Loratadine for Improvement of Bone Pain in Patients With Chronic Granulocyte-Colony Stimulating Factor (G-CSF) Use
Phase: PHASE2
Conditions: Bone Pain
Sponsor: University of Michigan

Revision Date: 02/04/19 
 
Loratadine for Improvement of Bone Pain in 
Patients with Chronic Granulocyte-Colony 
Stimulating Factor (G-CSF) Use 
 
NCT03883386 
 
Document Date:  02/04/2019

Revision Date: 02/04/19 
 
 
 
 
 
 
 
 
Loratadine for Improvement of Bone Pain in 
Patients with Chronic Granulocyte-Colony 
Stimulating Factor (G-CSF) Use 
 
Principal Investigator 
Kelly Walkovich, MD 
Department of Pediatrics  
Division of Hematology/Oncology 
University of Michigan 
 
 
 
 
 
 
 
 
 
Co-investigators 
David Frame, PharmD 
College of Pharmacy 
University of Michigan 
 
Thomas Michniacki, MD 
Department of Pediatrics 
Division of Hematology/Oncology 
University of Michigan 
 
Lauren Merz, BA 
Medical School  
University of Michigan 
 
 
 
 

Revision Date: 02/04/19 
 
Table of Contents 
 
Study Schema 
 
Table of Contents .................................................................................................. 3 
1. Background .................................................................................................... 4 
2. Rationale and Specific Aims ........................................................................... 5 
3. Inclusion/Exclusion Criteria ............................................................................ 5 
4. Enrollment/Randomization ............................................................................. 6 
5. Study Procedures ........................................................................................... 6 
6. Reporting of Adverse Events or Unanticipated Problems involving Risk to 
Participants or Others ........................................................................................... 9 
7. Study Withdrawal/Discontinuation ................................................................ 10 
8. Statistical Considerations ............................................................................. 10 
9. Privacy/Confidentiality Issues ....................................................................... 11 
10. 
Follow-up and Record Retention ............................................................... 11 
11. 
Budget ....................................................................................................... 11 
12.  Drug Information  ......................................................................................... 14 
 

Revision Date: 02/04/19 
1. 
Background 
 
Uses and mechanism of granulocyte-colony stimulating factor (G-CSF)  
Granulocyte-colony stimulating factor G-CSF is a glycoprotein that stimulates the bone 
marrow to produce granulocytes resulting in an increased number of circulating 
neutrophils. G-CSF is most often used to increase neutrophil counts in patients receiving 
myelosuppressive chemotherapies to reduce the duration of febrile neutropenia by 
enhancing neutrophil recovery, or to reduce the infectious and wound healing 
complications of neutropenia in patients with severe congenital neutropenia, cyclic 
neutropenia, or idiopathic neutropenia. Common forms of G-CSF include filgrastim, 
pegfilgrastim, and lenograstim.  
 
Incidence of bone pain in patients using G-CSF 
The incidence of bone pain secondary to G-CSF in patients with severe congenital 
neutropenia, cyclic neutropenia, or idiopathic neutropenia is not well reported. 
Additionally, reported incidences of bone pain in healthy donor and cancer patients vary 
with different formulations of G-CSF and for different indications of use. For example, the 
package insert for general use of filgrastim reports bone pain occurrence in 24% of 
patients and 31% of patients using pegfilgrastim. However, other studies of filgrastim 
and pegfilgrastim in cancer patients reports bone pain in 25-38%[1-3]. Studies of healthy 
donors using G-CSF report bone pain in 52-84% of patients[1, 4, 5].      
 
Mechanism of Bone pain from G-CSF 
G-CSF is often used chronically in patients with diseases such as severe congenital 
neutropenia, cyclic neutropenia and idiopathic neutropenia. Bone pain is a common side 
effect of G-CSF. The exact mechanism underlying this bone pain is unknown. Some 
theories include that the pain is caused by increases in hematopoietic progenitor cells 
that increase bone marrow pressure, edema in bone marrow from histamine release, 
and increased levels of bradykinin[1, 6-8]. Additionally, receptors for G-CSF have been 
found on nerve fibers that may be involved in pain modulation[9, 10]. 
 
Loratadine for bone pain during chemotherapy 
Naproxen or Loratadine and Neulasta (NOLAN) clinical trial[11]. This 2016 study of 600 
patients assessed the difference in bone pain in breast cancer patients receiving 
chemotherapy and pegfilgrastim and either no prophylactic intervention, prophylactic 
naproxen, or prophylactic loratadine. This study found no significantly significant 
difference in bone pain between no prophylaxis, naproxen, and loratadine. However, 
loratadine was associated with fewer treatment-related adverse events and 
discontinuations compared to naproxen.  
  
Evaluation of Loratadine for Prevention of Pegfilgrastim-Induced Pain[12]. This 2013 
study determined the incidence of pegfilgrastim-induced back and leg pain in cancer 
patients and evaluated if loratadine is an effective prophylactic strategy to prevent bone 
pain. This study found that prophylactic loratadine does not decrease the incidence of 
bone pain in this patient population.  
 
Evaluation of Loratadine for G-CSF Induced Bone Pain in Patients With Hematologic 
Malignancies[13]. This is a clinical trial that has not yet disseminated results assessing 
the effectiveness of loratadine in decreasing the incidence and severity of bone pain 
following G-CSF administration in patient with hematologic malignancies.    

Revision Date: 02/04/19 
 
Loratadine for bone pain for patients using G-CSF for non-malignant indications  
There is very little literature on loratadine for treatment of bone pain in patients using G-
CSF for non-malignant indications such as idiopathic neutropenia, cyclic neutropenia or 
severe congenital neutropenia. Currently, all the robust literature and clinical trials 
address the use of loratadine in patients using G-CSF with bone pain during 
myelosuppressive chemotherapy for various cancers or for blood cancers. Anecdotally, 
loratadine has been used for bone pain in patients using G-CSF for diseases like severe 
congenital neutropenia[14, 15], but there is no literature specifically describing the 
efficacy of loratadine for bone pain in chronic G-CSF use in patients with non-malignant 
chronic diseases.    
 
2. 
Rationale and Specific Aims 
 
Patients who have non-malignant forms of neutropenia such as severe congenital 
neutropenia, cyclic neutropenia and idiopathic neutropenia often require chronic G-CSF 
use to abrogate the risk of infectious complications and promote wound healing. G-CSF 
is known to frequently cause bone pain[1, 11, 12, 14]. Nonsteroidal anti-inflammatory 
drugs (NSAIDs) are a common first line treatment for bone pain[2, 11, 15]. However, 
NSAIDs can have side effects such as stomach ulcers or kidney toxicity. Additionally, 
NSAIDs may be ineffective for G-CSF related bone pain. Chronic bone pain can 
negatively impact quality of life, and impact long-term adherence to G-CSF. Although 
there is data on loratadine for bone pain with G-CSF use in patients with cancer, there is 
not currently robust data on loratadine for bone pain in chronic G-CSF use for non-
malignant indications. Therefore, it is critical to carefully determine the efficacy of 
loratadine vs placebo for bone pain and for the quality of life in patients using G-CSF for 
non-malignant indications.  
 
Specific Aim I: To determine the incidence and severity of bone pain in patients using G-
CSF for non-malignant indications. 
 
We hypothesize that 50% of our patients chronically using G-CSF for non-malignant 
indications (>3 months, at least 4x each month) will have bone pain of at least a mean of 
3/10 as assessed by the Brief Pain Inventory (BPI). We additionally hypothesize that the 
mean pain score of all patients included in the study will be 5/10 before treatment.   
 
Specific Aim #2: To determine the impact of 10mg of loratadine by mouth daily on bone 
pain as assessed by the Brief Pain Inventory (BPI). 
 
We hypothesize that loratadine will improve pain scores by at least 2 points as 
measured by the BPI as compared to baseline and as compared to the placebo arm.  
 
3. 
Inclusion/Exclusion Criteria 
 
Patients eligible for this study will be between the ages of 12-99 years old.  
 
Inclusion: 
1. Diagnosis of severe congenital neutropenia, idiopathic neutropenia, or cyclic 
neutropenia 
2. G-CSF use for at least 3 months at least 4 times per month  

Revision Date: 02/04/19 
3. Mean bone pain of at least a 3/10 as assessed by the BPI  
4. Informed consent 
 
Exclusion:     
1. Other sources of chronic pain   
2. Previously tried loratadine for 7 consecutive days or more for G-CSF bone pain  
3. Allergy to loratadine or any other components of the formulation 
4. Chronic daily usage of antihistamine without an acceptable alternative non-
antihistamine medication 
5. Inability to swallow capsule medications 
6. Inability to complete the survey accurately 
7. Glomerular filtration rate (GFR)< 30 ml/min 
8. ALT>100 U/L or AST>100 U/L 
9. Currently taking any interacting drugs listed in section 12 where the 
recommendation is to avoid or modify loratadine administration   
 
 
4. 
Enrollment/Randomization 
 
This is a phase II, randomized, placebo-controlled, crossover blinded study. Patients 
who use G-CSF or parents/guardians of patients who use G-CSF will be contacted by 
phone, by email, or face-to-face when in clinic for an appointment. Informed consent will 
be obtained by the PI or other research personnel in person. Assent will be obtained 
from children who have reached the proper age, adhering to local IRB guidelines. All 
registration will take place at the University of Michigan in the Department of Pediatrics 
and Communicable Diseases and the Department of Hematology/Oncology. We expect 
to identify 35-125 patients who use chronic G-CSF for non-malignant indications. We 
expect 25-85 patients to express interest in the trial, and 20-60 patients to fit criteria for 
inclusion. We anticipate the recruiting to take 2 months to complete. Patients will be 
randomized 1:1 into placebo first or loratadine first arms (see Study Procedure).    
   
 
5. 
Study Procedures 
 
 
Recruitment 
Week 
1 
Week 2 
Week 3 
Week 4 
Comprehensive metabolic 
panel 
X1 
 
 
 
 
Brief Pain Inventory (BPI) 
 
X2 
X1 
 
X1 
Loratadine or Placebo 
 
 
X 
 
X 
1 Only if CMP not recorded in the past 6 months 
2 Day 2, 4, and 6 by modified BPI and day 7 with full BPI 
 
Patients >= 12 years old who have severe congenital neutropenia, idiopathic 
neutropenia, or cyclic neutropenia and have used G-CSF for more than 3 months at 
least 4 times a month will be identified and contacted. If patients are interested in 
enrolling in the study, a screening questionnaire will be administered eliciting answers to 
the exclusion and inclusion criteria (see section 3.0). Patient charts will be checked to 
ensure that they have had a complete metabolic panel in the past 6 months. If not, they 

Revision Date: 02/04/19 
will have a blood draw and a comprehensive metabolic panel to check creatinine, AST, 
and ALT levels. This is part of standard of care. Additional labs will only be drawn if 
deemed clinically necessary or based on adverse events. If patients are eligible, they will 
be given an informed consent to review and sign. We expect recruitment to take 2 
months. Once recruited, patients will start treatment the following Monday or on a 
Monday of their choosing within one month of providing informed consent.  
 
Patients will be randomly assigned to two groups. The patients, providers, and 
statisticians will be blinded to which group they are a part of. Groups will have a one 
week observation period where baseline pain is assessed on day 2, 4, and 6 by modified 
BPI and on day 7 full BPI. The number of non-opioid pain medications required during 
the baseline week will be recorded. Patients will be asked to adhere to the same 
schedule, dosage, and type of pain medication throughout the next three weeks. The 
second week, one group will receive 10mg of loratadine once daily for 7 days and the 
other will receive the placebo daily. They will again be monitored with modified BPI on 
day 2, 4, and 6 and on day 7 full BPI. Adverse events will also be assessed during this 
time period. 
 
There will then be a 7 day "wash-out" period. This wash-out period was chosen because 
the active metabolite of loratadine, descarboethoxyloratadine, has a mean half-life of 28 
hours. It takes approximately 5 half-lives for elimination of drug from the system 
(28*5=140 5.8 days). There will be no assessment of pain or quality of life this week.  
 
In the fourth week, the groups will switch to either placebo or the loratadine (opposite of 
their second week treatment). They will take this treatment by mouth for 7 days. Pain will 
be assessed on day 2, 4, and 6 by modified BPI, and on day 7 with full BPI. Adverse 
events will also be assessed during this time period. We will also follow-up via phone call 
30 days after the last dose to assess for any additional adverse events.  
 
The surveys will be administered on the online platform QuestionPro. This is an online, 
secure, professional survey software that will collect data from the surveys. This can be 
used on computers, tablets, or smartphones. Patients will be de-identified, but they will 
have a unique identifier that links their surveys responses. The questions come the Brief 
Pain Inventory (BPI). The modified BPI will only include questions 3-7 of the BPI.  
 

Revision Date: 02/04/19 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Obtain informed consent. Screen potential participants by inclusion and 
exclusion criteria. Obtain CMP.   
Week 1: 
Monitor baseline pain with modified BPI on day 2, 4, and 6 and full BPI on 
day 7.   
Week 4: 
Take treatment for 7 days. Assess pain and QOL with modified BPI on 
days 2, 4, and 6, and full BPI on day 7.  
Week 3: 
No treatment in this week. Pain and QOL assessed on day 7 with full BPI. 
Final Assessments 
Compare mean BPI scores.  
Placebo first 
Loratadine first 
Week 2: 
Take treatment daily for 7 days. Assess pain and QOL with modified BPI 
on days 2, 4, and 6, and full BPI on day 7.  
Randomize 
Placebo 
second 
Loratadine 
second 

Revision Date: 02/04/19 
6. 
Reporting of Adverse Events or Unanticipated 
Problems involving Risk to Participants or Others 
 
Adverse Event Definition 
An adverse event (AE) is any untoward medical occurrence in a subject participating in an 
investigational study or protocol regardless of causality assessment.  An adverse event can 
be an unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
syndrome or disease associated with or occurring during the use of an investigational 
product whether or not considered related to the investigational product. 
 
These events may be: 
 
a. Definitely related: clearly associated with study drug/treatment 
b. Probably related:  likely associated with study drug/treatment 
c. Possibly related:  may be associated with study drug or other treatment 
d. Unlikely to be related, or 
e. Definitely not related to the study drug/treatment 
 
For reporting purposes, an AE should be regarded as definitely or probably related to the 
regimen if the investigator believes that at least one of following criteria are met: 
 
a. There is a clinically plausible time sequence between onset of the AE and the 
administration of the study drug or treatment. 
b. There is a biologically plausible mechanism for the study drug or treatment causing or 
contributing to the AE. 
c. The AE cannot be attributed solely to concurrent/underlying illness, other drugs, or 
procedures.  
d. A potential alternative cause does not exist. 
 
Serious Adverse Events (SAE):  An adverse drug experience occurring at any dose that 
results in any of the following outcomes: 
 
a. 
Death 
b. 
A life-threatening adverse drug experience 
c. 
Inpatient hospitalization or prolongation of existing hospitalization 
d. 
A persistent or significant disability &/or incapacity 
e. 
A congenital anomaly or birth defect 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. A 
serious adverse experience includes any experience that is fatal or immediately life 
threatening, results in a persistent or significant disability/incapacity, requires or prolongs in-
patient hospitalization, or is a congenital anomaly, cancer, or overdose. 
Other important medical events that may not result in death, not be life-threatening, or not 
require hospitalization may be considered a serious adverse experience when, based upon 
appropriate medical judgment, the event may jeopardize the subject/patient and may require 
medical or surgical intervention to prevent one of the outcomes listed previously. 
 

Revision Date: 02/04/19 
Expected adverse events are those listed in the protocol, drug labeling or in the study 
informed consent document.  Unexpected events are those events that are not 
described in the labeling, protocol or the study informed consent. This includes adverse 
events for which the specificity or severity is not consistent with the description in the 
informed consent.  
 
An unanticipated problem is a serious problem that has implications for the conduct of 
the study requiring a significant and usually safety related change in the protocol or the 
informed consent. Should an unanticipated problem occur during the investigation, the 
investigator will promptly report all unanticipated problems involves risks to human 
subjects or others to the IRBMED according to their guidance document. 
 
The severity or grade of an adverse event may be measured using the following definitions: 
 
Mild:  Noticeable to the subject, but does not interfere with subject’s expected daily 
activities, usually does not require additional therapy or intervention, dose reduction, or 
discontinuation of the study. 
 
Moderate:  Interferes with the subject’s expected daily activities, may require some 
additional therapy or intervention but does not require discontinuation of the study. 
 
Severe: Extremely limits the subject’s daily activities and may require discontinuation of 
study therapy, and/or additional treatment or intervention to resolve. 
 
Event Reporting 
All serious adverse events (SAEs) and adverse events (AEs) will be reported to the IRB 
according to the IRB reporting requirements and guidelines.  
  
7. 
Study Withdrawal/Discontinuation 
 
Subjects may withdraw from the study at any time. Subjects and/or their guardians may 
discontinue participation for any reason and no further samples will be collected. 
Samples collected prior to discontinuation will still be used as part of the study unless 
the participant or study team request in writing for the samples to be destroyed. The 
study investigators may also discontinue the participation of any subject if they feel 
necessary. Reasons for discontinuing a subject include but are not limited to subject 
safety or scientific validity. 
 
8. 
Statistical Considerations 
 
Power: For 80% power at a significance level of .05, a minimum of 10 patients will enter 
this two-treatment crossover study. This assumes a minimal detectable difference in 
means of 2 and standard deviation of the difference between the two treatments for the 
same patient of 2 as assessed by the BPI.  
 
Analysis: Scores will be analyzed with Chi-squared analysis. A binary yes/no designation 
will be given to each patient for improvement of BPI by 2 or more points during treatment 
arm when compared to baseline and placebo. Two sample t-test will also be used to 
compare means of BPI between treatment and placebo and treatment and baseline. Chi-
squared analysis and two sample t-test will also be used to compare between day 2 

Revision Date: 02/04/19 
modified BPI during treatment and placebo, between day 4 modified BPI during 
treatment and placebo, and between day 6 modified BPI during treatment and placebo.  
 
Confidence Interval: Confidence intervals will be analyzed and reported from the 
baseline, placebo, and treatment scores of the full BPI.  
 
Possible Pitfalls: Some patients may exit the clinical trial before completion. These 
patients will be included in an intention to treat analysis using analysis of the worst case 
scenario (no change from baseline pain and QOL scores) to fill in the missing data. 
Some patients may not complete all survey questions or may not complete all of the 
surveys even if they remain in the trial. These patients will still be included in the 
analysis, and missing data will be imputed with maximum likelihood method. A summary 
of missing response data will be included in the final report.  
 
9. 
Privacy/Confidentiality Issues 
 
Identifying data will not be published by this study. Identifying data are kept in a 
password protected file on an encrypted laptop as per guidelines of good clinical practice 
(GCP). A unique identifier will be assigned and used for each participating subject in 
order to link individual surveys together. The key linking the subject unique ID and 
personal identifying data will only be known to the local investigator and their study 
team. The confidentiality of records that could identify subjects will be protected, 
respecting the privacy and confidentiality rules in accordance with the applicable 
regulatory requirements. 
 
10. Follow-up and Record Retention 
 
Active subject participation and enrollment is expected to last approximately 1 month. 
Surveys collected will be de-identified using a unique ID. Data is expected to be retained 
for 7 years from the completion of the study per University of Michigan record keeping 
guidelines. 
 
11. Budget 
 
Item 
Cost 
Estimated Research Pharmacy Fee 
$4,435 
ESTIMATED TOTAL 
$4,435 
 
If a comprehensive metabolic panel (CMP) is required, it will be billed as part of standard 
of care. The billing calendar fee is waived for this study.  
 
 
12. Drug Information 
Loratadine 
 
Other names for the drug: Claritin 
 
 
Description: 10 mg of intact loratadine tablets are placed into an empty capsule with 
7 capsules per bottle   

Revision Date: 02/04/19 
 
 
Classification - type of agent: Active drug 
 
 
Mode of action: Long acting tricyclic antihistamine with selective peripheral histamine 
H1-receptor antagonist activity  
 
 
Pharmacokinetics: Anti-histamine effects begins within 1-3 hours reaching a 
maximum at 8-12 hours and lasting in excess of 24 hours. There is no evidence of 
tolerance after 28 days. Times to maximum concentration after oral administration is 
1.3 hours for loratadine and 2.5 hours for its major metabolite, 
descarboethoxyloratadine. The pharmacokinestics are independent of dose over the 
range of 10mg to 40mg and are not altered by duration of treatment. Loratadine is 
metabolized to descarboethoxyloratadine predominantly by cytochrome P450 3A4. 
80% of the loratadine dose is equally distributed between urine and feces in the form 
of metabolic products within 10 days. The mean elimination half-lives were 8.4 hours 
(range 3-20 hours) for loratadine, and 28 hours (range 8.8-92 hours) for 
descarboethoxyloratadine. The pharmacokinetic profile or loratadine in children is 
similar to that of adults.  
 
 
Side effects:   
 
1% to 10%:  
 
Central nervous system: Headache (adults: 8%), sedated state (adults: 8%), 
drowsiness (adults: 4%), fatigue (adults: 4%), nervousness (children: 4%) 
 
Gastrointestinal: Xerostomia (adults: 2% to 4%), abdominal pain (children: 
2%), vomiting (children: 2%), diarrhea (children: 1%) 
 
Neuromuscular & skeletal: Hyperkinetic muscle activity (children: 3%) 
 
Frequency not defined: 
 
Dermatologic: Skin rash (adults) 
 
Gastrointestinal: Gastritis (adults), nausea (adults) 
 
Hypersensitivity: Hypersensitivity reaction (adults) 
 
<1%, postmarketing, and/or case reports:  
 
Alopecia, anaphylaxis, cough, dizziness, dry nose, hepatic insufficiency, 
increased appetite, palpitations, seizure, tachycardia 
 
 
Drug Interactions: The patient drug list must be screened for interacting drugs listed 
below, and patients excluded if the recommendation is to avoid or modify therapy.  
 
 
AbobotulinumtoxinA: Anticholinergic Agents may enhance the anticholinergic 
effect of AbobotulinumtoxinA. Risk C: Monitor therapy 
 
Acetylcholinesterase Inhibitors: May diminish the therapeutic effect of 
Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic 
effect of Acetylcholinesterase Inhibitors. Risk C: Monitor therapy 
 
Aclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Risk 
X: Avoid combination 
 
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of 
Alcohol (Ethyl). Risk C: Monitor therapy 
 
Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk 
C: Monitor therapy 

Revision Date: 02/04/19 
 
Amantadine: May enhance the anticholinergic effect of Anticholinergic 
Agents. Risk C: Monitor therapy 
 
Amezinium: Antihistamines may enhance the stimulatory effect of 
Amezinium. Risk C: Monitor therapy 
 
Amiodarone: May increase the serum concentration of Loratadine. Management: 
Due to reported QT interval prolongation and Torsades de Pointes with this 
combination, consider an alternative to loratadine when possible. Risk D: 
Consider therapy modification 
 
Amphetamines: May diminish the sedative effect of Antihistamines. Risk C: 
Monitor therapy 
 
Anticholinergic Agents: May enhance the adverse/toxic effect of other 
Anticholinergic Agents. Risk C: Monitor therapy 
 
Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect 
of Azelastine (Nasal). Risk X: Avoid combination 
 
Benzylpenicilloyl Polylysine: Antihistamines may diminish the diagnostic effect of 
Benzylpenicilloyl Polylysine. Management: Suspend systemic H1 antagonists for 
benzylpenicilloyl-polylysine skin testing and delay testing until systemic 
antihistaminic effects have dissipated. A histamine skin test may be used to 
assess persistent antihistaminic effects. Risk D: Consider therapy modification 
 
Betahistine: Antihistamines may diminish the therapeutic effect of 
Betahistine. Risk C: Monitor therapy 
 
Blonanserin: CNS Depressants may enhance the CNS depressant effect of 
Blonanserin. Risk D: Consider therapy modification 
 
Brimonidine (Topical): May enhance the CNS depressant effect of CNS 
Depressants. Risk C: Monitor therapy 
 
Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk 
C: Monitor therapy 
 
Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk 
X: Avoid combination 
 
Buprenorphine: CNS Depressants may enhance the CNS depressant effect of 
Buprenorphine. Management: Consider reduced doses of other CNS 
depressants, and avoiding such drugs in patients at high risk of buprenorphine 
overuse/self-injection. Initiate buprenorphine patches (Butrans brand) at 5 mcg/hr 
in adults when used with other CNS depressants.Risk D: Consider therapy 
modification 
 
Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Risk 
C: Monitor therapy 
 
Cannabis: May enhance the CNS depressant effect of CNS Depressants. Risk C: 
Monitor therapy 
 
Chloral Betaine: May enhance the adverse/toxic effect of Anticholinergic 
Agents. Risk C: Monitor therapy 
 
Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. 
Management: Monitor closely for evidence of excessive CNS depression. The 
chlormethiazole labeling states that an appropriately reduced dose should be 
used if such a combination must be used. Risk D: Consider therapy modification 
 
Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS 
Depressants. Risk C: Monitor therapy 
 
Cimetropium: Anticholinergic Agents may enhance the anticholinergic effect of 
Cimetropium. Risk X: Avoid combination 

Revision Date: 02/04/19 
 
CNS Depressants: May enhance the adverse/toxic effect of other CNS 
Depressants. Risk C: Monitor therapy 
 
Dimethindene (Topical): May enhance the CNS depressant effect of CNS 
Depressants. Risk C: Monitor therapy 
 
Doxylamine: May enhance the CNS depressant effect of CNS Depressants. 
Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for 
use in pregnancy, specifically states that use with other CNS depressants is not 
recommended. Risk C: Monitor therapy 
 
Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Risk 
C: Monitor therapy 
 
Droperidol: May enhance the CNS depressant effect of CNS Depressants. 
Management: Consider dose reductions of droperidol or of other CNS agents 
(eg, opioids, barbiturates) with concomitant use. Exceptions to this monograph 
are discussed in further detail in separate drug interaction monographs. Risk D: 
Consider therapy modification 
 
Eluxadoline: Anticholinergic Agents may enhance the constipating effect of 
Eluxadoline. Risk X: Avoid combination 
 
Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of 
Flunitrazepam. Risk D: Consider therapy modification 
 
Gastrointestinal Agents (Prokinetic): Anticholinergic Agents may diminish the 
therapeutic effect of Gastrointestinal Agents (Prokinetic). Risk C: Monitor therapy 
 
Glucagon: Anticholinergic Agents may enhance the adverse/toxic effect of 
Glucagon. Specifically, the risk of gastrointestinal adverse effects may be 
increased. Risk C: Monitor therapy 
 
Glycopyrrolate (Oral Inhalation): Anticholinergic Agents may enhance the 
anticholinergic effect of Glycopyrrolate (Oral Inhalation). Risk X: Avoid 
combination 
 
Glycopyrronium (Topical): May enhance the anticholinergic effect of 
Anticholinergic Agents. Risk X: Avoid combination 
 
Hyaluronidase: Antihistamines may diminish the therapeutic effect of 
Hyaluronidase. Management: Patients receiving antihistamines (particularly at 
larger doses) may not experience the desired clinical response to standard doses 
of hyaluronidase. Larger doses of hyaluronidase may be required. Risk D: 
Consider therapy modification 
 
HYDROcodone: CNS Depressants may enhance the CNS depressant effect of 
HYDROcodone. Management: Avoid concomitant use of hydrocodone and 
benzodiazepines or other CNS depressants when possible. These agents should 
only be combined if alternative treatment options are inadequate. If combined, 
limit the dosages and duration of each drug. Risk D: Consider therapy 
modification 
 
HydrOXYzine: May enhance the CNS depressant effect of CNS 
Depressants. Risk C: Monitor therapy 
 
Ipratropium (Oral Inhalation): May enhance the anticholinergic effect of 
Anticholinergic Agents. Risk X: Avoid combination 
 
Itopride: Anticholinergic Agents may diminish the therapeutic effect of 
Itopride. Risk C: Monitor therapy 
 
Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Risk C: 
Monitor therapy 
 
Levosulpiride: Anticholinergic Agents may diminish the therapeutic effect of 
Levosulpiride. Risk X: Avoid combination 

Revision Date: 02/04/19 
 
Lofexidine: May enhance the CNS depressant effect of CNS Depressants. 
Management: Drugs listed as exceptions to this monograph are discussed in 
further detail in separate drug interaction monographs. Risk C: Monitor therapy 
 
Lumacaftor: May decrease the serum concentration of P-glycoprotein/ABCB1 
Substrates. Lumacaftor may increase the serum concentration of P-
glycoprotein/ABCB1 Substrates. Risk C: Monitor therapy 
 
Magnesium Sulfate: May enhance the CNS depressant effect of CNS 
Depressants. Risk C: Monitor therapy 
 
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect 
of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant 
effect of CNS Depressants. Management: Reduce adult dose of CNS depressant 
agents by 50% with initiation of concomitant methotrimeprazine therapy. Further 
CNS depressant dosage adjustments should be initiated only after clinically 
effective methotrimeprazine dose is established. Risk D: Consider therapy 
modification 
 
MetyroSINE: CNS Depressants may enhance the sedative effect of 
MetyroSINE. Risk C: Monitor therapy 
 
Mianserin: May enhance the anticholinergic effect of Anticholinergic Agents. Risk 
C: Monitor therapy 
 
Minocycline: May enhance the CNS depressant effect of CNS Depressants. Risk 
C: Monitor therapy 
 
Mirabegron: Anticholinergic Agents may enhance the adverse/toxic effect of 
Mirabegron. Risk C: Monitor therapy 
 
Mirtazapine: CNS Depressants may enhance the CNS depressant effect of 
Mirtazapine. Risk C: Monitor therapy 
 
Nabilone: May enhance the CNS depressant effect of CNS Depressants. Risk C: 
Monitor therapy 
 
Nitroglycerin: Anticholinergic Agents may decrease the absorption of 
Nitroglycerin. Specifically, anticholinergic agents may decrease the dissolution of 
sublingual nitroglycerin tablets, possibly impairing or slowing nitroglycerin 
absorption. Risk C: Monitor therapy 
 
OnabotulinumtoxinA: Anticholinergic Agents may enhance the anticholinergic 
effect of OnabotulinumtoxinA. Risk C: Monitor therapy 
 
Opioid Analgesics: CNS Depressants may enhance the CNS depressant effect of 
Opioid Analgesics. Management: Avoid concomitant use of opioid analgesics 
and benzodiazepines or other CNS depressants when possible. These agents 
should only be combined if alternative treatment options are inadequate. If 
combined, limit the dosages and duration of each drug. Risk D: Consider therapy 
modification 
 
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of 
Orphenadrine. Risk X: Avoid combination 
 
Oxatomide: May enhance the anticholinergic effect of Anticholinergic 
Agents. Risk X: Avoid combination 
 
Oxomemazine: May enhance the CNS depressant effect of CNS 
Depressants. Risk X: Avoid combination 
 
OxyCODONE: CNS Depressants may enhance the CNS depressant effect of 
OxyCODONE. Management: Avoid concomitant use of oxycodone and 
benzodiazepines or other CNS depressants when possible. These agents should 
only be combined if alternative treatment options are inadequate. If combined, 

Revision Date: 02/04/19 
limit the dosages and duration of each drug. Risk D: Consider therapy 
modification 
 
Paraldehyde: CNS Depressants may enhance the CNS depressant effect of 
Paraldehyde. Risk X: Avoid combination 
 
Perampanel: May enhance the CNS depressant effect of CNS Depressants. 
Management: Patients taking perampanel with any other drug that has CNS 
depressant activities should avoid complex and high-risk activities, particularly 
those such as driving that require alertness and coordination, until they have 
experience using the combination. Risk D: Consider therapy modification 
 
P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-
glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit 
the distribution of p-glycoprotein substrates to specific cells/tissues/organs where 
p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, 
etc.). Risk C: Monitor therapy 
 
P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-
glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the 
distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-
glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, 
etc.). Risk C: Monitor therapy 
 
Piribedil: CNS Depressants may enhance the CNS depressant effect of 
Piribedil. Risk C: Monitor therapy 
 
Pitolisant: Antihistamines may diminish the therapeutic effect of Pitolisant. Risk 
C: Monitor therapy 
 
Potassium Chloride: Anticholinergic Agents may enhance the ulcerogenic effect 
of Potassium Chloride. Management: Patients on drugs with substantial 
anticholinergic effects should avoid using any solid oral dosage form of 
potassium chloride. Risk X: Avoid combination 
 
Potassium Citrate: Anticholinergic Agents may enhance the ulcerogenic effect of 
Potassium Citrate. Risk X: Avoid combination 
 
Pramipexole: CNS Depressants may enhance the sedative effect of 
Pramipexole. Risk C: Monitor therapy 
 
Pramlintide: May enhance the anticholinergic effect of Anticholinergic Agents. 
These effects are specific to the GI tract.Risk D: Consider therapy modification 
 
Ramosetron: Anticholinergic Agents may enhance the constipating effect of 
Ramosetron. Risk C: Monitor therapy 
 
Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 
Substrates. Risk C: Monitor therapy 
 
Revefenacin: Anticholinergic Agents may enhance the anticholinergic effect of 
Revefenacin. Risk X: Avoid combination 
 
RimabotulinumtoxinB: Anticholinergic Agents may enhance the anticholinergic 
effect of RimabotulinumtoxinB. Risk C: Monitor therapy 
 
ROPINIRole: CNS Depressants may enhance the sedative effect of 
ROPINIRole. Risk C: Monitor therapy 
 
Rotigotine: CNS Depressants may enhance the sedative effect of 
Rotigotine. Risk C: Monitor therapy 
 
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. 
Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy 
 
Secretin: Anticholinergic Agents may diminish the therapeutic effect of Secretin. 
Management: Avoid concomitant use of anticholinergic agents and secretin. 

Revision Date: 02/04/19 
Discontinue anticholinergic agents at least 5 half-lives prior to administration of 
secretin. Risk D: Consider therapy modification 
 
Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the 
adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the 
risk of psychomotor impairment may be enhanced. Risk C: Monitor therapy 
 
Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. 
Management: Consider alternatives to combined use. When combined use is 
needed, consider minimizing doses of one or more drugs. Use of sodium oxybate 
with alcohol or sedative hypnotics is contraindicated. Risk D: Consider therapy 
modification 
 
Suvorexant: CNS Depressants may enhance the CNS depressant effect of 
Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS 
depressant may be necessary. Use of suvorexant with alcohol is not 
recommended, and the use of suvorexant with any other drug to treat insomnia is 
not recommended. Risk D: Consider therapy modification 
 
Tapentadol: May enhance the CNS depressant effect of CNS Depressants. 
Management: Avoid concomitant use of tapentadol and benzodiazepines or other 
CNS depressants when possible. These agents should only be combined if 
alternative treatment options are inadequate. If combined, limit the dosages and 
duration of each drug. Risk D: Consider therapy modification 
 
Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS 
Depressants. Risk C: Monitor therapy 
 
Tetrahydrocannabinol and Cannabidiol: May enhance the CNS depressant effect 
of CNS Depressants. Risk C: Monitor therapy 
 
Thalidomide: CNS Depressants may enhance the CNS depressant effect of 
Thalidomide. Risk X: Avoid combination 
 
Thiazide and Thiazide-Like Diuretics: Anticholinergic Agents may increase the 
serum concentration of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor 
therapy 
 
Tiotropium: Anticholinergic Agents may enhance the anticholinergic effect of 
Tiotropium. Risk X: Avoid combination 
 
Topiramate: Anticholinergic Agents may enhance the adverse/toxic effect of 
Topiramate. Risk C: Monitor therapy 
 
Trimeprazine: May enhance the CNS depressant effect of CNS 
Depressants. Risk C: Monitor therapy 
 
Umeclidinium: May enhance the anticholinergic effect of Anticholinergic 
Agents. Risk X: Avoid combination 
 
Zolpidem: CNS Depressants may enhance the CNS depressant effect of 
Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult 
dose to 1.75 mg for men who are also receiving other CNS depressants. No such 
dose change is recommended for women. Avoid use with other CNS 
depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy 
modification 
 
Storage and stability: Store between 20-25C. Loratadine must be stored in a 
secure, limited access area.   
 
 
Preparation and Dispensing: Repackaging into prescription bottles is allowed. Active 
loratadine is dispensed in a bottle of 7 units of 10mg loratadine blinded capsules. 
The subjects are required to be blinded if they are receiving loratadine or placebo. 10 

Revision Date: 02/04/19 
mg of intact loratadine will be placed into an empty capsule with 7 capsules per 
bottle by the research pharmacy in order to visually appear identical to the placebo 
capsules.  
 
 
Administration: Food does not impact the AUC of the active metabolite of loratadine, 
descarboethoxyloratadine, or the peak metabolite concentration. Therefore, the 
capsules can be taken with or without food. A dose should be taken at the same time 
every day +/- 4 hours. If a dose is missed by more than 12 hours, do not take the 
missed dose and continue to take the next dose as scheduled. The study team 
should be informed when there are missed doses. Compliance will be assessed with 
pill counts and a questionnaire at the end of the 7-day arm.   
 
 
Availability: Loratadine is commercially available. This drug will be free of charge to 
all study participants, and it will be purchased using study funds. Under no 
circumstance will the study medication, loratadine, be used other than as directed by 
the protocol.  
 
 
Return and Retention of Study Drug: Unused drug or empty bottles should be 
returned to the research pharmacy to be destroyed on site per the institution 
standard operating procedure for drug destruction. This destruction will be 
documented on the drug accountability logs. 
 
 
Drug Accountability: The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory and disposition of the 
investigational drug loratadine. The drug accountability records will capture drug 
receipt, drug dispensing, drug return and final disposition.  
 
Placebo 
 
 
Description: Placebo is a lactose filler covered by a capsule with 7 capsules per 
bottle 
 
 
Side effects: There are no expected side effects from a placebo  
 
 
Storage and stability: Store between 20-25C. Placebo capsules must be stored in a 
secure, limited access area.   
 
 
Preparation and Dispensing Placebo is a lactose filler covered by a capsule. The 
subjects are required to be blinded to if they are receiving loratadine or placebo. The 
placebo capsules visually appear identical to the capsules the loratadine pills are 
placed in.  
 
 
Administration: Capsules can be taken with or without food.  A dose should be taken 
at the same time every day +/- 4 hours. If a dose is missed by more than 12 hours, 
do not take the missed dose and continue to take the next dose as scheduled. The 
study team should be informed when there are missed doses. Compliance will be 
assessed with pill counts and a questionnaire at the end of the 7-day arm.   
 
 
Availability: The placebo are lactose fillers placed in a capsule, and these will be 

Revision Date: 02/04/19 
prepared by the Research Pharmacy and provided free of charge to all study 
participants. 
 
 
Return and Retention of Study Drug: Unused placebo or empty bottles should be 
returned to the research pharmacy to be destroyed on site per the institution 
standard operating procedure for drug destruction. This destruction will be 
documented on the drug accountability logs. 
 
 

Revision Date: 02/04/19 
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