criteria required for enrollment on Day 1.  These 
criteria include the following: no allergic reaction to SUBOXONE sublingual film, a daily dose 
of SUBOXONE sublingual film between 8 mg and 24 mg (inclusive) buprenorphine, a COWS 
score of ≤ 12, and an Opioid Craving VAS score of ≤ 20 mm.
Open-Label Treatment with RBP-6000:
On Day 1 of the study (first dose of RBP-6000), all subjects who meet enrollment criteria will 
receive a SC injection of 300 mg of buprenorphine in RBP-6000. Subsequent doses of RBP-6000 
may be adjusted down to 100 mg and back up to 300 mg based on the medical judgment of the 
Investigator. After injection of RBP-6000, subjects will not be permitted to receive supplemental 
SUBOXONE sublingual film during the RBP-6000 treatment period. Subjects who require 
supplemental SUBOXONE sublingual film or other sublingual buprenorphine pharmacotherapy 
during the RBP-6000 treatment period will be withdrawn from the study and referred for 
appropriate treatment.
Subjects will return to the clinic for monthly injection visits (every 28 ±2 days) for a total of up 
to 12 injections for de novo subjects or for a total of 6 injections for roll-over subjects. 
Continuous electrocardiogram (ECG) recordings will be collected from at least 30 minutes 
before each SC injection until at least 4 hours after injection using Holter monitoring devices. 
This real-time cardiovascular monitoring will be used to detect potential arrhythmias and 
abnormal ECGs. All ECGs will be interpreted by a central monitoring facility. Four-hour 
continuous pulse oximetry will be assessed from at least 30 minutes prior to the SC injection 


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through 4 hours post-RBP-6000 SC injection. Subject-reported injection site pain Visual Analog 
Scale scores (VAS) will be collected at various times for 2 hours after each injection. Local 
injection site grading will be collected at various time points starting immediately after injection; 
the injection site will evaluated for pain, tenderness, warmth, itching, erythema, inflammation or 
swelling, and bruising using a 4-point severity scale. At each visit after injections begin, the 
injection site will be assessed by site staff for potential reaction and will also be evaluated for 
evidence of attempts to remove the depot.
Subjects will return to the clinic weekly for the first 3 months and biweekly for the rest of the 
study period for urine drug screens (UDS), Timeline Followback (TLFB) interviews, opioid 
craving VAS evaluation, COWS and subject reported outcomes (Subjective Opiate Withdrawal 
Scale [SOWS]).  Subjects will continue to receive counseling (manual-guided behavioral 
therapy) during the study.  
Safety assessments will be collected at each injection visit and/or at injection follow-up visits 
and will include the following: vital signs, electronic Columbia Suicide Severity Rating Scale 
(eC-SSRS) responses, ECGs, laboratory tests (hematology, chemistry, urinalysis, and pregnancy 
test), use of concomitant medications, and the frequency of AEs. 
Sparse PK blood samples will be collected for population PK analysis. ECGs will be performed 
between 30 minutes and 2 hours before PK sample collection. The following health economic 
and outcome assessments will also be collected: Beck Depression Inventory (BDI-II), brief pain 
inventory (BPI), EuroQol EQ-5D-5L (EQ-5D-5L), 36-Item Short Form Health Survey, Version 2 
(SF-36v2), Medication Satisfaction Questionnaire (MSQ), healthcare resource utilization 
(HCRU), Treatment Effectiveness Assessment (TEA), and Addiction Severity Index Lite (ASI).
SUBOXONE Transition Period/Safety Follow-up:
At the end of the RBP-6000 treatment period, subjects will enter a 4-week SUBOXONE 
transition period/safety follow-up where they will receive the same dose of SUBOXONE 
sublingual film that they received at Day -1, and their ongoing treatment options will be 
reviewed.
Study Population:
Approximately 300 de novo subjects will be enrolled into this study, as well as approximately 
300 roll-over subjects. The study population will consist of individuals diagnosed with opioid 
use disorder who are seeking treatment. 
Test Product, Dose, and Mode of Administration:
300 mg buprenorphine in RBP-6000, subcutaneous injection
100 mg buprenorphine in RBP-6000, subcutaneous injection
Duration of Study Treatment:
This will be a multiple-dose study, with the first investigational product administration 
(RBP-6000 containing 300 mg buprenorphine) on Day 1. The expected maximum duration of 
participation for de novo subjects is up to approximately 55 weeks, consisting of up to 7 days of 
screening, up to 14 days SUBOXONE sublingual film Run-In, up to a 48-week open-label 
treatment period, and a 4-week follow-up period. The expected maximum duration of 
participation for roll-over subjects is up to approximately 31 weeks, consisting of up to a 7-day 
screening period, up to 14 days SUBOXONE sublingual film Run-In, a 24-week open-label


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treatment period, and a 4-week follow-up period.
Safety Assessments:
Safety objectives for this study are to evaluate the safety and tolerability of RBP-6000 (100 mg 
and 300 mg) SC injection treatment in subjects with opioid use disorder. Safety assessments will 
include the following: frequency of all AEs, serious AEs (SAEs), discontinuations from study 
due to AEs; local injection site tolerability (e.g., injection site grading); injection site pain using a 
subject-reported VAS; suicidality using the eC-SSRS, use of concomitant medications; changes 
in clinical laboratory results; vital sign measurements; 12-lead ECGs, which will be interpreted 
by a central facility; physical examination results; body weight, height, and body mass index 
(BMI), and abdominal fat measurement (waist-to-hip ratio).
Clinical Outcome Assessments:
Clinical outcome assessments will include the UDS for opioids and other drugs; self-reported use 
of illicit opioids, other drugs, and alcohol on the TLFB; COWS, SOWS, and Opioid Craving 
VAS.
PK Assessments:
Sparse plasma samples will be collected for population PK analysis.
Health Economics and Outcomes Assessments: 
Health economics and outcomes assessments will include: BDI-II, BPI, EQ-5D-5L, SF-36v2, 
MSQ, HCRU, TEA, and ASI-Lite.


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Statistical Methods:
A Statistical Analysis Plan (SAP) will be prepared after the protocol is approved and before 
database lock occurs.  The SAP will provide further details regarding the definition of analysis 
endpoints, data handling rules, and the statistical methodology to be used to address all study 
objectives.  The SAP will also include formats for the summary and analysis tables, listings, and 
graphical displays.
Determination of Sample Size:
Approximately 300 de novo subjects as well as approximately 300 subjects who completed the 
RB-US-13-0001 study will be enrolled into this long-term safety study to ensure 100 subjects 
reach 1 year of treatment with RBP-6000. No power analysis will be done corresponding to the 
sample sizes, but the large numbers proposed are clinically acceptable to provide adequate and 
relevant clinical conclusions from this study.
Safety Analyses:
Safety variables will include AEs, local injection site tolerability (e.g., injection site grading); 
injection site pain using a subject-reported VAS; suicidality using the eC-SSRS, concomitant 
medications; changes in clinical laboratory results (hematology, chemistry and urinalysis); vital 
sign measurements; 12-lead ECGs, physical examination results; body weight, height, BMI, and 
abdominal fat measurement (waist-to-hip ratio).  Safety variables will be analyzed on the safety 
population using descriptive statistics for continuous endpoints (e.g., mean, median, SD, 
minimum and maximum) and frequency counts with percentages for discrete endpoints.
Baseline is defined as the last non-missing value prior to SC injection on Day 1.  No imputation 
of missing values will be performed.
Clinical Outcomes Assessments:
COWS, SOWS and Opioid Craving VAS total scores will be summarized using descriptive 
statistics (mean, median, SD, minimum, maximum), including change from baseline.  Subjects’ 
self-reported illicit drug use from the TLFB will be summarized as descriptive statistics.
The cumulative distribution function (CDF) of the percentage of urine samples negative for 
opioids, the CDF of the percentage of self-reports from the TLFB negative for illicit opioid use, 
and other outcome measures will be calculated.
Population PK/PD Analysis:
The population PK model established using the data collected in the double-blind, placebo-
controlled, efficacy study (Study RB-US-13-0001) will be refined using the sparse PK samples 
collected in the present study to characterize the disposition of buprenorphine and 
norbuprenorphine following SC injections of RBP-6000, with the assessment of potential 
covariates affecting the PK of both compounds.  Subsequently, the relationships between 
buprenorphine plasma concentrations and clinical outcomes assessments will be investigated.  
These relationships will be initially assessed in a descriptive manner, and, if applicable, 
appropriate PK/PD models will be developed to describe these relationships.  A stand-alone 
modeling analysis plan will be generated, and the results will be reported in a standalone 
modeling report.


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Health Economic and Outcomes Research Analyses:
The health economic and outcomes research endpoints for this study are: BDI-II, BPI, EQ-5D-
5L, SF-36v2, MSQ, Health Insurance, HCRU, TEA, and ASI-Lite. 
Summary scores for these measures will be calculated, as appropriate. Categorical variables will 
be summarized using frequencies and percentages. Continuous measures will be summarized 
using descriptive statistics (mean, standard deviation, median, minimum, maximum) as 
appropriate. An analysis of change will be conducted. Supplementary analyses using general 
linear, mixed, or non-parametric methods will be performed as appropriate. 
A stand-alone SAP will be developed prior to database lock with full detail regarding health 
economics and outcomes analyses.
Date of Original Approved Protocol: 14 April 2015


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TABLE OF CONTENTS
SYNOPSIS.................................................................................................................................2
LIST OF IN-TEXT TABLES ..................................................................................................13
LIST OF IN-TEXT FIGURES.................................................................................................13
LIST OF APPENDICES..........................................................................................................13
LIST OF ABBREVIATIONS..................................................................................................15
1
INTRODUCTION ...........................................................................................................18
1.1
Opioid Use Disorder ..............................................................................................18
1.2
Buprenorphine........................................................................................................19
1.3
ATRIGEL Delivery System...................................................................................19
1.4
Buprenorphine in the ATRIGEL Delivery System (RBP-6000)...........................20
1.4.1
Summary of Nonclinical Data .....................................................................20
1.4.2
Summary of Previous Clinical Data ............................................................21
1.4.3
Pharmacokinetic/Pharmacodynamic Modeling of RBP-6000.....................22
1.5
Rationale for Dose Selection .................................................................................23
1.6
Known and Potential Risks and Benefits...............................................................26
2
STUDY OBJECTIVES....................................................................................................27
2.1
Primary Objective..................................................................................................27
2.2
Secondary Objectives.............................................................................................27
2.3
Tertiary Objectives.................................................................................................27
3
INVESTIGATIONAL PLAN..........................................................................................28
3.1
Overall Study Design and Plan..............................................................................28
3.2
Rationale for Study Design....................................................................................32
3.3
Study Duration and Dates......................................................................................32
4
STUDY POPULATION SELECTION ...........................................................................33
4.1
Study Population....................................................................................................33
4.2
Inclusion Criteria ...................................................................................................33
4.3
Exclusion Criteria ..................................................................................................34
4.4
Day -1/Enrollment Criteria ....................................................................................36
5
STUDY TREATMENTS.................................................................................................37
5.1
Description of Treatments......................................................................................37
5.1.1
SUBOXONE Sublingual Film.....................................................................37
5.1.2
Investigational Medicinal Products..............................................................37
5.2
Treatments Administered.......................................................................................37
5.2.1
Run-In Treatment Period .............................................................................37
5.2.1.1
SUBOXONE Sublingual Film Induction (De novo Subjects)...........37
5.2.1.2
SUBOXONE Sublingual Film Induction (Roll-over Subjects).........38


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5.2.2
Dose Adjustment Period (All Subjects).......................................................39
5.2.3
Active Study Treatment ...............................................................................39
5.2.4
SUBOXONE Transition Period/Safety Follow-up......................................40
5.3
Selection and Timing of Dose for Each Subject....................................................40
5.4
Method of Assigning Subjects to Treatment Groups.............................................40
5.5
Blinding..................................................................................................................40
5.6
Concomitant Therapy.............................................................................................40
5.6.1
Permitted Concomitant Medications............................................................41
5.6.2
Prohibited Concomitant Medications ..........................................................41
5.7
Restrictions ............................................................................................................42
5.7.1
Prior Therapy ...............................................................................................42
5.7.2
Subject Activity Restrictions .......................................................................42
5.8
Protocol Compliance..............................................................................................42
5.9
Packaging and Labeling.........................................................................................42
5.10
Storage and Accountability....................................................................................42
5.11
Investigational Product Retention at Study Site ....................................................43
6
STUDY PROCEDURES .................................................................................................44
6.1
Informed Consent...................................................................................................44
6.1.1
General Information.....................................................................................44
6.2
Medical History .....................................................................................................44
6.3
Physical Examination.............................................................................................44
6.4
Vital Signs..............................................................................................................45
6.5
Electrocardiograms ................................................................................................45
6.5.1
12-Lead Electrocardiograms........................................................................45
6.6
Clinical Laboratory Tests.......................................................................................46
6.6.1
Laboratory Parameters.................................................................................46
6.6.2
Sample Collection, Storage, and Shipping ..................................................48
6.6.3
Reference Ranges.........................................................................................48
6.6.4
Laboratory Results Review..........................................................................48
6.6.5
Good Laboratory Practice Compliance........................................................48
6.7
Pharmacokinetic Assessments ...............................................................................48
6.8
Administration of Study Drug ...............................................................................49
6.9
Safety and Suicidality Assessments.......................................................................49
6.9.1
Local Injection Site Tolerability..................................................................49
6.9.1.1
Injection Site Grading........................................................................49
6.9.1.2
Injection Site Pain Visual Analogue Scale (VAS).............................50
6.9.2
Suicidality....................................................................................................50
6.9.2.1
Columbia Suicide Severity Rating Scale...........................................50


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6.10
Adverse Events Assessments.................................................................................50
6.10.1
Definition.....................................................................................................50
6.10.2
Performing Adverse Events Assessments....................................................51
6.10.3
Timing..........................................................................................................51
6.10.4
Severity ........................................................................................................51
6.10.5
Relationship .................................................................................................52
6.10.6
Expectedness................................................................................................52
6.10.7
Clinical Significance....................................................................................52
6.10.8
Clinical Laboratory Adverse Events............................................................53
6.10.9
Serious Adverse Events ...............................................................................53
6.10.9.1
Definition...........................................................................................53
6.10.9.2
Reporting Serious Adverse Events ....................................................53
6.10.10
Treatment-Emergent Adverse Events..........................................................54
6.10.11
Procedures and Follow-Up of Subjects with Ongoing SAEs or Experiencing 
SAEs after Completion of or Withdrawal from the Study...........................54
6.10.12
Pregnancy.....................................................................................................54
6.11
Clinical Outcome Assessments..............................................................................55
6.11.1
Timeline Followback Interview...................................................................55
6.11.2
Opioid Craving Visual Analog Scale...........................................................55
6.11.3
Clinical Opiate Withdrawal Scale................................................................55
6.11.4
Subjective Opiate Withdrawal Scale ...........................................................56
6.12
Health Economics and Outcomes Assessments.....................................................56
6.12.1
EuroQoL-5 Dimensions-5 Levels (EQ-5D-5L) and EQ-VAS.....................56
6.12.2
Medical Outcomes Study Short Form-36 (SF-36v2)...................................56
6.12.5
Treatment Effectiveness Assessment (TEA) ...............................................57
6.12.6
Addiction Severity Index (ASI) Lite............................................................57
6.12.7
Beck Depression Inventory II (BDI-II)........................................................58
6.12.8
Brief Pain Inventory (BPI) Short Form .......................................................58
6.13
Concomitant Medication Assessments ..................................................................59
6.14
Removal of Subjects from the Study .....................................................................59
6.14.1
Early Removal of RBP-6000 .......................................................................60
6.14.2
Stopping Rules.............................................................................................60
6.14.3
Screen Failures.............................................................................................60
6.15
Other Study Procedures .........................................................................................61
6.15.1
Counseling/Behavioral Therapy ..................................................................61
6.15.2
Unscheduled Visits ......................................................................................61
6.15.3
Additional Care of Study Subjects Following Completion of the Study.....61
6.15.4
Treating Toxicity .........................................................................................61


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6.15.5
Ancillary Medications..................................................................................61
6.16
Appropriateness of Measurements.........................................................................62
7
STUDY ACTIVITIES .....................................................................................................63
8
QUALITY CONTROL AND ASSURANCE .................................................................64
8.1
Quality Control ......................................................................................................64
8.2
Quality Assurance..................................................................................................64
9
PLANNED STATISTICAL METHODS ........................................................................65
9.1
General Considerations..........................................................................................65
9.2
Determination of Sample Size ...............................................................................65
9.3
Analysis Populations..............................................................................................65
9.3.1
Safety Population.........................................................................................65
9.3.2
Clinical Outcome Assessment and PK Populations.....................................65
9.4
Demographics and Baseline Characteristics..........................................................66
9.5
Primary Analysis....................................................................................................66
9.5.1
Safety Endpoints..........................................................................................66
9.5.1.1
Adverse Events ..................................................................................66
9.5.1.2
Laboratory Data .................................................................................66
9.5.1.3
Vital Signs..........................................................................................66
9.5.1.4
Other Variables Related to Safety......................................................66
9.6
Secondary Analysis................................................................................................67
9.6.1
Clinical Outcomes Assessments ..................................................................67
9.7
Other Analyses.......................................................................................................67
9.7.1
PK/PD Modeling..........................................................................................67
9.7.2
Health Economic and Outcomes Assessment..............................................68
9.8
Handling of Missing Data......................................................................................68
9.9
Subjects Who are Withdrawn from the Study .......................................................68
9.10
Interim Analyses ....................................................................................................69
10
ADMINISTRATIVE CONSIDERATIONS....................................................................70
10.1
Investigators and Study Administrative Structure.................................................70
10.1.1
Reckitt Benckiser Pharmaceuticals Inc........................................................70
10.1.2
Investigational Site(s) ..................................................................................70
10.1.3
Laboratories .................................................................................................70
10.2
Institutional Review Board or Independent Ethics Committee Approval .............70
10.3
Ethical Conduct of the Study.................................................................................71
10.4
Subject Information and Consent...........................................................................71
10.5
Subject Confidentiality ..........................................................................................71
10.6
Study Monitoring...................................................................................................72
10.6.1
Study and Site Closure.................................................................................72


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10.7
Case Report Forms and Study Records .................................................................72
10.8
Data Monitoring Committee..................................................................................73
10.9
Protocol Deviations................................................................................................73
10.10 Access to Source Documentation ..........................................................................74
10.11 Data Generation and Analysis ...............................................................................74
10.11.1
Data Collection and Data Management.......................................................74
10.11.2
Database Quality Assurance ........................................................................74
10.12 Retention of Data...................................................................................................75
10.13 Financial Disclosure...............................................................................................75
10.14 Publication and Disclosure Policy .........................................................................75
11
REFERENCE LIST .........................................................................................................76
LIST OF IN-TEXT TABLES
Table 1
PK Parameters of the Simulated Typical PK Profile of Buprenorphine after 
Repeated RBP-6000 Injections for the Phase 3 Efficacy Study (RB-US-13-0001)....25
Table 2
List of Laboratory Tests...............................................................................47
LIST OF IN-TEXT FIGURES
Figure 1
Model-Predicted Buprenorphine Plasma Concentrations and Mu-Opioid 
Receptor Occupancy in Each Treatment Group on RBP-6000 Following the Proposed 
Design of the Current Study ........................................................................................24
Figure 2
Study Overview:  De novo Subjects ............................................................30
Figure 3
Study Overview:  Roll-over Subjects from RB-US-13-0001 ......................31
Figure 4
Injection Locations.....................................................................................125
LIST OF APPENDICES
Appendix 1
Schedule of Events – Screening and SUBOXONE Film Induction ..80
Appendix 2
Schedule of Events – RBP-6000 Injection 1 – 3 Visits .....................83
Appendix 3
Schedule of Events – RBP-6000 Injection 4 – 6 Visits for all Subjects 
and End of Study/Early Termination and Follow-Up Visits for Roll-over Subjects...86
Appendix 4
Schedule of Events – RBP-6000 Injection 7 – 9 Visits for de novo
Subjects
90
Appendix 5
Schedule of Events – RBP-6000 Injection 10 – 12 Visits and End of 
Study/Early Termination Visit and Follow-Up for de novo Subjects..........................93
Appendix 6
Pharmacokinetic Sampling Schedule.................................................97
Appendix 7
SUBOXONE® (Buprenorphine/Naloxone) Sublingual Film Full 
Prescribing Information ...............................................................................................98


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Appendix 8
Study Drug Preparation, Administration, and Depot Removal 
Instructions
124
Appendix 9
Prohibited Cytochrome P450 Inhibitors and Inducers.....................127
Appendix 10
Columbia Suicide Severity Rating Scale (eC-SSRS) --
Baseline/Screening Version.......................................................................................128
Appendix 11
Columbia Suicide Severity Rating Scale (eC-SSRS) -- Since Last 
Visit Version
130
Appendix 12
Clinical Opiate Withdrawal Scale (COWS) ....................................132
Appendix 13
Subjective Opiate Withdrawal Scale (SOWS).................................134
Appendix 14
Opioid Craving Visual Analog Scale (Opioid Craving VAS).........135
Appendix 15
Injection Site Grading Scale ............................................................136
Appendix 16
Injection Site Pain Visual Analog Scale (Injection Site Pain VAS)137
Appendix 17
Timeline Followback (TLFB) Interview .........................................138
Appendix 18
Euro QoL EQ-5D-5L Health Questionnaire....................................139
Appendix 19
Short Form (36) Health Survey v2...................................................141
Appendix 20
Medication Satisfaction Questionnaire............................................145
Appendix 21
Health Care Resource Utilization Questionnaire.............................146
Appendix 22
Treatment Effectiveness Assessment (TEA) ...................................148
Appendix 23
Addiction Severity Index (ASI) Lite................................................149
Appendix 24
Beck Depression Inventory II (BDI-II)............................................165
Appendix 25
Brief Pain Inventory (BPI) Short Form ...........................................166
Appendix 26
Sponsor Signatures...........................................................................167
Appendix 27
Investigator’s Signature ...................................................................168


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LIST OF ABBREVIATIONS
AE
adverse event
AIDS
acquired immunodeficiency syndrome
ANOVA
analysis of variance
ASI-Lite
Addiction Severity Index Lite
AUC
area under the plasma concentration-time curve
BDI-II
Beck Depression Inventory II
BMI
body mass index
BP
blood pressure
BPI
Brief Pain Inventory Short Form
Cavg
average plasma concentration
Cmax
maximum plasma concentration
Ctrough
plasma concentration at trough, i.e. before the next injection 
CDF
cumulative distribution function
CNS
central nervous system
COWS
Clinical Opiate Withdrawal Scale
CRA
clinical research associate
DAWN
Drug Abuse Warning Network
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition
EC50
concentration yielding 50% of the maximal effect
eCRF
electronic case report form
e C-SSRS
Electronic Columbia Suicide Severity Rating Scale
Emax
maximum effect
ECG
electrocardiogram
ED
emergency department
EOS
end of study
ET
early termination
EQ-5D
EuroQol EQ-5D (standard instrument)
EQ-5D-5L
EuroQol EQ-5D-5L (self-complete version)


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EQ-VAS
EQ-5D using visual analog scale
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HbA1c
hemoglobin A1c
HBsAg
hepatitis B surface antigen 
hCG
urine human chorionic gonadotropin
HCl
hydrochloride
HCRU
healthcare resource utilization 
HEOR
health economics and outcomes research
HIV
human immunodeficiency virus
IB
investigator’s brochure
ICF
informed consent form
ICH
International Conference on Harmonisation 
IEC
independent ethics committee
IM
intramuscular
IMP
investigational medicinal product
IND
investigational new drug application (i.e., Notice of Claimed 
Investigational Exemption for a New Drug)
INR
international normalized ratio
IRB
institutional review board
IV
intravenous
IWRS
interactive web response system
MAR
missing at random 
MCAR
missing completely at random 
MMRM
mixed model repeated measures
MSQ
Medication Satisfaction Questionnaire
NMP
N-methyl pyrrolidone
NOAEL
no observable adverse effect level
OTC
over-the-counter


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PD
pharmacodynamic or pharmacodynamics
PE
physical examination
PK
pharmacokinetic or pharmacokinetics
PLG or PLGH
poly (DL-lactide-co-glycolide) 
PET
positron emission tomography 
PI
Principal Investigator
PT
prothrombin time
PTT
partial thromboplastin time
RBP
Reckitt Benckiser Pharmaceuticals Inc.
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SD
standard deviation
SF-36v2
36-Item Short Form Health Survey, Version 2
SL
sublingual
SOE
schedule of events
SOP
standard operating procedure
SOWS
Subjective Opiate Withdrawal Scale
tmax
time to maximum plasma concentration
TEA
Treatment Effectiveness Assessment 
TEAE
treatment-emergent adverse event
TLFB
timeline followback
UDS
urine drug screen
ULN
upper limit of normal
US/USA
United States/United States of America
VAS
visual analog scale


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1
INTRODUCTION
1.1
Opioid Use Disorder
Opioid use disorder, as defined in the Diagnostic and Statistical Manual of Mental Disorders, 
Fifth Edition (DSM-5; American Psychiatric Association 2013), is a neurobehavioral syndrome 
characterized by the repeated, compulsive seeking or use of an opioid despite adverse social, 
psychological, and/or physical consequences.  Opioid use disorder is a medical illness with high 
costs to individuals, families, and society.  Direct and indirect costs attributable to illicit drug use 
are estimated in 3 principal areas: crime, productivity, and health (US Department of Justice, 
Economic Impact of Illicit Drug Use on American Society, 2011).  Approximately one-third of 
all acquired immunodeficiency syndrome (AIDS) cases diagnosed in the United States (US) 
through 2009 (Centers for Disease Control and Prevention: HIV/AIDS Surveillance Report, 
2009) and many cases of hepatitis C (National Institute on Drug Abuse 2000; Thomas 2001) 
were associated with injection drug use.  
The increasing abuse of and addiction to prescription opioids is another major concern.  
According to the Substance Abuse and Mental Health Services Administration’s Office of 
Applied Studies, the incidence of abuse of prescription opioid pain medications (narcotic 
analgesics) such as hydrocodone, oxycodone, meperidine, and propoxyphene has risen markedly 
in recent years (Crane 2003).  The incidence of emergency department (ED) visits related to 
these medications has been increasing since the 1990s and has more than doubled between 1994 
and 2001 (Crane 2003).  The most recently published data from the Drug Abuse Warning 
Network (Drug Abuse Warning Network, 2009: National Estimates of Drug-Related Emergency 
Department Visits, 2011) estimated that about 2.1 million ED visits resulted from drug misuse or 
abuse, which was the equivalent of 674.4 ED visits per year per 100,000 population.  Although 
the overall number of ED visits attributable to drug misuse or abuse was stable from 2004 to 
2009, increases were seen in ED visits involving nonmedical use of pharmaceuticals with no 
other drug involvement (117% increase).  An estimated 1,079,683 ED visits in 2009 involved the 
nonmedical use of prescription drugs, over-the-counter (OTC) medicines, or other types of 
pharmaceuticals, representing about a quarter of all drug-related ED visits and over half of ED 
visits for drug abuse or misuse.  Pain relievers were the most common type of drugs reported in 
the nonmedical use category of ED visits (47.8%).  Among specific types of pain relievers, 
narcotic pain relievers such as oxycodone, hydrocodone, and methadone (13.7%, 8.0%, and 
5.8%, respectively) were most prevalent (Drug Abuse Warning Network, 2009: National 
Estimates of Drug-Related Emergency Department Visits, 2011).
The economic burden of prescription opioid abuse is very high.  Total US societal costs of 
prescription opioid abuse were estimated at $55.7 billion in 2007 (US dollars in 2009).  
Workplace costs accounted for $25.6 billion (46%), health care costs accounted for $25.0 billion 
(45%), and criminal justice costs accounted for $5.1 billion (9%) (Birnbaum 2011).  Mean 
annual direct health care costs for opioid abusers were more than 8 times higher than for 
nonabusers.  Hospital inpatient and physician outpatient costs accounted for 46% and 31% 
respectively, of opioid abusers' health care costs.  The high costs of opioid abuse are driven 
primarily by high comorbidity rates and high utilization rates of medical services and 
prescription drugs (White 2005).  It was also found that opioid use results in lower quality of life, 


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including significantly worse physical and psychological health, compared with the general 
population (Ryan 1996).
Given the high costs of opioid addiction to individuals, families, and society, treatments for this 
disease therefore aim to reduce the use of prescription or illicit opioids as well as the risks 
associated with injection, including transmission of human immunodeficiency virus (HIV) and 
hepatitis C virus.  Implantable formulations of opioid receptor partial agonists and antagonists 
represent an innovative alternative to daily dosing regimens, and several delivery systems are 
currently in clinical trials (Ling 2010, Rosenthal 2013).  The goal of this study is to determine 
whether RBP-6000, which is a sustained release formulation of buprenorphine in the ATRIGEL®
delivery system, is a safe and effective treatment for opioid use disorder.
1.2
Buprenorphine
In the central nervous system (CNS), opioid receptors are found in high concentrations in the
limbic system and the spinal cord. The natural ligands for these receptors are a group of 
neuropeptides known as endorphins. Opioid analgesics mimic the action of endorphins but have 
a more prolonged action because the analgesics are not subject to rapid local metabolism.
Three major opioid receptor subclasses have been identified: mu, kappa, and delta.  These 
subclasses mediate distinct actions with natural endorphins and opioid analgesics.  Different 
endorphin and opioid analgesic ligands demonstrate different binding affinities for the various 
subclasses of receptors.  
Buprenorphine is a member of the large family of opioid analgesics used in the treatment of 
moderate and severe acute and chronic pain. Opioid receptors are found in both the CNS and the 
periphery. Buprenorphine is a partial agonist at the mu receptor, producing a sub-maximal 
response compared to that of a full agonist. Hence, buprenorphine provides a greater margin of 
safety regarding respiratory depression in comparison to full agonist opioids. Buprenorphine is 
also an antagonist at the kappa receptor (Cowan 1977, Jasinski 1978).
Buprenorphine has been reported to have a lower physical dependence liability than pure agonist 
analgesics such as morphine, and at a sufficient dose, it can suppress opioid withdrawal signs 
and symptoms for at least 24 hours.  Limited euphoric and respiratory depressant effects have led 
to its therapeutic use as a pharmacotherapy for opioid use disorder.
Selected pharmacokinetic (PK) parameters for buprenorphine when administered sublingually as 
buprenorphine/naloxone films are in the SUBOXONE sublingual film prescribing information 
(Appendix 7).  Further details on the PK of buprenorphine in the ATRIGEL delivery system are 
described in Section 1.4.2.
1.3
ATRIGEL Delivery System
The ATRIGEL Delivery System is a sterile, polymeric solution of a biodegradable 
poly DL-lactide-co-glycolide (PLGH) copolymer, dissolved in the water-miscible, biocompatible 
solvent N-methyl pyrrolidone (NMP).  The polymers belong to a family of poly α-hydroxy acids 
that are used in medical devices such as resorbable sutures and degradable drug delivery 


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systems.  Polymerization, which is initiated with glycolic acid, leads to a linear polymer 
containing a carboxylic acid end group.  The ATRIGEL Delivery System can be formulated to 
deliver different active ingredients for various lengths of time.
The ATRIGEL Delivery System is well characterized.  It is currently used in 7 approved 
products worldwide, including 4 ELIGARD® products (subcutaneous [SC] depot formulations of 
leuprolide acetate), ATRIDOX® (doxycycline hyclate applied to the periodontal pocket), the 
ATRISORB® Bioabsorbable Guided Tissue Regeneration Barrier for periodontal application, and 
the ATRISORB-D Barrier (ATRISORB with doxycycline) for periodontal guided tissue 
regeneration.
Clinical studies with these products demonstrated that the ATRIGEL Delivery System was well 
tolerated and provided consistent sustained release of the incorporated drug over the designated 
dosing interval.  Injection site reactions are expected to be mild and appear early in treatment, as 
observed in previous local irritation ATRIGEL studies (RBP-6000 Investigator’s Brochure [IB], 
Edition 4, 24 February 2014).
1.4
Buprenorphine in the ATRIGEL Delivery System (RBP-6000)
RBP-6000 is a subcutaneously injected depot product under development for the treatment of 
opioid addiction. It contains buprenorphine in the ATRIGEL Delivery System and provides 
sustained plasma levels of buprenorphine over a minimum of 28 days. There is no currently 
approved, parenterally administered, sustained-release buprenorphine formulation for the 
treatment of opioid use disorder. Such a formulation could offer advantages over existing 
buprenorphine products by improving subject compliance and reducing diversion, abuse, and 
unintended exposure (e.g., in pediatric exposure), and reduce chances of swallowing drug.
The safety profile and clinical efficacy of RBP-6000 are expected to be similar to and 
comparable with that of buprenorphine or SUBOXONE sublingual treatment.
1.4.1
Summary of Nonclinical Data
Nonclinical data suggest that toxicity from RBP-6000 is unlikely at the doses planned for this 
clinical study.  The no observable adverse effect levels (NOAELs) were determined to be 250 
mg/kg (rat) and 40 mg/kg (dog) following single SC injections of RBP-6000 in 4-week toxicity 
studies.  These levels are equivalent to human buprenorphine doses of 2419 mg and 1333 mg, 
respectively (based on 60 kg body weight and calculated according US Food and Drug 
Administration guidance [FDA 2005]).  These levels provide approximately 8.1x (rat) and 4.4x 
(dog) safety margins when compared to the 300-mg buprenorphine dose in humans (based on 
60 kg body weight and calculated according US Food and Drug Administration guidance 
[FDA 2005]).  Systemic effects seen in the rat and dog 4-week toxicity studies were related to 
the pharmacology of buprenorphine or local tolerance effects of the formulation as a result of 
high dose and volume, so the safety margins are considered acceptable.
Chronic repeated-dose studies were conducted in rats and dogs dosed with RBP-6000 once every 
4 weeks for 6 or 9 months, respectively.  These studies demonstrated systemic effects consistent 
with buprenorphine administration, such as stained fur, aggressive behavior, decreased activity, 


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reduced food consumption and body weight gain, and abnormal feces.  Minimal to mild lung 
alveolar macrophage infiltration and pancreatic acinar cell apoptosis were seen with increased 
incidence in rats, but not dogs, treated with RBP-6000.  Injection site findings were seen in both 
species, characterized microscopically by minimal to moderate granuloma formation.  Injection 
volumes were high, being 2.73 mL/m2 in rats and 3.64 mL/ m2 in dogs, compared with a volume 
of 0.62 mL/ m2 at the highest proposed clinical dose, contributing to these local findings.  
Systemic chronic NOAELs were considered to be 10 mg/kg in rats and 40 mg/kg in dogs.  
Overall, the extensive preclinical data on both the buprenorphine and SUBOXONE products and 
nonclinical PK and toxicity studies in rats and dogs support the clinical development of 
RBP-6000.  Systemic exposure to buprenorphine is not considered to pose any significant safety 
concerns following SC administration of RBP-6000.  Additionally, this clinical study will be 
conducted in subjects who have a current diagnosis of opioid use disorder and who would thus 
be expected to have a certain degree of cross-tolerance to the opioid agonist effects of 
buprenorphine.  Minimal to moderate irritation at the injection site, seen in both rats and dogs, 
may warrant attention to ensure local tolerability (RBP-6000 IB, Edition 4, 24 February 2014).
1.4.2
Summary of Previous Clinical Data
In the first-in-human trial to evaluate the safety, tolerability, and PK of RBP-6000, 12 subjects 
received a single SC injection of RBP-6000 containing 20 mg of buprenorphine.  Of these 
12 subjects, 6 subjects completed the study through Day 85.  The majority (94%) of 
treatment-emergent adverse events (TEAEs) were mild, 5.4% were moderate, and 1 was severe 
in intensity.  TEAEs considered related to the study drug included injection site pain, injection 
site warmth, and injection site bruising, erythema, and edema.  All subjects experienced mild to 
moderate symptoms of withdrawal at study entry, prior to study drug injection, and after study 
drug injection.  One serious adverse event (SAE) was reported.  The SAE was notably identified 
psychosocial stressors and intermittent withdrawal, for which the subject had prolonged 
hospitalization for treatment.  This SAE was not considered to be related to the study drug.  No 
respiratory depression, temperature elevations, clinically significant lowering of oxygen 
saturation, or electrocardiogram (ECG) abnormalities were observed.  There was 1 clinically 
significant laboratory adverse event (AE; elevated hepatic enzymes), which resolved.  No 
unexpected side effects occurred in the RBP-6000 depot formulation of buprenorphine 
(RBP-6000 IB, Edition 4, 24 February 2014).  Buprenorphine was rapidly absorbed over the first 
day and peaked on the second day, with a slow decrease in plasma concentrations thereafter that 
is consistent with the slow release of buprenorphine from the ATRIGEL Delivery System.  
The PK of 50, 100, and 200 mg buprenorphine (as RBP-6000) was also evaluated in a single-
ascending-dose study in 51 subjects (RB-US-11-0020).  In this study, median buprenorphine 
time to peak concentration (tmax) in the initial burst period was observed at 24 hours for all 3 
dosages.  Buprenorphine mean plasma terminal half-life increased slightly with the increase in 
dose from 50 mg to 200 mg (1078 hours [44.9 days] at 50 mg, 1376 hours at 100 mg, and 1573 
hours at 200 mg).  Buprenorphine exhibited overall geometric mean average concentration 
values of 0.356, 0.624, and 1.108 ng/mL, respectively with 50, 100 and 200 mg buprenorphine 
while overall geometric mean Cmax values of 0.999, 1.518, and 2.381 ng/mL were observed for 
buprenorphine doses of 50, 100, and 200 mg, respectively.  With an increase in dose of RBP-


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6000 from 50 to 200 mg, mean buprenorphine exposure parameters increased less than 
proportionally to dose (RBP-6000 IB, Edition 4, 24 February 2014). A single SC injection of 
RBP-6000 was generally safe and well tolerated.  A total of 46 of 51 subjects (90.2%) had at 
least 1 TEAE.  A total of 30 of 51 subjects (58.8%) had TEAEs that were related to treatment 
with RBP-6000.  The majority of AEs were qualified as moderate in severity (68.6%).  
Two subjects reported TEAEs that were considered to be severe but unrelated to RBP-6000.  No 
subjects withdrew from the study because of an AE.
The safety profile of multiple-dose SC injections of RBP-6000 containing 50 mg, 100 mg, 
200 mg, and 300 mg of buprenorphine in treatment-seeking, opioid-dependent subjects in an 
open-label, multiple-dose study has recently been examined.  The results suggest that all doses 
were safe and well-tolerated following a 13-day induction and stabilization on SUBUTEX.  In 
addition, a study investigating the blockade of subjective opioid effects demonstrated that RBP-
6000 was safe and well tolerated after the SC administration of 2 monthly 300-mg doses of 
buprenorphine in RBP-6000, following a 14-day induction and stabilization period on 
SUBOXONE Film.
1.4.3
Pharmacokinetic/Pharmacodynamic Modeling of RBP-6000
A population PK model was developed to characterize the disposition of buprenorphine and 
norbuprenorphine following SC injection of RBP-6000 (Nasser 2014).  This model was built 
using plasma concentration data collected in 36 opioid-dependent subjects who received single 
doses (50 mg, 100 mg, and 200 mg) of RBP-6000 in the single-ascending-dose study (RB-US-
11-0020).  Analysis of the PK profiles of RBP-6000 revealed a complex and multi-phase 
absorption profile, presenting double peaks and a prolonged plasma terminal half-life.  These 
distinguishing features of the PK of RBP-6000 required the development of a complex structural 
PK model accounting for this dual absorption process: a first absorption process that was 
associated with an initial, rapid delivery from the SC injection site, and a second absorption 
process that was associated with the slow release of buprenorphine from the ATRIGEL Delivery 
System into the systemic circulation.  The population PK model accurately predicted the PK data 
after repeated doses of RBP-6000 in the multiple ascending dose study (RB-US-12-0005) and in 
the opioid blockade study (RB-US-13-0002). 
Another population PK/PD model was developed to characterize the link between buprenorphine 
plasma concentration and mu opioid receptor occupancy (Nasser 2014).  Individual data from 15 
heroin-dependent subjects were taken from two published clinical trials (Greenwald 2003; 
Greenwald 2007).  A saturable maximum effect (Emax) model with 0.67 ng/mL effective 
concentration at 50% of maximum (EC50) and 91% Emax best described mu opioid receptor 
occupancy versus buprenorphine plasma concentrations.  At buprenorphine concentrations 
greater than 2 ng/mL, saturation occurred on mu opioid receptor occupancy where a 4.5-fold 
increase in observed buprenorphine concentrations resulted in observed mu opioid receptor 
occupancy between 70% and 90%.
Positron emission tomography (PET) scan data were obtained in 2 subjects participating in the 
multiple-ascending dose study RB-US-12-0005 (PET scan sub-study) and receiving either 200 or 
300 mg of RBP-6000.  The PET scans were conducted at 7 days and 28 days post-dose following 


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the 12th SC injection for the first subject receiving 200 mg, and following the 6th SC injection for 
the second subject receiving 300 mg.  Both subjects were considered to be at steady-state for 
buprenorphine at the time of the PET scan measurements.  The mu opioid receptor availabilities 
of four different regions in the brain were measured, and the mu opioid receptor occupancy in 
the whole brain was calculated as described in Greenwald et al. (2003).
The subject receiving 200 mg of RBP-6000 in the PET scan sub-study showed 79% and 75% mu 
opioid receptor occupancy on Day 7 and Day 28, respectively, following the 12th SC injection of 
RBP-6000.  The subject receiving 300 mg of RBP-6000 in the PET scan sub-study showed 92% 
and 81% mu opioid receptor occupancy on Day 7 and Day 28, respectively, following the 6th SC 
injection of RBP-6000.  These values and the corresponding PK concentrations were in 
agreement with the model predictions and the previous individual observations used to build the 
population PK/PD model.
Linear relationships were found between mu opioid receptor occupancy and opioid withdrawal 
symptoms, and between mu opioid receptor occupancy and hydromorphone agonist blockade, 
based on the data from 15 heroin-dependent subjects (Nasser 2014).  These data suggest that a 
mean buprenorphine plasma concentration of 2 ng/mL is able to provide 70 % mu opioid 
receptor occupancy associated with low reported agonist drug effects and withdrawal symptoms 
(scores ≤2).
Model simulations indicated that the desired 70% mu opioid receptor occupancy may be 
achieved after multiple doses of 200 mg of RBP-6000 (Nasser 2014).  The 300 mg dose was 
considered to be a full opioid blockade dose.
1.5
Rationale for Dose Selection
The results of the opioid blockade study (RB-US-13-0002) showed that 300 mg was a full opioid 
blocking dose (i.e., for the “drug liking” VAS scores the upper bound of the 95% confidence 
interval ≤11), which is consistent with PK/PD modeling and simulation results. The least means 
“drug liking” VAS scores in the opioid blockade study showed that the blockade was achieved 
from the first SC injection and was maintained after the second SC injection until week 12 (i.e., 2 
months after the second injection).
The population PK and PK/PD models presented in Section 1.4.3 were used to simulate the 
double-blind efficacy study (RB-US-13-0001).  The results of these simulations are displayed in 
Figure 1 for the two treatment arms on RBP-6000 receiving either 6 SC injections of 300 mg 
(300 mg × 2 + 300 mg × 4), or 2 SC injections of 300 mg followed by 4 SC injections of 100 mg 
(300 mg ×2  + 100 mg × 4).


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Figure 1
Model-Predicted Buprenorphine Plasma Concentrations and Mu-
Opioid Receptor Occupancy in Each Treatment Group on RBP-
6000 Following the Proposed Design of the Current Study
The blue line represents the median model prediction; the yellow areas represent the 5th and the 95th
percentiles of the predictions; -ORO: mu opioid receptor occupancy; wks: weeks.
The PK parameters calculated from the simulated typical PK profile of buprenorphine are listed 
in Table 1.  Average buprenorphine plasma concentration (Cavg) over the monthly dosing interval 
was 1.9 ng/mL after the first SC injection at 300 mg, and 3.1 ng/mL after the second SC 
injection at 300 mg. 
For the subjects receiving 6 monthly SC injections of RBP-6000 at 300 mg, the predicted Cavg
value after the 4th SC injection was 5.1 ng/mL, which is close to mean value of 4.8 ng/mL 
observed in the multiple-ascending dose study.  The predicted Cavg value after the 6th SC 
injection was 6.0 ng/mL.  For the patients receiving 2 monthly SC injections at 300 mg followed 
by 4 monthly SC injections at 100 mg, the predicted Cavg after the 6th SC injection was 
2.6 ng/mL.  All these values were above the 2 ng/mL threshold for achieving the desired 
efficacy.
Overall, the modeling and simulation work and the opioid blockade study have shown that the 
300 mg SC dose is an appropriate dose to assess for efficacy. The current study will therefore 
evaluate the long-term safety and tolerability of this dose. It is recognized, however, that some 
individuals may need lower doses based on genetic variations, abuse behavior, etc. Accordingly, 
subsequent doses of RBP-6000 may be adjusted down to 100 mg and back up to 300 mg based 
on the medical judgment of the Investigator.


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Table 1
PK Parameters of the Simulated Typical PK Profile of Buprenorphine after Repeated RBP-6000 
Injections for the Phase 3 Efficacy Study (RB-US-13-0001)
Buprenorphine 
(ng/mL)
SC Injection Number
1
2
3
4
5
6
Cmax
Cavg
Cmax Ctrough
Cavg
Cmax
Ctrough
Cavg
Cmax
Ctrough
Cavg
Cmax
Ctrough
Cavg
Cmax
Ctrough
Cavg
300mgx2 + 
100mgx4
2.9
1.9
4.2
1.3
3.1
3.5
2.5
3.0
3.6
2.6
3.0
3.5
2.5
2.8
3.2
2.3
2.6
300mgx2 + 
300mgx4
2.9
1.9
4.2
1.3
3.1
5.4
2.5
4.3
6.4
3.5
5.1
7.1
4.2
5.7
7.5
4.6
6.0
Cmax: maximum plasma concentration; Cavg : average plasma concentration; Ctrough: plasma concentration at trough (ie, before the next injection).


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1.6
Known and Potential Risks and Benefits
The AE profile of buprenorphine is well-characterized; commonly reported effects include 
constipation, nausea, vomiting, and headache.  Buprenorphine is approved for use by various 
routes of administration (e.g., SL, intramuscular [IM], intravenous [IV], transdermal, and rectal).
Studies of buprenorphine receptor binding in human subjects have consistently and reproducibly 
established that buprenorphine is a highly lipophilic, mu-opioid receptor partial agonist with 
slow receptor association and dissociation kinetics.  Buprenorphine has an improved safety 
profile relative to mu-opioid receptor full agonists due to its partial agonist properties.  These 
attributes of buprenorphine allow it to perform well as substitution therapy for opioid-dependent 
individuals over short-term and long-term durations.  The experiments used to establish the 
binding profile of buprenorphine were consistent across differing parenteral routes of 
administration (IV, IM, and SL); therefore, RBP-6000 is expected to perform similarly when 
administered as a SC depot in the ATRIGEL Delivery System.
The efficacy of buprenorphine in the treatment of opioid dependence has been well established 
(see for example, New Drug Applications 20-732; 20-733; 22-410).  Buprenorphine has been 
used for medically-supervised taper (i.e., detoxification) medication and as a long-term 
medication assisted therapy (i.e., maintenance).  A recent Cochrane Review meta-analysis 
revealed that buprenorphine is statistically significantly superior to placebo in the retention of 
subjects and reduction of opioid-positive urine tests, and that buprenorphine and methadone may 
be equally efficacious at adequate dose levels of both medications (Mattick 2008).
A sustained-release formulation of buprenorphine using the ATRIGEL Delivery System offers a 
number of potential benefits relative to shorter-acting formulations, including improved subject 
compliance, reduced diversion and misuse, as well as a reduced risk to subjects, their families, 
and the community. 


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2
STUDY OBJECTIVES
Reckitt Benckiser Pharmaceuticals Inc. (RBP) is developing RBP-6000, a long-acting 
formulation of buprenorphine for monthly SC administration, for the treatment of opioid use 
disorder.  
2.1
Primary Objective
To assess the long-term safety and tolerability of RBP-6000 subcutaneous (SC) injections in 
subjects with opioid use disorder.
2.2
Secondary Objectives
To collect clinical outcome data with RBP-6000 SC injections in subjects with opioid use 
disorder.
2.3
Tertiary Objectives
To evaluate the:

PK of RBP-6000, 

Relationship between RBP-6000 PK and clinical outcome data, and

Impact of RBP-6000 on health and economic outcomes.


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3
INVESTIGATIONAL PLAN
3.1
Overall Study Design and Plan
This is a multicenter, open-label, long-term safety study in which approximately 600 subjects 
diagnosed with opioid use disorder will be enrolled (approximately 300 subjects who did not 
participate in the RB-US-13-0001 study [hereafter referred to as “de novo” subjects] and 
approximately 300 subjects that completed the RB-US-13-0001 study [hereafter referred to as 
“roll-over subjects”]).  Subject participation will be based on the Investigator’s determination 
that initiation or continuation of study treatment is appropriate; and, that among subjects who are 
continuing from the RB-US-13-0001 study, there have been no significant protocol deviations or 
clinically relevant AEs that would preclude inclusion of the subject in this study. All subjects 
will need to provide written informed consent before any protocol-related procedures commence. 
At the Screening Visit (which is up to 3 days after the End of Study [EOS] Visit (Day 169 + 3]), 
for roll-over subjects), potential subjects will be reviewed for eligibility against inclusion and 
exclusion criteria, and eligible subjects will be enrolled into the trial. 
Before receiving the first injection of RBP-6000 in this safety study, all subjects will undergo a 
Run-In period with SUBOXONE® (buprenorphine/naloxone) sublingual film to avoid 
precipitating a withdrawal syndrome and to preserve the blind in subjects treated with placebo in 
the RB-US-13-0001 study. Subjects will be inducted onto SUBOXONE sublingual film 
consistent with the SUBOXONE sublingual film label; they will then complete a 1 to 11 day 
SUBOXONE sublingual film Dose Adjustment period (Section 5.2.1). SUBOXONE dose 
adjustments will be made based on COWS scores as well as physician judgment (Section 5.2.2).  
Once subjects meet the criteria (on Day -11 to Day -1) of no significant opioid craving (≤20 mm 
on the Opioid Craving Visual Analog Scale [VAS] and no significant withdrawal (≤ 12 on the 
Clinical Opiate Withdrawal Scale [COWS]) they may receive the first SC injection of RBP-6000 
(containing 300 mg buprenorphine). Subjects with significant withdrawal signs/symptoms 
(defined as >12 on the COWS) or significant cravings for opioids (defined as >20 mm on the 
Opioid Craving VAS) after the end of the 2-week SUBOXONE sublingual film Run-In period 
will not be eligible to continue in the study and will be referred for treatment. 
On Day 1 of the study (initiation of study drug injections), all subjects will receive a SC injection 
of 300 mg of buprenorphine in RBP-6000. Subsequent doses of RBP-6000 may be adjusted 
down to 100 mg and back up to 300 mg based on the medical judgment of the Investigator. After 
injection of RBP-6000, subjects will not be permitted to receive supplemental SUBOXONE 
sublingual film during the RBP-6000 treatment period. Subjects who require supplemental 
SUBOXONE sublingual film or other sublingual buprenorphine pharmacotherapy during the 
RBP-6000 treatment period will be withdrawn from the study and referred for appropriate 
treatment.
Subjects will return to the clinic for monthly injection visits (every 28 ±2 days) for a total of up 
to 12 injections for de novo subjects or for a total of 6 injections for roll-over subjects. 
Continuous ECG recordings will be collected from at least 30 minutes before each SC injection 
until at least 4 hours after injection using Holter monitoring devices. This real-time 


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cardiovascular monitoring will be used to detect potential arrhythmias and abnormal ECGs.  All 
ECGs will be interpreted by a central monitoring facility. Four-hour continuous pulse oximetry 
will be assessed from 30 minutes prior to the SC injection through 4 hours post RBP-6000 SC 
injection. Subject-reported injection site pain Visual Analog Scale scores (VAS) will be 
collected at various times for 2 hours after each injection. Local injection site grading will be 
collected at various time points starting immediately after injection and will be evaluated for 
pain, tenderness, warmth, itching, erythema, inflammation or swelling, and bruising using a 4-
point severity scale. At each visit after injections begin, the injection site will be assessed by site 
staff and will also be evaluated for evidence of attempts to remove the depot. 
Subjects will need to return to the clinic weekly for the first 3 months and biweekly for the rest 
of the study period for urine drug screens (UDS), Timeline Followback (TLFB) interviews, 
opioid craving VAS evaluation, COWS and subject reported outcomes (Subjective Opiate 
Withdrawal Scale [SOWS]). Subjects will continue to receive counseling (manual-guided 
behavioral therapy) during the study. 
Safety assessments will be collected at each injection visit and/or at injection follow-up visits 
and will include the following:  vital signs, electronic Columbia Suicide Severity Rating Scale 
(eC-SSRS) responses, ECGs, laboratory tests (hematology, chemistry, urinalysis, and pregnancy 
test), concomitant medications, and AEs.  
Sparse PK blood samples will be collected for population PK analysis. ECGs will be performed 
between 30 minutes and 2 hours before PK sample collection. The following depression, pain, 
and health economic outcome assessments will also be collected: Beck Depression Inventory 
(BDI-II), brief pain inventory (BPI), EuroQol EQ-5D-5L (EQ-5D-5L), 36-Item Short Form 
Health Survey, Version 2 (SF-36v2), Medication Satisfaction Questionnaire (MSQ), healthcare 
resource utilization (HCRU), Treatment Effectiveness Assessment (TEA) and Addiction Severity 
Index Lite (ASI-Lite).
At the end of the RBP-6000 treatment period, subjects will enter a 4-week SUBOXONE
transition period/safety follow-up where they will receive the same dose of SUBOXONE that 
they received at Day -1 and their ongoing treatment options will be reviewed.
A schematic depicting the study design for de novo subjects is in Figure 2 and a schematic for 
roll-over subjects is in Figure 3.  A complete list of procedures and assessments for subjects is in 
the Schedule of Events (SOE) in Appendix 1, Appendix 2, Appendix 3, Appendix 4, and
Appendix 5.


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Figure 2
Study Overview:  De novo Subjects
Injection No. 7 (Week 25/Day 169)
Followed by biweekly assessment visits
Injection No. 8 (Week 29/Day 197) 
Followed by biweekly assessment visits
Injection No. 9 (Week 33/Day 225) 
Followed by biweekly assessment visits
Injection No. 10 (Week 37/Day 253) 
Followed by biweekly assessment visits
Injection No. 11 (Week 41/Day 281) 
Followed by biweekly assessment visits
Injection No. 12 (Week 45/Day 309) 
Followed by biweekly assessment visits
SUBOXONE - Sublingual Film Transition (Day 337)
End of Study Visit (Day 365)/Early Termination (Up to Day 365)
Subjects return to clinic for this visit
Injection No. 1 (Week 1/Day 1) 
Followed by weekly assessment visits
Injection No. 2 (Week 5/Day 29) 
Followed by weekly assessment visits
Injection No. 3 (Week 9/Day 57) 
Followed by weekly assessment visits
Injection No. 4 (Week 13/Day 85) 
Followed by biweekly assessment visits
Injection No. 5 (Week 17/Day 113) 
Followed by biweekly assessment visits
Injection No. 6 (Week 21/Day 141) 
Followed by biweekly assessment visits
SUBOXONE Sublingual Film Run-In

Induction (3 days)
Subjects complete daily visits on Day -14 to Day -12 

Dose Adjustment (1-11 days)
Subjects complete visits on Day -11, Day -8, Day -4, and Day -1 (all visits not required)
Early 
Termin
ation
Subjects 
return 
to clinic 
for this 
visit
Screening 
Screening (Day -21 to Day -15) 
study


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Figure 3
Study Overview:  Roll-over Subjects from RB-US-13-0001
Injection No. 1 (Week 1/Day 1)
Followed by weekly assessment visits
Injection No. 2 (Week 5/Day 29) 
Followed by weekly assessment visits
Injection No. 3 (Week 9/Day 57) 
Followed by weekly assessment visits
Injection No. 4 (Week 13/Day 85) 
Followed by biweekly assessment visits
Injection No. 5 (Week 17/Day 113) 
Followed by biweekly assessment visits
Injection No. 6 (Week 21/Day 141) 
Followed by biweekly assessment visits
SUBOXONE Sublingual Film Run-In

Induction (3 days)
Subjects complete daily visits on Day -14 to Day -12 

Dose Adjustment (1-11 days)
Subjects complete visits on Day -11, Day -8, Day -4, and Day -1 (all visits not required)
SUBOXONE
Sublingual Film
Transition
(Day 169)
End of Study Visit (Day 197)/Early Termination (Up to Day 197)
Subjects return to clinic for this visit
Early 
Termin
ation
Subjects 
return to 
clinic 
for this 
visit
Screening
(Days -21 to -15 [Up to 3 days after EOS Visit/Day169 + 3 for Subject’s Completing 
Study RB-US-13-0001]) 
Note: RB-US-13-0001 assessments completed at EOS/Day 169 will serve as screening 
assessments 


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3.2
Rationale for Study Design
This study is designed to assess the long-term safety, tolerability, and clinical outcomes of 
RBP-6000 SC injections in subjects with opioid use disorder.  The planned number of subjects 
was designed to ensure at least 100 subjects reach 1 year of treatment with RBP-6000 (as advised 
in the ICH-E1A Guideline - The Extent of Population Exposure to Assess Clinical Safety: For 
Drugs Intended for Long-term Treatment of Non-Life-Threatening Conditions).  The safety 
assessments used include evaluations of AEs, serious AEs (SAEs), discontinuations from study 
due to AEs; local injection site tolerability (e.g., injection site grading); injection site pain using a 
subject-reported VAS; suicidality using the eC-SSRS, concomitant medications; changes in 
clinical laboratory results; vital sign measurements; 12-lead ECGs, and physical examination 
results.  The instruments used to measure clinical outcomes (e.g., COWS, SOWS, Opioid 
Craving VAS, and eC-SSRS) were developed to measure the specific symptoms exhibited by 
and the challenges facing opioid-dependent individuals.  
3.3
Study Duration and Dates
The expected maximum duration of participation for de novo subjects is up to approximately 55 
weeks consisting of up to a 7-day screening period, up to a 14-day SUBOXONE sublingual film 
Run-In, up to a 48-week open-label treatment period, and a 4-week follow-up and transition 
period when subjects will receive the same dose of SUBOXONE that they received at Day -1 
and their ongoing treatment options will be reviewed.
The expected maximum duration of participation for roll-over subjects is up to approximately 31 
weeks, consisting of up to a 7-day screening period, up to a 14-day SUBOXONE sublingual film 
Run-In, a 24-week open-label treatment period, and a 4-week follow-up and transition period 
when they will receive the same dose of SUBOXONE that they received at Day -1 and their 
ongoing treatment options will be reviewed.
If a sufficient number of subjects reach 1 year of exposure to RBP-6000, the study may be 
stopped early, and all remaining subjects will complete EOS procedures and enter the 
SUBOXONE Transition Period/Safety Follow-up.
Subjects who receive at least 1 dose of RBP-6000 and discontinue the trial for any reason will be 
required to complete the Early Termination (ET) visit.


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4
STUDY POPULATION SELECTION
4.1
Study Population
Approximately 300 de novo subjects will be enrolled into this study as well as approximately 
300 roll-over subjects. The study population will consist of individuals diagnosed with opioid 
use disorder who are seeking treatment.
4.2
Inclusion Criteria
A. De novo Subjects: Subjects who have not participated in Study RB-US-13-0001 must meet
the following criteria to be enrolled in this study:
1. Subjects seeking treatment for opioid use disorder who currently, and by medical history 
over the previous 3 months, meet the DSM-5 criteria for moderate or severe opioid use 
disorder. 
2. Subjects who provide written informed consent to participate in this study.
3. Subjects who are an appropriate candidate for opioid partial-agonist treatment in the 
opinion of the Investigator or medically responsible physician.
4. Either male or female.
5. Age ≥ 18 to ≤ 65 years.
6. Have a body mass index (BMI) of ≥ 18.0 to ≤ 35.0 kg/m2.
7. Females: Women of childbearing potential (defined as all women who are not surgically 
sterile or postmenopausal for at least 1 year prior to informed consent), must have a 
negative pregnancy test prior to enrollment and must agree to use a medically acceptable 
means of contraception from screening through at least 6 months after the last dose of 
investigational medicinal product (IMP).
Males: Subjects with female partners of child-bearing potential must agree to use 
medically acceptable contraception after signing the informed consent form (ICF)
through at least 6 months after the last dose of IMP. Male subjects must also agree not to 
donate sperm during the study and for 6 months after receiving the last dose of IMP.
The following methods of contraception are considered to be medically acceptable: 
established use of oral, injected or implanted hormonal contraception; placement of an 
intrauterine device or intrauterine system; use of a double-barrier method of 
contraception (condom or occlusive cap with use of a spermicide) or male sterilization. 
8. Subjects must agree not to take any buprenorphine products other than those administered 
during the current study throughout participation in the study.
9. Subjects must be willing to adhere to study procedures.
B. Roll-Over Subjects: Subjects who have successfully completed Study RB-US-13-0001 in its 
entirety must meet only the following criteria to be enrolled in this study:
1. Provide written consent to participate in this study.
2. Be considered eligible in the medical judgment of the Investigator.
3. Females: Women of childbearing potential (defined as all women who are not surgically 
sterile or postmenopausal for at least 1 year prior to informed consent) must have a negative 


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pregnancy test prior to enrollment and must agree to use a medically acceptable means of 
contraception from screening through at least 6 months after the last dose of IMP.
Males: Subjects with female partners of child-bearing potential must agree to use medically 
acceptable contraception after signing the ICF through at least 6 months after the last dose of 
IMP. Male subjects must also agree not to donate sperm during the study and for 6 months 
after receiving the last dose of IMP.
The following methods of contraception are considered to be medically acceptable:  
established use of oral, injected or implanted hormonal contraception; placement of an 
intrauterine device or intrauterine system; use of a double-barrier method of contraception 
(condom or occlusive cap with use of a spermicide) or male sterilization.  
4. Subjects must agree not to take any buprenorphine products other than those administered 
during the current study throughout participation in the study.
5. Subjects must be willing to adhere to study procedures.
4.3
Exclusion Criteria
A. De novo Subjects who meet any of the following criteria will be excluded from the study:
1. Current diagnosis, other than opioid use disorder, requiring chronic opioid treatment.
2. Current substance use disorder, as defined by DSM-5 criteria, with regard to any 
substances other than opioids, cocaine, cannabis, tobacco, or alcohol.
3. Positive UDS result at screening for cocaine or cannabis AND meets DSM-5 criteria for 
either moderate or severe cocaine or cannabis use disorder, respectively.
4. Meets DSM-5 criteria for moderate or severe alcohol use disorder.
5. Treatment for opioid use disorder required by court order.  
6. Current incarceration or pending incarceration/legal action that could interfere with a 
subject’s ability to participate in the study.
7. Pregnant or lactating females.
8. Current use of prescription or OTC medications that are clinically relevant cytochrome 
P450 3A4 or cytochrome P450 2C8 inducers or inhibitors (e.g., rifampicin, azole 
antifungals [e.g., ketoconazole], macrolide antibiotics [e.g., erythromycin]) with the 
exception of marijuana.  More examples are provided in the excluded medications list 
(Appendix 9).
9. History of suicidal ideation within 30 days prior to providing written informed consent as 
evidenced by answering “yes’ to questions 4 or 5 on the suicidal ideation portion of the 
eC-SSRS completed at the screening visit or history of a suicide attempt (per the eC-
SSRS) in the 6 months prior to informed consent.
10. Current or history (within the 6 months prior to providing written informed consent) of 
chest pain or palpitation with either exertion or drug use, peripheral or generalized 
edema, clinically significant cardiovascular disease, including myocardial infarction, 
heart failure, uncontrolled hypertension, clinically significant orthostatic hypotension, 
endocarditis, or myocarditis. 
11. Clinically significant abnormal systolic blood pressure (BP) or diastolic BP, in the 
opinion of the Investigator.


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12. Uncontrolled medical or psychiatric illness that, in the opinion of the Investigator or 
Sponsor, may place the subject at risk or interfere with outcome measures or a subject’s 
ability to participate in the study.
13. Clinically significant abnormality (e.g., severe respiratory insufficiency) in past medical 
history or at the screening physical examination that, in the opinion of the Investigator or 
Sponsor, may place the subject at risk or interfere with outcome variables. 
14. History or presence of allergic or adverse response (including rash or anaphylaxis) to 
buprenorphine, naloxone, or the ATRIGEL Delivery System.
15. Total bilirubin ≥ 1.5x the upper limit of normal (ULN), alanine aminotransferase (ALT) 
≥3xULN, aspartate aminotransferase (AST) ≥ 3xULN, serum creatinine > 2xULN, 
international normalized ratio (INR) >1.5xULN, lipase >3xULN, amylase >3xULN, or 
any abnormal pancreatic enzyme value above ULN that is associated with clinically 
significant, active pancreatic disorder.
16. Congenital long QT syndrome, history of prolonged QT in the 3 months prior to 
screening, or a corrected QT interval (Fridericia’s – QTcF) >450 msec (male) or >470 
msec (female) or history of risk factors for Torsades de Pointes.
17. Diagnosis of acquired immunodeficiency syndrome (AIDS).
18. Affiliated with, or a family member of, site staff directly involved in the study.
19. Unable, in the opinion of the Investigator or the medically responsible physician, to 
comply fully with the study requirements.  
20. Clinically significant anemia or low hemoglobin (levels < 9 g/dL) at Screening. 
21. Donation of > 250 mL of blood or plasma within the 30 days prior to providing written 
informed consent 
22. Participation in any other clinical trial within 30 days prior to informed consent 
23. Received medication-assisted treatment for opioid use disorder (e.g., methadone, 
buprenorphine) in the 90 days prior to providing written informed consent 
24. Previously received RBP-6000.
25. Use of (within the past 30 days prior to providing written informed consent) or positive 
UDS result at screening for barbiturates, benzodiazepines, methadone, or buprenorphine .
B. Roll-Over Subjects who meet any of the following criteria will be excluded from the study:
1. Discontinued early from Study RB-US-13-0001
2. Experienced any major protocol deviations or adverse events during the RB-US-13-0001 
study which, in the opinion of the Investigator, could potentially compromise subject 
safety.
3. Women of childbearing potential who have a positive pregnancy test at EOS/Day 169, 
who are pregnant or breastfeeding, seeking pregnancy, or failing to use adequate 
contraceptive methods during the study.


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4.4
Day -1/Enrollment Criteria
Beginning on the 4th day of SUBOXONE sublingual film dosing (Study Day -11) through the 
14th day of dosing, subjects will be evaluated for Day -1 criteria.  Subjects must meet the 
following criteria in order to be enrolled:
1. No allergic reaction to SUBOXONE sublingual film.
2. Daily dose of SUBOXONE sublingual film between 8 mg/2 mg - 24 mg/6 mg (inclusive) 
buprenorphine/naloxone.
3. COWS score of ≤ 12.
4. Opioid Craving VAS score of ≤ 20 mm.


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5
STUDY TREATMENTS
5.1
Description of Treatments
5.1.1
SUBOXONE Sublingual Film
SUBOXONE sublingual film is supplied as an orange rectangular sublingual film with a white 
printed logo.  Each SUBOXONE sublingual film contains buprenorphine HCl and naloxone HCl 
dihydrate at a 4:1 ratio expressed as the free bases.  Films are intended for SL administration and 
are available in 4 dosage strengths (2 mg/0.5 mg; 4 mg/1 mg; 8 mg/2 mg; and 12 mg/3 mg).  
5.1.2
Investigational Medicinal Products
RBP-6000 uses buprenorphine base in the ATRIGEL Delivery System, which is currently used 
in a number of approved commercial products.  RBP-6000 will be supplied as a single-syringe 
system, which is prefilled with RBP-6000.  The entire contents of the prefilled syringe will be 
administered.  (See Appendix 8: Study Drug Preparation and Dispensing Procedures for detailed 
dosage instructions).  
RBP-6000 is manufactured by Reckitt Benckiser Pharmaceuticals Inc. (RBP) according to Good 
Manufacturing Practice standards.
All used syringes components will be disposed of in accordance with the site’s standard 
operating procedures (SOP) or pharmacy destruction policy. The site’s clinical research associate 
(CRA) will review the site’s SOP and/or pharmacy destruction policy.  All IMP packaging will 
be retained for CRA verification.
5.2
Treatments Administered
5.2.1
Run-In Treatment Period
5.2.1.1
SUBOXONE Sublingual Film Induction (De novo Subjects)
De novo subjects will receive their first dose of SUBOXONE sublingual film on Induction 
Day 1.  Subjects will be started with an initial dose of 2 mg/0.5 mg or 4 mg/1 mg and may titrate 
upwards in 2 or 4 mg increments of buprenorphine, at approximately 2-hour intervals, under 
clinical supervision, to 8 mg/2 mg based on therapeutic response. 
On Induction Day 2, subjects with a COWS score > 12, or subjects reporting withdrawal 
signs/symptoms overnight, will receive a dose of SUBOXONE sublingual film equal to the total 
dose given on Induction Day 1 plus 4 mg. (For example, if a subject received a total dose of 8 
mg on Induction Day 1, the starting dose of buprenorphine for Induction Day 2 would be 12 mg).  
If the COWS score is still > 12 one hour later, another 4 mg dose can be given. The subject 
should not exceed a maximum dose of 16 mg/4 mg for Induction Day 2. Subsequent 
SUBOXONE sublingual film doses must be separated by at least 1 hour from the preceding dose. 
SUBOXONE sublingual film doses may also be adjusted downward if necessary. 


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On Induction Day 3, subjects will be titrated to therapeutic response based on COWS scores as 
well as physician judgment. Most subjects will only require a single dose on Induction Day 3 
which will equal the Induction Day 2 dose or the Induction Day 2 dose plus 4 mg buprenorphine. 
Additional doses may also be administered on Induction Day 3 (up to 24 mg). Subsequent 
SUBOXONE sublingual film doses must be separated by at least 1 hour from the preceding dose.  
Subjects should reach a daily dose of between 8 mg/2 mg and 24 mg/6 mg by Induction Day 3 
and continue on that dose through the remainder of the SUBOXONE sublingual film Run-In 
period, with additional dose adjustments if necessary. 
The SUBOXONE sublingual film(s) will be administered under the tongue, close to the base on 
the left or right side, until they are dissolved.  If an additional sublingual film is required, it 
should be placed on the opposite side from the first film.  Subjects should be instructed to hold 
the films under the tongue until they dissolve.  If a third film is required, it should be placed 
under the tongue after the first 2 films have dissolved.  
For more information about SUBOXONE sublingual film administration, please refer to the 
SUBOXONE Full Prescribing Information (See Appendix 7).
5.2.1.2
SUBOXONE Sublingual Film Induction (Roll-over Subjects)
Following screening, roll-over subjects will be inducted on SUBOXONE sublingual film to 
achieve daily doses between 8 mg to 24 mg buprenorphine according to the SUBOXONE 
sublingual film prescribing instructions. Subjects must be titrated to a minimum dose of 8 mg 
SUBOXONE by the end of the 3-day Induction period regardless of their COWS scores and/or 
the presence or absence of withdrawal symptoms.  
Subjects will receive their first induction dose on Induction Day 1. Subjects should be started 
with an initial dose of 2 mg/0.5 mg or 4 mg/1 mg buprenorphine/naloxone and may titrate 
upwards in 2 or 4 mg increments of buprenorphine, at approximately 2-hour intervals, under 
supervision, to a total dose of up to 8 mg/2 mg buprenorphine/naloxone based on the control of 
acute withdrawal symptoms. 
On Induction Day 2, subjects with a score for COWS of > 12, or subjects reporting opioid 
withdrawal signs/symptoms overnight, should receive a dose of study drug equal to the total dose 
given on Induction Day 1 plus 4 mg.  If the COWS score is still > 12 one hour later, another 4 
mg dose can be given.  The subject should not exceed a maximum dose of 16 mg/4 mg 
buprenorphine/naloxone for Induction Day 2.  Subsequent SUBOXONE sublingual film doses 
must be separated by at least 1 hour from the preceding dose.  SUBOXONE sublingual film 
doses may also be adjusted downward if necessary.  
On Induction Day 3, subjects will be titrated to therapeutic response until a therapeutic dosage is 
reached, based on COWS scores as well as physician judgment. Most subjects will only require a 
single dose on Induction Day 3 which will equal the Induction Day 2 dose or the Induction Day 2 
dose plus 4 mg. Additional doses may also be administered on Induction Day 3 (up to 24 mg).  
Subsequent SUBOXONE sublingual film doses must be separated by at least 1 hour from the 
preceding dose.  Although subjects should reach a daily dose of between 8 mg and 24 mg by 


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Induction Day 3 and continue on that dose through the remainder of the SUBOXONE sublingual 
film Run-In period, dose adjustments may be necessary during the Run-In period. 
The SUBOXONE sublingual film(s) will be administered under the tongue, close to the base on 
the left or right side, until they are dissolved.  If an additional sublingual film is required, it 
should be placed on the opposite side from the first film.  Subjects should be instructed to hold 
the films under the tongue until they dissolve.  If a third film is required, it should be placed 
under the tongue after the first 2 films have dissolved.  
For more information about SUBOXONE sublingual film administration, please refer to the 
SUBOXONE Full Prescribing Information (See Appendix 7).
5.2.2
Dose Adjustment Period (All Subjects)
Beginning at Day -11, subjects will be assessed to determine whether they meet Day -1
/enrollment criteria as defined in Section 4.4.  Once subjects meet the enrollment criteria (no 
significant opioid craving (≤20 mm on the Opioid Craving Visual Analog Scale [VAS] and no 
significant withdrawal (≤ 12 on the Clinical Opiate Withdrawal Scale [COWS]), they are eligible 
to receive the first SC injection of RBP-6000 (containing 300 mg buprenorphine). Subjects with 
significant withdrawal signs/symptoms (defined as >12 on the COWS) or significant cravings for 
opioids (defined as >20 mm on the Opioid Craving VAS) after the end of the 2-week 
SUBOXONE sublingual film Run-In period will not be eligible to continue in the study and will 
be referred for treatment.  
5.2.3 Active Study Treatment
On Day 1 of the study (initiation of study drug injections), all subjects will receive a SC injection 
of 300 mg of buprenorphine in RBP-6000. Subsequent doses of RBP-6000 may be adjusted 
down to 100 mg and back up to 300 mg based on the medical judgment of the Investigator.   All 
subjects will receive injections of RBP-6000 separated by 28 (± 2) days.  
After injection of RBP-6000, subjects will not be permitted to receive supplemental 
SUBOXONE sublingual film during the RBP-6000 treatment period. Subjects who require 
supplemental SUBOXONE sublingual film or other sublingual buprenorphine pharmacotherapy 
during the RBP-6000 treatment period will be withdrawn from the study and referred for 
appropriate treatment.
A single SC dose will be injected by an individual who is medically qualified to perform the 
procedure and delegated by the Principal Investigator to perform the task.  Injections of RBP-
6000 will be administered in the abdominal area below the waist but above the hip bone; more 
specifically, injection should occur in the region where the body curves at the side to about 2 
inches from the middle of the abdomen with adequate amounts of subcutaneous tissue that does 
not have excessive pigment, nodules, lesions, or hair.  RBP-6000 will form a solid polymer depot 
that contains the buprenorphine.  As the depot degrades, buprenorphine will be released into the 
systemic circulation at a consistent rate over an approximately 28-day period.  For detailed 
instructions on use, see Appendix 8.


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5.2.4
SUBOXONE Transition Period/Safety Follow-up
At the end of the RBP-6000 open-label treatment period, subjects will enter a 4-week 
SUBOXONE transition period/safety follow-up where they will receive the same dose of 
SUBOXONE that they received at Day -1, and their ongoing treatment options will be reviewed.
5.3
Selection and Timing of Dose for Each Subject
The study schedule is designed so that each of the injections will be separated by a maximum of 
30 days (28 days ± 2 days) and will be given on alternate sides of the subject’s abdomen (see 
Appendix 8 and the Pharmacy Manual for detailed information on administration).  
5.4
Method of Assigning Subjects to Treatment Groups
When a de novo or roll-over subject signs the ICF, she/he will be assigned a unique subject 
number in numerical sequence, which will be used for the duration of the study. Roll-over 
subjects will retain the subject number assigned to them in the RB-US-13-0001 study. De novo
subjects will be assigned a unique subject number, consisting of the site number followed by 9 
and a 3 digit number in numerical sequence (e.g., the first de novo subject screened at site # 001 
will be assigned the number 0019001).  The subject number will be recorded in the source 
document and electronic case report form (eCRF).
All subjects will be assigned to receive the 300 mg RBP-6000 dose. Subsequent doses of 
RBP-6000 may be adjusted down to 100 mg and back up to 300 mg based on the medical 
judgment of the Investigator
5.5
Blinding
Not applicable; this is an open-label study 
5.6
Concomitant Therapy
Concomitant therapies are defined as prescribed medications and OTC preparations, including 
herbal preparations and vitamins, other than study medication and supplementary medication that 
the subject receives within 30 days of screening and for the during the course of the study.  Any 
medication taken by the subject is to be reported by the subject and noted on the subject’s source 
document and concomitant medication page.  Any changes in concomitant therapy during the 
study will be documented, including cessation of therapy, initiation of therapy, and dose 
changes.
Roll-over subjects who started on a benzodiazepine during the RB-US-13-0001 study will be 
evaluated on a case-by-case basis for inclusion in the RB-US-13-0003 study.  The investigator 
will discuss these subjects with the medical monitor before enrolling into the RB-US-13-0003 
study.
The Investigator or designee will also record any medications given for the treatment of AEs on 
the concomitant medication page.  


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5.6.1
Permitted Concomitant Medications
Following screening and enrollment, ancillary medications (ibuprofen, acetaminophen, 
methocarbamol, hydroxyzine, and loperamide) may be administered to subjects to help alleviate 
signs and symptoms of opioid withdrawal as deemed necessary by the Investigator or medically 
qualified sub-investigator.  Details on acceptable administration of these medications and 
preparations are provided below:

Ibuprofen (400 mg orally) may be given every 4 to 6 hours as needed for pain up to a 
maximum of 2400 mg per day.  Subjects for whom ibuprofen is contraindicated or not 
tolerated may be given acetaminophen (325 to 1000 mg every 4 to 6 hours) as needed up 
to a maximum of 3000 mg per day.  Caution should be exercised when using 
acetaminophen concomitantly with other medications that have potential hepatotoxic 
effects.  Methocarbamol may also be given as needed for relief of muscle pain in 
clinically appropriate doses based on physician assessment.

Hydroxyzine (50 to 100 mg orally) may be given every 6 hours as needed for anxiety, 
nausea, or vomiting.  Additionally, hydroxyzine (50 to 100 mg orally) may be given at 
bedtime as needed for sleep.  The hydroxyzine daily dose should not exceed a maximum 
of 600 mg per day.

Loperamide (2 to 4 mg orally) may be given as needed for diarrhea up to a maximum of 
16 mg per day.
5.6.2
Prohibited Concomitant Medications
Concomitant therapies subject to the restrictions indicated under Prohibited Concomitant 
Medications may be used only following approval by the Sponsor unless an immediate medical 
need necessitates their use.  These are listed below:  

Use of buprenorphine.

Ongoing prescription that are clinically relevant P450 3A4 inducers or inhibitors, such as 
azole antifungals (e.g., ketoconazole) and macrolide antibiotics (e.g., erythromycin).

Herbal supplements that have the potential to cause prolongation of the QTc interval.  

Over-the-counter medications that have the potential to cause prolongation of the QTc 
interval.  This does not apply to over-the-counter medications listed under Concomitant 
Therapies above that are prescribed by the Investigator, or over-the counter medications 
that may be used by the Investigator for an immediate medical need that necessitates their 
use. The medical monitor should be consulted for any questions.

Medications, in the addition to those listed above, which may be expected to significantly 
interfere with the metabolism or excretion of buprenorphine that may be associated with 
a significant drug interaction with buprenorphine, or may pose a significant risk to 
subjects’ participation in the study.
Other concomitant medications, OTC preparations, or therapies that are not allowed during study 
participation are listed in Appendix 9.


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5.7
Restrictions
5.7.1
Prior Therapy
All prior medications including OTC, dietary supplements, and herbal preparations taken by the 
subject within the 30 days prior to screening will be recorded.
5.7.2
Subject Activity Restrictions
Subjects should be advised to avoid strenuous exercise.
5.8
Protocol Compliance
This study involves the SC injection of multiple doses of RBP-6000 containing 100 or 300 mg of 
buprenorphine (see the SOE, Appendix 2).  The Investigator may terminate a subject based on 
the subject’s inability or willingness to comply with the protocol requirements.
IMP will be administered by designated and qualified study personnel at the site.  The time and 
duration, the dose delivered, and any dosing observations will be recorded in source 
documentation.  The Investigator or designated individual will maintain a log of all study drugs 
dispensed and returned (if applicable).  Drug supplies will be inventoried and accounted 
throughout the study.
5.9
Packaging and Labeling
RBP-6000 will be packaged and labeled in a manner consistent with the study design and 
applicable regulations.  The study medication will be provided to the investigator(s) by the 
Sponsor or contractor.  
The SUBOXONE sublingual film will be supplied as bulk films in the following buprenorphine 
dosage strengths: 2mg /0.5 mg; 4 mg/1 mg; 8 mg/2 mg; and 12 mg/3 mg.  Containers will be 
labeled with a single panel disclosing the product name, lot number, contents, Sponsor name and 
address, route of administration, and appropriate precautionary statements.
The study drug, RBP-6000, will be identified as an investigational compound.
The following components will be used in the preparation of RBP-6000:

One sealed foil pouch containing a syringe prefilled with RBP-6000 and an oxygen 
absorber pack.

One sterile 19-gauge, 1-inch hypodermic safety needle.
5.10
Storage and Accountability
RBP-6000 should be stored under refrigerated conditions between 2-8ºC (36-46°F).  
SUBOXONE sublingual films should be stored at 25°C (77°F) with excursions permitted 


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between 15-30°C (59-86°F).  Temperature excursions outside of these ranges should be reported 
to the Sponsor immediately and approval for use should be obtained.
The PI or designee is responsible for ensuring that all study drug received at the site is 
inventoried and accounted for throughout the study. Drug accountability is the responsibility of 
the PI or designee, with verification by the CRA. Study drug must be handled strictly in 
accordance with the protocol, handling guidelines and the label, and must be stored in a locked, 
limited access area under appropriate environmental conditions. The PI must ensure that proper 
conditions exist for storage of study treatments. The dispensing of study drug to the subject must
be documented on the drug dispensing form.
Unused study drug must be available for verification by the Sponsor’s site monitor during on-site
monitoring visits. The return to the Sponsor of unused study drug will be documented on the 
Study Drug Return Form.
The Investigator agrees not to supply RBP-6000 to any person except study personnel for SC 
injection of subjects in this study.  
5.11
Investigational Product Retention at Study Site
The PI or medically-qualified designee agrees to conduct a study drug supply inventory for 
RBP-6000, to record results of this inventory, and to return all unused study drug to the Sponsor 
at times specified by RBP. RBP will arrange for the appropriate and timely destruction of all 
returned, unused RBP-6000. All used needles and syringes from RBP-6000 will be disposed of 
into an appropriate secure biohazard container per the standard operating procedures (SOPs) at 
the clinical site. 
All used IMP packaging (e.g. carton, foil pouch) will be retained at the study site until 
reconciliation is performed by the CRA.  After reconciliation is completed, the used IMP 
packaging may be disposed of per the SOPs at the study site.


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6
STUDY PROCEDURES
The schedule of events for this study is provided in Appendix 1, Appendix 2, Appendix 3, 
Appendix 4, and Appendix 5.
For roll-over subjects, study procedures completed at EOS/Day 169 will serve as screening 
assessments for the open-label study.  
6.1
Informed Consent
6.1.1
General Information
Prior to entering the study, the Investigator or designated individual will explain to each subject 
the nature of the study, its purpose, procedures, expected duration, alternative therapies 
available, and the benefits and risks involved in study participation. Subjects will be given the 
Institutional Review Board (IRB)-approved ICF to review and the opportunity to ask questions.  
Subjects will be informed of their right to withdraw from the study at any time without prejudice.  
The potential subjects should be able to answer simple questions about the study after the ICF 
has been reviewed and explained.  After this explanation and before any study-specific 
procedures have been performed, the subject will voluntarily sign and date the ICF to indicate 
the desire to participate in the study.  Prior to participation in the study, the subject will receive a 
copy of the signed and dated ICF.  
Roll-over subjects will complete all Day 169/EOS procedures prior to signing the ICF
6.2
Medical History
For de novo subjects, a detailed medical history will be obtained by the PI or medically qualified 
designee during the screening visit (Visit 1). This will include information regarding the 
subject’s full history of medical and psychiatric conditions, diagnoses, procedures, treatments, 
concomitant medications, demographic information, and use of tobacco, drugs of abuse, alcohol, 
and caffeine, and any other noteworthy medical information, including suicidality measured 
using the eC-SSRS. Any updates to medical history information that the PI or medically 
qualified designee becomes aware of will be captured throughout the study.  All prior 
medications, OTC health, and dietary supplements taken by the subject within 30 days will be 
recorded.  In addition, hospitalizations in the past 3 months and the reason for admission 
(medical/surgical/psychiatric/other) will be recorded.  
For roll-over subjects medical history will not be re-obtained, except for new information.
6.3
Physical Examination
A complete physical examination (PE) will be performed by the Investigator or medically 
qualified designee.  The physical examination will consist of an examination of the following:  
general appearance, skin, head, eyes, ears, nose, throat, neck (including thyroid), lymph nodes, 
chest and lungs, heart, abdomen, extremities, body weight, and a brief neurological assessment.  
The examination will not include a pelvic, breast, or rectal examination.  If any clinically 


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significant abnormal findings started before the date that informed consent was given, these 
findings should be recorded on the Medical History case report form (eCRF).  
If any clinically significant change from screening (Visit 1 for de novo subjects; Study RB-US-
13-0001 EOS visit (Day 169) for roll-over subjects) is noted, it will be reported as an AE and 
followed up to resolution or until reaching a stable end point.
Weight (kg) will be assessed (in ordinary indoor clothing with shoes off) and will be recorded at 
screening as well as periodically throughout the study.  Height (cm) will be recorded at screening 
only.  BMI will be calculated at screening as well as periodically throughout the study.  BMI is 
defined as the subject’s weight in kg divided by the square of the subject’s height in meters 
(kg/m2).  The amount of abdominal fat will be measured using the waist-to-hip ratio and will be 
recorded at screening as well as periodically throughout the study.  
Procedures performed at Day 169/EOS in the RB-US-13-0001 study will not be repeated at the 
screening visit for roll-over subjects.
Assessments are performed at the time points detailed in the SOEs (Appendix 1, Appendix 2, 
Appendix 3, Appendix 4, and Appendix 5).
6.4
Vital Signs
Evaluation of vital signs will be performed after the subject has been supine for ≥ 3 minutes and 
will include a measurement of systolic and diastolic BP, pulse rate, pulse oximetry, respiratory 
rate, and oral temperature.  On the day of RBP-6000 dosing, 4-hour continuous pulse oximetry 
will be assessed from at least 30 minutes prior to the SC injection through 4 hours post RBP-
6000 SC injection.  Pulse oximetry readings from within 30 minutes prior to injection and at 4 
hours post-injection will be recorded in the source documents and CRF.
If clinically significant findings, as determined by the Investigator or medically qualified sub-
investigator, occur in any vital sign measurement, that measurement will be captured as an AE 
and repeated at medically appropriate intervals until the value returns to an acceptable range, a 
specific diagnosis is established, or the condition is otherwise explained.
Assessments are performed at the time points detailed in the SOE (Appendix 1, Appendix 2, 
Appendix 3, Appendix 4, and Appendix 5).
6.5
Electrocardiograms
6.5.1
12-Lead Electrocardiograms
Resting 12-lead ECGs will be recorded with the subject in supine position following a 10-minute 
rest period and will be performed prior to the PK blood sampling (Appendix 6).
Resting 12-lead ECGs will be taken as indicated in the SOEs (Appendix 1, Appendix 2, 
Appendix 3, Appendix 4, and Appendix 5).  ECGs performed at screening will be recorded in 
triplicate, at approximately 2 - 5 minute intervals. 


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ECG intervals including HR, QT, QTcF, QTcB, RR, PR, QRS and T wave changes will be 
recorded.  ECGs will be reviewed by the Investigator during the visits for any immediate 
abnormalities. ECGs will also be reviewed by a central facility.  
The findings of the ECGs as determined by the central facility will be assessed by the 
Investigator and marked as normal, abnormal-not clinically significant, or abnormal-clinically 
significant.  All clinically significant abnormalities will be captured as AEs.  In the event that a 
clinically significant AE related to an ECG assessment occurs during the study, the Investigator 
should contact the RBP Medical Monitor.
6.5.2
Holter Monitoring
A Holter monitor will be used to obtain continuous ECG recordings from at least 30 minutes 
before SC injection through 4 hours post SC injection dosing on study visits as indicated in the 
SOEs (Appendix 1, Appendix 2, Appendix 3, Appendix 4, and Appendix 5).  An appropriately 
trained individual will set up the Holter monitor, and a central facility will be used to review all 
recordings.  All clinically significant abnormalities will be captured as AEs. Specific 12-lead 
ECG tracings of 10-second duration will be extracted in triplicate at the following predefined 
time points: immediately prior to injection and 4 hours post-injection.  The Holter must be 
applied prior to PK sampling for pre-sample ECG extraction.  
6.6
Clinical Laboratory Tests
6.6.1
Laboratory Parameters
All clinical laboratory assessments will be performed by a clinical laboratory accredited by the 
College of American Pathologists or with a certificate of compliance (or certificate of waiver for 
CLIA-waived tests) issued by the Center for Medicare & Medicaid Services or Clinical 
Laboratory Improvement Amendments.  The laboratory assessments will include routine and 
screening laboratory tests.  
See the SOEs in Appendix 1, Appendix 2, Appendix 3, Appendix 4, and Appendix 5 for the 
timing of the specific required laboratory tests which are listed in Table 2. 
Any abnormal hematology, chemistry, or urinalysis test result deemed clinically significant by 
the Investigator will be repeated, including test results obtained on the final study day.  For any 
test abnormality deemed clinically significant, an AE will be recorded (unless the result was 
considered erroneous) and repeat analysis will be performed until resolution or until the 
Investigator determines that resolution of the laboratory abnormality is not expected.  
Subjects will be in a seated or supine position during blood collection.  Clinical laboratory panels 
are listed in Table 2.


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Table 2
List of Laboratory Tests
Hematology:
Hematocrit
Hemoglobin 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin concentration 
Mean corpuscular volume 
Platelet count
Pancreatic enzymes
Red blood cell count
White blood cell count with differential
Urinalysis:
Appearance
Bilirubin
Color
Glucose
Ketones
Leucocyte esterase
Microscopic examination of sedimenta
Nitrite
Occult blood
pH
Protein
Specific gravity
Urobilinogen
Hormone Panel:
Adrenocorticotropic hormone (ACTH) Follicle Stimulating 
Hormone
Testosterone (total and free)
Pregnancy:
Urine Pregnancy (only for females not postmenopausal or 
surgically sterile for at least 1 year)
Serum Pregnancy
Screening:   
Hemoglobin A1c 
HIV-1 and -2 antibodies
PTT
PT with INR
Serum pregnancy
Serum Chemistry:
Albumin
Alkaline phosphatase
Alanine aminotransferase (ALT)
Amylase
Aspartate aminotransferase (AST)
Blood urea nitrogen
Calcium
Calculated creatinine clearance
Carbon dioxide
Chloride
Creatinine
Creatine kinase and subtypes
Gamma-glutamyl transferase
Globulin
Glucose (non-fasting)
Immunoreactive trypsinogen
Lactate dehydrogenase
Lipase
Magnesium
Phosphorus
Potassium
Sodium
Total bilirubin
Direct bilirubin
Total cholesterol
Total protein
Triglycerides
Uric acid
Urine Drug Screen (UDS):
Opioidsb
Cocaine
Amphetamines
Methadone
Cannabinoids
Barbiturates
Buprenorphinec
Benzodiazepines
Methamphetamine
Phencyclidine
Anti-HIV = human immunodeficiency virus antibodies; hCG = human chorionic gonadotropin; INR = 
international normalized ratio; IRT = immunoreactive trypsinogen; PT = prothrombin time; and PTT = 
partial thromboplastin time.
a
Microscopic examination of sediment will be performed only if the results of the urinalysis evaluation are 
positive (microscopic examination may include but is not limited to WBC count, RBC count, casts, and crystals).
b
Oxycodone may not show up in all opiate assays and should be assessed separately.
c
Buprenorphine will only be included in the UDS at Screening.


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6.6.2
Sample Collection, Storage, and Shipping
All blood sampling will be by individual venipuncture or with the use of a saline lock.  Blood 
and urine sample collection and processing procedures will be outlined in a separate reference 
manual to be provided to the site.
6.6.3
Reference Ranges
Up-to-date reference ranges for the above investigations must be obtained for the laboratory 
performing analyses prior to the start of the study and be updated as appropriate during the 
course of the study.
6.6.4
Laboratory Results Review
The Investigator will review the results and comment on the laboratory results sheet for all 
abnormal values, identifying those that are abnormal but not clinically significant as well as 
those that are significantly abnormal.  The Investigator will sign and date the laboratory results 
sheet to indicate that the review has taken place.
Clinical Laboratory Changes:  It is the Investigator’s responsibility to review the results of all 
laboratory tests as they become available.  This review will be documented by the Investigator 
on the laboratory report.  For each abnormal laboratory test result, the Investigator needs to 
ascertain if this is a clinically significant abnormal change from baseline for that individual 
subject. 
6.6.5
Good Laboratory Practice Compliance
Confirmation of compliance with Good Laboratory Practice (GLP) will be obtained from the 
designated Bio-Analytical Laboratory prior to the start of the study.
6.7
Pharmacokinetic Assessments
Blood samples for PK analyses will be collected from subjects at the time points indicated in the 
PK sampling schedule (Appendix 6). The plasma concentrations of buprenorphine and 
norbuprenorphine will be quantified using specific and validated liquid chromatography tandem 
mass spectrometry methods. A laboratory manual for PK sample collection, processing, storage, 
and shipping will be supplied.
A PK sample will be taken as soon as possible after any SAE is reported.  If possible, an 
additional sample should be collected when the SAE has been resolved.
The exact times (to the minute) of PK blood sampling as well as the exact times of drug 
administration will be recorded in the source and eCRF.  


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6.8
Administration of Study Drug
The study drug will be assigned by an IWRS system. Injections will be administered by a 
physician or suitably-qualified designee (e.g., physician, nurse, nurse practitioner, PA) who has 
been delegated to perform the task.  Study drug will be supplied only to subjects participating in 
the study. The Investigator agrees not to allow the study drug to be administered from, nor stored 
at, any site other than the study site agreed upon with the Sponsor.
See Appendix 7 for detailed descriptions of dosing for the SUBOXONE sublingual film.  
Detailed instructions for the preparation and administration of RBP-6000 are in Appendix 8.
If at an injection visit there is a safety concern with administration of RBP-6000 or placebo, after 
discussion with the medical monitor or sponsor, dosing can be delayed up to one week.  In the 
event this occurs, the subsequent doses will be delayed.  There must be at least 26 days between 
injections of study medication.
All used syringe components will be disposed of into an appropriate secure biohazard container 
or per the SOPs at the study site.
All used IMP packaging (e.g., carton, foil pouch) will be retained at the study site until the CRA 
conducts a visit to perform reconciliation.  After the reconciliation is completed, the used IMP 
packaging may then be disposed of per the SOPs at the study site.
Unused IMP and returned SUBOXONE sublingual film must be available for verification by the 
Sponsor’s site monitor during on-site monitoring visits.  The return of unused or used returned 
IMP for destruction will be documented on the drug return form.
6.9
Safety and Suicidality Assessments
Safety will be assessed by AEs, vital signs, continuous pulse oximetry, ECGs, clinical laboratory 
assessments, local injection site grading scale, injection site pain VAS, and eC-SSRS responses.  
See the SOE for specific timing of assessments (Appendix 1, Appendix 2, Appendix 3, Appendix 
4, and Appendix 5).
6.9.1
Local Injection Site Tolerability
6.9.1.1
Injection Site Grading
Local injection site grading will be performed by the Investigator or a trained and qualified 
health care professional, according to the SOE in Appendix 2, Appendix 3, Appendix 4, and
Appendix 5.  Injection sites will be assessed for pain, tenderness, erythema/redness, induration, 
or swelling.  Local injection site tolerability will be assigned a severity grade, including none 
(grade 0), mild (grade 1), moderate (grade 2), severe (grade 3), or potentially life threatening 
(grade 4) utilizing the Injection Site Grading Scale in Appendix 15.  The local injection site 
grading assessment will be completed electronically on injection days immediately after each 
injection (within 10 minutes) and at 4 hours (± 30 minutes) and 24 hours (± 4 hours) after each 
injection.


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6.9.1.2
Injection Site Pain Visual Analogue Scale (VAS) 
Injection site pain will be assessed by the subject at each injection visit electronically with a 
100mm VAS scale, where 0 represents no pain and 10 represents maximum pain (Appendix 16).  
The injection site-pain VAS scores will be obtained (after the completion of the injection) within 
1 minute and then at 5, 10, 15, 30, 60, and 120 minutes (±5 minutes).  The timing of the Injection 
Site Pain VAS should be measured from the end of the injection.  In addition to rating pain levels 
by marking on the line the point they feel best represents their perception of their current state, 
the subject will also answer the following question with either a Yes or No: Are you currently 
experiencing any burning or stinging at the injection site?
6.9.2
Suicidality
6.9.2.1
Columbia Suicide Severity Rating Scale
The eC-SSRS will be administered according to the SOE in Appendix 1, Appendix 2, Appendix 
3, Appendix 4, and Appendix 5.  The eC-SSRS is a questionnaire designed for assessment of 
suicidal ideation and behavior in adolescents and adults (Posner 2011).  The questionnaire will 
be administered as an electronic, self-rated version (eC-SSRS).  Clinical trial versions of the 
questionnaire are available for trial screening and follow up visits.  A sample section from the 
Baseline/Screening eC-SSRS and the follow up eC-SSRS are presented in Appendix 10 and 
Appendix 11, respectively.  
If a subject becomes suicidal during the study, the investigator should provide the appropriate 
treatment to the subject.  If the suicidality is deemed to be related to IMP and it is within 14 days 
of an injection, the depot may be removed (Section 6.14.1).
The eC-SSRS should be completed prior to SUBOXONE and RBP-6000 injection and at 
approximately the same time each day ±2 hours.
If, there is a positive on the eC-SSRS after screening the subject will be evaluated by the 
investigator for continuation in the study.  If needed, the investigator can consult with the 
medical monitor on continuation in the study of subjects with a positive eC-SSRS.
6.10
Adverse Events Assessments
6.10.1
Definition
In accordance with ICH and US FDA guidance, any untoward medical occurrence incurred by a 
subject that occurs after the first study-related procedure to the completion of the protocol-
defined safety surveillance period and is associated with the use of the drug, regardless of the 
presence of causal relationship, is a reportable AE.  
Abnormal results of diagnostic procedures, including laboratory test abnormalities, are 
considered AEs if they:

Result in discontinuation from the study,


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
Require treatment or any other therapeutic intervention,

Require further diagnostic evaluation (excluding a repetition of the same procedure to 
confirm the abnormality), or

Are associated with clinical signs or symptoms that would have a significant clinical 
impact, as determined by the Investigator.
6.10.2
Performing Adverse Events Assessments
The Investigator is ultimately responsible for assessing and reporting all AEs as outlined in the 
protocol.  The assessment of AEs may be delegated to a medically qualified sub-investigator, 
trained on this study protocol, who is listed on the FDA Form 1572 or equivalent document, and 
on the delegation of authority form.
AEs should be volunteered by the subject or solicited from the subject using a standard 
statement, obtained from examination of the subject at a clinic visit, or from observations of 
clinically significant laboratory values or special examination abnormal values.  If an event 
assessed by one of the study scales requires intervention, or if in the opinion of the Investigator, 
it is clinically significant, then it will be reported as an AE.
All AEs are to be assessed and recorded in a timely manner and followed to resolution or until 
the Investigator determines that there is not an anticipated resolution.  Each AE is to be 
documented with reference to severity, date of occurrence, duration, treatment, and outcome.  
Furthermore, each AE is to be classified as being serious or non-serious.  In addition, the 
Investigator must assess whether the AE is drug-related or not.  Changes in severity of AEs 
should be documented as one event at the maximum severity that occurred during the study.
6.10.3
Timing
AEs will be captured from the time the subject gives informed consent until the subject 
completes the study.
Surgical procedures, planned before enrollment of the subject in the study, are not considered 
AEs if the condition was known before study inclusion.  In this case the medical condition 
should be reported in the subject’s medical history.  
If a subject experiences the onset of an SAE within 30 days following study completion and in 
the opinion of the Investigator, that SAE is associated with the study, it will be followed and 
reported as described in Section 6.10.9.2.
If a SAE occurs a PK sample will be taken as soon as possible after the event is reported.  If 
possible, an additional sample should be collected when the SAE has been resolved.
6.10.4
Severity
Adverse events with changes in severity should be documented as one event at the maximum 
severity.


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Intensity
Definition
Mild
Causes transient or mild discomfort ; no limitation of usual activities; no 
medical intervention required
Moderate
Causes mild to moderate limitation in activity; some limitation of usual 
activities: no or minimal medical intervention or therapy is required.
Severe
Causes marked limitation in activity; some assistance is usually required; 
medical intervention or therapy is required; hospitalization is probable.  
The term “severe” is used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe); the event itself, however, may be of relatively minor medical significance 
(such as a severe headache). This is not the same as “serious,” which is based on subject/event 
outcome or action criteria usually associated with events that pose a threat to a subject’s life or 
functioning. Seriousness (not severity) serves as a guide for defining regulatory reporting 
obligations.
6.10.5
Relationship
The Investigator or a medically qualified sub-investigator, trained on this study protocol, listed 
on the 1572 form or equivalent document and on the delegation of authority form is responsible 
for determining the AE relationship to the investigational product.
The following categories will be used to define the relationship of an AE to the administration of 
the investigational product:
Not Related:
Data are available to identify a clear alternative cause for the AE other than 
the investigational product.
Related:
The cause of the AE is related to the investigational product and cannot be 
reasonably explained by other factors (e.g., the subject’s clinical state, 
concomitant therapy, and/or other interventions).
6.10.6
Expectedness
An unexpected AE is any AE, the nature and severity of which is not consistent with the 
applicable product information (e.g., Investigator’s Brochure for an investigational product or 
product label/summary of product characteristics for an approved product).
6.10.7
Clinical Significance
The Investigator or medically qualified sub-investigator, trained on this study protocol, listed on 
the 1572 form or equivalent document and on the delegation of authority form is responsible for 
determining clinical significance of abnormal assessment results (e.g., laboratory or ECG results) 
for the subject.


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6.10.8
Clinical Laboratory Adverse Events
Changes in laboratory values or vital signs, or other safety parameters (e.g., ECG, neurological 
and clinical symptom assessments) as noted in the protocol are a subset of AEs and are 
reportable only if considered to be clinically significant by the investigator or medically qualified 
sub-investigator except that:
•
Baseline assessments are differentiated from AE/symptoms that are incurred post 
informed consent.  These baseline lab assessments, if determined to be clinically 
significant abnormal values, reflect the status of the subject prior to study participation.  
These clinically significant pre-dose abnormal assessments without clinical symptoms 
will not be reported as AEs. 
6.10.9
Serious Adverse Events
6.10.9.1
Definition
A SAE is defined as any AE occurring at any dose that results in any of the following outcomes: 

death, 

life-threatening AE,

hospitalization or prolongation of existing hospitalization, 

a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or

a congenital anomaly or birth defect.
“Important medical events may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.” 
6.10.9.2
Reporting Serious Adverse Events
All SAEs will be reported to the Sponsor by the Investigator or designee by email or fax within 
24 hours of discovery, using the form provided by the Sponsor.  The SAE report should also be 
emailed to the Sponsor Medical Monitor.
In the event of an SAE, the Investigator or designee will notify Reckitt Benckiser 
Pharmacovigilance:
Email: PatientSafetyNA@indivior.com
Fax: (804) 423-8951
Reckitt Benckiser Pharmaceuticals Inc.
10710 Midlothian Turnpike, Suite 430
Richmond, VA 23235
In the event that medical discussion is required for an SAE, the Sponsor Medical Monitor should 
be contacted:


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The Investigator or designee must inform the IRB immediately regarding any AE (does not have 
to be causally related) that is both serious and unexpected; or that represents a series of AEs that 
on analysis is unanticipated, or occurs at an unanticipated frequency, or otherwise represents an 
unanticipated safety risk to the study subject. The IRB may subsequently choose to modify the 
informed consent or request changes to the protocol or Investigator’s Brochure.  A PK sample 
will be taken as soon as possible after any SAE is reported. If possible, an additional sample 
should be collected when the SAE has been resolved.
6.10.10 Treatment-Emergent Adverse Events
A TEAE is an AE that either commenced following initiation of study drug or was present prior 
to the initiation of study drug, but increased in frequency or severity following initiation of 
treatment, regardless of causality.
6.10.11 Procedures and Follow-Up of Subjects with Ongoing SAEs or Experiencing 
SAEs after Completion of or Withdrawal from the Study
Subjects with SAEs ongoing at the end of the study or after ET will be followed by the 
Investigator until stabilization or resolution.  If a subject experiences the onset of an SAE within 
a period of 30 days following study completion or withdrawal and, in the opinion of the 
Investigator or medically qualified sub-investigator, it is associated with the study, it will be 
followed up and reported as described for other SAEs.
6.10.12 Pregnancy
If a female subject believes she is pregnant (e.g., missed period, self-administered pregnancy 
test) the subject will be instructed to return to the clinical unit within 48 hours to undergo a 
serum pregnancy test.  If a pregnancy in a subject is confirmed at any time during the study 
through a serum pregnancy performed by the study laboratory, the subject will be discontinued 
from the study and will undergo all final study visit procedures (with the exception of a urine 
pregnancy test).  If the partner of a study subject becomes pregnant, the pregnancy will be 
reported to the clinical unit within 48 hours of the subject’s knowledge of the pregnancy.  
All confirmed pregnancies that occur within this study will be followed until resolution (i.e., 
termination [voluntary or spontaneous] or birth).  
Pregnancy ([study subject or the partner of a study subject] [without associated unexpected or 
adverse sequelae]) is not a reportable AE but must be reported to the Sponsor within 24 hours of 
the Investigator or study staff first being aware of the subject’s condition.


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6.11
Clinical Outcome Assessments
Clinical outcome assessments will include the UDS for opioids and other drugs; self-reported use 
of illicit opioids, other drugs, and alcohol on the TLFB; COWS, SOWS, and Opioid Craving 
VAS.
6.11.1
Timeline Followback Interview
The TLFB Interview will be administered according to the SOE in Appendix 1, Appendix 2, 
Appendix 3, Appendix 4, and Appendix 5. The TLFB Interview is a method to assess recent drug 
use and will be administered electronically.  The questionnaire should be administered by an 
interviewer.  The interview instrument asks subjects to retrospectively estimate their drug use in 
the 30 days prior to screen at the screening visit and since the last visit at all subsequent visits.  
Only occurrence of use is captured (i.e., used or did not use) (Fals-Stewart 2000). The interview 
takes approximately 10-30 minutes to complete and is appropriate for males and females 14 
years of age and older.  Drugs to be assessed in this study include opioids, methadone, 
buprenorphine, cocaine, barbiturates, benzodiazepines, amphetamines/methamphetamine, 
phencyclidine, and ethanol (Appendix 17).
The timeline followback interview should be completed prior to SUBOXONE and RBP-6000 
injection and at approximately the same time each day ± 2 hours.
6.11.2
Opioid Craving Visual Analog Scale 
The Opioid Craving VAS will be administered electronically according to the SOE in Appendix 
1, Appendix 2, Appendix 3, Appendix 4, and Appendix 5.  A VAS is an instrument that 
measures a characteristic or attitude that is believed to range across a continuum of values and 
cannot easily be directly measured.  The amount of opioid craving that a subject feels for illicit 
opioids (not the buprenorphine used for treatment of opioid use disorder) can be recorded along a 
continuum from “no craving at all” to “strongest craving ever” (McMillan and Gilmore-Thomas 
1996).  Operationally, the VAS is a horizontal line, 100 millimeters (mm) in length, anchored by 
word descriptors at each end, as illustrated in Appendix 14.  The subject indicates the point on 
the line that he/she feels represents his/her perception of their current state.  The VAS score is 
the difference from the left hand end of the line to the point that the subject marks and will be 
electronically calculated.
6.11.3
Clinical Opiate Withdrawal Scale 
The COWS assessment will be administered electronically according to the SOE in Appendix 1, 
Appendix 2, Appendix 3, Appendix 4, and Appendix 5.  The COWS is an 11-item, validated 
instrument used to assess symptoms of opiate withdrawal (Wesson 2003, Tompkins 2009).  The 
score is the sum of the response to each of the 11 items.  The COWS is sometimes used by 
clinicians treating subjects with buprenorphine.  A score of 5 to 12 is considered mild, 13 to 24 is 
moderate, 25 to 36 is moderately severe, and a score of exceeding 36 is considered severe 
withdrawal.  COWS scores will be electronically calculated.  Each subject should be assessed by 
the same qualified and trained individuals throughout the course of the study as much as 
possible.  This scale is presented in Appendix 12.


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6.11.4
Subjective Opiate Withdrawal Scale
The SOWS (Handlesman 1987) will be administered electronically according to the SOE in 
Appendix 1, Appendix 2, Appendix 3, Appendix 4, and Appendix 5.  The SOWS is a 16-item 
scale completed by the subject and used to assess the subject’s perception of opiate withdrawal 
symptoms. SOWS scores will be electronically calculated.  This scale is presented in Appendix 
13.
6.12
Health Economics and Outcomes Assessments
Health economics and outcomes assessments will include: EQ 5D-5L, SF-36v2, MSQ, HCRU, 
TEA, ASI-Lite, BDI-II, and BPI. 
All questionnaires will be completed at the appropriate study visits as indicated in the following 
sections.
6.12.1
EuroQoL-5 Dimensions-5 Levels (EQ-5D-5L) and EQ-VAS
The EQ-5D-5L will be used to record subjects’ health-related quality of life throughout the study 
at the time points indicated in the SOEs (Appendix 1, Appendix 2, Appendix 3, Appendix 4, and
Appendix 5).  It will be administered electronically. 
The EQ-5D-5L is a widely-used, generic health-related quality of life instrument, which consists 
of 2 sections:  the EQ-5D-5L descriptive system and the EQ visual analogue scale (EQ VAS)
(Appendix 18).  The EQ-5D-5L is comprised of 5 questions/dimensions (mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression) each of which can take 1 of 5 
responses.  The responses record 5 levels of severity (no problems/slight problems/moderate 
problems/severe problems/extreme problems) within a particular EQ-5D dimension.  EQ-5D -5L 
health states can be converted to a single summary index (range: 0-1) by using value sets that 
attaches values to each of the levels in each dimension.  The EQ-VAS is a standard, vertical, 20 -
cm visual analogue scale and will be used for recording a subject’s rating for their current health-
related quality of life state (Herdman 2007).  
6.12.2
Medical Outcomes Study Short Form-36 (SF-36v2)
The SF-36v2 is a generic, subject-reported outcome instrument used to assess quality of life, 
which will be administered electronically at the time points indicated in the SOEs (Appendix 1, 
Appendix 2, Appendix 3, Appendix 4, and Appendix 5). 
The SF-36v2 is a 36-question instrument, which assesses 8 health concepts: 1) limitations in 
physical activities because of health problems; 2) limitations in social activities because of 
physical or emotional problems; 3) limitations in usual role activities because of physical health 
problems; 4) bodily pain; 5) general mental health (psychological distress and well-being); 6) 
limitations in usual role activities because of emotional problems; 7) vitality (energy and 
fatigue); and 8) general health perceptions (Appendix 19).  The scale score of each domain is 
calculated based on the summed score across items included in the domain and is rescaled to 0 to 
100 with higher scores indicating better health states.


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The SF-36v2 provides scores for each of the eight health domains and psychometrically-based 
physical component summary (PCS) and mental component summary (MCS) scores. The 
physical functioning, role physical, bodily pain, and general health can be used to construct a 
PCS score, while the vitality, social functioning, role emotional, and mental health scales are 
used to construct the MCS Scores (Ware 2007).
6.12.3
Medication Satisfaction Questionnaire (MSQ)
The MSQ is a single-item, patient-rated questionnaire (Appendix 20) that evaluates patient 
satisfaction with opioid medication. (Vernon 2010).  Medication satisfaction will be measured 
with the MSQ at the time points indicated in the SOEs (Appendix 2, Appendix 3, Appendix 4, 
and Appendix 5) electronically.
6.12.4
Healthcare Resource Utilization (HCRU) Questionnaire
The Healthcare Resource Utilization questionnaire will be completed by the Investigator or 
designee at the time points indicated in the SOEs (Appendix 1, Appendix 2, Appendix 3, 
Appendix 4, and Appendix 5).  The HCRU will be used to collect current health insurance status, 
hospitalizations; residential substance abuse treatment; general practitioner, specialist, and 
counseling visits; and ED visits (Appendix 21).  It will be administered electronically.
The outpatient services captured on this questionnaire are ones conducted outside the study.  
Visits to the study site for scheduled study visits should not be reported here.
6.12.5
Treatment Effectiveness Assessment (TEA)
The TEA is a patient-reported instrument which will be measured at the time points indicated in 
the SOEs (Appendix 1, Appendix 2, Appendix 3, Appendix 4, and Appendix 5).
The TEA is a 4-item scale completed by the subject and used to assess the subject’s perception 
of treatment effectiveness (Ling 2012).  Patients respond to the TEA questions providing both 
numerical responses and brief feedback about their situation on four domains: substance use 
(drugs, alcohol, tobacco), health (e.g., physical, emotional health), lifestyle (e.g., housing or 
living situation, family, employment, relationships), and community (e.g., obeying laws and 
becoming a responsible member of society).  The TEA scale is presented in Appendix 22.
6.12.6
Addiction Severity Index (ASI) Lite
The ASI Lite is a patient-reported instrument that is conducted via interview by a team member 
trained in the administration of the ASI Lite.  ASI Lite will be administered at the time points 
indicated in the SOEs (Appendix 2, Appendix 3, Appendix 4, and Appendix 5).  Given the nature 
of the ASI Lite, this instrument can be administered after injection, and is recommended for 
administration between the 2 hour injection site pain VAS and 4 hour local injection site grading 
assessments. 
The ASI Lite, in an interview used to assess the subject’s addiction severity, covers 7 potential 
problem areas: medical, employment/support status, alcohol, drug, legal, family/social, and 
psychiatric problems (Strain 1996). The ASI Lite interview text is presented in Appendix 23. The 


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ASI obtains lifetime information about problem behaviors, as well as problems within the 
previous 30 days. Of note, some items of the ASI Lite are only asked once at the initial visit; at 
subsequent time points only items indicated in the questionnaire should be administered. 
Below is a brief description of each of the scales that will be included within the trial:  
The medical status section of the ASI gathers basic information about the patient's medical 
history. It addresses information about lifetime hospitalizations, long-term medical problems and 
recent physical ailments.  The employment/support status section of the ASI gathers information 
about the resources a patient can record on a job application, as well as his or her current sources 
of income. Many items have a 30-day recall period regarding current employment. The 
drug/alcohol section of the ASI gathers information about the patient's substance abuse history. It 
addresses information about current and lifetime substance abuse, consequences of abuse, 
periods of abstinence, treatment episodes, and financial burden of substance abuse. While 
lifetime versions of these items are also available, this would only be assessed at first interview.  
The legal status section of the ASI gathers information about the patient's legal history. It 
addresses information about probation or parole, charges, convictions, incarcerations or 
detainments, and illegal activities.  The family/social relationships section is designed to 
summarize the psychiatric, alcohol and drug abuse problems of the patient's relatives in each of 
the specified categories.  The psychiatric problem section gathers information on psychiatric 
symptoms experienced by the patient.
6.12.7
Beck Depression Inventory II (BDI-II)
Depression is highly prevalent in patients with opioid use disorders.  Studies have been 
conducted using buprenorphine as a treatment for major depressive disorder. 
The Beck Depression Inventory II (BDI-II) is used to measure the severity of depression in 
adults and adolescents.  The BDI-II is scored on a 4 point Likert scale, each item ranging from 0-
3; it has a 2 week recall period, can be self-administered or administered by interview and takes 
5-10 minutes to complete. 
The strengths of the BDI-II include its ease of use; also, it is widely known and the results are 
easy to score and interpret. The BDI-II has been successfully used to discriminate and measure 
depression in chronic pain patients on opioid therapy (Geisser 1997, Farren 2002, McCauley 
2014).  
The BDI-II assessment will be administered electronically according to the SOE in Appendix 1, 
Appendix 2, Appendix 3, Appendix 4, and Appendix 5.  This scale is presented in Appendix 24. 
Roll-over subjects who did not complete the BDI-II at EOS/Day 169 will complete this 
assessment at the screening visit.
6.12.8
Brief Pain Inventory (BPI) Short Form
A substantial number of patients in the US with opioid use disorder began by using prescription 
pain medications and subsequently developed dependence. Many of these patients are concerned 
at the beginning of therapy that their pain may worsen when they are no longer taking their 
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The Brief Pain Inventory Short Form (BPI-SF) is used to measure the severity of pain and the 
impact of pain on daily functions in adults. The BPI-SF has a 24-hour recall period and can be 
self-administered or administered by an interviewer. It takes approximately 5 minutes to 
complete an instrument. 
The BPI has been widely used to measure pain severity among opioid users (Rosenblum 2003).  
BPI-SF consists of a combination of yes/no questions, an item based on human figure drawing, 
open-ended questions, and items based on a numeric rating scale.  Key strengths of the BPI-SF 
are that it is easy to administer and can provide rapid assessment of pain. BPI has been translated 
in many languages and is widely used. It captures all the components of pain: structural, intensity 
and its effect on patients.  
The BPI assessment will be administered electronically according to the SOE in Appendix 1, 
Appendix 2, Appendix 3, Appendix 4, and Appendix 5.  This scale is presented in Appendix 25. 
Roll-over subjects who did not complete the BPI at EOS/Day 169 will complete this assessment 
at the screening visit.
6.13
Concomitant Medication Assessments
The Investigator or designee will record any concomitant therapies given for 30 days prior to the 
start of and during the course of the study on the concomitant medication page of the subject’s 
source documentation and CRF. Any changes in concomitant therapy during the study will also 
be documented, including cessation of therapy, initiation of therapy, and dose changes.
6.14
Removal of Subjects from the Study
Subjects will be free to withdraw at any time for any reason, or they may be withdrawn if 
necessary, to protect their health and safety or the integrity of the study data.  
The Investigator or medically qualified sub-investigator may choose to withdraw a subject from 
the study at any time.  Reasons for removing a subject from the study may include, but are not 
limited to the following:
•
Protocol deviation that might compromise data integrity, protocol compliance, or subject 
safety,
•
An AE is reported that compromises or potentially compromises subject safety,
•
The Sponsor or Investigator terminates the study, or

The subject requests to be discontinued from the study (i.e., subject declines further study 
participation).
If a subject withdraws prematurely from the study after receiving IMP, the primary reason for 
withdrawal will be documented as 1 of the above, lost to follow-up, or other in the source 
documentation. 


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In the event a subject is lost to follow up, the site staff must make reasonable attempts to contact 
the subject.  A minimum of 2 documented telephone calls followed by a certified mailed letter is 
considered reasonable.
6.14.1
Early Removal of RBP-6000
In the event of an emergency or if a subject withdraws or is withdrawn within the first 14 days of 
receiving an injection of RBP-6000, subjects may have the option to have the depot surgically 
removed by a physician delegated to perform surgery. The medically responsible physician 
should carefully discuss this option with subjects given the use of ATRIGEL Delivery System 
and the feasibility of extracting the depot. The surgical procedure requires a small incision in the 
abdomen where the depot was placed, removal of the depot with forceps, and suturing to close 
the incision.  The subject should have the EOS assessments performed at the time of early 
removal of RBP-6000. Subjects that have had an RBP-6000 depot removed should have follow-
up telephone contact(s) within 7 to 14 days to assess status and for resolution of related AEs. In 
the event a subject cannot be contacted for the follow-up telephone contact, a minimum of 2 
documented telephone calls followed by a certified mailed letter is considered reasonable. At this 
point, the subject may be considered lost to follow-up.
The extracted RBP-6000 depot will be disposed of into an appropriate, secure biohazard 
container per the standard operating procedures (SOPs) at the clinical site. 
Detailed RBP-6000 depot removal instructions are in Appendix 8.
6.14.2
Stopping Rules
The Investigator must contact the Sponsor immediately to discuss whether to suspend dosing if 
an AE or laboratory abnormalities indicates that continued dosing of subsequent subjects would 
not be tolerated or would jeopardize the subjects’ safety.  The Sponsor alone may suspend dosing 
at any time for any reason.
Factors that must be considered for suspension of dosing include the frequency, severity, clinical 
significance, possible causality, and anticipated reversibility of all observed AEs or laboratory 
abnormalities for each specific SC injection group.  If dosing is suspended, the IRB will be 
notified in accordance with IRB requirements.
6.14.3
Screen Failures
A screen failure subject is one from whom informed consent is obtained and is documented in 
writing (i.e., the subject signs the ICF) but who did not receive study medication.
Rescreening of a de novo subject may be permitted after consultation with the study medical 
monitor.


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6.15
Other Study Procedures
6.15.1
Counseling/Behavioral Therapy
After enrollment, subjects will receive manual-guided, individual behavioral therapy once a 
week to accompany the pharmacotherapy as indicated in the SOEs (Appendix 2, Appendix 3, 
Appendix 4, and Appendix 5).  Behavioral therapy will continue through the end of the study 
(EOS/ET visit) at a minimum frequency of once a week.  Additional behavioral counseling 
above this standard frequency, as well as the reason(s) that additional counseling was provided, 
will be documented.  Behavioral therapy can be complete by any appropriately trained staff 
member at the site.
An Individual Drug Counseling (IDC) reference manual will be provided to each site.  
6.15.2
Unscheduled Visits
If unscheduled visits occur, the Investigator must record the following in the subject’s source 
documentation:

Any AEs

Reason for unscheduled visit

Recording of any changes or additions to concomitant medications dose or regimen

COWS (if deemed appropriate)

Any clinical assessments deemed appropriate for the clinical care of the subject
Unscheduled visits should not alter the timing of the routine study schedule.
6.15.3
Additional Care of Study Subjects Following Completion of the Study
Each subject will be evaluated on his or her final study day.  Subjects who experience SAEs at 
the EOS, or experience the onset of an SAE after the final visit, will be followed up as described 
in Section 6.10.11.  No other additional care of study subjects will take place following 
completion of the study. 
6.15.4
Treating Toxicity
Treatment of suspected RBP-6000 toxicity should be at the judgment of the Investigator or 
medically-qualified sub-investigator and may include an attempt to remove the depot if toxicity 
is discovered within the first 14 days post injection.  Subjects who have had RBP-6000 removed 
will be followed up according to the procedures described in the SOE (EOS/ET Visit; Appendix 
3 and Appendix 5) and Section 6.14.
6.15.5
Ancillary Medications
Treatment of signs and symptoms of opioid withdrawal after enrollment can be treated with 
ancillary medications allowed by the protocol, as clinically indicated by the Investigator or 
physician Sub-Investigator.  Subjects whose symptoms are not manageable will be discontinued 


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from the study and will be followed up according to the procedures described in the SOE 
(EOS/ET Visit; Appendix 3 and Appendix 5) and Section 6.14.
6.16
Appropriateness of Measurements
Within the study population of opioid-dependent subjects, certain common signs and symptoms 
are displayed that must be evaluated for safety and efficacy of treatment during clinical trials.  
The instruments used (e.g., COWS, SOWS, Opioid Craving VAS, and eC-SSRS) were 
developed to measure the specific symptoms exhibited by and challenges facing opioid-
dependent individuals.


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7
STUDY ACTIVITIES
This study will be conducted as a fully non-residential (outpatient) study.  An overview of the 
study is shown in Figure 2 and Figure 3.  Details on procedures/activities for this study are 
provided in Section 6 and SOEs are provided in Appendix 1, Appendix 2, Appendix 3, Appendix 
4, and Appendix 5.


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8
QUALITY CONTROL AND ASSURANCE
8.1
Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study centers, review of protocol procedures with the investigators 
and associated personnel before the study, periodic monitoring visits by the Sponsor, and direct 
transmission of clinical laboratory data from a central laboratory into the Sponsor’s (or 
designee’s) database.  Written instructions will be provided for study drug preparation and 
dosing, collection, preparation, and shipment of blood, plasma, and urine samples.  Guidelines 
for eCRF completion will be provided and reviewed with study personnel before the start of the 
study.  The Sponsor (or designee) will review eCRFs for accuracy and completeness during on-
site monitoring visits and after transmission to the Sponsor (or designee).  Any discrepancies will 
be resolved with the Investigator or suitably qualified designee, as appropriate.
8.2
Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, Standard 
Operating Procedures (SOPs), working practice documents, and applicable regulations and 
guidelines.  
In accordance with the standards defined in Sponsor SOPs and applicable regulatory 
requirements, clinical studies sponsored by Sponsor are subject to Sponsor Quality Audits at the 
study sites that will be conducted by personnel from an appropriate unit.  Site audits will be 
made periodically by the Sponsor’s (or contractor’s) qualified compliance auditing team, which 
is an independent function from the study conduct team.  Audits will include review of, but are 
not limited to, drug supply, presence of required documents, the informed consent process, and 
comparison of eCRFs with source documents.  The investigator agrees to participate with audits 
conducted at a reasonable time in a reasonable manner.  Full consultation with the Investigator 
will be made prior to and during such an audit, which will be conducted according to the Quality 
Assurance Unit SOPs.  In addition, this study is subject to inspection by regulatory authorities.  
If such a regulatory inspection occurs, the Investigator agrees to allow the regulatory inspector 
direct access to all relevant study documents.  The investigator should contact the Sponsor 
immediately if this occurs and must fully cooperate with the inspection conducted at a reasonable 
time in a reasonable manner.


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9
PLANNED STATISTICAL METHODS
9.1
General Considerations
A Statistical Analysis Plan (SAP) will be prepared after the protocol is approved and before 
database lock occurs.  The SAP will provide further details regarding the definition of analysis 
endpoints, data handling rules, and the statistical methodology to be used to address all study 
objectives.  The SAP will also include formats for the summary and analysis tables, listings, and
graphical displays.
This section describes methods for sample size determination, analysis populations, and planned 
analyses for, safety, PK, and clinical outcomes endpoints.  Additional unplanned analyses may 
be required after all planned analyses have been completed.  Any unplanned analyses will be 
clearly identified in the clinical study report.  Any deviations from the analyses described below 
will be included in the SAP, which will form Appendix 16.1.9 of the clinical study report.
Continuous variables will be summarized using descriptive statistics such as means, standard 
deviations (SD), medians, minimums, and maximums.  Categorical variables will be reported as 
frequency counts (including number missing) and the percentage of subjects in corresponding 
categories.  Individual subject data will be presented by subject in data listings.  Data listings will 
include all data collected from the initial screening visit to the end of study for all subjects 
enrolled.  
9.2
Determination of Sample Size
There is no formal sample size calculation. Approximately 300 de novo subjects as well as 
approximately 300 subjects who completed the RB-US-13-0001 efficacy study will be enrolled 
into this study to ensure at least 100 subjects reach 1 year of treatment with RBP-6000.
9.3
Analysis Populations
The following populations will be used for data analyses:
9.3.1
Safety Population
The Safety Population comprises all subjects who received at least 1 dose of RBP-6000 during 
the open-label treatment phase of the study. This population will be used for all safety analyses. 
9.3.2
Clinical Outcome Assessment and PK Populations
The Clinical Outcome Assessment population will include subjects who were dosed with 
RBP-6000 and have at least 1 post-dose Clinical Outcome Assessment value. 
The PK Population will include any subject who receives a dose of RBP-6000 or at least 1 dose 
of SUBOXONE sublingual film and has at least 1 sample collected post-dose.  
  


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9.4
Demographics and Baseline Characteristics
Demographic and baseline characteristics (gender, race, age, weight, height) will be summarized 
by treatment group using descriptive statistics.  Qualitative variables (gender, race) will be 
summarized using frequencies while quantitative variables (age, weight, height) will be 
summarized using mean, SD, median, minimum, and maximum.
9.5
Primary Analysis
9.5.1
Safety Endpoints
Safety variables will include AEs, local injection site tolerability (e.g., injection site grading); 
injection site pain using a subject-reported VAS; suicidality using the eC-SSRS, concomitant
medications; changes in clinical laboratory results (hematology, chemistry and urinalysis); vital 
sign measurements; 12-lead ECGs, physical examination results; body weight, height, BMI, and 
abdominal fat measurement (waist-to-hip ratio). Safety variables will be analyzed using the 
safety population. 
Baseline is defined as the last non-missing value prior to SC injection on Day 1.  No imputation 
of missing values will be performed.
9.5.1.1
Adverse Events
All AEs will be coded using the most up-to-date version of the Medical Dictionary for 
Regulatory Activities (MedDRA) and reported to the FDA. AEs that began more than 30 days 
after the last study subject assessment day will not be included in the safety analysis. Only 
TEAEs occurring post administration of RBP-6000 will be included in the safety analysis (See 
Section 6.10.10).
The incidence of AEs (number and percent of subjects reporting the AE at least once during the 
study) will be summarized for all AEs, by the relationship to study drug and by severity.
9.5.1.2
Laboratory Data
At each visit where clinical laboratory assessments are conducted, summary statistics for the 
absolute laboratory value and the changes from baseline will be presented.  
9.5.1.3
Vital Signs
Vital signs measurements will be assessed for clinical relevance and be performed as deemed 
medically necessary by research personnel.  Oral temperature, pulse rate, and respiration rate will 
be taken after the subject has completed a minimum 3-minute rest in the supine position.  
Systolic and diastolic BP measurements will be assessed while supine throughout the trial.
9.5.1.4
Other Variables Related to Safety
Results from 12-lead ECGs will be categorized as normal, abnormal clinically significant, or 
abnormal not clinically significant and will be summarized by time point using frequency counts 


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and percentages.  ECG interval measurements as well as change from baseline will also be 
summarized by time point using descriptive statistics (mean, median, SD, minimum, maximum).  
Additional analysis of ECG parameters will be outlined in the SAP.
Medical history will be coded using MedDRA and summarized by treatment group as described 
for AEs (Section 9.5.1.1).  Body weight, height, BMI, and abdominal fat measurement (waist-to-
hip ratio) will be summarized using descriptive statistics (mean, median, SD, minimum, 
maximum), including change from baseline.
Total eC-SSRS scores will be summarized using descriptive statistics (mean, median, SD, 
minimum, maximum), including change from baseline.  Subjects’ self-reported illicit drug use 
from the TLFB will be summarized as descriptive statistics.
Prior and concomitant medications will be coded using the most recent version of the World 
Health Organization (WHO) Drug dictionary.  Incidence (number and percent of subjects 
reporting the medication at least once during the study) will be summarized for all concomitant 
medications.
Local injection site tolerability as assessed by the Injection Site Grading scale will be 
summarized by category and severity using frequency counts and percentages similar to 
summaries for AEs (Section 9.5.1.1).  Injection Site Pain VAS scores will be summarized by 
dose, injection, and time point after injection.  The burning/stinging categorical variable 
(Yes/No) will be summarized by percent of responses in each treatment.
9.6
Secondary Analysis
9.6.1
Clinical Outcomes Assessments
COWS, SOWS and Opioid Craving VAS total scores will be summarized using descriptive 
statistics (mean, median, SD, minimum, maximum), including change from baseline. Subjects’ 
self-reported illicit drug use from the TLFB will be summarized using descriptive statistics.
The cumulative distribution function (CDF) of the percentage of urine samples negative for 
opioids, the CDF of the percentage of self-reports from the TLFB negative for illicit opioid use, 
and other outcome measures will be calculated.  
9.7
Other Analyses
9.7.1
PK/PD Modeling
The population PK model established using the data collected in the double-blind, placebo-
controlled, efficacy study (Study RB-US-13-0001) will be refined using the sparse PK samples 
collected in the present study to characterize the disposition of buprenorphine and 
norbuprenorphine following SC injections of RBP-6000, with the assessment of potential 
covariates affecting the PK of both compounds.  Subsequently, the relationships between 
buprenorphine plasma concentrations and clinical outcomes assessments will be investigated.  
These relationships will be initially assessed in a descriptive manner, and, if applicable, 


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appropriate PK/PD models will be developed to describe these relationships.  A stand-alone 
modeling analysis plan will be generated, and the results will be reported in a standalone 
modeling report. 
9.7.2
Health Economic and Outcomes Assessment
The health economic and outcomes research endpoints for this study are:

EQ-5D-5L

SF-36v2 

MSQ 

HCRU 

TEA

ASI Lite

BDI-II

BPI
Summary scores for these measures will be calculated, as appropriate. Categorical variables will 
be summarized using frequencies and percentages. Continuous measures will be summarized 
using descriptive statistics (mean, standard deviation, median, minimum, maximum) as 
appropriate. An analysis of change will be conducted. A stand-alone statistical analysis plan will 
be developed prior to database lock for health economics and outcomes research assessments. 
A separate stand-alone SAP will be developed prior to database lock with full detail regarding 
health economics and outcomes analyses.
9.8
Handling of Missing Data
For dichotomous outcome measures such as UDS results (negative; non-negative) and self-
reports for illicit opioid use (negative; non-negative), any missing observation will be recorded 
as “non-negative.” For all continuous endpoints (e.g., COWS, SOWS, and VAS), the missing 
data mechanism will be assumed to be either missing completely at random (MCAR) or missing 
at random (MAR).  The missing data will not be imputed because the analysis method, mixed 
model for repeated measures (MMRM), does not require any imputation and no sensitivity 
analyses will be performed on these variables.  For time-to-event variables, if the event of 
interest is not observed prior to withdrawal or end of treatment, the observations will be censored 
at the time of withdrawal or at the end of treatment.  For example, if some subjects still have not 
had a urine sample negative for opioids combined with self-reports negative for illicit opioid use 
when the study ends or at the time of withdrawal from the study, then the time to first urine 
sample negative for opioids combined with self-reports negative for illicit opioid use will be 
censored at the last time they were assessed.
9.9
Subjects Who are Withdrawn from the Study
Subjects who withdraw after receiving RBP-6000 will not be replaced.


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9.10
Interim Analyses
No interim analysis will be performed for this study.  


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10 ADMINISTRATIVE CONSIDERATIONS
10.1
Investigators and Study Administrative Structure
10.1.1
Reckitt Benckiser Pharmaceuticals Inc.
Reckitt Benckiser Pharmaceuticals Inc.
A subsidiary of Indivior PLC
10710 Midlothian Turnpike, Suite 430
Richmond, VA 23235
10.1.2
Investigational Site(s)
This study will be conducted at up to 50 sites in the US.
10.1.3
Laboratories
The safety laboratory tests (serum chemistry, hematology, serology, and urinalysis), as well as 
the specialty laboratory tests (Bioanalytical and Pharmacokinetic) will be conducted at a central 
laboratory that is certified and accredited to perform the assigned assessments.
Collection of safety laboratory samples is described in Section 6.6.2.  The Clinical Laboratory 
will provide normal ranges and collection, processing, and shipping instructions to the sites in a 
separate laboratory reference manual.
10.2
Institutional Review Board or Independent Ethics Committee 
Approval
The protocol will be reviewed by an independent, appropriately constituted, centralized IRB/ 
Independent Ethics Committee (IEC).  Study enrolment and protocol related procedures, which 
do not form part of the subject’s normal clinical treatment, will not be performed until the 
IRB/IEC of record has provided written approval of the protocol or a modification thereof.  The 
IRB/IEC must be constituted and operate in accordance with the principles and requirements of 
ICH GCP.
Study drug can only be supplied to the Investigator after documentation on all ethical and legal 
requirements for starting the study has been received by the Sponsor.  This documentation must 
also include an IRB/IEC membership list that contains member’s occupations.  If the IRB/IEC 
will not disclose the names of the committee members, the IRB/IEC Federalwide Assurance 
Number may be accepted as a substitute for this list.  Formal approval by the IRB/IEC should 
mention the study title, study code, study site (or region or area of jurisdiction, as applicable), 
and any other documents reviewed.  It must mention the date on which the decision was made 
and must be officially signed by a committee member.


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10.3
Ethical Conduct of the Study
The Investigator is responsible for ensuring that the clinical study is performed in accordance 
with the protocol, current ICH GCP guidelines, and applicable regulatory and country-specific 
requirements.  GCP is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects.  
Compliance with this standard provides the public assurance that the rights, safety, and 
well-being of study subjects are protected and that the clinical study data are credible.
10.4
Subject Information and Consent
Prior to the subject incurring the first study related procedure, the Investigator or designated 
individual will explain to each subject the nature of the study, its purpose, procedures, expected 
duration, alternative therapies available, and the benefits and risks involved in study 
participation. It should also be mentioned that all informed consent documents and other 
documents used in the conduct of the study have been approved by an IRB/IEC.
In the case of a non-medically qualified person conducting the consent process, he/she should 
have ready access to a medically qualified investigator to whom any questions from the study 
subject may be referred. Subjects will be given consent documents to review and the opportunity 
to ask questions. Subjects will be informed of their right to withdraw from the study at any time 
without prejudice. 
After this explanation and before any study-specific procedures have been performed, the subject 
will voluntarily sign and date the ICF to indicate he/she wishes to participate in study.  The 
Investigator or the individual designated to conduct the consent discussion for the Investigator 
will also sign and date the ICF. The time (hour and minute) the consent is signed must also be 
recorded in the subject’s source notes, by the person obtaining consent from the subject. Verbal 
informed consent followed by a signed consent short form is not acceptable to Sponsor.
Prior to participation in the study, the subject will receive a copy of the signed and dated ICF 
along with an emergency card with contact information for the Investigator and site staff in the 
event of a medical emergency during the study.
10.5
Subject Confidentiality
All subject-identifying documentation generated in this study must be considered confidential 
and must not be disclosed to any persons not directly concerned with the study without written 
permission from the subject.  However, authorized regulatory officials and Sponsor personnel (or 
their representatives) will be allowed full access to inspect and copy the records.  All subject 
bodily fluids, and/or other materials collected shall be used solely in accordance with this 
protocol and the informed consent signed by the subject, unless otherwise agreed to in writing by 
the Sponsor.
Each subject will be identified by initials and an assigned subject number when reporting study 
information to any entity outside of the study center.  Data containing subject identification will 
not be removed from the study center without subject identifiers having been redacted.


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A Certificate of Confidentiality will be obtained for this study prior to subject screening.
10.6
Study Monitoring
In accordance with applicable regulations, GCP, and Sponsor procedures, the clinical monitor(s) 
will periodically contact the site, including conducting on-site visits at intervals agreed by the 
Investigator and documented in the Clinical Monitoring Plan and the Site Initiation Visit Report.  
The clinical monitor(s) will contact the site prior to the start of the study to discuss the protocol 
and data collection procedures with site personnel.  In accordance with applicable regulations 
and GCP guidelines, the Investigator shall make available for direct access all study-related 
records upon request of the Sponsor, the Sponsor’s agents, clinical monitor(s), auditors, and/or 
IRB/IEC.  The Sponsor’s monitors will visit the site during the study in addition to maintaining 
frequent telephone and written communication.  The extent, nature, and frequency of on-site 
visits will be based on such considerations as the study objectives and/or endpoints, the purpose 
of the study, study design complexity, and enrolment rate.  
The Investigator must allow the clinical monitor(s) direct access to all relevant documents and to 
allocate his/her time and the time of his/her staff to the clinical monitor(s) to discuss findings and 
any relevant issues.
10.6.1
Study and Site Closure
Upon completion of the study, study closeout activities must be conducted by the Sponsor or its 
designee in conjunction with the Investigator, as appropriate.
In addition, the Sponsor reserves the right to temporarily suspend or prematurely discontinue this 
study at any time and for any reason.  If such action is taken, the Sponsor will discuss this with 
the Investigator (including the reason[s] for taking such action) at that time.  The Sponsor will 
also inform the regulatory authorities of the suspension or termination of the study and the 
reason(s) for the action.  If required by applicable regulations, the Investigator must inform the 
IRB/IEC promptly and provide the reason(s) for the suspension or termination.  If the study is 
prematurely discontinued, all study data and study drug remaining on site must be returned to the 
Sponsor or its designee.
10.7
Case Report Forms and Study Records
The Investigator is responsible for the quality of the data recorded in the electronic Case Report 
Forms (eCRFs).  The data recorded should be a complete and accurate account of the subject’s 
record collected during the study.  Study data are not to be gathered directly onto the eCRF but 
must be gathered onto primary source documents at the clinical site. Completion of source 
documents will precede the completion of the eCRF.  Source documents may be electronic, hard 
copy, or a combination of both.  Source documents are defined as the results of original 
observations and activities of a clinical investigation. Source documents will include, but are not 
limited to, progress notes, electronic data, screening logs, and recorded data from automated 
instruments. All source documents pertaining to this study will be maintained by the 
investigators and made available for direct inspection by the authorized study personnel outlined 


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in the ICF. The ePRO tablet will be considered the source document for individual ePRO 
elements such as study-specific scales when collected directly onto the tablet.
Data collection will be completed according to the guidelines provided by Sponsor or its 
designee.  
For all subjects who signed an informed consent, all required data are to be recorded using 
source documents and reported on the eCRF, except for study scales that are recorded directly on 
the ePRO tablet.  Site staff will receive training on the eCRF completion guidelines and 
requirements for source documentation.
Completed eCRFs will be reviewed by the study monitor in line with CRF completion guidelines 
for the study to ensure completeness and consistency.  The study monitor will review every 
subject’s eCRF with source data verification for at least all critical data points.  The source data 
verification plan for this study will define the level of source data verification required for 
non-critical data points.  Screen failure data and source documents require only source data 
verification for critical data points such as informed consent, demographics, AEs, reason for 
termination, i.e., inclusion/exclusion.  Any discrepancies found during the eCRF review will be 
clarified by the Investigator or designated individual.  This includes eCRF reviews at the site by 
Sponsor or its designee, or during quality assurance review of the data.  
An explanation must be documented for any missing data.  Any changes to information in the 
study progress notes and other source documents will be initialled and dated on the day the 
change is made by a site staff member authorized to make the change.  Changes will be made by 
striking a single line through erroneous data (so as not to obliterate the original data), and clearly 
entering the correct data (e.g., wrong data right data).  If the reason for the change is not 
apparent, a brief explanation for the change will be written in the source documentation by the 
clinician.
The Investigator must sign and date a declaration attesting to his/her responsibility for the quality 
of all data recorded, and that the data represents a complete and accurate record of each subject’s 
participation in the study.  
All eCRF entries, corrections, and alterations must be made by the Investigator or designated 
individual.  The Investigator or designated individual must adjust the eCRF (if applicable) and 
complete the query.
10.8
Data Monitoring Committee
Not applicable; there will be no data monitoring committee for this study.
10.9
Protocol Deviations
This study is intended to be conducted as described in this protocol.  At the outset of the study, a 
process for defining and handling protocol deviations will be established.  This will include 
determining which violations will be designated “key” and require immediate notification to the 
Sponsor.  In the event of a deviation from the protocol due to an emergency, accident, or 


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mistake, the Investigator or designated individual must contact the Sponsor at the earliest 
possible time by telephone.  This will allow an early joint decision regarding the subject’s 
continuation in the study.  This decision will be documented by the Investigator and the Sponsor, 
and reviewed by the monitor.  Deviations from the protocol are to be documented.  The 
Investigator or designated individual will be responsible for identifying and reporting all 
deviations, which are defined as isolated occurrences involving a procedure that did not follow 
the study protocol or study-specific procedure.  Deviations will be reported as required to the 
IRB and in the final study report.
10.10 Access to Source Documentation
The Investigator must agree to complete a subject identification and enrolment log to permit easy 
identification of each subject during and after the study.  This document will be reviewed by the 
Sponsor site contact for completeness.  The subject identification and enrollment log will be 
treated as confidential and will be filed by the Investigator in the study center file.  To ensure 
subject confidentiality, no copy will be made.  All reports and communications relating to the 
study will identify subjects by initials and assigned number only.  The Investigator must also 
complete a subject-screening log, which reports on all subjects who were seen to determine 
eligibility for inclusion in the study.
At a minimum, source documentation must be available for the following to confirm data 
collected in the eCRF: subject identification, eligibility, and study identification; study 
discussion and date of informed consent; dates of visits; results of safety and efficacy parameters 
as required by the protocol; record of all AEs; concomitant medications; study drug 
administered; date of study completion or early discontinuation, and reason for early 
discontinuation if applicable.
10.11 Data Generation and Analysis
10.11.1 Data Collection and Data Management
Study specific data that has been outlined in the protocol will be entered into the clinical 
database by individual(s) designated by the Investigator in accordance with the CRF Completion 
Guidelines.  Data is verified electronically using a series of on-line programmed edit checks that 
have been created by the CDM (Clinical Data Manager) and programmed by the Clinical Data 
Programmer or Designee.  Data discrepancies will be brought to the attention of the clinical team 
and investigated by the CRA and Site Study Coordinator.  CRAs will review and verify all data 
collected in the eCRF against source documentation during scheduled monitoring visits.  The 
CRA will work closely with the Site Study Coordinator to address any discrepancies which have 
been found so that proper resolutions can be made and documented into the clinical database.  
An audit trail within the system will track all changes made to the data.
10.11.2 Database Quality Assurance 
The clinical database will be reviewed and checked for omissions, apparent errors, and values 
requiring further clarification using computerized and manual procedures.  Data queries 
requiring clarification will be generated and addressed by the investigational site.  Only 


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authorized personnel will make corrections to the clinical database, and all corrections will be 
documented in an audit trail.  
10.12 Retention of Data
All documents pertaining to the study, including all versions of the approved study protocol, 
copy of the informed consent document and Health Insurance Portability and Accountability Act 
documents, completed eCRFs, source documents (subject records, subject diaries, hospital 
records, laboratory records, drug accountability records, etc.), and other study-related documents 
will be retained in the permanent archives of the study site.
The Investigator must therefore notify and obtain approval in writing from the Sponsor prior to 
destruction of any study records or provide an opportunity for the Sponsor to collect such 
records.  If the investigator withdraws from the study (e.g., relocation, retirement) all study-
related records should be transferred, in a written agreement with the Sponsor, to a mutually 
agreed upon designee within a Sponsor-specified timeframe.
10.13 Financial Disclosure
RBP requires, for each study, the disclosure of any financial interests from each investigator or 
sub-investigator, including financial interests of the spouse and each dependent child of the 
investigator who is directly involved in the treatment or evaluation of research subjects that 
could affect the reliability of data submitted to regulatory authorities. The collection of this 
financial interest information at the start of the study, as well as any updates should this 
information change, is required by the FDA when submitting a marketing application and is in 
line with the GCP requirement to consider any potential conflicts of interest.
10.14 Publication and Disclosure Policy
A clinical study report will be prepared following completion of the study.  The report will be a 
record of the total study conduct and will be subject to Sponsor approval and restrictions on 
distribution/disclosure.  
The study data will be owned by Sponsor.  Publication of any and all data will be at the 
discretion of Sponsor.  The Investigator will not disseminate, present, or publish any of the study 
data without the prior written approval of Sponsor to do so.


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the SF-36 health survey questionnaire. Addiction. 91(1):39-45.
Sheehan DV, Lecrubier Y, Sheehan KH, et al (1998).  The Mini-International Neuropsychiatric 
Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric 
interview for DSM–IV and ICD-10. J Clin Psychiatry. 59: 22–33.
Strain EC, Stitzer ML, Liebson IA, Bigelow GE (1996).  Buprenorphine versus methadone in the 
treatment of opioid dependence: self-reports, urinalysis, and addiction severity index. Journal of 
Clinical Psychopharmacology. 16 (1):58-67.
SUBOXONE® (buprenorphine and naloxone) sublingual film Prescribing Information. Reckitt 
Benckiser Pharmaceuticals Inc. April 2014.
Substance Abuse and Mental Health Services Administration (SAMHSA), Office of Applied 
Studies. Mortality Data From the Drug Abuse Warning Network, 2001. DAWN Series D-23, 
DHHS Pub. No. (SMA) 03-3781. Rockville, MD, 2002.
Thomas J. Drug injectors sharing cookers and cotton increase their risk of hepatitis C (2001). 
NIDA Notes 16(3):9–11.
Tompkins D, Bigelow G, Harrison J, Johnson R, Fudala P, Strain E (2009).  Concurrent 
validation of the Clinical Opiate Withdrawal Scale (COWS) and single-item indices against the 
Clinical Institute Narcotic Assessment (CINA) opioid withdrawal instrument.  Drug Alcohol 
Depend. 105:154–159.


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Clinical Study Protocol: RB-US-13-0003
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Page 79 of 168
Confidential
United Nations Office on Drugs and Crime. World Drug Report 2012. Available at 
http://www.unodc.org/unodc/en/data-and-analysis/WDR-2012.html. Accessed 14 April 2015.
U.S. Department of Health and Human Services, Food and Drug Administration, Center for 
Biologics Evaluation and Research, September 2007.  Guidance for Industry: Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials. [pdf] Available at: 
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInform
ation/Guidances/Vaccines/ucm091977.pdf.  Accessed 14 April 2015.
Vernon MK, Revicki DA, Awad AG, et al (2010).  Psychometric evaluation of the Medication 
Satisfaction Questionnaire (MSQ) to assess satisfaction with antipsychotic medication among 
schizophrenia patients. Schizophr Res. 118(1-3):271-278. 
Walsh SL, Preston KL, Stitzer ML, Cone EJ, Bigelow GE (1994).  Clinical pharmacology of 
buprenorphine: ceiling effects at high doses. Clin Pharmacol Ther. 55:569–580.
Ware JE, Jr, Kosinski M, Bjorner JB, Turner-Bowker, DM, Gandek, B. and Maruish, ME 
(2007).  User's Manual for the SF-36v2TM Health Survey (2nd Ed). Lincoln, RI, QualityMetric 
Incorporated.
White AG, Birnbaum HG, Mareva MN, et al (2005).  Direct costs of opioid abuse in an insured 
population in the United States. J Manag Care Pharm. 11(6):469-479.
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Buprenorphine in Experienced Opioid Abusers.  J Clin Psychopharmacol. 24(5):479-487.


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Appendix 1
Schedule of Events – Screening and SUBOXONE Film Induction
Evaluation
Screening
Visit 
(Up to 3 days after 
EOS Visit/Day169 
of RB-US-13-
0001for roll-over 
subjects)
SUBOXONE sublingual film
Run-In
Induction 
(3 days)
Dose Adjustment 
(1 to 11 days)
Days 
-21 to -15
Day 
-14 
Day 
-13
Day
-12
Day
-11
Day
-8
Day
-4
Day
-1
+1 day
±1 day
-1 day
Informed Consent
X
Inclusion/Exclusion Criteria Reviewed
X
IWRS
X
X
X
X
X
X
X
X
Demographics1
X
Medical History1
X
eC-SSRS (Baseline Version)
X14
Physical Examination2
X14
Vital Signs3
X14
X
X
X
X
X
X
X
Body Weight
X14
BMI Calculation
X14
Hip-to-Waist Ratio
X14
12-lead ECG (supine > 10 min)4
X14
Urine Drug Screen (UDS)
X5,14
Urine Pregnancy Test6
X
Screening Labs / Hormone Panel
X14
Urinalysis/ Hematology/Serum Chemistry
X14
Opioid Craving VAS7
X14
X
X
X
X
Clinical Opiate Withdrawal Scale (COWS)7
X14
X
X
X
X
X
X
X


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Evaluation
Screening
Visit 
(Up to 3 days after 
EOS Visit/Day169 
of RB-US-13-
0001for roll-over 
subjects)
SUBOXONE sublingual film
Run-In
Induction 
(3 days)
Dose Adjustment 
(1 to 11 days)
Days 
-21 to -15
Day 
-14 
Day 
-13
Day
-12
Day
-11
Day
-8
Day
-4
Day
-1
+1 day
±1 day
-1 day
Subjective Opiate Withdrawal Scale (SOWS)7
X14
X
X
X
X
X
X
X
BDI-II
X14,15
BPI
X14,15
TLFB Interview
X14
Concomitant Medications
X8,14
X
X
X
X
X
X
X
AE Assessment9
X14
X
X
X
X
X
X
X
Day -1 Criteria Reviewed
X10
X10
X10
X11
SUBOXONE SL film administration12
X
X
X
X13
X13
X13
X13
EQ-5D-5L
X14
SF-36v2
X14
Health Insurance
X14
HCRU
X14
TEA
X
AE = adverse event; BDI-II = Beck Depression Inventory II; BMI = body mass index; BPI = Brief Pain Inventory Short Form; COWS = Clinical Opiate 
Withdrawal Scale; eC-SSRS = electronic Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; EQ-5D-5L = EuroQol EQ-5D-5L;; 
HCRU = Healthcare resource utilization; IXRS=Interactive voice/web response system; MSQ = Medication Satisfaction Questionnaire; SF-36v2 = 36-
Item Short Form Health Survey, Version 2; SL = sublingual; SOWS = subjective opiate withdrawal scale; TEA = Treatment Effectiveness Assessment; 
TLFB = Timeline Followback; VAS = Visual Analog Scale
1.
A complete medical and psychiatric history, including use of tobacco, drugs of abuse, alcohol and caffeine.  Update demographics and medical history, 
including use of tobacco, drugs of abuse, alcohol, and caffeine for roll-over subjects.
2.
Complete examination (excluding pelvic, breast, and rectal), including general appearance, skin, head, eyes, ears, nose, throat, neck, thyroid, 
chest/lungs, heart, abdomen, lymph nodes, extremities, and a brief neurological assessment.  


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3.
Includes blood pressure (BP; supine ≥ 3 minutes), pulse oximetry, pulse rate, respiratory rate, oral temperature, and height (screening visit only).  Vital 
signs will be assessed within < 60 minutes before administration of SUBOXONE sublingual film.
4.
Must be performed prior to labs
5.
Buprenorphine is included in the UDS at Screening only.  Additional unscheduled screens may be performed if abuse is suspected.
6.
Only for female subjects who are of childbearing potential (not postmenopausal or surgically sterile for at least 1 year).
7.
Assessments should be performed prior to each SUBOXONE SL film dosing and at approximately the same time each day (±2 hours). 
8.
Include a review of previous (within 30 days prior to screen) and ongoing medications.
9.
A PK sample will be taken as soon as possible after any SAE is reported.  If possible, an additional sample should be collected when the SAE has been 
resolved.
10. This visit becomes Day -1 if the following criteria are met:

No allergic reaction to SUBOXONE sublingual film

Daily dose of SUBOXONE sublingual film between 8 mg/2 mg - 24 mg/6 mg (inclusive) buprenorphine/naloxone.

COWS score of ≤ 12

Opioid Craving VAS score of ≤ 20 mm
If Day -1 criteria are met, the subject will be scheduled the following day (Injection Visit 1/Day 1) to receive the first injection of RBP-6000 after 
enrollment criteria are met. 
11. If Day -1 criteria are not met after 14 days of SUBOXONE sublingual film treatment, and a subject still has significant withdrawal signs/symptoms and 
opioid cravings (COWS score >12 and Opioid Craving VAS >20 mm), they will not be eligible to continue in the study.  They will be provided with 
information on the options for opioid use disorder treatment.
12. SUBOXONE SL film dosing should take place at the same time of day (± 2 hours).  
13. Subjects should not take their dose of SUBOXONE SL film until after it has been determined if they have met Day -1 criteria (footnote #10).
14. RB-US-13-0001 roll-over subjects study procedures completed at EOS/Day 169 will serve as the screening assessments for Protocol RB-US-13-0003
15. Roll-over subjects who did not complete the BDI-II and the BPI at EOS/Day 169 visit will complete these assessments at Screening for Protocol RB-
US-13-0003


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Appendix 2
Schedule of Events – RBP-6000 Injection 1 – 3 Visits
Evaluation
Inj 1
Post Inj 1 Assessments
Inj 2
Post Inj 2 Assessments
Inj 3
Post Inj 3 Assessments
Wk1
D
1
Wk1
D
2
Wk2
D
8
Wk3
D
15
Wk4
D
22
Wk5
D
29
Wk5
D
30
Wk6
D
36
Wk7
D
43
Wk8
D
50
Wk9
D
57
Wk9
D
58
Wk10
D
64
W11
D
71
Wk12
D
78
Window 
+1
±2
±2
±2
±2
+1
±2
±2
±2
±2
+1
±2
±2
±2
IWRS
X
X
X
Enrollment
X
Vital Signs1
X2
X
X
X
X
X2
X
X
X
X
X2
X
X
X
X
Body Weight
X
BMI Calculation
X
Hip-to-Waist Ratio
X
12-lead ECG 
(supine > 10 min)3
X
X
X
X
X
X
X
X
X
4-hr Continuous Pulse 
Oximetry4
X
X
X
Holter Monitor
Recording5
X
X
X
Hematology/ Serum 
Chemistry6
X
X
X
X
X
X
Hormone Panel
X
Urinalysis6
X
X
X
X
X
X
Urine Pregnancy Test7
X
X
X
X
X
X
Urine Drug Screen8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK Sampling9
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE Assessment10
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
eC-SSRS (Since last-visit-
version) 11
X
X
X
X
X
X
X
X
X
X
X
X
TLFB Interview11
X
X
X
X
X
X
X
X
X
X
X
X


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Evaluation
Inj 1
Post Inj 1 Assessments
Inj 2
Post Inj 2 Assessments
Inj 3
Post Inj 3 Assessments
Wk1
D
1
Wk1
D
2
Wk2
D
8
Wk3
D
15
Wk4
D
22
Wk5
D
29
Wk5
D
30
Wk6
D
36
Wk7
D
43
Wk8
D
50
Wk9
D
57
Wk9
D
58
Wk10
D
64
W11
D
71
Wk12
D
78
Window 
+1
±2
±2
±2
±2
+1
±2
±2
±2
±2
+1
±2
±2
±2
Opioid Craving VAS11
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
COWS11
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SOWS11
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
BDI-II11
X
X
X
BPI11
X
X
X
RBP-6000 Injection
X
X
X
Injection Site Grading Scale12
X
X
X
X
X
X
Injection Site Pain VAS13
X
X
X
Injection Site Evaluation14
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Behavioral Therapy15
X
X
X
X
X
X
X
X
X
X
X
X
EQ-5D-5L11
X
X
SF-36v211
X
X
MSQ11
X
Health Insurance 11
X
X
X
HCRU 
X
X
X
TEA11
X
X
X
ASI Lite
X
X16
X16
AE = adverse event; ASI = Addiction Severity Index; BDI-II = Beck Depression Inventory II; BMI = body mass index; BPI = Brief Pain Inventory Short Form; 
COWS = Clinical Opiate Withdrawal Scale; eC-SSRS = electronic Columbia Suicide Severity Rating Scale; D = Day; ECG = electrocardiogram; EQ-5D-5L =
EuroQol EQ-5D-5L; HCRU = Healthcare resource utilization; Inj. = injection; IXRS=Interactive voice/web response system; MSQ = Medication Satisfaction 
Questionnaire; PK = pharmacokinetic/pharmacokinetics; SF-36v2 = 36-Item Short Form Health Survey, Version 2; SC = subcutaneous; SOWS = subjective 
opiate withdrawal scale; TEA = Treatment Effectiveness Assessment; TLFB = Timeline Followback; VAS = Visual Analog Scale
1.
Includes blood pressure (BP; supine ≥ 3 minutes), pulse oximetry, pulse rate, respiratory rate, and oral temperature.  
2.
Vital signs on injection days will be taken ≤ 60 minutes prior to SC injection, and then 0.5, 2, and 4 hours post SC injection (± 15 minutes).
3.
An ECG will be performed at approximately the same time of day as the Day 1 pre-injection ECG.  Must be performed prior to labs and between 30 
minutes and 2 hours before PK sample collection.


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4.
Pulse oximetry will be measured from at least 30 minutes prior to SC injection through 4 hours post injection.  Results will be recorded within 30 
minutes prior to injection and at approximately 4 hours post-injection
5.
Holter monitor recording will be obtained from at least 30 minutes prior to SC injection through 4 hours post injection.
6.
On injection days blood and urine samples will be taken ≤ 60 minutes prior to SC injection.
7.
Only for female subjects who are of childbearing potential (not postmenopausal or surgically sterile for at least 1 year).
8.
An additional urine drug screen can be done if use is suspected.  Oxycodone may not show up in all opiate assays and should be assessed separately.
9.
See PK table (Appendix 6) for exact time points.
10. A PK sample will be taken as soon as possible after any SAE is reported.  If possible, an additional sample should be collected when the SAE has been 
resolved.
11. Assessments should be performed prior to RBP-6000 injection and at approximately the same time each day ±2 hours.
12. Local injection site grading will be performed at time of SC injection (within 10 minutes), 4 hours (± 30 minutes), and 24 hours (±4 hours) post SC 
injection.
13. Injection Site Pain VAS will be completed by the subject within 1 minute after the completion of the injection and then at  5, 10, 15, 30, 60, and 120 
minutes (± 5 minutes) post-completion of injection.
14. Injection site will be evaluated for evidence of attempted removal.  
15. Subjects will receive manual-guided, individual behavioral therapy.
16. Collect information for the Employment/Support Status, Alcohol, Drug, Legal, Family/Social, and Psychological section only. Follow-up 
version of the questionnaire (only circled items, no lifetime recall).


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Appendix 3
Schedule of Events – RBP-6000 Injection 4 – 6 Visits for all Subjects and End of 
Study/Early Termination and Follow-Up Visits for Roll-over Subjects
Evaluation
Inj 4
Post Inj 4 
Assessments
Inj 5
Post Inj 5 
Assessments
Inj 6
Post Inj 6 
Assessments
EOS/ET/
Safety Follow-Up
Wk13D
85
Wk13
D
86
W15
D
99
Wk17
D
113
Wk17
D
114
Wk19
D
127
Wk21
D
141
Wk21
D
142
W23
D
155
Wk25
D
16917
Wk29
D
197
Window 
±2
+1
±2
±2
+1
±2
±2
+1
±2
±2
±2
IWRS
X
X
X
X18
X
Vital Signs 1
X2
X
X
X2
X
X
X2
X
X
X
X
Body Weight
X
X
X
BMI Calculation
X
X
X
Hip-to-Waist Ratio
X
X
X
12-lead ECG 
(supine > 10 min)3
X
X
X
X
X
4-hr Continuous 
Pulse Oximetry4
X
X
X
Holter Monitor Recording5
X
X
X
Hematology/ Serum 
Chemistry6
X
X
X
X
X
X
X
X
Hormone Panel
X
X
X
Urinalysis6
X
X
X
X
X
X
X
X
Urine Pregnancy 
Test 7
X
X
X
X
X
X
X
Serum Pregnancy Test7
X
Urine Drug Screen8
X
X
X
X
X
X
X
X
X
X
PK Sampling9
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
AE Assessment10
X
X
X
X
X
X
X
X
X
X
X


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Evaluation
Inj 4
Post Inj 4 
Assessments
Inj 5
Post Inj 5 
Assessments
Inj 6
Post Inj 6 
Assessments
EOS/ET/
Safety Follow-Up
Wk13D
85
Wk13
D
86
W15
D
99
Wk17
D
113
Wk17
D
114
Wk19
D
127
Wk21
D
141
Wk21
D
142
W23
D
155
Wk25
D
16917
Wk29
D
197
Window 
±2
+1
±2
±2
+1
±2
±2
+1
±2
±2
±2
eC-SSRS (Since last-visit-
version) 11
X
X
X
X
X
X
X
TLFB Interview11
X
X
X
X
X
X
X
Opioid Craving 
VAS11
X
X
X
X
X
X
X
X
X
X
COWS 11
X
X
X
X
X
X
X
X
X
X
SOWS 11
X
X
X
X
X
X
X
X
X
X
BDI-II11
X
X
X
X
BPI11
X
X
X
X
RBP-6000 Injection
X
X
X
Injection Site 
Grading Scale12
X
X
X
X
X
X
Injection Site Pain 
VAS13
X
X
X
Injection Site 
Evaluation14
X
X
X
X
X
X
X
X
X
X
X
Behavioral Therapy15
X
X
X
X
X
X
X
EQ-5D-5L11
X
X
SF-36v211
X
X
MSQ11
X
X
Health Insurance11
X
X
X
X
HCRU 
X
X
X
X
TEA11
X
X
X
X
ASI Lite
X16
X16
X16
X21


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Evaluation
Inj 4
Post Inj 4 
Assessments
Inj 5
Post Inj 5 
Assessments
Inj 6
Post Inj 6 
Assessments
EOS/ET/
Safety Follow-Up
Wk13D
85
Wk13
D
86
W15
D
99
Wk17
D
113
Wk17
D
114
Wk19
D
127
Wk21
D
141
Wk21
D
142
W23
D
155
Wk25
D
16917
Wk29
D
197
Window 
±2
+1
±2
±2
+1
±2
±2
+1
±2
±2
±2
Physical Examination19
X
Review of Treatment 
Options
X
X
SUBOXONE SL film 
administration20
X
EOS
X
AE = adverse event; ASI = Addiction Severity Index; BDI-II = Beck Depression Inventory II; BMI = body mass index; BPI = Brief Pain Inventory Short Form; 
COWS = Clinical Opiate Withdrawal Scale; eC-SSRS = electronic Columbia Suicide Severity Rating Scale; D = Day; ECG = electrocardiogram; EOS/ET = End 
of Study/Early Termination;EQ-5D-5L = EuroQol EQ-5D-5L; HCRU = Healthcare resource utilization; Inj. = injection; IXRS=Interactive voice/web response 
system; MSQ = Medication Satisfaction Questionnaire; PK = pharmacokinetic/pharmacokinetics; SF-36v2 = 36-Item Short Form Health Survey, Version 2; SC 
= subcutaneous; SL = sublingual; SOWS = subjective opiate withdrawal scale; TEA = Treatment Effectiveness Assessment; TLFB = Timeline Followback; 
VAS = Visual Analog Scale.
1.
Includes blood pressure (BP; supine ≥ 3 minutes), pulse oximetry, pulse rate, respiratory rate, and oral temperature.  
2.
Vital signs on injection days will be taken ≤ 60 minutes prior to SC injection, and then 0.5, 2, and 4 hours post SC injection (± 15 minutes).
3.
An ECG will be performed at approximately the same time of day as the Day 1 pre-injection ECG.  Must be performed prior to labs and between 30 minutes 
and 2 hours before PK sample collection.
4.
Pulse oximetry will be measured from at least 30 minutes prior to SC injection through 4 hours post injection.  Results will be recorded within 30 minutes 
prior to injection and at approximately 4 hours post injection. 
5.
Holter monitor recording will be obtained from at least 30 minutes prior to SC injection through 4 hours post injection. 
6.
On injection days blood and urine samples will be taken ≤ 60 min prior to SC injection.
7.
Only for female subjects who are of childbearing potential (not postmenopausal or surgically sterile for at least 1 year).
8.
An additional urine drug screen can be done if use is suspected.  Oxycodone may not show up in all opiate assays and should be assessed separately.
9.
See PK table (Appendix 6) for exact time points. 
10. A PK sample will be taken as soon as possible after any SAE is reported.  If possible, an additional sample should be collected when the SAE has been 
resolved.
11. Assessments should be performed prior to RBP-6000 injection and at approximately the same time each day ±2 hours.
12. Local injection site grading will be performed at time of SC injection (within 10 minutes), 4 hours (± 30 minutes), and 24 hours (±4 hours) post SC injection. 
13. Injection Site Pain VAS will be completed by the subject within 1 minute after completion of the injection and then at  5, 10, 15, 30, 60, and 120 (± 5 
minutes) post-completion of injection.


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14. Injection site will be evaluated for evidence of attempted removal.  
15. Subjects will receive manual-guided, individual behavioral therapy at least once a week.
16. Collect information for the Employment/Support Status, Alcohol, Drug, Legal, Family/Social, and Psychological section only.  Follow-up version of the 
questionnaire (only circled items, no lifetime recall.)
17. For roll-over subjects, the procedures at Week 25/Day 169 will serve as the EOS assessments.  For de novo subjects who discontinued participation in the 
study after receiving RBP-6000, the procedures at Week 25/Day 169 will serve as the ET assessments.
18. IXRS contacted to confirm study completion or discontinuation status (date and reason for discontinuation).
19. Complete examination (excluding pelvic, breast, and rectal), including general appearance, skin, head, eyes, ears, nose, throat, neck, thyroid, chest/lungs, 
heart, abdomen, lymph nodes, extremities, and a brief neurological assessment.  
20. Return to the same dose that was used on Day -1.
21. Complete all ASI-Lite scales. Follow-up version of the questionnaire (only circled items, no lifetime recall).


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Clinical Study Protocol: RB-US-13-0003
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Appendix 4
Schedule of Events – RBP-6000 Injection 7 – 9 Visits for de novo Subjects 
Evaluation
Inj 7
Post Inj 7 
Assessments
Inj 8
Post Inj 8 
Assessments
Inj 9
Post Inj 9 
Assessments
Wk25
D
169
Wk25
D
170
W27
D
183
Wk29
D
197
Wk29
D
198
Wk31
D
211
Wk33
D
225
Wk33
D
226
W35
D
239
Window 
±2
+1
±2
±2
+1
±2
±2
+1
±2
IWRS
X
X
X
Vital Signs 1
X2
X
X
X2
X
X
X2
X
X
Body Weight
X
BMI Calculation
X
Hip-to-Waist Ratio
X
12-lead ECG 
(supine > 10 min) 3
X
X
X
4-hr Continuous 
Pulse Oximetry4
X
X
X
Holter Monitor Recording5
X
X
X
Hematology/ Serum Chemistry6
X
X
X
X
X
X
Hormone Panel
X
Urinalysis 6
X
X
X
X
X
X
Urine Pregnancy 
Test 7
X
X
X
X
X
X
Urine Drug Screen8
X
X
X
X
X
X
X
X
X
PK Sampling9
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
AE Assessment10
X
X
X
X
X
X
X
X
X
eC-SSRS (Since last-visit-version) 11
X
X
X
X
X
X
TLFB Interview11
X
X
X
X
X
X


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Clinical Study Protocol: RB-US-13-0003
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Evaluation
Inj 7
Post Inj 7 
Assessments
Inj 8
Post Inj 8 
Assessments
Inj 9
Post Inj 9 
Assessments
Wk25
D
169
Wk25
D
170
W27
D
183
Wk29
D
197
Wk29
D
198
Wk31
D
211
Wk33
D
225
Wk33
D
226
W35
D
239
Window 
±2
+1
±2
±2
+1
±2
±2
+1
±2
Opioid Craving 
VAS11
X
X
X
X
X
X
X
X
X
COWS11
X
X
X
X
X
X
X
X
X
SOWS11
X
X
X
X
X
X
X
X
X
BDI-II11
X
X
X
BPI11
X
X
X
RBP-6000 Injection
X
X
X
Injection Site 
Grading Scale12
X
X
X
X
X
X
Injection Site Pain 
VAS13
X
X
X
Injection Site 
Evaluation14
X
X
X
X
X
X
X
X
X
Behavioral Therapy15
X
X
X
X
X
X
EQ-5D-5L11
X
SF-36v211
X
MSQ11
X
Health Insurance11
X
X
X
HCRU 
X
X
X
TEA11
X
X
X
ASI Lite
X16
X16
X16
AE = adverse event; ASI = Addiction Severity Index; BDI-II = Beck Depression Inventory II; BMI = body mass index; BPI = Brief Pain Inventory Short 
Form; COWS = Clinical Opiate Withdrawal Scale; eC-SSRS = electronic Columbia Suicide Severity Rating Scale; D = Day; ECG = electrocardiogram; EQ-
5D-5L = EuroQol EQ-5D-5L; HCRU = Healthcare resource utilization; Inj. = injection; IXRS=Interactive voice/web response system; MSQ = Medication 
Satisfaction Questionnaire; PK = pharmacokinetic/pharmacokinetics; SF-36v2 = 36-Item Short Form Health Survey, Version 2; SC = subcutaneous; SOWS 
= subjective opiate withdrawal scale; TEA = Treatment Effectiveness Assessment; TLFB = Timeline Followback; VAS = Visual Analog Scale


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1.
Includes blood pressure (BP; supine ≥ 3 minutes), pulse oximetry, pulse rate, respiratory rate, and oral temperature. 
2.
Vital signs on injection days will be taken ≤ 60 minutes prior to SC injection, and then 0.5, 2, and 4 hours post SC injection (± 15 minutes).
3.
An ECG will be performed at approximately the same time of day as the Day 1 pre-injection ECG.  Must be performed prior to labs and between 30 
minutes and 2 hours before PK sample collection.
4.
Pulse oximetry will be measured from at least 30 minutes prior to SC injection through 4 hours post injection. Results will be recorded within 30 
minutes prior to injection and at approximately 4 hours post-injection.
5.
Holter monitor recording will be obtained  at least 30 minutes prior to SC injection through 4 hours post injection. 
6.
On injection days blood and urine samples will be taken ≤ 60 min prior to SC injection.
7.
Only for female subjects who are of childbearing potential (not postmenopausal or surgically sterile for at least 1 year).
8.
An additional urine drug screen can be done if use is suspected.  Oxycodone may not show up in all opiate assays and should be assessed separately.
9.
See PK table (Appendix 6) for exact time points. 
10. A PK sample will be taken as soon as possible after any SAE is reported.  If possible, an additional sample should be collected when the SAE has been 
resolved.
11. Assessments should be performed prior to RBP-6000 injection and at approximately the same time each day ±2 hours.
12. Local injection site grading will be performed at time of SC injection (within 10 minutes), 4 hours (± 30 minutes), and 24 hours (±4 hours) post SC 
injection. 
13. Injection Site Pain VAS will be completed by the subject within 1 minute after the completion of the injection and then at  5, 10, 15, 30, 60, and 120 
minutes (± 5 minutes) post-completion of injection.
14. Injection site will be evaluated for evidence of attempted removal.  
15. Subjects will receive manual-guided, individual behavioral therapy.
16. Collect information for the Employment/Support Status, Alcohol, Drug, Legal, Family/Social, and Psychological section only. Follow-up version of the 
questionnaire (only circled items, no lifetime recall).


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Clinical Study Protocol: RB-US-13-0003
14 April 2015
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Appendix 5
Schedule of Events – RBP-6000 Injection 10 – 12 Visits and End of Study/Early 
Termination Visit and Follow-Up for de novo Subjects 
Evaluation
Inj 
10
Post Inj 10 
Assessments
Inj 11
Post Inj 11 
Assessments
Inj 12
Post Inj 12 
Assessments
EOS/ET/
Safety Follow-Up
Wk37
D
253
Wk37
D
254
W39
D
267
Wk41
D
281
Wk41
D
282
Wk43
D
295
Wk45
D
309
Wk45
D
310
W47
D
323
Wk49
D
3377
Wk53
D
365
Window 
±2
+1
±2
±2
+1
±2
±2
+1
±2
±2
±2
IWRS
X
X
X
X18
X
Vital Signs1
X2
X
X
X2
X
X
X2
X
X
X
X
Body Weight
X
X
X
BMI Calculation
X
X
X
Hip-to-Waist Ratio
X
X
X
12-lead ECG 
(supine > 10 min)3
X
X
X
X
X
4-hr Continuous 
Pulse Oximetry4
X
X
X
Holter Monitor
Recording5
X
X
X
Hematology/ Serum 
Chemistry6
X
X
X
X
X
X
X
X
Hormone Panel
X
X
X
Urinalysis6
X
X
X
X
X
X
X
X
Urine Pregnancy 
Test7
X
X
X
X
X
X
X
Serum Pregnancy Test7
X
Urine Drug Screen8
X
X
X
X
X
X
X
X
X
X
PK Sampling9
X
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
AE Assessment10
X
X
X
X
X
X
X
X
X
X
X


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Clinical Study Protocol: RB-US-13-0003
14 April 2015
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Evaluation
Inj 
10
Post Inj 10 
Assessments
Inj 11
Post Inj 11 
Assessments
Inj 12
Post Inj 12 
Assessments
EOS/ET/
Safety Follow-Up
Wk37
D
253
Wk37
D
254
W39
D
267
Wk41
D
281
Wk41
D
282
Wk43
D
295
Wk45
D
309
Wk45
D
310
W47
D
323
Wk49
D
3377
Wk53
D
365
Window 
±2
+1
±2
±2
+1
±2
±2
+1
±2
±2
±2
eC-SSRS (Since last-
visit-version) 11
X
X
X
X
X
X
X
TLFB Interview11
X
X
X
X
X
X
X
Opioid Craving 
VAS11
X
X
X
X
X
X
X
X
X
X
COWS11
X
X
X
X
X
X
X
X
X
X
SOWS11
X
X
X
X
X
X
X
X
X
X
BDI-II11
X
X
X
X
BPI11
X
X
X
RBP-6000 Injection
X
X
X
Injection Site 
Grading Scale12
X
X
X
X
X
X
Injection Site Pain 
VAS13
X
X
X
Injection Site 
Evaluation14
X
X
X
X
X
X
X
X
X
X
X
Behavioral Therapy15
X
X
X
X
X
X
X
EQ-5D-5L11
X
X
SF-36v211
X
X
MSQ11
X
X
Health Insurance11
X
X
X
X
HCRU 
X
X
X
X
TEA11
X
X
X
X
ASI Lite
X 16
X 16
X 16
X 21


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Clinical Study Protocol: RB-US-13-0003
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Evaluation
Inj 
10
Post Inj 10 
Assessments
Inj 11
Post Inj 11 
Assessments
Inj 12
Post Inj 12 
Assessments
EOS/ET/
Safety Follow-Up
Wk37
D
253
Wk37
D
254
W39
D
267
Wk41
D
281
Wk41
D
282
Wk43
D
295
Wk45
D
309
Wk45
D
310
W47
D
323
Wk49
D
3377
Wk53
D
365
Window 
±2
+1
±2
±2
+1
±2
±2
+1
±2
±2
±2
Physical Examination19
X
Review of Treatment 
Options
X
X
SUBOXONE SL film 
administration20
X
EOS
X
AE = adverse event; ASI = Addiction Severity Index; BDI-II = Beck Depression Inventory II; BMI = body mass index; BPI = Brief Pain Inventory Short Form; 
COWS = Clinical Opiate Withdrawal Scale; eC-SSRS = electronic Columbia Suicide Severity Rating Scale; D = Day; ECG = electrocardiogram; EOS/ET = End 
of Study/Early Termination;EQ-5D-5L = EuroQol EQ-5D-5L; HCRU = Healthcare resource utilization; Inj. = injection; IXRS=Interactive voice/web response 
system; MSQ = Medication Satisfaction Questionnaire; PK = pharmacokinetic/pharmacokinetics; SF-36v2 = 36-Item Short Form Health Survey, Version 2; SC 
= subcutaneous; SL = sublingual; SOWS = subjective opiate withdrawal scale; TEA = Treatment Effectiveness Assessment; TLFB = Timeline Followback; 
VAS = Visual Analog Scale.
1.
Includes blood pressure (BP; supine ≥ 3 minutes), pulse oximetry, pulse rate, respiratory rate, and oral temperature.
2.
Vital signs on injection days will be taken ≤ 60 minutes prior to SC injection, and then 0.5, 2, and 4 hours post SC injection (± 15 minutes).
3.
An ECG will be performed at approximately the same time of day as the Day 1 pre-injection ECG.  Must be performed prior to labs and between 30 minutes 
and 2 hours before PK sample collection.
4.
Pulse oximetry will be measured from at least 30 minutes prior to SC injection through 4 hours post injection.  Results will be recorded within 30 minutes 
prior to injection and at approximately 4 hours post-injection
5.
Holter monitor recording will be obtained at least 30 minutes prior to SC injection through 4 hours post injection.
6.
On injection days blood and urine samples will be taken ≤ 60 min prior to SC injection.
7.
Only for female subjects who are of childbearing potential (not postmenopausal or surgically sterile for at least 1 year).
8.
An additional urine drug screen can be done if use is suspected.  Oxycodone may not show up in all opiate assays and should be assessed separately.
9.
See PK table (Appendix 6) for exact time points. 
10. A PK sample will be taken as soon as possible after any SAE is reported.  If possible, an additional sample should be collected when the SAE has been 
resolved.
11. Assessments should be performed prior to RBP-6000 injection and at approximately the same time each day ±2 hours.
12. Local injection site grading will be performed at time of SC injection (within 10 minutes), 4 hours (± 30 minutes), and 24 hours (±4 hours) post SC injection. 
13. Injection Site Pain VAS will be completed by the subject within 1 minute after the completion of the injection and then at  5, 10, 15, 30, 60, and 120 minutes 
(± 5 minutes) post-completion of injection.
14. Injection site will be evaluated for evidence of attempted removal.


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Clinical Study Protocol: RB-US-13-0003
14 April 2015
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15. Subjects will receive manual-guided, individual behavioral therapy.
16. Collect information for the Employment/Support Status, Alcohol/Drugs, Legal, Family/Social, and Psychiatric status scales only. Follow-up version of the 
questionnaire (only circled items, no lifetime recall).
17. For de novo subjects who discontinue participation in this study after receiving RBP-6000, the procedures at Week 49/Day 337 will serve as the ET 
assessments.
18. IXRS contacted to confirm study completion or discontinuation status (date and reason for discontinuation).
19. Complete examination (excluding pelvic, breast, and rectal), including general appearance, skin, head, eyes, ears, nose, throat, neck, thyroid, chest/lungs, 
heart, abdomen, lymph nodes, extremities, and a brief neurological assessment.  
20. Return to the same dose that was used on Day -1.
21. Complete all ASI-Lite scales. Follow-up version of the questionnaire (only circled items, no lifetime recall).


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Clinical Study Protocol: RB-US-13-0003
14 April 2015
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Appendix 6
Pharmacokinetic Sampling Schedule
Sample 
Number1
Sample 
Class
Time
Study Phase
Comments
1
PK
Day 1
Treatment phase (SC)
Within 1 hour prior to 1st SC injection 
2
PK
Day 8
Treatment phase (SC)
Post 1st SC injection
3
PK
Day 15
Treatment phase (SC)
Post 1st SC injection
4
PK
Day 22
Treatment phase (SC)
Post 1st SC injection
5
PK
Day 29
Treatment phase (SC)
Within 1 hour prior to 2nd SC injection 
6
PK
Day 36
Treatment phase (SC)
Post 2nd SC injection
7
PK
Day 43
Treatment phase (SC)
Post 2nd SC injection
8
PK
Day 50
Treatment phase (SC)
Post 2nd SC injection
9
PK
Day 57
Treatment phase (SC)
Within 1 hour prior to 3rd SC injection 
10
PK
Day 64
Treatment phase (SC)
Post 3rd SC injection
11
PK
Day 71
Treatment phase (SC)
Post 3rd SC injection
12
PK
Day 78
Treatment phase (SC)
Post 3rd SC injection
13
PK
Day 85
Treatment phase (SC)
Within 1 hour prior to 4th SC injection 
14
PK
Day 99
Treatment phase (SC)
Post 4th SC injection
15
PK
Day 113
Treatment phase (SC)
Within 1 hour prior to 5th SC injection
16
PK
Day 127
Treatment phase (SC)
Post 5th SC injection
17
PK
Day 141
Treatment phase (SC)
Within 1 hour prior to 6th SC injection
18
PK
Day 155
Treatment phase (SC)
Post 6th SC injection
19
PK
Day 169 or 
ET Visit
Treatment phase (SC)
Post 6th SC injection
20
PK
Day 337 or 
ET Visit
Treatment phase (SC)
Post 12th SC injection
PK = pharmacokinetic/pharmacokinetics; SC = subcutaneous
1 A PK sample will also be taken as soon as possible after any SAE is reported.  If possible, an additional sample 
should be collected when the SAE has been resolved.


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Clinical Study Protocol: RB-US-13-0003
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Appendix 7
SUBOXONE® 
(Buprenorphine/Nalo
xone) Sublingual 
Film Full Prescribing 
Information
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use 
SUBOXONE safely and effectively.  See full prescribing information for 
SUBOXONE.
SUBOXONE® (buprenorphine and naloxone) sublingual film for sublingual 
administration CIII
Initial U.S. Approval: 2002
----------------------------------RECENT MAJOR CHANGES---------------------------------
Dosage and Administration, Induction (2.1)
04/2014
Dosage and Administration, Patients With 
     Hepatic Impairment (2.5)
04/2014
Warnings and Precautions, Use in Patients
      With Impaired Hepatic Function (5.11)
04/2014
----------------------------------INDICATIONS AND USAGE---------------------------------
SUBOXONE sublingual film is a partial-opioid agonist indicated for treatment 
of opioid dependence.  Prescription use of this product is limited under the 
Drug Addiction Treatment Act. (1)
------------------------------DOSAGE AND ADMINISTRATION-----------------------------

For patients dependent on short-acting opioid products who are in opioid 
withdrawal; on Day 1, administer up to 8 mg/ 2 mg SUBOXONE sublingual 
film (in divided doses).  On Day 2, administer up to 16 mg/4 mg of 
SUBOXONE sublingual film as a single dose. (2.1)

For patients dependent on methadone or long-acting opioid products, 
induction onto sublingual buprenorphine monotherapy is recommended 
on Days 1 and 2 of treatment. (2.1)

For maintenance treatment, the target dosage of SUBOXONE sublingual 
film is usually 16 mg/4 mg as a single daily dose. (2.2)

Place the SUBOXONE sublingual film under the tongue, close to the base 
on the left or right side and allow to completely dissolve.  Film should not 
be chewed, swallowed, or moved after placement. (2.3)
-----------------------------DOSAGE FORMS AND STRENGTHS----------------------------
Sublingual film:  2 mg buprenorphine with 0.5 mg naloxone, 4 mg 
buprenorphine with 1 mg naloxone, 8 mg buprenorphine with 2 mg naloxone 
and 12 mg buprenorphine with 3 mg naloxone. (3) 
-------------------------------------CONTRAINDICATIONS------------------------------------
Hypersensitivity to buprenorphine or naloxone. (4)
-------------------------------WARNINGS AND PRECAUTIONS-----------------------------

Buprenorphine can be abused in a similar manner to other opioids. 
Clinical monitoring appropriate to the patient’s level of stability is 
essential. Multiple refills should not be prescribed early in treatment or 
without appropriate patient follow-up visits. (5.1) 

Significant respiratory depression and death have occurred in association 
with buprenorphine, particularly when taken by the intravenous (IV) 
route in combination with benzodiazepines or other CNS depressants 
(including alcohol). (5.2)

Consider dose reduction of CNS depressants, SUBOXONE sublingual film, 
or both in situations of concomitant prescription. (5.3)

Store SUBOXONE sublingual film safely out of the sight and reach of 
children. Buprenorphine can cause severe, possibly fatal, respiratory 
depression in children. (5.4)  

Chronic administration produces opioid-type physical dependence.  
Abrupt discontinuation or rapid dose taper may result in opioid 
withdrawal syndrome. (5.5)

Monitor liver function tests prior to initiation and during treatment and 
evaluate suspected hepatic events. (5.6)

Do not administer SUBOXONE sublingual film to patients with known 
hypersensitivity to buprenorphine or naloxone. (5.7)

An opioid withdrawal syndrome is likely to occur with parenteral misuse 
of SUBOXONE sublingual film by individuals physically dependent on full 
opioid agonists or by sublingual administration before the agonist effects
of other opioids have subsided. (5.8)

Neonatal withdrawal has been reported following use of buprenorphine 
by the mother during pregnancy. (5.9) 

SUBOXONE sublingual film is not appropriate as an analgesic. There have 
been reported deaths of opioid naïve individuals who received a 2 mg 
sublingual dose. (5.10)

Buprenorphine/naloxone products are not recommended in patients 
with severe hepatic impairment and may not be appropriate for patients 
with moderate hepatic impairment (5.11)

Caution patients about the risk of driving or operating hazardous 
machinery. (5.12)
-------------------------------------ADVERSE REACTIONS-------------------------------------
Adverse events commonly observed with the sublingual administration of 
the SUBOXONE sublingual film were oral hypoesthesia, glossodynia, oral 
mucosal erythema, headache, nausea, vomiting, hyperhidrosis, constipation, 
signs and symptoms of withdrawal, insomnia, pain, and peripheral edema. 
(6.1)    
To report SUSPECTED ADVERSE REACTIONS, contact Reckitt Benckiser 
Pharmaceuticals Inc. at 1-877-782-6966 or FDA at 1-800-FDA-1088 or 
www.fda.gov/medwatch.
--------------------------------------DRUG INTERACTIONS-----------------------------------

Monitor patients starting or ending CYP3A4 inhibitors or inducers for 
potential over or under dosing.  (7.1) 

Use caution in prescribing SUBOXONE sublingual film for patients 
receiving benzodiazepines or other CNS depressants and warn patients 
against concomitant self-administration/misuse. (7.3)
---------------------------------USE IN SPECIFIC POPULATIONS----------------------------

Pregnancy: Based on animal data, may cause fetal harm. (8.1)

Nursing mothers: Caution should be exercised when administered to a 
nursing woman. (8.3)

Safety and effectiveness of SUBOXONE sublingual film in patients below 
the age of 16 has not been established. (8.4)

Administer SUBOXONE sublingual film with caution to elderly or 
debilitated patients. (8.5)

Buprenorphine/naloxone products are not recommended in patients 
with severe hepatic impairment and may not be appropriate for 
patients with moderate hepatic impairment.  (8.6)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised:  April 2014


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Clinical Study Protocol: RB-US-13-0003
14 April 2015
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FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
        2.1
Induction
        2.2
Maintenance
        2.3
Method of Administration
        2.4
Clinical Supervision
        2.5
Patients With Hepatic Impairment
        2.6
Unstable Patients
        2.7
Stopping Treatment
        2.8
Switching Between Buprenorphine and 
Naloxone Sublingual Tablets and SUBOXONE 
Sublingual Film
        2.9
Switching Between SUBOXONE Sublingual Film 
Strengths
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
        5.1
Abuse Potential
        5.2
Respiratory Depression 
        5.3
CNS Depression 
        5.4
Unintentional Pediatric Exposure
        5.5
Dependence
        5.6
Hepatitis, Hepatic Events
        5.7
Allergic Reactions 
        5.8
Precipitation of Opioid Withdrawal Signs and 
Symptoms
        5.9
Neonatal Withdrawal
        5.10
Use in Opioid Naïve Patients
        5.11
Use in Patients With Impaired Hepatic Function
        5.12
Impairment of Ability to Drive or Operate 
Machinery 
        5.13
Orthostatic Hypotension
        5.14
Elevation of Cerebrospinal Fluid Pressure 
        5.15
Elevation of Intracholedochal Pressure
        5.16
Effects in Acute Abdominal Conditions
        5.17
General Precautions
6
ADVERSE REACTIONS
        6.1
Clinical Trials Experience
        6.2
Postmarketing Experience
7
DRUG INTERACTIONS  
        7.1
Cytochrome P-450 3A4 (CYP3A4) Inhibitors and 
Inducers
        7.2
Antiretrovirals
        7.3
Benzodiazepines
8
USE IN SPECIFIC POPULATIONS
        8.1
Pregnancy
        8.3
Nursing Mothers
        8.4
Pediatric Use
        8.5
Geriatric Use 
        8.6
Hepatic Impairment
        8.7 
Renal Impairment
9
DRUG ABUSE AND DEPENDENCE
        9.1
Controlled Substance
        9.2
Abuse
        9.3
Dependence
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
        12.1
Mechanism of Action
        12.2
Pharmacodynamics
        12.3
Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
        13.1
Carcinogenesis, Mutagenesis, Impairment of 
Fertility
16
HOW SUPPLIED / STORAGE AND HANDLING
17
PATIENT COUNSELING INFORMATION
        17.1
Safe Use
        17.2
Disposal of Unused SUBOXONE Sublingual Films
*
Sections and subsections omitted from the full 
prescribing information are not listed.


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FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
SUBOXONE sublingual film is indicated for treatment of opioid dependence and should be used as part 
of a complete treatment plan to include counseling and psychosocial support. 
Under the Drug Addiction Treatment Act (DATA) codified at 21 U.S.C. 823(g), prescription use of this 
product in the treatment of opioid dependence is limited to physicians who meet certain qualifying 
requirements, and who have notified the Secretary of Health and Human Services (HHS) of their intent 
to prescribe this product for the treatment of opioid dependence and have been assigned a unique 
identification number that must be included on every prescription.  
2
DOSAGE AND ADMINISTRATION
2.1
Induction
Prior to induction, consideration should be given to the type of opioid dependence (i.e., long- or short-
acting opioid products), the time since last opioid use, and the degree or level of opioid dependence.  To 
avoid precipitating an opioid withdrawal syndrome, the first dose of buprenorphine/naloxone should be 
started only when objective signs of moderate withdrawal appear.
On Day 1, an induction dosage of up to 8 mg /2 mg SUBOXONE sublingual film is recommended.  
Clinicians should start with an initial dose of 2 mg/ 0.5 mg or 4 mg/1 mg buprenorphine/naloxone and 
may titrate upwards in 2 or 4 mg increments of buprenorphine, at approximately 2-hour intervals, under 
supervision, to 8 mg/2 mg buprenorphine/naloxone based on the control of acute withdrawal 
symptoms.  
On Day 2, a single daily dose of up to 16 mg/4 mg SUBOXONE sublingual film is recommended. 
Medication should be prescribed in consideration of the frequency of visits. Provision of multiple refills is 
not advised early in treatment or without appropriate patient follow-up visits.
Patients dependent on methadone or long-acting opioid products
Patients dependent upon methadone or long-acting opioid products may be more susceptible to 
precipitated and prolonged withdrawal during induction than those on short-acting opioid products.  
Buprenorphine/naloxone combination products have not been evaluated in adequate and well-
controlled studies for induction in patients on long-acting opioid products, and contain naloxone, which 
is absorbed in small amounts by the sublingual route and could cause worse precipitated and prolonged 
withdrawal.  For this reason, buprenorphine monotherapy is recommended in patients taking long-
acting opioids when used according to approved administration instructions.  Following induction, the 
patient may then be transitioned to once-daily SUBOXONE sublingual film.
Patients dependent on heroin or other short-acting opioid products 
Patients dependent on heroin or short-acting opioid products may be inducted with either SUBOXONE 
sublingual film or with sublingual buprenorphine monotherapy.  The first dose of SUBOXONE sublingual 
film or buprenorphine should be administered when objective signs of moderate opioid withdrawal 
appear, and not less than 6 hours after the patient last used an opioid.


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It is recommended that an adequate maintenance dose, titrated to clinical effectiveness, be achieved as 
rapidly as possible.  In some studies, a too-gradual induction over several days led to a high rate of drop-
out of buprenorphine patients during the induction period.
2.2
Maintenance 
The dosage of SUBOXONE sublingual film from Day 3 onwards should be progressively adjusted in 
increments/decrements of 2 mg/0.5 mg or 4 mg/1 mg buprenorphine/naloxone to a level that holds the 
patient in treatment and suppresses opioid withdrawal signs and symptoms.
After treatment induction and stabilization, the maintenance dose of SUBOXONE sublingual film is 
generally in the range of 4 mg/1 mg buprenorphine/naloxone to 24 mg/6 mg buprenorphine/naloxone per 
day depending on the individual patient and clinical response.  The recommended target dosage of 
SUBOXONE sublingual film during maintenance is 16 mg/4 mg buprenorphine/naloxone/day as a single 
daily dose.  Dosages higher than 24 mg/6 mg daily have not been demonstrated to provide a clinical 
advantage. 
2.3
Method of Administration
Do not cut, chew, or swallow SUBOXONE sublingual film.  Place the SUBOXONE sublingual film under the 
tongue, close to the base on the left or right side.  If an additional sublingual film is necessary to achieve 
the prescribed dose, place the additional sublingual film sublingually on the opposite side from the first 
film.  Place the sublingual film in a manner to minimize overlapping as much as possible.  The sublingual 
film must be kept under the tongue until the film is completely dissolved.  SUBOXONE sublingual film 
should NOT be moved after placement. Proper administration technique should be demonstrated to the 
patient. 
2.4 
Clinical Supervision
Treatment should be initiated with supervised administration, progressing to unsupervised 
administration as the patient’s clinical stability permits. SUBOXONE sublingual film is subject to 
diversion and abuse. When determining the prescription quantity for unsupervised administration, 
consider the patient’s level of stability, the security of his or her home situation, and other factors likely 
to affect the ability to manage supplies of take-home medication.
Ideally patients should be seen at reasonable intervals (e.g., at least weekly during the first month of 
treatment) based upon the individual circumstances of the patient. Medication should be prescribed in 
consideration of the frequency of visits. Provision of multiple refills is not advised early in treatment or 
without appropriate patient follow-up visits. Periodic assessment is necessary to determine compliance 
with the dosing regimen, effectiveness of the treatment plan, and overall patient progress.
Once a stable dosage has been achieved and patient assessment (e.g., urine drug screening) does not 
indicate illicit drug use, less frequent follow-up visits may be appropriate. A once-monthly visit schedule 
may be reasonable for patients on a stable dosage of medication who are making progress toward their 
treatment objectives. Continuation or modification of pharmacotherapy should be based on the 
physician’s evaluation of treatment outcomes and objectives such as:
1. Absence of medication toxicity.


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2. Absence of medical or behavioral adverse effects.
3. Responsible handling of medications by the patient.
4. Patient’s compliance with all elements of the treatment plan (including recovery-oriented activities, 
psychotherapy, and/or other psychosocial modalities).
5. Abstinence from illicit drug use (including problematic alcohol and/or benzodiazepine use). 
If treatment goals are not being achieved, the physician should re-evaluate the appropriateness of 
continuing the current treatment. 
2.5 
Patients With Hepatic Impairment 
Because the doses of this fixed combination product cannot be individually titrated, severe hepatic 
impairment results in a reduced clearance of naloxone to a much greater extent than buprenorphine, 
and moderate hepatic impairment also results in a reduced clearance of naloxone to a greater extent 
than buprenorphine, the combination product should generally be avoided in patients with severe 
hepatic impairment and may not be appropriate for patients with moderate hepatic impairment [see 
Warnings and Precautions (5.11)].
2.6
Unstable Patients
Physicians will need to decide when they cannot appropriately provide further management for 
particular patients.  For example, some patients may be abusing or dependent on various drugs, or 
unresponsive to psychosocial intervention such that the physician does not feel that he/she has the 
expertise to manage the patient.  In such cases, the physician may want to assess whether to refer the 
patient to a specialist or more intensive behavioral treatment environment.  Decisions should be based 
on a treatment plan established and agreed upon with the patient at the beginning of treatment.
Patients who continue to misuse, abuse, or divert buprenorphine products or other opioids should be 
provided with, or referred to, more intensive and structured treatment.
2.7
Stopping Treatment
The decision to discontinue therapy with SUBOXONE sublingual film after a period of maintenance 
should be made as part of a comprehensive treatment plan.  Taper patients to avoid opioid withdrawal 
signs and symptoms.


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2.8
Switching Between Buprenorphine or Buprenorphine and Naloxone Sublingual Tablets and 
SUBOXONE Sublingual Film
Patients being switched between buprenorphine and naloxone or buprenorphine only sublingual tablets 
and SUBOXONE sublingual film should be started on the corresponding dosage of the previously 
administered product.  However, dosage adjustments may be necessary when switching between 
products.  Not all strengths and combinations of the SUBOXONE sublingual films are bioequivalent to 
the SUBOXONE (buprenorphine and naloxone) sublingual tablets as observed in pharmacokinetic studies 
[see Clinical Pharmacology (12.3)].  Therefore, systemic exposures of buprenorphine and naloxone may 
be different when patients are switched from tablets to film or vice-versa. Patients should be monitored 
for symptoms related to over-dosing or under-dosing.
2.9
Switching Between SUBOXONE Sublingual Film Strengths
As indicated in Table 1, the sizes and the compositions of the four units of SUBOXONE sublingual films, 
i.e., 
2 mg/0.5 mg, 4 mg/1 mg, 8 mg/2 mg and the 12 mg/3 mg units, are different from one another. If 
patients switch between various combinations of lower and higher strength units of SUBOXONE 
sublingual films to obtain the same total dose, (e.g., from three 4 mg/1 mg units to a single 12 mg/3 mg 
unit, or vice-versa), systemic exposures of buprenorphine and naloxone may be different and patients 
should be monitored for over-dosing or under-dosing.  For this reason, pharmacist should not substitute 
one or more film strengths for another without approval of the prescriber.
Table 1.  Comparison of Available SUBOXONE Sublingual Film Strengths by Dimensions and Drug 
Concentrations.
SUBOXONE sublingual film unit strength 
(buprenorphine/naloxone)
SUBOXONE sublingual 
film unit dimensions
Buprenorphine 
Concentration
% (w/w)
Naloxone 
Concentration
% (w/w)
2 mg/0.5 mg
22.0 mm x 12.8 mm
5.4
1.53
4 mg/1 mg 
(2 times the length of the 2 mg/0.5 mg unit)
22.0 mm x 25.6 mm
5.4
1.53
8 mg/2 mg 
22.0 mm x 12.8 mm
17.2
4.88
12 mg/3 mg
(1.5 times the length of the 8 mg/2 mg unit)
22 mm X 19.2 mm
17.2
4.88
3
DOSAGE FORMS AND STRENGTHS
SUBOXONE sublingual film is supplied as an orange rectangular sublingual film with a white printed logo 
in four dosage strengths:

buprenorphine/naloxone 2 mg/0.5 mg, 


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
buprenorphine/naloxone 4 mg/1 mg,

buprenorphine/naloxone 8 mg/2 mg and

buprenorphine/naloxone 12 mg/3 mg
4
CONTRAINDICATIONS
SUBOXONE sublingual film should not be administered to patients who have been shown to be 
hypersensitive to buprenorphine or naloxone as serious adverse reactions, including anaphylactic shock, 
have been reported [see Warnings and Precautions (5.7)].
5
WARNINGS AND PRECAUTIONS
5.1
Abuse Potential 
Buprenorphine can be abused in a manner similar to other opioids, legal or illicit. Prescribe and dispense 
buprenorphine with appropriate precautions to minimize risk of misuse, abuse, or diversion, and ensure 
appropriate protection from theft, including in the home. Clinical monitoring appropriate to the 
patient’s level of stability is essential. Multiple refills should not be prescribed early in treatment or 
without appropriate patient follow-up visits [see Drug Abuse and Dependence (9.2)].
5.2
Respiratory Depression 
Buprenorphine, particularly when taken by the IV route, in combination with benzodiazepines or other 
CNS depressants (including alcohol), has been associated with significant respiratory depression and 
death.  Many, but not all, post-marketing reports regarding coma and death associated with the 
concomitant use of buprenorphine and benzodiazepines involved misuse by self-injection. Deaths have 
also been reported in association with concomitant administration of buprenorphine with other 
depressants such as alcohol or other CNS depressant drugs.  Patients should be warned of the potential 
danger of self-administration of benzodiazepines or other depressants while under treatment with 
SUBOXONE sublingual film [see Drug Interactions (7.3)].
In the case of overdose, the primary management should be the re-establishment of adequate 
ventilation with mechanical assistance of respiration, if required.  Naloxone may be of value for the 
management of buprenorphine overdose. Higher than normal doses and repeated administration may 
be necessary.
SUBOXONE sublingual film should be used with caution in patients with compromised respiratory 
function (e.g., chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, 
hypoxia, hypercapnia, or pre-existing respiratory depression).
5.3
CNS Depression 
Patients receiving buprenorphine in the presence of opioid analgesics, general anesthetics, 
benzodiazepines, phenothiazines, other tranquilizers, sedative/hypnotics, or other CNS depressants 
(including alcohol) may exhibit increased CNS depression.  Consider dose reduction of CNS depressants, 
SUBOXONE sublingual film, or both in situations of concomitant prescription [see Drug Interactions 
(7.3)].
5.4
Unintentional Pediatric Exposure
Buprenorphine can cause severe, possibly fatal, respiratory depression in children who are accidentally 
exposed to it.  Store buprenorphine-containing medications safely out of the sight and reach of children.


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5.5
Dependence
Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces 
physical dependence of the opioid type, characterized by withdrawal signs and symptoms upon abrupt 
discontinuation or rapid taper.  The withdrawal syndrome is typically milder than seen with full agonists 
and may be delayed in onset.  Buprenorphine can be abused in a manner similar to other opioids.  This 
should be considered when prescribing or dispensing buprenorphine in situations when the clinician is 
concerned about an increased risk of misuse, abuse, or diversion [see Drug Abuse and Dependence 
(9.3)].
5.6
Hepatitis, Hepatic Events
Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving 
buprenorphine in clinical trials and through post-marketing adverse event reports.  The spectrum of 
abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports 
of death, hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy.  In many 
cases, the presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C 
virus, concomitant usage of other potentially hepatotoxic drugs, and ongoing injecting drug use may 
have played a causative or contributory role.  In other cases, insufficient data were available to 
determine the etiology of the abnormality.  Withdrawal of buprenorphine has resulted in amelioration 
of acute hepatitis in some cases; however, in other cases no dose reduction was necessary.  The 
possibility exists that buprenorphine had a causative or contributory role in the development of the 
hepatic abnormality in some cases.  Liver function tests, prior to initiation of treatment are 
recommended to establish a baseline.  Periodic monitoring of liver function during treatment is also 
recommended.  A biological and etiological evaluation is recommended when a hepatic event is 
suspected.  Depending on the case, SUBOXONE sublingual film may need to be carefully discontinued to 
prevent withdrawal signs and symptoms and a return by the patient to illicit drug use, and strict 
monitoring of the patient should be initiated. 
5.7
Allergic Reactions 
Cases of hypersensitivity to buprenorphine and naloxone containing products have been reported both 
in clinical trials and in the post-marketing experience.  Cases of bronchospasm, angioneurotic edema, 
and anaphylactic shock have been reported. The most common signs and symptoms include rashes, 
hives, and pruritus.  A history of hypersensitivity to buprenorphine or naloxone is a contraindication to 
the use of SUBOXONE sublingual film. 
5.8
Precipitation of Opioid Withdrawal Signs and Symptoms 
Because it contains naloxone, SUBOXONE sublingual film is likely to produce withdrawal signs and 
symptoms if misused parenterally by individuals dependent on full opioid agonists such as heroin, 
morphine, or methadone.  Because of the partial agonist properties of buprenorphine, SUBOXONE 
sublingual film may precipitate opioid withdrawal signs and symptoms in such persons if administered 
sublingually before the agonist effects of the opioid have subsided. 


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5.9
Neonatal Withdrawal
Neonatal withdrawal has been reported in the infants of women treated with buprenorphine during 
pregnancy.  From post-marketing reports, the time to onset of neonatal withdrawal signs ranged from 
Day 1 to Day 8 of life with most cases occurring on Day 1.  Adverse events associated with the neonatal 
withdrawal syndrome included hypertonia, neonatal tremor, neonatal agitation, and myoclonus, and 
there have been reports of convulsions, apnea, respiratory depression, and bradycardia. 
5.10
Use in Opioid Naïve Patients
There have been reported deaths of opioid naive individuals who received a 2 mg dose of 
buprenorphine as a sublingual tablet for analgesia. SUBOXONE sublingual film is not appropriate as an 
analgesic.
5.11
Use in Patients With Impaired Hepatic Function
Buprenorphine/naloxone products are not recommended in patients with severe hepatic impairment 
and may not be appropriate for patients with moderate hepatic impairment.  Because hepatic 
impairment results in a reduced clearance of naloxone to a much greater extent than buprenorphine, 
the doses of buprenorphine and naloxone in this fixed-dose combination product cannot be individually 
titrated. Therefore, patients with severe hepatic impairment will be exposed to substantially higher 
levels of naloxone than patients with normal hepatic function. This may result in an increased risk of 
precipitated withdrawal at the beginning of treatment (induction) and may interfere with 
buprenorphine’s efficacy throughout treatment.  In patients with moderate hepatic impairment, the 
differential reduction of naloxone clearance compared to buprenorphine clearance is not as great as in 
subjects with severe hepatic impairment.  Therefore, buprenorphine/naloxone products are not 
recommended for initiation of treatment (induction) in patients with moderate hepatic impairment due 
to the increased risk of precipitated withdrawal. However, buprenorphine/naloxone products may be 
used with caution for maintenance treatment in patients with moderate hepatic impairment who have 
initiated treatment on a buprenorphine product without naloxone. However, patients should be 
carefully monitored and consideration given to the possibility of naloxone interfering with 
buprenorphine’s efficacy [see Use in Specific Populations (8.6)].
5.12
Impairment of Ability to Drive or Operate Machinery 
SUBOXONE sublingual film may impair the mental or physical abilities required for the performance of 
potentially dangerous tasks such as driving a car or operating machinery, especially during treatment 
induction and dose adjustment.  Patients should be cautioned about driving or operating hazardous 
machinery until they are reasonably certain that SUBOXONE sublingual film therapy does not adversely 
affect his or her ability to engage in such activities.  
5.13
Orthostatic Hypotension
Like other opioids, SUBOXONE sublingual film may produce orthostatic hypotension in ambulatory 
patients.
5.14
Elevation of Cerebrospinal Fluid Pressure 
Buprenorphine, like other opioids, may elevate cerebrospinal fluid pressure and should be used with 
caution in patients with head injury, intracranial lesions, and other circumstances when cerebrospinal 
pressure may be increased.  Buprenorphine can produce miosis and changes in the level of 
consciousness that may interfere with patient evaluation.


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5.15
Elevation of Intracholedochal Pressure
Buprenorphine has been shown to increase intracholedochal pressure, as do other opioids, and thus 
should be administered with caution to patients with dysfunction of the biliary tract.
5.16
Effects in Acute Abdominal Conditions
As with other opioids, buprenorphine may obscure the diagnosis or clinical course of patients with acute 
abdominal conditions.
5.17
General Precautions
SUBOXONE sublingual film should be administered with caution in debilitated patients and those with 
myxedema or hypothyroidism, adrenal cortical insufficiency (e.g., Addison's disease); CNS depression or 
coma; toxic psychoses; prostatic hypertrophy or urethral stricture; acute alcoholism; delirium tremens; 
or kyphoscoliosis.
6
ADVERSE REACTIONS
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 
the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and 
may not reflect the rates observed in practice.  
6.1
Clinical Trials Experience
The safety of SUBOXONE sublingual film is supported by clinical trials using SUBUTEX (buprenorphine) 
sublingual tablets and SUBOXONE (buprenorphine and naloxone) sublingual tablets, and other trials 
using buprenorphine sublingual solutions, as well as an open-label study in 194 patients treated with 
SUBOXONE sublingual film.  In total, safety data from clinical studies are available from over 3000 
opioid-dependent subjects exposed to buprenorphine at doses in the range used in the treatment of 
opioid dependence. Few differences in the adverse event profile were noted among SUBOXONE 
sublingual film, SUBOXONE (buprenorphine and naloxone) sublingual tablets, SUBUTEX (buprenorphine) 
sublingual tablets and a buprenorphine ethanolic sublingual solution.  
The most common adverse event (>1%) associated with the sublingual administration of the SUBOXONE 
sublingual film was oral hypoesthesia. Other adverse events were constipation, glossodynia, oral 
mucosal erythema, vomiting, intoxication, disturbance in attention, palpitations, insomnia, withdrawal 
syndrome, hyperhidrosis, and blurred vision.
Other adverse event data were derived from larger, controlled studies of SUBOXONE (buprenorphine 
and naloxone) and SUBUTEX (buprenorphine) tablets and of buprenorphine sublingual solution.  In a 
comparative study of SUBOXONE (buprenorphine and naloxone) and SUBUTEX (buprenorphine) 
sublingual tablets, adverse event profiles were similar for subjects treated with 16 mg/4 mg SUBOXONE 
(buprenorphine and naloxone) sublingual tablets or 16 mg SUBUTEX (buprenorphine) sublingual tablets.  
The following adverse events were reported to occur by at least 5% of patients in a 4 week study of 
SUBOXONE (buprenorphine and naloxone) sublingual tablets and SUBUTEX (buprenorphine) sublingual 
tablets.


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Table 2.  Adverse Events (5%) by Body System and Treatment Group in a 4 Week Study
Body System/ Adverse Event 
(COSTART Terminology)
SUBOXONE 
(buprenorphine and 
naloxone) sublingual 
tablets
16 mg/4 mg/day
N=107
n (%)
SUBUTEX 
(buprenorphine) 
sublingual tablets
16 mg/day
N=103
n (%)
Placebo
N=107
n (%)
Body as a Whole
Asthenia
7 (6.5%)
5 (4.9%)
7 (6.5%)
Chills
8 (7.5%)
8 (7.8%)
8 (7.5%)
Headache
39 (36.4%)
30 (29.1%)
24 (22.4%)
Infection
6 (5.6%)
12 (11.7%)
7 (6.5%)
Pain
24 (22.4%)
19 (18.4%)
20 (18.7%)
Pain abdomen
12 (11.2%)
12 (11.7%)
7 (6.5%)
Pain back
4 (3.7%)
8 (7.8%)
12 (11.2%)
Withdrawal syndrome
27 (25.2%)
19 (18.4%)
40 (37.4%)
Cardiovascular System
Vasodilation
10 (9.3%)
4 (3.9%)
7 (6.5%)
Digestive System
Constipation
13 (12.1%)
8 (7.8%)
3 (2.8%)
Diarrhea
4 (3.7%)
5 (4.9%)
16 (15.0%)
Nausea
16 (15.0%)
14 (13.6%)
12 (11.2%)
Vomiting
8 (7.5%)
8 (7.8%)
5 (4.7%)
Nervous System
Insomnia
15 (14.0%)
22 (21.4%)
17 (15.9%)
Respiratory System
Rhinitis
5 (4.7%)
10 (9.7%)
14 (13.1%)
Skin And Appendages
Sweating
15 (14.0%)
13 (12.6%)
11 (10.3%)
Abbreviations: COSTART = Coding Symbols for Thesaurus of Adverse Reaction Terms.
The adverse event profile of buprenorphine was also characterized in the dose-controlled study of a 
buprenorphine ethanolic solution, over a range of doses in four months of treatment.  Table 3 shows 
adverse events reported by at least 5% of subjects in any dose group in the dose-controlled trial.


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Table 3.  Adverse Events (5%) by Body System and Treatment Group in a 16 Week Study
Body 
System/ 
Adverse 
Event
(COSTART 
Terminology)
Buprenorphine Dose
Very 
Low*
N=184
n (%)
Low*
N=180
n (%)
Moderate*
N=186
n (%)
High*
N=181
n (%)
Total*
N=731
n (%)
Body as a Whole
Abscess
9 (5%)
2 (1%)
3 (2%)
2 (1%)
16 (2%)
Asthenia
26 (14%)
28 (16%)
26 (14%)
24 (13%)
104 
(14%)
Chills
11 (6%)
12 (7%)
9 (5%)
10 (6%)
42 (6%)
Fever
7 (4%)
2 (1%)
2 (1%)
10 (6%)
21 (3%)
Flu syndrome
4 (2%)
13 (7%)
19 (10%)
8 (4%)
44 (6%)
Headache
51 (28%)
62 (34%)
54 (29%)
53 (29%)
220 
(30%)
Infection
32 (17%)
39 (22%)
38 (20%)
40 (22%)
149 
(20%)
Injury 
accidental
5 (3%)
10 (6%)
5 (3%)
5 (3%)
25 (3%)
Pain
47 (26%)
37 (21%)
49 (26%)
44 (24%)
177 
(24%)
Pain back
18 (10%)
29 (16%)
28 (15%)
27 (15%)
102 
(14%)
Withdrawal 
syndrome
45 (24%)
40 (22%)
41 (22%)
36 (20%)
162 
(22%)
Digestive System
Constipation
10 (5%)
23 (13%)
23 (12%)
26 (14%)
82 (11%)
Diarrhea
19 (10%)
8 (4%)
9 (5%)
4 (2%)
40 (5%)
Dyspepsia
6 (3%)
10 (6%)
4 (2%)
4 (2%)
24 (3%)
Nausea
12 (7%)
22 (12%)
23 (12%)
18 (10%)
75 (10%)
Vomiting
8 (4%)
6 (3%)
10 (5%)
14 (8%)
38 (5%)
Nervous System
Anxiety
22 (12%)
24 (13%)
20 (11%)
25 (14%)
91 (12%)
Depression
24 (13%)
16 (9%)
25 (13%)
18 (10%)
83 (11%)
Dizziness
4 (2%)
9 (5%)
7 (4%)
11 (6%)
31 (4%)


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Insomnia
42 (23%)
50 (28%)
43 (23%)
51 (28%)
186 
(25%)
Nervousness
12 (7%)
11 (6%)
10 (5%)
13 (7%)
46 (6%)
Somnolence
5 (3%)
13 (7%)
9 (5%)
11 (6%)
38 (5%)
Respiratory System
Cough 
increase
5 (3%)
11 (6%)
6 (3%)
4 (2%)
26 (4%)
Pharyngitis
6 (3%)
7 (4%)
6 (3%)
9 (5%)
28 (4%)
Rhinitis
27 (15%)
16 (9%)
15 (8%)
21 (12%)
79 (11%)
Skin and Appendages
Sweat
23 (13%)
21 (12%)
20 (11%)
23 (13%)
87 (12%)
Special Senses
Runny eyes
13 (7%)
9 (5%)
6 (3%)
6 (3%)
34 (5%)
*Sublingual solution.  Doses in this table cannot necessarily be delivered in tablet form, but for 
comparison purposes:
1 mg solution would be less than a tablet dose of 2 mg
4 mg solution approximates a 6 mg tablet dose
8 mg solution approximates a 12 mg tablet dose
16 mg solution approximates a 24 mg tablet dose
The safety of SUBOXONE sublingual film during treatment induction is supported by a clinical trial using 16 
patients treated with SUBOXONE sublingual film and 18 treated with a buprenorphine-only sublingual film.  
Few differences in the adverse event profiles were noted between SUBOXONE sublingual film and the 
buprenorphine-only sublingual film.  
The most common adverse event occurring during treatment induction and the 3 days following induction 
using SUBOXONE sublingual film was restlessness. Other adverse events were anxiety, piloerection, 
stomach discomfort, irritability, headache, rhinorrhea, cold sweat, arthralgia, and lacrimation increased.
Four subjects left the study early on the first day of sublingual film administration.  However, there was 
not evidence to suggest that any of the four subjects experienced precipitated withdrawal secondary to 
the administration of buprenorphine or buprenorphine/naloxone sublingual films. 


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6.2
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of SUBOXONE sublingual 
film. Because these reactions are reported voluntarily from a population of uncertain size, it is not 
always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The most frequently reported postmarketing adverse events were peripheral edema, stomatitis, 
glossitis, and tongue disorder. 
7
DRUG INTERACTIONS
7.1
Cytochrome P-450 3A4 (CYP3A4) Inhibitors and Inducers
Buprenorphine is metabolized to norbuprenorphine primarily by cytochrome CYP3A4; therefore, 
potential interactions may occur when SUBOXONE sublingual film is given concurrently with agents that 
affect CYP3A4 activity.  The concomitant use of SUBOXONE sublingual film with CYP3A4 inhibitors (e.g., 
azole antifungals such as ketoconazole, macrolide antibiotics such as erythromycin, and HIV protease 
inhibitors) should be monitored and may require dose-reduction of one or both agents.
The interaction of buprenorphine with CYP3A4 inducers has not been studied; therefore, it is 
recommended that patients receiving SUBOXONE sublingual film be monitored for signs and symptoms 
of opioid withdrawal if inducers of CYP3A4 (e.g., efavirenz, phenobarbital, carbamazepine, phenytoin, 
rifampicin) are co-administered [see Clinical Pharmacology (12.3)].
7.2
Antiretrovirals
Three classes of antiretroviral agents have been evaluated for CYP3A4 interactions with buprenorphine.  
Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme 
pathway, thus no interactions with buprenorphine are expected.  Non-nucleoside reverse transcriptase 
inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine and etravirine are 
known CYP3A inducers whereas delaviridine is a CYP3A inhibitor. Significant pharmacokinetic 
interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in 
clinical studies, but these pharmacokinetic interactions did not result in any significant 
pharmacodynamic effects. It is recommended that patients who are on chronic buprenorphine 
treatment have their dose monitored if NNRTIs are added to their treatment regimen.  Studies have 
shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, 
lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant 
pharmacodynamic effects.  Other PIs with CYP3A4 inhibitory activity (atazanavir and 
atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine and patients in 
one study reported increased sedation. Symptoms of opioid excess have been found in post-marketing 
reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly.  
Monitoring of patients taking buprenorphine and atazanavir with and without ritonavir is 
recommended, and dose reduction of buprenorphine may be warranted.
7.3
Benzodiazepines
There have been a number of post-marketing reports regarding coma and death associated with the 
concomitant use of buprenorphine and benzodiazepines.  In many, but not all, of these cases, 
buprenorphine was misused by self-injection.  Preclinical studies have shown that the combination of 
benzodiazepines and buprenorphine altered the usual ceiling effect on buprenorphine-induced 
respiratory depression, making the respiratory effects of buprenorphine appear similar to those of full 


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opioid agonists.  SUBOXONE sublingual film should be prescribed with caution to patients taking 
benzodiazepines or other drugs that act on the CNS, regardless of whether these drugs are taken on the 
advice of a physician or are being abused/misused.  Patients should be warned that it is extremely 
dangerous to self-administer non-prescribed benzodiazepines while taking SUBOXONE sublingual film, 
and should also be cautioned to use benzodiazepines concurrently with SUBOXONE sublingual film only 
as directed by their physician.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category C.
Risk Summary 
There are no adequate and well-controlled studies of SUBOXONE sublingual film or 
buprenorphine/naloxone in pregnant women. Limited published data on use of buprenorphine, the 
active ingredient in SUBOXONE, in pregnancy, have not shown an increased risk of major malformations. 
All pregnancies, regardless of drug exposure, have a background risk of 2-4% for major birth defects, and 
15-20% for pregnancy loss. Reproductive and developmental studies in rats and rabbits identified 
adverse events at clinically relevant doses. Pre-and postnatal development studies in rats demonstrated 
dystocia, increased neonatal deaths, and developmental delays. No clear teratogenic effects were seen 
with a range of doses equivalent to or greater than the human dose. However, in a few studies, some 
events such as acephalus, omphalocele, and skeletal abnormalities were observed but these findings 
were not clearly treatment-related. Embryofetal death was also observed in both rats and rabbits.
SUBOXONE sublingual film should be used during pregnancy only if the potential benefit justifies the 
potential risk to the fetus. 
Clinical Considerations
Disease-associated maternal and embryo-fetal risk
Opioid dependence in pregnancy is associated with adverse obstetrical outcomes such as low birth 
weight, preterm birth, and fetal death.
Fetal/neonatal adverse reactions
Neonatal abstinence syndrome may occur in newborn infants of mothers who were on buprenorphine 
maintenance treatment. Observe newborns for poor feeding, diarrhea, irritability, tremor, rigidity, and 
seizures, and manage accordingly [see Warnings and Precautions (5.9)].
Labor or Delivery
As with all opioids, use of buprenorphine prior to delivery may result in respiratory depression in the 
newborn. Closely monitor neonates for signs of respiratory depression. An opioid antagonist such as
naloxone should be available for reversal of opioid induced respiratory depression in the neonate.
Data
Human Data
Studies have been conducted to evaluate neonatal outcomes in women exposed to buprenorphine 
during pregnancy. Limited published data on malformations from trials, observational studies, case 
series, and case reports on buprenorphine use in pregnancy have not shown an increased risk of major 
malformations. Based on these studies the incidence of neonatal abstinence syndrome is not clear and 
there does not appear to be a dose-response relationship.


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Animal Data
Effects on embryo-fetal development were studied in Sprague-Dawley rats and Russian white rabbits 
following oral (1:1) and intramuscular (IM) (3:2) administration of mixtures of buprenorphine and 
naloxone.  Following oral administration to rats and rabbits, no teratogenic effects were observed at 
buprenorphine doses up to 250 mg/kg/day and 40 mg/kg/day, respectively (estimated exposure 
approximately 150 times and 50 times, respectively, the recommended human daily sublingual dose of 
16 mg on a mg/m² basis).  No definitive drug-related teratogenic effects were observed in rats and 
rabbits at IM doses up to 30 mg/kg/day (estimated exposure approximately 20 times and 35 times, 
respectively, the recommended human daily dose of 16 mg on a mg/m² basis).  Acephalus was observed 
in one rabbit fetus from the low-dose group and omphalocele was observed in two rabbit fetuses from 
the same litter in the mid-dose group; no findings were observed in fetuses from the high-dose group.  
Following oral administration of buprenorphine to rats, dose-related post-implantation losses, 
evidenced by increases in the numbers of early resorptions with consequent reductions in the numbers 
of fetuses, were observed at doses of 10 mg/kg/day or greater (estimated exposure approximately 
6 times the recommended human daily sublingual dose of 16 mg on a mg/m² basis).  In the rabbit, 
increased post-implantation losses occurred at an oral dose of 40 mg/kg/day.  Following IM 
administration in the rat and the rabbit, post-implantation losses, as evidenced by decreases in live 
fetuses and increases in resorptions, occurred at 30 mg/kg/day.  
Buprenorphine was not teratogenic in rats or rabbits after IM or subcutaneous (SC) doses up to 5 
mg/kg/day (estimated exposure was approximately 3 and 6 times, respectively, the recommended 
human daily sublingual dose of 16 mg on a mg/m2 basis), after IV doses up to 0.8 mg/kg/day (estimated 
exposure was approximately 0.5 times and equal to, respectively, the recommended human daily 
sublingual dose of 16 mg on a mg/m2 basis), or after oral doses up to 160 mg/kg/day in rats (estimated 
exposure was approximately 95 times the recommended human daily sublingual dose of 16 mg on a 
mg/m2 basis) and 25 mg/kg/day in rabbits (estimated exposure was approximately 30 times the 
recommended human daily sublingual dose of 16 mg on a mg/m2 basis). Significant increases in skeletal 
abnormalities (e.g., extra thoracic vertebra or thoraco-lumbar ribs) were noted in rats after SC
administration of 1 mg/kg/day and up (estimated exposure was approximately 0.6 times the 
recommended human daily sublingual dose of 16 mg on a mg/m2 basis), but were not observed at oral 
doses up to 160 mg/kg/day.  Increases in skeletal abnormalities in rabbits after IM administration of 5 
mg/kg/day (estimated exposure was approximately 6 times the recommended human daily sublingual 
dose of 16 mg on a mg/m2 basis) or oral administration of 1 mg/kg/day or greater (estimated exposure 
was approximately equal to the recommended human daily sublingual dose of 16 mg on a mg/m2 basis) 
were not statistically significant.
In rabbits, buprenorphine produced statistically significant pre-implantation losses at oral doses of 1 
mg/kg/day or greater and post-implantation losses that were statistically significant at IV doses of 0.2 
mg/kg/day or greater (estimated exposure approximately 0.3 times the recommended human daily 
sublingual dose of 16 mg on a mg/m2 basis).
Dystocia was noted in pregnant rats treated intramuscularly with buprenorphine 5 mg/kg/day 
(approximately 3 times the recommended human daily sublingual dose of 16 mg on a mg/m² basis).  
Fertility, peri-, and post-natal development studies with buprenorphine in rats indicated increases in 
neonatal mortality after oral doses of 0.8 mg/kg/day and up (approximately 0.5 times the recommended 
human daily sublingual dose of 16 mg on a mg/m² basis), after IM doses of 0.5 mg/kg/day and up 
(approximately 0.3 times the recommended human daily sublingual dose of 16 mg on a mg/m² basis), 
and after SC doses of 0.1 mg/kg/day and up (approximately 0.06 times the recommended human daily 
sublingual dose of 16 mg on a mg/m² basis).  An apparent lack of milk production during these studies 
likely contributed to the decreased pup viability and lactation indices.  Delays in the occurrence of 


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righting reflex and startle response were noted in rat pups at an oral dose of 80 mg/kg/day 
(approximately 50 times the recommended human daily sublingual dose of 16 mg on a mg/m² basis).
8.3
Nursing Mothers
Risk Summary
Based on two studies in 13 lactating women, buprenorphine and its metabolite norbuprenorphine are 
present in low levels in human milk and infant urine, and available data have not shown adverse 
reactions in breastfed infants. There are no data on the combination product buprenorphine/naloxone 
in breastfeeding, however oral absorption of naloxone is minimal. Caution should be exercised when 
SUBOXONE is administered to a nursing woman. The developmental and health benefits of 
breastfeeding should be considered along with the mother’s clinical need for SUBOXONE and any 
potential adverse effects on the breastfed child from the drug or from the underlying maternal 
condition.
Clinical Considerations
Advise the nursing mother taking SUBOXONE to monitor the infant for increased drowsiness and 
breathing difficulties.
Data
Based on limited data from a study of 6 lactating women who were taking a median oral dose of 
buprenorphine of 0.29 mg/kg/day 5-8 days after delivery, breast milk contained a median infant dose of 
0.42 mcg/kg/day of buprenorphine and 0.33 mcg/kg/day of norbuprenorphine, which are equal to 0.2% 
and 0.12% of the maternal weight-adjusted dose.
Based on limited data from a study of 7 lactating women who were taking a median oral dose of 
buprenorphine of 7 mg/day an average of 1.12 months after delivery, the mean milk concentrations of 
buprenorphine and norbuprenorphine were 3.65 mcg/L and 1.94 mcg/L respectively. Based on the 
limited data from this study, and assuming milk consumption of 150 mL/kg/day, an exclusively breastfed 
infant would receive an estimated mean of 0.55 mcg/kg/day of buprenorphine and 0.29 mcg/kg/day of 
norbuprenorphine, which are 0.38% and 0.18% of the maternal weight-adjusted dose.
No adverse reactions were observed in the infants in these two studies.
8.4
Pediatric Use
The safety and effectiveness of SUBOXONE sublingual film have not been established in pediatric 
patients.  This product is not appropriate for the treatment of neonatal abstinence syndrome in 
neonates, because it contains naloxone, an opioid antagonist. 
8.5
Geriatric Use
Clinical studies of SUBOXONE sublingual film, SUBOXONE (buprenorphine and naloxone) sublingual 
tablets, or SUBUTEX (buprenorphine) sublingual tablets did not include sufficient numbers of subjects 
aged 65 and over to determine whether they responded differently than younger subjects.  Other 
reported clinical experience has not identified differences in responses between the elderly and younger 
patients.  In general, dose selection for an elderly patient should be cautious, usually starting at the low 
end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac 
function, and of concomitant disease or other drug therapy.


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8.6
Hepatic Impairment
The effect of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone has been 
evaluated in a pharmacokinetic study. Both drugs are extensively metabolized in the liver. While no 
clinically significant changes have been observed in subjects with mild hepatic impairment; the plasma 
levels have been shown to be higher and half-life values have been shown to be longer for both 
buprenorphine and naloxone in subjects with moderate and severe hepatic impairment. The magnitude 
of the effects on naloxone are greater than that on buprenorphine in both moderately and severely 
impaired subjects. The difference in magnitude of the effects on naloxone and buprenorphine are 
greater in subjects with severe hepatic impairment than in subjects with moderate hepatic impairment, 
and therefore the clinical impact of these effects is likely to be greater in patients with severe hepatic 
impairment than in patients with moderate hepatic impairment. Buprenorphine/naloxone products 
should be avoided in patients with severe hepatic impairment and may not be appropriate for patients 
with moderate hepatic impairment [see Warnings and Precautions (5.11) and Clinical Pharmacology 
(12.3)].   
8.7
Renal Impairment 
No differences in buprenorphine pharmacokinetics were observed between 9 dialysis-dependent and 
6 normal patients following IV administration of 0.3 mg buprenorphine.  The effects of renal failure on 
naloxone pharmacokinetics are unknown.
9
DRUG ABUSE AND DEPENDENCE
9.1
Controlled Substance
Buprenorphine is a Schedule III narcotic under the Controlled Substances Act.
Under the Drug Addiction Treatment Act (DATA) codified at 21 U.S.C. 823(g), prescription use of this 
product in the treatment of opioid dependence is limited to physicians who meet certain qualifying 
requirements, and who have notified the Secretary of Health and Human Services (HHS) of their intent 
to prescribe this product for the treatment of opioid dependence and have been assigned a unique 
identification number that must be included on every prescription.
9.2
Abuse

Buprenorphine, like morphine and other opioids, has the potential for being abused and is 
subject to criminal diversion. This should be considered when prescribing or dispensing buprenorphine 
in situations when the clinician is concerned about an increased risk of misuse, abuse, or diversion.  
Healthcare professionals should contact their state professional licensing board or state controlled 
substances authority for information on how to prevent and detect abuse or diversion of this product.

Patients who continue to misuse, abuse, or divert buprenorphine products or other opioids 
should be provided with or referred for more intensive and structured treatment.  

Abuse of buprenorphine poses a risk of overdose and death.  This risk is increased with the 
abuse of buprenorphine and alcohol and other substances, especially benzodiazepines.

The physician may be able to more easily detect misuse or diversion by maintaining records of 
medication prescribed including date, dose, quantity, frequency of refills, and renewal requests of 
medication prescribed.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of 
therapy, and proper handling and storage of the medication are appropriate measures that help to limit 
abuse of opioid drugs.


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9.3
Dependence 
Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces 
physical dependence of the opioid type, characterized by moderate withdrawal signs and symptoms 
upon abrupt discontinuation or rapid taper.  The withdrawal syndrome is typically milder than seen with 
full agonists and may be delayed in onset [see Warnings and Precautions (5.5)].
A neonatal withdrawal syndrome has been reported in the infants of women treated with 
buprenorphine during pregnancy [see Warnings and Precautions (5.9)].
10
OVERDOSAGE
The manifestations of acute overdose include pinpoint pupils, sedation, hypotension, respiratory 
depression, and death. 
In the event of overdose, the respiratory and cardiac status of the patient should be monitored 
carefully.  When respiratory or cardiac functions are depressed, primary attention should be given to the 
re-establishment of adequate respiratory exchange through provision of a patent airway and institution 
of assisted or controlled ventilation.  Oxygen, IV fluids, vasopressors, and other supportive measures 
should be employed as indicated.
In the case of overdose, the primary management should be the re-establishment of adequate 
ventilation with mechanical assistance of respiration, if required.  Naloxone may be of value for the 
management of buprenorphine overdose.  Higher than normal doses and repeated administration may 
be necessary. 
11
DESCRIPTION
SUBOXONE (buprenorphine and naloxone) sublingual film is an orange film, imprinted with a logo 
identifying the product and strength in white ink.  It contains buprenorphine HCl, a mu-opioid receptor 
partial agonist and a kappa-opioid receptor antagonist, and naloxone HCl dihydrate, an opioid receptor 
antagonist, at a ratio of 4:1 (ratio of free bases).  It is intended for sublingual administration and is 
available in four dosage strengths, 2 mg buprenorphine with 0.5 mg naloxone, 4 mg buprenorphine with 1 
mg naloxone,  8 mg buprenorphine with 2 mg naloxone and 12 mg buprenorphine with 3 mg naloxone.  
Each sublingual film also contains polyethylene oxide, hydroxypropyl methylcellulose, maltitol, acesulfame 
potassium, lime flavor, citric acid, sodium citrate, FD&C yellow #6, and white ink.
Chemically, buprenorphine HCl is (2S)-2-[17-Cyclopropylmethyl-4,5-epoxy-3-hydroxy-6-methoxy-
6,14-ethano-14-morphinan-7-yl]-3,3-dimethylbutan-2-ol hydrochloride.  It has the following 
chemical structure:
HO
CH3O
C(CH3)3
CH3
HO
N
O
HCl
Buprenorphine HCl has the molecular formula C29 H41 NO4 HCl and the molecular weight is 504.10.  It is 
a white or off-white crystalline powder, sparingly soluble in water, freely soluble in methanol, soluble in 
alcohol, and practically insoluble in cyclohexane.


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Chemically, naloxone HCl dihydrate is 17-Allyl-4,5 α -epoxy-3, 14-dihydroxymorphinan-6-one 
hydrochloride dihydrate.  It has the following chemical structure: 
                                                    HCl 2H2O
Naloxone hydrochloride dihydrate has the molecular formula C19H21NO4 HCl 2H2O and the molecular 
weight is 399.87.  It is a white to slightly off-white powder and is freely soluble in water, soluble in 
alcohol, and practically insoluble in toluene and ether.  
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
SUBOXONE sublingual film contains buprenorphine and naloxone.  Buprenorphine is a partial agonist at 
the mu-opioid receptor and an antagonist at the kappa-opioid receptor. Naloxone is a potent antagonist 
at mu-opioid receptors and produces opioid withdrawal signs and symptoms in individuals physically 
dependent on full opioid agonists when administered parenterally.
12.2
Pharmacodynamics

Subjective Effects:
Comparisons of buprenorphine to full opioid agonists such as methadone and hydromorphone suggest 
that sublingual buprenorphine produces typical opioid agonist effects which are limited by a ceiling 
effect. 
In opioid-experienced subjects who were not physically dependent, acute sublingual doses of 
buprenorphine/naloxone tablets produced opioid agonist effects which reached a maximum between 
doses of 8 mg/2 mg and 16 mg/4 mg buprenorphine/naloxone.  
Opioid agonist ceiling-effects were also observed in a double-blind, parallel group, dose-ranging 
comparison of single doses of buprenorphine sublingual solution (1, 2, 4, 8, 16, or 32 mg), placebo and a 
full agonist control at various doses.  The treatments were given in ascending dose order at intervals of 
at least one week to 16 opioid-experienced subjects who were not physically dependent.  Both active 
drugs produced typical opioid agonist effects.  For all measures for which the drugs produced an effect, 
buprenorphine produced a dose-related response.  However, in each case, there was a dose that 
produced no further effect.  In contrast, the highest dose of the full agonist control always produced the 
greatest effects.  Agonist objective rating scores remained elevated for the higher doses of 
buprenorphine (8-32 mg) longer than for the lower doses and did not return to baseline until 48 hours 
after drug administration.  The onset of effects appeared more rapidly with buprenorphine than with 
the full agonist control, with most doses nearing peak effect after 100 minutes for buprenorphine 
compared to 150 minutes for the full agonist control.
HO
N
O
OH
O


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
Physiologic Effects:
Buprenorphine in IV (2, 4, 8, 12 and 16 mg) and sublingual (12 mg) doses has been administered to 
opioid-experienced subjects who were not physically dependent to examine cardiovascular, respiratory, 
and subjective effects at doses comparable to those used for treatment of opioid dependence.  
Compared to placebo, there were no statistically significant differences among any of the treatment 
conditions for blood pressure, heart rate, respiratory rate, O2 saturation, or skin temperature across 
time.  Systolic BP was higher in the 8 mg group than placebo (3 hour AUC values).  Minimum and 
maximum effects were similar across all treatments.  Subjects remained responsive to low voice and 
responded to computer prompts. Some subjects showed irritability, but no other changes were 
observed. 
The respiratory effects of sublingual buprenorphine were compared with the effects of methadone in a 
double-blind, parallel group, dose ranging comparison of single doses of buprenorphine sublingual 
solution (1, 2, 4, 8, 16, or 32 mg) and oral methadone (15, 30, 45, or 60 mg) in non-dependent, opioid-
experienced volunteers. In this study, hypoventilation not requiring medical intervention was reported 
more frequently after buprenorphine doses of 4 mg and higher than after methadone. Both drugs 
decreased O2 saturation to the same degree.
Effect of Naloxone:
Physiologic and subjective effects following acute sublingual administration of buprenorphine tablets 
and buprenorphine/naloxone tablets were similar at equivalent s of buprenorphine.  Naloxone had no 
clinically significant effect when administered by the sublingual route, although blood levels of the drug 
were measurable.  Buprenorphine/naloxone, when administered sublingually to an opioid-dependent 
cohort, was recognized as an opioid agonist, whereas when administered intramuscularly, combinations 
of buprenorphine with naloxone produced opioid antagonist actions similar to naloxone.  This finding 
suggests that the naloxone in buprenorphine/naloxone tablets may deter injection of 
buprenorphine/naloxone tablets by persons with active substantial heroin or other full mu-opioid 
dependence.  However, clinicians should be aware that some opioid-dependent persons, particularly 
those with a low level of full mu-opioid physical dependence or those whose opioid physical 
dependence is predominantly to buprenorphine, abuse buprenorphine/naloxone combinations by the 
intravenous or intranasal route.  In methadone-maintained patients and heroin-dependent subjects, IV 
administration of buprenorphine/naloxone combinations precipitated opioid withdrawal signs and 
symptoms and was perceived as unpleasant and dysphoric.  In morphine-stabilized subjects, 
intravenously administered combinations of buprenorphine with naloxone produced opioid antagonist 
and withdrawal signs and symptoms that were ratio-dependent; the most intense withdrawal signs and 
symptoms were produced by 2:1 and 4:1 ratios, less intense by an 8:1 ratio.  


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12.3
Pharmacokinetics
Absorption:  
In pharmacokinetic studies, the 2 mg/0.5 mg and 4 mg/1 mg doses administered as SUBOXONE 
sublingual films showed comparable relative bioavailability to the same total dose of SUBOXONE 
(buprenorphine and naloxone) sublingual tablets, whereas the 8 mg/2 mg and 12 mg/3 mg doses 
administered as SUBOXONE sublingual films showed higher relative bioavailability for both 
buprenorphine and naloxone compared to the same total dose of SUBOXONE (buprenorphine and 
naloxone) sublingual tablets.  A combination of one 8 mg/2 mg and two 2 mg/0.5 mg SUBOXONE 
sublingual films (total dose of 12 mg/ 3 mg) showed comparable relative bioavailability to the same total 
dose of SUBOXONE (buprenorphine and naloxone) sublingual tablets [see Dosage and Administration 
(2.6 and 2.7)].
Distribution: 
Buprenorphine is approximately 96% protein bound, primarily to alpha and beta globulin.
Naloxone is approximately 45% protein bound, primarily to albumin.
Metabolism:
Buprenorphine undergoes both N-dealkylation to norbuprenorphine and glucuronidation.  The N-
dealkylation pathway is mediated primarily by the CYP3A4.  Norbuprenorphine, the major metabolite, 
can further undergo glucuronidation. Norbuprenorphine has been found to bind opioid receptors in 
vitro; however, it has not been studied clinically for opioid-like activity. Naloxone undergoes direct 
glucuronidation to naloxone-3-glucuronide as well as N-dealkylation, and reduction of the 6-oxo group.
Elimination:
A mass balance study of buprenorphine showed complete recovery of radiolabel in urine (30%) and 
feces (69%) collected up to 11 days after dosing.  Almost all of the dose was accounted for in terms of 
buprenorphine, norbuprenorphine, and two unidentified buprenorphine metabolites.  In urine, most of 
buprenorphine and norbuprenorphine was conjugated (buprenorphine, 1% free and 9.4% conjugated; 
norbuprenorphine, 2.7% free and 11% conjugated).  In feces, almost all of the buprenorphine and 
norbuprenorphine were free (buprenorphine, 33% free and 5% conjugated; norbuprenorphine, 21% free 
and 2% conjugated). Based on all studies performed with SUBOXONE sublingual film, buprenorphine has 
a mean elimination half-life from plasma ranging from 24 to 42 hours and naloxone has a mean 
elimination half-life from plasma ranging from 2 to 12 hours.

Drug-drug Interactions:
CYP3A4 Inhibitors and Inducers:  Subjects receiving SUBOXONE sublingual film should be monitored if 
inhibitors of CYP3A4 such as azole antifungal agents (e.g., ketoconazole), macrolide antibiotics (e.g., 
erythromycin) or HIV protease inhibitors and may require dose-reduction of one or both agents.  The 
interaction of buprenorphine with all CYP3A4 inducers has not been studied, therefore it is 
recommended that patients receiving SUBOXONE sublingual film be monitored for signs and symptoms 
of opioid withdrawal if inducers of CYP3A4 (e.g., phenobarbital, carbamazepine, phenytoin, rifampicin) 
are co-administered [see Drug Interactions (7.1)].
Buprenorphine has been found to be a CYP2D6 and CYP3A4 inhibitor and its major metabolite, 
norbuprenorphine, has been found to be a moderate CYP2D6 inhibitor in in vitro studies employing 
human liver microsomes. However, the relatively low plasma concentrations of buprenorphine and 
norbuprenorphine resulting from therapeutic doses are not expected to raise significant drug-drug 
interaction concerns. 


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
Special Populations:
Hepatic Impairment: In a pharmacokinetic study, the disposition of buprenorphine and naloxone were 
determined after administering a SUBOXONE 2.0/0.5 mg (Buprenorphine/Naloxone) sublingual tablet in 
subjects with varied degrees of hepatic impairment as indicated by Child-Pugh criteria. The disposition 
of buprenorphine and naloxone in patients with hepatic impairment were compared to disposition in 
subjects with normal hepatic function. 
In subjects with mild hepatic impairment, the changes in mean Cmax, AUC0-last, and half-life values of both 
buprenorphine and naloxone were not clinically significant. No dosing adjustment is needed in patients 
with mild hepatic impairment.
For subjects with moderate and severe hepatic impairment, mean Cmax, AUC0-last, and half-life values of 
both buprenorphine and naloxone were increased; the effects on naloxone are greater than that on 
buprenorphine (Table 4). 
Table 4.  Changes in Pharmacokinetic Parameters in Subjects With Moderate and Severe Hepatic 
Impairment
Hepatic 
Impairment
PK Parameters
Increase in buprenorphine 
compared to healthy subjects
Increase in naloxone 
compared to healthy 
subjects
Moderate
Cmax
8%
170%
AUC0-last
64%
218%
Half-life
35%
165%
Severe
Cmax
72%
1030%
AUC0-last
181%
1302%
Half-life
57%
122%
The difference in magnitude of the effects on naloxone and buprenorphine are greater in subjects with 
severe hepatic impairment than subjects with moderate hepatic impairment, and therefore the clinical 
impact of these effects is likely to be greater in patients with severe hepatic impairment than in patients 
with moderate hepatic impairment. Buprenorphine/naloxone products should be avoided in patients 
with severe hepatic impairment and may not be appropriate for patients with moderate hepatic 
impairment [see Warnings and Precautions (5.11) and Use in Specific Populations (8.6)].
HCV infection: In subjects with HCV infection but no sign of hepatic impairment, the changes in the 
mean Cmax, AUC0-last, and half-life values of buprenorphine and naloxone were not clinically significant in 
comparison to healthy subjects without HCV infection.  No dosing adjustment is needed in patients with 
HCV infection.


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13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity:  
Carcinogenicity data on SUBOXONE sublingual film are not available.
A carcinogenicity study of buprenorphine/naloxone (4:1 ratio of the free bases) was performed in 
Alderley Park rats.  Buprenorphine/naloxone was administered in the diet at doses of approximately 7, 
31, and 123 mg/kg/day for 104 weeks (estimated exposure was approximately 4, 18, and 44 times the 
recommended human sublingual dose of 16 mg/4 mg buprenorphine/naloxone based on buprenorphine 
AUC comparisons).  A statistically significant increase in Leydig cell adenomas was observed in all dose 
groups.  No other drug-related tumors were noted.
Carcinogenicity studies of buprenorphine were conducted in Sprague-Dawley rats and CD-1 mice. 
Buprenorphine was administered in the diet to rats at doses of 0.6, 5.5, and 56 mg/kg/day (estimated 
exposure was approximately 0.4, 3, and 35 times the recommended human daily sublingual dose of 16 
mg on a mg/m2 basis) for 27 months.  As in the buprenorphine/naloxone carcinogenicity study in rat, 
statistically significant dose-related increases in Leydig cell tumors occurred.  In an 86-week study in 
CD-1 mice, buprenorphine was not carcinogenic at dietary doses up to 100 mg/kg/day (estimated 
exposure was approximately 30 times the recommended human daily sublingual dose of 16 mg on a 
mg/m2 basis).
Mutagenicity:
The 4:1 combination of buprenorphine and naloxone was not mutagenic in a bacterial mutation assay 
(Ames test) using four strains of S. typhimurium and two strains of E. coli. The combination was not 
clastogenic in an in vitro cytogenetic assay in human lymphocytes or in an IV micronucleus test in the 
rat. 
Buprenorphine was studied in a series of tests utilizing gene, chromosome, and DNA interactions in both 
prokaryotic and eukaryotic systems.  Results were negative in yeast (S. cerevisiae) for recombinant, gene 
convertant, or forward mutations; negative in Bacillus subtilis “rec” assay, negative for clastogenicity in 
CHO cells, Chinese hamster bone marrow and spermatogonia cells, and negative in the mouse 
lymphoma L5178Y assay.
Results were equivocal in the Ames test: negative in studies in two laboratories, but positive for frame 
shift mutation at a high dose (5mg/plate) in a third study.  Results were positive in the Green-Tweets (E. 
coli) survival test, positive in a DNA synthesis inhibition (DSI) test with testicular tissue from mice, for 
both in vivo and in vitro incorporation of [3H]thymidine, and positive in unscheduled DNA synthesis 
(UDS) test using testicular cells from mice.
Impairment of Fertility: 
Dietary administration of buprenorphine in the rat at dose levels of 500 ppm or greater (equivalent to 
approximately 47 mg/kg/day or greater; estimated exposure approximately 28 times the recommended 
human daily sublingual dose of 16 mg on a mg/m2 basis) produced a reduction in fertility demonstrated 
by reduced female conception rates.  A dietary dose of 100 ppm (equivalent to approximately 10 
mg/kg/day; estimated exposure approximately 6 times the recommended human daily sublingual dose 
of 16 mg on a mg/m2 basis) had no adverse effect on fertility.


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16
HOW SUPPLIED / STORAGE AND HANDLING
SUBOXONE sublingual film is supplied as an orange rectangular sublingual film with a white printed logo 
in child-resistant polyester/foil laminated pouches:

NDC 12496-1202-3 (buprenorphine/naloxone 2 mg/0.5 mg/film; content expressed in terms of 
free base) - 30 films per carton

NDC 12496-1204-3 (buprenorphine/naloxone 4 mg/1 mg/film; content expressed in terms of 
free base) - 30 films per carton

NDC 12496-1208-3 (buprenorphine/naloxone 8 mg/2 mg/film; content expressed in terms of 
free base) -30 films per carton

NDC 12496-1212-3 (buprenorphine/naloxone 12 mg/3 mg/film; content expressed in terms of 
free base) - 30 films per carton
Store at 25°C (77°F), excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]

Patients should be advised to store buprenorphine-containing medications safely and out of 
sight and reach of children.  

Rx only
17
PATIENT COUNSELING INFORMATION
See FDA-approved patient labeling (Medication Guide)
Patients should be advised NOT to cut, chew or swallow SUBOXONE sublingual film.
17.1
Safe Use
Before initiating treatment with SUBOXONE, explain the points listed below to caregivers and 
patients. Instruct patients to read the Medication Guide each time SUBOXONE is dispensed because 
new information may be available.
Patients should be warned that it is extremely dangerous to self-administer non-prescribed 
benzodiazepines or other CNS depressants (including alcohol) while taking SUBOXONE sublingual 
film.  Patients prescribed benzodiazepines or other CNS depressants should be cautioned to use 
them only as directed by their physician [see Warnings and Precautions (5.2), Drug Interactions 
(7.3)].
Patients should be advised that SUBOXONE sublingual film contains an opioid that can be a target for 
people who abuse prescription medications or street drugs.  Patients should be cautioned to keep 
their films in a safe place, and to protect them from theft.
Patients should be instructed to keep SUBOXONE sublingual film in a secure place, out of the sight and 
reach of children.  Accidental or deliberate ingestion by a child may cause respiratory depression 
that can result in death.  Patients should be advised that if a child is exposed to SUBOXONE 
sublingual film, medical attention should be sought immediately.  
Patients should be advised never to give SUBOXONE sublingual film to anyone else, even if he or she has 
the same signs and symptoms.  It may cause harm or death.
Patients should be advised that selling or giving away this medication is against the law.
Patients should be cautioned that SUBOXONE sublingual film may impair the mental or physical abilities 
required for the performance of potentially dangerous tasks such as driving or operating machinery.  
Caution should be taken especially during drug induction and dose adjustment and until individuals 


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are reasonably certain that buprenorphine therapy does not adversely affect their ability to engage 
in such activities [see Warnings and Precautions (5.11)].
Patients should be advised not to change the dosage of SUBOXONE sublingual film without consulting 
their physician.
Patients should be advised to take SUBOXONE sublingual film once a day.
Patients should be advised that if they miss a dose of SUBOXONE they should take it as soon as they 
remember. If it is almost time for the next dose, they should skip the missed dose and take the next 
dose at the regular time.
Patients should be informed that SUBOXONE sublingual film can cause drug dependence and that 
withdrawal signs and symptoms may occur when the medication is discontinued.
Patients seeking to discontinue treatment with buprenorphine for opioid dependence should be advised 
to work closely with their physician on a tapering schedule and should be apprised of the potential 
to relapse to illicit drug use associated with discontinuation of opioid agonist/partial agonist 
medication-assisted treatment.
Patients should be cautioned that, like other opioids, SUBOXONE sublingual film may produce 
orthostatic hypotension in ambulatory individuals [see Warnings and Precautions (5.12)].
Patients should inform their physician if any other prescription medications, over-the-counter 
medications, or herbal preparations are prescribed or currently being used [see Drug Interactions 
(7.1, 7.2 and 7.3)].
Women of childbearing potential who become pregnant or are planning to become pregnant, should be 
advised to consult their physician regarding the possible effects of using SUBOXONE sublingual film
during pregnancy [see Use in Specific Populations (8.1)].
Advise women who are breastfeeding to monitor the infant for drowsiness and difficulty breathing [see 
Use in Specific Populations (8.3)].  
Patients should inform their family members that, in the event of emergency, the treating physician or 
emergency room staff should be informed that the patient is physically dependent on an opioid and 
that the patient is being treated with SUBOXONE sublingual film.
Refer to the Medication Guide for additional information regarding the counseling information.
17.2
Disposal of Unused SUBOXONE Sublingual Films
Unused SUBOXONE sublingual films should be disposed of as soon as they are no longer needed. 
Unused films should be flushed down the toilet. 
Revised: April 2014
Manufactured for Reckitt Benckiser
Pharmaceuticals Inc.,
Richmond, VA 23235 by: 
MonoSol Rx, LLC, 
Warren, NJ 07059
Distributed by:
Reckitt Benckiser Pharmaceuticals Inc.
Richmond, VA 23235


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Appendix 8
Study Drug Preparation, Administration, and Depot 
Removal Instructions
RBP-6000 PREPARATION AND DOSING PROCEDURE

100 MG BUPRENORPHINE

300 MG BUPRENORPHINE
IMPORTANT:  Only qualified study personnel can prepare the study drug. Protective gloves 
(latex or nitrile) should be worn when preparing and dosing RBP-6000.  Remove the product 
from the refrigerator at least 15 minutes before use to allow the product to reach room 
temperature before dosing.  Product may be left at room temperature up to 8 hours prior to use.  
If product is not used that day it should be marked appropriately.  
  
FOLLOW THE INSTRUCTIONS AS DIRECTED TO ENSURE PROPER DOSING
Preparation of the Product Prior to Administration: 
The following components will be used in the preparation of RBP-6000:
•
One sealed foil pouch containing a syringe pre-filled with RBP-6000 and an oxygen 
absorber pack. 
•
One sterile 19-gauge, one-inch hypodermic safety needle
1. On a clean field, open the foil pouch and remove the contents. Discard the oxygen absorber 
pack.   The pouch must be retained for accountability.
2. Un-cap the pre-filled RBP-6000 syringe and attach the safety needle cartridge by pushing in 
and turning the needle until it is finger tight. Do not strip the threaded fitting by over-
tightening the needle. Position the sheath at 90 degrees to the needle.  Pull off the needle 
cartridge cover.   More complete documentation on the usage of the SurGuard2 safety needle 
can be found in the included instruction sheet. 
3. While holding the syringe vertically with the tip upwards, expel air bubbles by stroking the 
plunger up and down.
4. The product is now ready for administration.  Carefully recap the needle.
Administration Procedure:
IMPORTANT: Once prepared (removed from foil pouch), the product must be 
administered within a maximum of 30 minutes.
Choose an injection site below the waist but above the hip bone; from where the body curves at 
the side to about 2 inches from the middle of the abdomen with adequate amounts of 
subcutaneous tissue that does not have excessive pigment, nodules, lesions, or hair.  Since you 
can vary the injection site with a subcutaneous injection, choose an area that has not recently 
been used.  
Possible injection site locations and an injection rotation pattern are shown in Figure 4.


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Figure 4
Injection Locations
1. Cleanse the injection-site area with an alcohol swab.  
2. Using the thumb and forefinger of your non-dominant hand, grab and bunch the area of skin 
around the injection site.
3. Using your dominant hand, insert approximately half the needle length quickly. The 
approximate angle you use will depend on the amount and fullness of the subcutaneous tissue 
and the length of the needle.
4. After the needle is inserted, release the skin with your nondominant hand.
5. Pull back on the plunger to check for blood.  If blood is present in the syringe, do not inject.  
Withdraw the needle and discard all components safely in an appropriate biohazard 
container.  Repeat the “Preparation of the Product Prior to Administration” procedures and 
the “Administration Procedure” using a different abdominal injection site with another 
syringe of RBP-6000 and associated components.
6. Inject the product using a slow, steady push. Press down on the plunger until the syringe is 
empty.
7. Withdraw the needle at the same angle used for insertion. Do not rub the injection area.  If 
there is bleeding, apply minimal pressure with a gauze pad or bandage.  Engage the safety 
sheath on the needle as per the SurGuard2 needle instructions.  
8. Discard all components safely in an appropriate biohazard container.
Hipbones
Waist
1 / 5
2 / 6
3
4


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PROCEDURE FOR REMOVAL OF THE RBP-6000 DEPOT
In the event of an emergency or if a subject withdraws or is withdrawn within the first 14 days of 
receiving an injection of RBP-6000, subjects may have the option to have the depot surgically 
removed by a physician delegated to perform surgery. The medically responsible physician 
should carefully discuss this option with subjects given the use of ATRIGEL Delivery System 
and the feasibility of extracting the depot.
The following surgical procedure should be followed:
1.
Palpate the depot and surrounding area to confirm its exact location.
2.
Cleanse the area with an antiseptic solution (e.g., Betadine).  
3.
Infiltrate the area with a local anesthesia (e.g., Lidocaine 1% or a lidocaine/adrenaline 
[epinephrine] mixture) and wait for it to take effect.
4.
Cover the area with a sterile drape.
5.
Incise the skin up to the subcutaneous tissues using a scalpel. 
6.
Using blunt and sharp dissection, identify the plane between the depot and surrounding 
subcutaneous tissues.  Once the plane is identified, separate the superficial 25% of the 
circumference of the depot with blunt dissection. 
7.
Gently lift the incised ellipse of skin and depot with forceps.  
8.
Once the depot is removed, ensure hemostasis, and close the skin with non-absorbable 
sutures.  
9.
The extracted RBP-6000 depot will be disposed of into an appropriate, secure biohazard 
container per the SOP at the clinical site.


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Appendix 9
Prohibited Cytochrome P450 Inhibitors and Inducers
The following medications are prohibited during the study:
Cytochrome
P450 3A4
Inhibitors
Cytochrome 
P450 3A4
Inducers
Cytochrome
P450 2C8
Inhibitors
Cytochrome
P450 2C8
Inducers
Amiodarone
Ketoconazole
Barbiturates
Gemifibrozil
Rifampicin
Amprenavir
Metronidazole
Carbamazepine
Trimethoprim
Aprepitant
Mibefradil
Dexamethasone
Glitazones
Chloramphenicol
Miconazole
Efavirenz
Montelukast
Cimetidine
Mifepristone
Ethosuximide
Quercetin
Ciprofloxacin
Nefazodone
Glucocorticoids
Clarithromycin
Nelfinavir
Glutethimide
Clotrimazole
Nicardipine
Modafinil
Cyclosporine
Norfloxacin
Nevirapine
Delavirdine
Norfluoxetine
Oxcarbazepine
Diethyl-
dithiocarbamate
Propofol
Phenobarbital
Diltiazem
Quinine
Phenytoin
Ethinyl estradiol
Ritonavir
Pioglitazone
Erythromycin
Saquinavir
Primidone
Fluconazole
Sertraline
Rifabutin
Fluoxetine
Starfruit
Rifampin
Fluvoxamine
Telithromycin
Hypericum 
perforatum
Gestodene
Troleandomycin
Sulfadimidine
Grapefruit juice
Verapamil
Sulfinpyrazone
Imatinib
Voriconazole
Troglitazone
Indinavir
Zafirlukast
Troleandomycin
Itraconazole
Source:  http://medicine.iupui.edu/clinpharm/ddis/clinical-table/


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Appendix 10
Columbia Suicide Severity Rating Scale (eC-SSRS) --
Baseline/Screening Version


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Appendix 11
Columbia Suicide Severity Rating Scale (eC-SSRS) --
Since Last Visit Version


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Appendix 12
Clinical Opiate Withdrawal Scale (COWS)
0 - Pulse rate 80 or below
1 - Pulse rate 81 - 100
2 - Pulse rate 101 - 120
4 - Pulse rate greater than 120
1. Resting Pulse Rate: Measured after patient is sitting or lying for one minute.
0 - No GI symptoms
1 - Stomach cramps
2 - Nausea or loose stool
3 - Vomiting or diarrhea
5 - Multiple episodes of diarrhea or vomiting
2. GI upset: Over last 1/2 hour.
0 - No report of chills or flushing
1 - Subjective report of chills or flushing
2 - Flushed or observable moistness on face
3 - Beads of sweat on brow or face
4 - Sweat streaming off face
3. Sweating:
Over past 1/2 hour not accounted for by room temperature or patient activity.
0 - No tremor
1 - Tremor can be felt, but not observed
2 - Slight tremor observable
4 - Gross tremor or muscle twitching
4. Tremor:
Observation of outstretched hands.
0 - Able to sit still
1 - Reports difficulty sitting still, but is able to do so
3 - Frequent shifting or extraneous movements of legs/arms
5 - Unable to sit still for more than a few seconds
5. Restlessness:
For each item, mark the choice that best describes the subject's signs or symptom. Rate on just the
apparent relationship to opiate withdrawal. For example, if heart rate is increased because the patient was
jogging just prior to assessment, the increased pulse rate would not add to the score.
beats/min
Observation during assessment.
0 - No yawning
1 - Yawning once or twice during assessment
2 - Yawning three or more times during assessment
4 - Yawning several times/minute
6. Yawning: Observation durring assessment.
CLINICAL OPIOID WITHDRAWAL SCALE (COWS)
OPIATE


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0 - Not present
1 - Nasal stuffiness or unusually moist eyes
2 - Nose running or tearing
4 - Nose constantly running or tears streaming down cheeks
11. Runny nose or tearing:
0 - None
1 - Patient reports increasing irritability or anxiousness
2 - Patient obviously irritable or anxious
4 - Patient so irritable or anxious that participation in the assessment is difficult
8. Anxiety or Irritability:
0 - Not present
1 - Mild diffuse discomfort
2 - Patient reports severe diffuse aching of joints/muscle
4 - Patient is rubbing joints or muscles and is unable to sit still because of discomfort
9. Bone or Joint aches:
0 - Skin is smooth
3 - Piloerection of skin can be felt or hairs standing up on arms
5 - Prominent piloerection
10. Gooseflesh skin:
0 - Pupils pinned or normal size for room light
1 - Pupils possibly larger than normal for room light
2 - Pupils moderately dilated
5 - Pupils so dilated that only the rim of the iris is visible
7. Pupil Size:
If patient was having pain previously, only the additional component attributed to opiate
withdrawal is scored.
Not accounted for by cold symptoms or allergies.
TOTAL SCORE (sum of all 11 items):
Score Interpretation: 5 - 12= Mild, 13 - 24= Moderate, 25 - 36=Moderately Severe, More than 36= Severe Withdrawal


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Appendix 13
Subjective Opiate Withdrawal Scale (SOWS)
Modified from : Handelsman L, Cochrane KJ, Aronson MJ, Ness R, Rubenstein KJ, Kanof PD 
(1987). Two new rating scales for opiate withdrawal.  Am J Drug Alcohol Abuse 13:293-308.


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Appendix 14
Opioid Craving Visual Analog Scale (Opioid Craving VAS)
No craving
_________________________________________Strongest craving ever
100 mm scale


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Appendix 15
Injection Site Grading Scale
Injection 
Site 
Reactions
None
(Grade 0)
Mild
(Grade 1)
Moderate
(Grade 2)
Severe
(Grade 3)
Potentially Life
Threatening
(Grade 4)
Pain
None
Does not 
interfere with 
activity
Repeated use of non-
narcotic pain reliever 
> 24 hours or 
interferes with activity 
Any use of narcotic 
pain reliever or 
prevents daily 
activity
Emergency room 
(ER) visit or 
hospitalization 
Tenderness
None
Mild discomfort 
to touch.
Discomfort with 
movement.
Significant 
discomfort at rest 
ER visit or 
hospitalization
Erythema/
Redness*
(quantitative)
None
2.5 – 5 cm
5.1 – 10 cm
> 10 cm
Necrosis or
exfoliative 
dermatitis
Induration **
None
2.5 – 5 cm and 
does not interfere 
with activity 
5.1 – 10 cm or 
interferes with 
activity 
> 10 cm or 
prevents daily 
activity 
Necrosis 
Swelling **
(subjective)
None
2.5 – 5 cm and 
does not interfere 
with activity 
5.1 – 10 cm or 
interferes with 
activity 
> 10 cm or 
prevents daily 
activity 
Necrosis 
* In addition to grading the measured local reaction at the greatest single diameter, the measurement should be 
recorded as a continuous variable. 
** Induration/Swelling should be evaluated and graded using the functional scale as well as the actual measurement. 
Modified from:  
U.S. Department of Health and Human Services, Food and Drug Administration, Center for 
Biologics Evaluation and Research, September 2007.  Guidance for Industry: Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials. [pdf] Available at: 
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInform
ation/Guidances/Vaccines/ucm091977.pdf.  Accessed 14 April 2015.


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Appendix 16
Injection Site Pain Visual Analog Scale (Injection Site Pain 
VAS)
How would you rate your injection site pain today?
                  No _________________________________________ Pain as bad 
                  Pain                                                                                  as it could be
Please answer the following question by checking the box with either a “Yes” or “No”:
Are you currently experiencing any burning or stinging at the injection site?
YES  
NO


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Appendix 17
Timeline Followback (TLFB) Interview
Ethanol


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Appendix 18
Euro QoL EQ-5D-5L Health Questionnaire


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Appendix 19
Short Form (36) Health Survey v2


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Appendix 20
Medication Satisfaction Questionnaire 
Overall, how satisfied are you with your current opioid dependence medication?
1 = extremely dissatisfied
2 = very dissatisfied
3 = somewhat dissatisfied
4 = neither satisfied nor dissatisfied
5 = somewhat satisfied
6 = very satisfied
7 = extremely satisfied


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Appendix 21
Health Care Resource Utilization Questionnaire
HEALTH INSURANCE
Primary Health Insurance 
(Please check all  that apply)
Commercial (for example, Blue Cross Blue  
Shield, Aetna, Humana, United, Cigna)
Medicare
Medicaid
Veterans Affairs
Workers compensation
Other insurance
Self-pay / Out of pocket/No insurance
INPATIENT ADMISSIONS

Please list in the table below all inpatient admissions in the past 30 days.  If patient is currently 
hospitalized, please check the box in the “Ongoing” column.

If patient has had no previous hospitalizations in the past 30 days, please check the 
appropriate box below.
No hospitalizations since the last study visit
Admission Date 
(dd / mmm / yyyy)
Discharge Date
(dd / mmm / yyyy)
Ongoing?
Type of Admission
1.
_ _ / _ _ _ / _ _ _ _
_ _ / _ _ _ / _ _ _ _
Medical
Surgical
Psychiatric
Other
2.
_ _ / _ _ _ / _ _ _ _
_ _ / _ _ _ / _ _ _ _
Medical
Surgical
Psychiatric
Other
3.
_ _ / _ _ _ / _ _ _ _
_ _ / _ _ _ / _ _ _ _
Medical
Surgical
Psychiatric
Other


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EMERGENCY ROOM VISITS 

Please list how many times the patient has been to the Emergency Room in the past 30 days.
Type of Problem
Number of Visits
Substance abuse-related
visits
Other medical problems
visits
OUTPATIENT SERVICES

Please list how many times the patient has seen 1 of the following health professionals in the 
past 30 days. The outpatient services captured on this questionnaire are ones conducted 
outside the study
Health Professional
Number of Visits
General practitioner / Internist
visits
Addiction Medicine Specialist
visits
Therapist / Counselor
visits
Other: Specialist
visits
Other:  Non-Specialist 
visits


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Appendix 22
Treatment Effectiveness Assessment (TEA)


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Appendix 23
Addiction Severity Index (ASI) Lite


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Appendix 24
Beck Depression Inventory II (BDI-II)
To be supplied by RBP.  
http://www.pearsonclinical.com/psychology/products/100000159/beck-depression-inventoryii-
bdi-ii.html?Pid=015-8018-370&Mode=summary#tab-details


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Appendix 25
Brief Pain Inventory (BPI) Short Form
To be supplied by RBP.  
http://www.mdanderson.org/education-and-research/departments-programs-and-
labs/departments-and-divisions/symptom-research/symptom-assessment-
tools/BPI_UserGuide.pdf




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14 April 2015
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Appendix 27
Investigator’s Signature
Study Title:
An Open-Label, Long-Term Safety and Tolerability Study of Depot 
Buprenorphine (RBP-6000) in Treatment-Seeking Subjects With 
Opioid Use Disorder
Study Number:
RB-US-13-0003
Final Date:
14 April 2015
I have read the protocol described above. I agree to comply with all applicable regulations and to 
conduct the study as described in the protocol.  [enter additional text, if applicable]
Signed:
Date:
Printed Name and Credentials:
Title:
Site Name:
Address:
Telephone: