An Open-Label Study To Evaluate the Efficacy and Safety of Ocrelizumab in Patients With Relapsing Multiple Sclerosis Who Have A Suboptimal Response to an Adequate Course of Disease-Modifying Treatment
Phase: PHASE3
Conditions: Multiple Sclerosis, Relapsing-Remitting
Sponsor: Hoffmann-La Roche

 
Official Title: 
An Open-Label Study to Evaluate the Efficacy and Safety of 
Ocrelizumab in Patients With Relapsing Remitting Multiple Sclerosis 
who Have a Suboptimal Response to an Adequate Course of 
Disease-Modifying Treatment  
NCT Number: 
NCT02861014 
Document Date: 
Protocol Version 5: 04-November-2018 
 
 
 

 
 
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PROTOCOL TITLE: 
AN OPEN-LABEL STUDY TO EVALUATE THE EFFICACY 
AND SAFETY OF OCRELIZUMAB IN PATIENTS WITH 
RELAPSING REMITTING MULTIPLE SCLEROSIS WHO 
HAVE A SUBOPTIMAL RESPONSE TO AN ADEQUATE 
COURSE OF DISEASE-MODIFYING TREATMENT 
PROTOCOL NUMBER: 
MA30005 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
2015-005597-38 
IND NUMBER: 
Not applicable 
TEST PRODUCT: 
Ocrelizumab (RO4964913) 
MEDICAL MONITOR: 
 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version 1:  12 February 2016 
DATES AMENDED: 
Version 2:  03 June 2016 
Version 3:  28 March 2017  
Version 4:  05 October 2017 
Version 5: See electronic date stamp below 
PROTOCOL AMENDMENT APPROVAL 
 
 
 
 
 
 
 
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, 
especially any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its 
control) and therefore is provided to you in confidence as an investigator, potential investigator, 
or consultant, for review by you, your staff, and an applicable Ethics Committee or Institutional 
Review Board.  It is understood that this information will not be disclosed to others without written 
authorization from Roche except to the extent necessary to obtain informed consent from 
persons to whom the drug may be administered. 
 
 
04-Nov-2018 19:16:13
Title
Approver's Name
Company Signatory
Date and Time (UTC)

 
 
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PROTOCOL AMENDMENT, VERSION 5:  
RATIONALE 
Protocol MA30005 has been amended with the following: 
1. Updates to the safety risks associated with Ocrelizumab 
Section 5.1 (Safety Plan) was updated in order to include information based on the 
updated core safety text and interim results of the vaccination study BN29739 
(VELOCE), which evaluated the effects of ocrelizumab on the immune response in 
patients with relapsing forms of multiple sclerosis. This new information is considered a 
substantial change because it may impact the safety of the patients. The information 
pertaining to the risk of ‘impaired immunization response’ has been updated accordingly 
in the protocol and has been moved from ‘Potential risks’ to ‘Identified Risks and 
Adverse Drug Reactions’. The Addendum to Investigators Brochure (IB) v16, dated April 
2018, also includes this relevant information, and this amendment aligns the MA30005 
protocol with the latest IB. 
 
2. 
Clarification about the “Follow-up Period” for patients switching to 
commercial drug 
Text was added to clarify that those patients who decide to leave the study and switch to 
commercially marketed ocrelizumab, either after completion of the 96 weeks Treatment 
Period or after early discontinuation of the 96 weeks Treatment Period, will not enter the 
safety Follow-up Period. 
 
3. 
Changes in Section 6: STATISTICAL CONSIDERATIONS AND ANALYSIS 
PLAN 
Minor changes in the text were applied to clarify the statistical approach and to align with 
the rest of the ocrelizumab clinical development program. 
 
4. 
Clarification about the pregnancy and treatment discontinuation 
Clarification was added to the study treatment discontinuation rules (Section 4.6.2): “in 
case of pregnancy, treatment should be interrupted, and the patient should be monitored 
for safety; however, the patient can be re-started with the treatment after the pregnancy 
and breastfeeding period.  During pregnancy and breastfeeding, the patient will continue 
to come for regular schedule visits as per the protocol and will perform all assessments 
except MRI”  
This does not change the existing requirement for the patients who become pregnant to 
discontinue study treatment, but allows the return to the study treatment after the end of 
pregnancy (independent of the pregnancy outcome).  
 

 
 
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5. Correction of the frequency of HBV DNA PCR test to 24 weeks instead of 12 
weeks 
For enrolled patients with negative HBsAg and positive total HBcAb, HBV DNA 
screening (by PCR) must be repeated every 24 weeks. In the previous protocol versions, 
it was erroneously stated the PCR test must be repeated every 12 weeks. The change to 
24 weeks aligns the PCR frequency with the 24-week-frequency of the clinical visits as 
per Schedule of Assessment. 
 
6. 
Inclusion of instructions around the optional use of a Patient Diary 
Section 4.5.12 and Appendix 7 were included to provide instructions about the use of a 
Patient Diary and as optional additional tool to help the patient and the site with the 
collection and reporting of AEs and concomitant medications. 
 
 
7. 
Correction of the start of safety follow-up for patients who discontinue study 
treatment early 
Throughout the protocol, the change was made to clarify that the patients who 
discontinue treatment early will be followed up for at least 96 weeks after the Early 
Treatment Discontinuation Visit, and not after the last infusion of study drug. 
 
8. 
Correction in the adverse event reporting period 
Throughout the protocol, the inconsistencies in the adverse event reporting period was 
corrected from ‘48 weeks after the last dose of the study drug’ to ‘96 weeks after the end 
of the Treatment Period’ to align with the duration of the Safety Follow-up of 96 weeks.   
 
 

 
 
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PROTOCOL AMENDMENT, VERSION 5:  
SUMMARY OF CHANGES 
 
 
Substantive new information appears in italics. Deleted text is shown in strike-through 
mode. 
 
PROTOCOL SYNOPSIS  
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
3.1 DESCRIPTION OF THE STUDY 
Follow-up Period:  Patients who discontinue treatment early will be followed up for at 
least 96 weeks after the Early Treatment Discontinuation Visit last infusion of study drug. 
Patients who complete the 96 weeks Treatment Period and, in agreement with their 
treating neurologist, decide not to continue in a separate long-term extension (LTE) 
study, will be followed up for at least 96 weeks after the end of the Treatment Period. 
Patients who decide to leave the study and switch to commercially marketed Ocrelizumab, either 
after completion of the 96 weeks Treatment Period or after early discontinuation of the 96 weeks 
Treatment Period, will not enter the safety Follow-up Period. 
3.1.3 Treatment Period 
Patients who discontinue treatment early will be followed up for at least 96 weeks after 
the Early Treatment Discontinuation Visit last infusion of study drug. Patients who 
complete the 96 weeks Treatment Period and, in agreement with their treating 
neurologist, decide not to continue in a separate long term extension (LTE) study, will be 
followed up for at least 96 weeks after the end of the Treatment Period (see Section 
3.1.4). Patients who decide to leave the study and switch to commercially marketed Ocrelizumab, 
either after completion of the 96 weeks Treatment Period or after early discontinuation of the 96 
weeks Treatment Period, will not enter the safety Follow-up Period. 
3.1.4 Follow-up Period 
Patients who discontinue treatment early will be followed up for at least 96 weeks after 
the Early Treatment Discontinuation Visit last infusion of study drug . Patients who 
complete the 96 weeks Treatment Period and, in agreement with their treating 
neurologist, decide not to continue in a separate long term extension (LTE) study, will be 
followed up for at least 96 weeks after the end of the Treatment Period.  
Patients who decide to leave the study and switch to commercially marketed Ocrelizumab, either 
after completion of the 96 weeks Treatment Period or after early discontinuation of the 96 weeks 
Treatment Period, will not enter the safety Follow-up Period.  

 
 
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Any patient whose peripheral blood B-cell count remains depleted after this period will 
continue to be monitored at 24-week intervals until the B-cell count has returned to the 
baseline value or to lower limit of normal (LLN) range, whichever is lower.   
Figure 4 provides an overview of the Follow-up Period, which is the variable B-cell 
monitoring period.  A schedule of assessments for the Follow-up Period is presented in 
Appendix 2.  
During the Follow-up Period, patients will be formally assessed at clinical visits every 
24 weeks and by telephone contacts every 8 weeks.  If further B-cell monitoring is 
required and the patient is not receiving any other B-cell targeted therapy, assessments 
will take place at clinical visits every 24 weeks and by telephone contacts every 8 weeks 
until the B-cells are repleted.  See Appendix 2 for further details. 
After initiation of study drug, all adverse events will be reported until 96 weeks after the end of 
the Treatment Period but may be extended in patients whose B-cells take longer to replete.  
Related SAEs must be collected and reported regardless of the time elapsed from the 
last study drug administration, even if the study has been closed. 
Unrelated SAEs must be collected and reported during the study through the end of the 
Safety Follow Up Period, which is at least 96 weeks after the last infusion, but may be 
extended in patients whose B cells take longer to replete. Non serious adverse events 
have to be reported until the end of Safety Follow up Period. 
4.5.8 Laboratory, Biomarker, and Other Biological Samples 
• 
Viral serology and detection: 
− 
For enrolled patients with negative HBsAg and positive total HBcAb, Hepatitis B 
virus (HBV) DNA (by PCR) must be repeated every 1224 weeks 
 
4.5.12 Patient Diary (optional) 
Due to the low frequency of study visits (every 6 months) and the structured telephone 
interviews (every 8 weeks between the study visits), patient diaries are proposed as an additional 
optional tool to help further improve the collection and documentation of Adverse Events and 
concomitant medications. The decision to use the patient diary is left to the discretion of each 
investigator. The investigator must ensure that required EC/IRB approval was obtained before 
implementing the patient diary at his/her site. 
Additional instructions around the use of an optional Patient Diary are provided in Appendix 7. 
4.6.2 Study Treatment Discontinuation 

 
 
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• 
Ongoing pregnancy or breastfeeding (in case of pregnancy, treatment should be 
interrupted, and the patient should be monitored for safety; however, the patient can be re-
started with the treatment after the pregnancy and breastfeeding period. During pregnancy 
and breastfeeding, the patient will continue to come for the regular schedule visits as per the 
protocol and will perform all assessments except MRI). 
4.6.4 End of study treatment 
At the end of the study treatment the patients will be encouraged to be included in a 
separate Long term Extension (LTE) study to further evaluate the efficacy and safety of 
their DMT treatment, and this is independent of the DMT. This LTE will also aim to 
evaluate the relationship between the primary endpoint of this study and long-term 
outcome. 
Patients who discontinue treatment early will be followed up for at least 96 weeks after 
the Early Treatment Discontinuation Visit last infusion of study drug. Patients who 
complete the 96 weeks Treatment Period and, in agreement with their treating 
neurologist, decide not to continue in a separate long term extension (LTE) study, will be 
followed up for at least 96 weeks after the end of the Treatment Period. (see Section 
3.1.4). Patients who decide to leave the study and switch to commercially marketed Ocrelizumab, 
either after completion of the 96 weeks Treatment Period or after early discontinuation of the 96 
weeks Treatment Period, will not enter the safety Follow-up Period. 
Section 5.1 SAFETY PLAN 
Administration of ocrelizumab will be performed in a hospital, clinic environment or 
doctor’s office/practice under close supervision of the investigator or a medically 
qualified staff member with immediate availability of full resuscitation facilities.  All 
adverse events and serious adverse events will be recorded during the study and until 
at 24, and 48 96 weeks after the end of the Treatment Periodlast dose of ocrelizumab as 
provided through this study.   
 
5.1.1.1 Identified Risks and Adverse Drug Reactions 
Infusion-Related Reactions (IRRs) 
All CD20 depleting agents administered via the intravenous route, including ocrelizumab 
have been associated with acute IRRs. Following the approved administration regimen 
(which includes the use of premedication prior to treatment with ocrelizumab in order to reduce 
frequency and severity of IRRs), Ssymptoms of IRRs may occur during any ocrelizumab 
infusion but have been more frequently reported during the first infusion. Physicians 
should alert patients that IRRs can occur within 24 hours of the infusion. Across the RMS 
and PPMS trials, symptoms associated with IRRs included, but were not limited to: These 
reactions may present as pruritus, rash, urticaria, erythema, throat irritation, 

 
 
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oropharyngeal pain, dyspnoea, pharyngeal or laryngeal edema, flushing, hypotension, 
pyrexia, fatigue, headache, dizziness, nausea and tachycardia. 
Infections  
Peripheral B cell depletion is an expected outcome of ocrelizumab use. Beyond the 
clinical trial experience of patients switching from beta interferon or glatiramer acetate to 
ocrelizumab, there are limited data on switching patients from other disease modifying 
therapies. 
When switching patients from another disease modifying therapy to ocrelizumab, the 
half life and mode of action of the other therapy must be considered, to take into 
consideration the potential for overlapping pharmacodynamic effects, whilst at the same 
time minimising the risk of disease reactivation.  
In interventional clinical studies  Tthere were no reports of hepatitis B reactivation in MS 
patients treated with ocrelizumab, but it had been reported in one RA patient treated with 
ocrelizumab. 
For PML see “Potential risks” below.Delay ocrelizumab administration in patients with an 
active infection until the infection is resolved. 
For PML see “Potential risks” below. 
Decrease in immunoglobulins 
Treatment with ocrelizumab resulted in a decrease in total immunoglobulins (Ig) over the 
controlled period of the studies, mainly driven by reduction in IgM, with no observed 
association with serious infections during the controlled periods. The proportion of patients 
with decrease in Igs below LLN increased over time and with successive dosing. Based 
on additional patient exposure, in cases of continuous decrease over time, a higher risk 
of serious infection cannot be ruled out (see below in potential risks section).  
Impaired Response to Vaccination 
After treatment with ocrelizumab over 2 years in pivotal clinical trials, the proportion of patients 
with positive antibody titers against streptococcus pneumoniae, mumps, rubella, and varicella 
were generally similar to the proportions at baseline. 
The results of the randomized, open-label Phase IIIb study (BN29739) that assessed if 
ocrelizumab recipients with RMS raise adequate humoral responses to selected vaccines indicate 
that patients treated with ocrelizumab were able to mount humoral responses, albeit decreased, to 
tetanus toxoid, 23-valent pneumococcal polysaccharide, keyhole limpet hemocyanin neoantigen, 
and seasonal influenza vaccines. The results are summarized in the current version of the IB.  
Physicians should review the immunization status of patients being considered for treatment 
with ocrelizumab. Patients who require vaccination should complete it at least 6 weeks prior to 
initiation of ocrelizumab. For seasonal influenza vaccines, it is still recommended to vaccinate 

 
 
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patients on ocrelizumab. Vaccination with live or live-attenuated vaccines are not recommended 
during the treatment with ocrelizumab and until B cells have returned to normal levels.  
Due to the potential depletion of B-cells in neonates and infants of mothers, who have been 
exposed to ocrelizumab during pregnancy, it is recommended that vaccination with live or live-
attenuated vaccines should be delayed until B-cells have recovered; therefore, measuring CD19-
positive B cell level, in neonates and infants, prior to vaccination is recommended.  
It is recommended that all vaccinations other than live or live-attenuated should follow the local 
immunization schedule and measurement of vaccine-induced response titers should be considered 
to check whether individuals can mount a protective immune response because the efficacy of the 
vaccination may be decreased.   
5.1.1.2 Potential Risks 
PML 
PML is an important potential risk for ocrelizumab and it has only been reported with 
ocrelizumab where the risk for PML was preexisting, specifically from prior 
immunosuppressive treatment (e.g. natalizumab or fingolimod treatment) because of prior 
natalizumab or fingolimod treatment. In all of these PML cases, the causality with ocrelizumab 
was not considered plausible. Based on the available information, it is reasonable to consider that 
the PML started before the first administration of ocrelizumab, given new symptom onset and/or 
MRI changes had already occurred on the previous therapy or during the wash out period, and 
was related to prior immunosuppressive treatment. Physicians should be vigilant for early signs 
and symptoms of PML, which can include any new onset, or worsening of neurological signs or 
symptoms as these can be similar to an MS relapse. If PML is suspected, dosing with ocrelizumab 
must be withheld. Evaluation of PML, including MRI, confirmatory CSF testing for JC Viral 
DNA and repeat neurological assessments, should be considered. If PML is confirmed, 
ocrelizumab must be discontinued permanently. Please refer to Appendix 6 for guidance for 
diagnosis of PML. Please see the IB for more details. 
Serious infections related to decrease in immunoglobulins (particularly in patients 
previously exposed to immunosuppressive/ immunomodulatory drugs or with pre-
existing hypogammaglobulinaemia) 
Based on additional patient exposure an apparent association between sustained 
decrease in immunoglobulins (IgA, IgG, IgM) and serious infections with ocrelizumab 
treatment was observed. However, no pattern (e.g. type of infections, safety laboratory 
abnormalities beyond the decrease in Ig, latency, duration) was found that could identify 
a subset of patients at higher risk of serious infections. There was no difference in the 
pattern (type, latency, duration, outcome) of the serious infections reported in this subset of 
patients compared to the overall serious infections profile. In addition, risk factors for a subset of 
patients at higher risk of serious infections could not be identified. 
Impaired Response to Vaccination 

 
 
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The degree of impairment of B cell dependent humoral response to neo antigens and 
polysaccharide antigens and its clinical relevance are currently unknown in patients with 
MS.  
After treatment with ocrelizumab over 2 years, the proportion of patients with positive 
antibody titers against Streptococcus pneumoniae, mumps, rubella, and varicella were 
generally similar to the proportions at baseline.  
No data are available on the effects of vaccination in patients receiving ocrelizumab. 
Physicians should review the immunization status of patients being considered for 
treatment with ocrelizumab. Patients who require vaccination should complete it at least 
6 weeks prior to initiation of ocrelizumab. 
The safety of immunization with live or live attenuated viral vaccines, following 
ocrelizumab therapy has not been studied and vaccination with live attenuated or live 
vaccines is not recommended while B cells are depleted. 
Neutropenia 
In the controlled treatment period, decreased neutrophils were observed in 12 to 15% of 
MS patients treated with ocrelizumab, in PPMS and RMS respectively. Most were mild to 
moderate in severity, and approximately 1% of the patients had Grade 3 or 4 
neutropenia; no temporal association with infections was identified. Based on additional 
patient exposure, an association between neutropenia and serious infections with ocrelizumab 
treatment was not observed. 
5.3.1 Adverse Event Reporting Period 
After initiation of study drug, all adverse events will be reported until 48 96 weeks 
after the last dose of the study drug end of the Treatment Period, but may be extended in 
patients whose B-cells take longer to replete.  
Related SAEs must be collected and reported regardless of the time elapsed from the 
last study drug administration, even if the study has been closed. 
Unrelated SAEs must be collected and reported during the study through the end of the 
Safety Follow Up Period, which is at least 96 weeks after the last infusion, but may be 
extended in patients whose B cells take longer to replete.  
Section 5.4.2.2 Events that Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events will be reported until 48 96 weeks 
after the end of the Treatment Period last dose of study drug.   
Related SAEs must be collected and reported regardless of the time elapsed from the last study 
drug administration, even if the study has been closed. 

 
 
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5.6 POST-STUDY ADVERSE EVENTS 
The Sponsor should be notified if the investigator becomes aware of any serious and 
non-serious adverse event that occurs after the end of the adverse event reporting 
period (defined as 4896 weeks after the last dose of the study drug end of the Treatment 
Period), if the event is believed to be related to prior study drug treatment.   
6. STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The analysis of this single-arm non-comparative study will be exploratory and primarily 
based on descriptive statistical methods. Unless otherwise specified, statistical tests will 
be two-sided and the statistical significance level will be 5%. Corresponding 95% CIs will 
be presented as appropriate. Although multiple statistical tests may be conducted, no 
adjustments to the Type 1 error rate will be made. No correction for multiple testing will be 
applied. 
6.4.4 Analysis Methods 
Patients not completing the study will be defined as not reaching the NEDA endpoint 
(“NEDA=no”). More dDetails about the missing data handling, as well as sensitivity 
analyses based on alternative imputation approaches, will be specified in the statistical 
analysis plan. 
6.7 HANDLING OF MISSING DATA 
Patients not completing the study will be defined as not reaching the NEDA endpoint 
(“NEDA=no”). More dDetails about the missing data handling will be specified in 
statistical analysis plan 
Figure 3 
Overview of End of Treatment Period  
Figure 3 has been revised to reflect changes to the protocol 
APPENDIX 1 Schedule of Assessments: Screening through the End of Treatment 
Period 
Appendix 1 has been revised to reflect the changes to the protocol. 
 
APPENDIX 2 Follow-up Schedule of Assessments 
Appendix 2 has been revised to reflect the changes to the protocol.  

 
 
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APPENDIX 7 PATIENT DIARY 
Appendix 7 was included to provide instructions about the use of a Patient Diary and as 
optional additional tool to help the patient and the site with the collection and reporting of 
AEs and concomitant medications 
SAMPLE INFORMED CONSENT FORM 
The sample Informed Consent Form has been revised to reflect the changes to the 
protocol. 
 

 
 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 16 
PROTOCOL SYNOPSIS .................................................................................... 17 
1. 
BACKGROUND ........................................................................................... 28 
1.1 
Background on Multiple Sclerosis ........................................................ 28 
1.2 
Background on Ocrelizumab ................................................................ 29 
1.3 
Study Rationale and Benefit-Risk Assessment .................................... 32 
2. 
OBJECTIVES AND ENDPOINTS ................................................................ 34 
2.1 
Efficacy Objectives ............................................................................... 34 
2.1.1 Primary Efficacy Objective ................................................................ 34 
2.1.2 Secondary Efficacy Objectives ......................................................... 35 
2.1.3 Exploratory Efficacy Objective .......................................................... 36 
2.2 
Safety Objective ................................................................................... 36 
3. 
STUDY DESIGN ......................................................................................... 36 
3.1 
Description of the Study ....................................................................... 36 
3.1.1 Overview of Study Design ................................................................ 38 
3.1.2 Screening ......................................................................................... 38 
3.1.3 Treatment Period .............................................................................. 39 
3.1.4 Follow-up Period ............................................................................... 40 
3.1.5 Planned Total Sample Size .............................................................. 42 
3.2 
End of Study and Length of Study ........................................................ 42 
3.3 
Rationale for Study Design ................................................................... 42 
3.3.1 Rationale for Ocrelizumab Dose and Schedule ................................ 42 
3.3.2 Rationale for Patient Population ....................................................... 43 
4. 
MATERIALS AND METHODS ..................................................................... 43 
4.1 
Patients ................................................................................................ 43 
4.1.1 Inclusion Criteria ............................................................................... 43 
4.1.2 Exclusion Criteria .............................................................................. 44 
4.2 
Method of Treatment Assignment and Blinding .................................... 47 
4.3 
Study Treatment ................................................................................... 47 
4.3.1 Formulation, Packaging, and Handling ............................................. 47 
4.3.1.1 Ocrelizumab .............................................................................. 47 
4.3.2 Dosage, Administration, and Compliance ......................................... 48 
4.3.2.1 Ocrelizumab .............................................................................. 48 
4.3.3 Prophylactic Treatment ..................................................................... 49 
4.3.4 Investigational Medicinal Product Accountability .............................. 50 
4.3.5 Post-Trial Access to Ocrelizumab ..................................................... 50 
4.4 
Concomitant Therapy ........................................................................... 50 
4.4.1 Permitted Therapy ............................................................................ 50 
4.4.2 Prohibited Therapy ........................................................................... 51 
4.5 
Study Assessments .............................................................................. 51 
4.5.1 Informed Consent Forms and Screening Log ................................... 51 
4.5.2 Medical History and Demographic Data ........................................... 51 
4.5.3 Physical Examinations ...................................................................... 52 

 
 
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4.5.4 Neurological Examinations ............................................................... 52 
4.5.5 Vital Signs ......................................................................................... 53 
4.5.6 Assessment of Disability ................................................................... 54 
4.5.7 Brain Magnetic Resonance Imaging ................................................. 54 
4.5.8 Laboratory, Biomarker, and Other Biological Samples ..................... 54 
4.5.9 Patient-Reported Outcomes ............................................................. 56 
4.5.10 
BICAMS ........................................................................................ 56 
4.5.11 
Telephone Interviews .................................................................... 57 
4.5.12 
Patient Diary (optional) .................................................................. 57 
4.6 
Patient, Treatment, Study, and Site Discontinuation ............................ 57 
4.6.1 Patient Discontinuation ..................................................................... 57 
4.6.2 Study Treatment Discontinuation ...................................................... 58 
4.6.3 Study and Site Discontinuation ......................................................... 58 
4.6.4 End of study treatment ...................................................................... 59 
5. 
ASSESSMENT OF SAFETY ....................................................................... 59 
5.1 
Safety Plan ........................................................................................... 59 
5.1.1 Risks Associated with Ocrelizumab .................................................. 60 
5.1.1.1 Identified Risks and Adverse Drug Reactions ........................... 60 
5.1.1.2 Potential Risks ........................................................................... 62 
5.1.2 Risks Associated with Corticosteroids .............................................. 63 
5.1.3 Risks Associated with Antihistamines ............................................... 63 
5.1.4 Management of Patients Who Experience Specific Adverse Events 64 
5.2 
Safety Parameters and Definitions ....................................................... 64 
5.2.1 Adverse Events................................................................................. 65 
5.2.2 Serious Adverse Events (Immediately Reportable to the Sponsor) .. 65 
5.2.3 Adverse Events of Special Interest (Immediately Reportable to the 
Sponsor) ...................................................................................................... 66 
5.3 
Methods and Timing for Capturing and Assessing Safety Parameters 66 
5.3.1 Adverse Event Reporting Period ...................................................... 66 
5.3.2 Eliciting Adverse Event Information .................................................. 67 
5.3.3 Assessment of Severity of Adverse Events ...................................... 67 
5.3.4 Assessment of Causality of Adverse Events .................................... 68 
5.3.5 Procedures for Recording Adverse Events ....................................... 69 
5.3.5.1 Infusion-Related Reactions........................................................ 69 
5.3.5.2 Diagnosis versus Signs and Symptoms .................................... 69 
5.3.5.3 Adverse Events That Are Secondary to Other Events ............... 70 
5.3.5.4 Persistent or Recurrent Adverse Events .................................... 70 
5.3.5.5 Abnormal Laboratory Values ..................................................... 71 
5.3.5.6 Abnormal Vital Sign Values ....................................................... 71 
5.3.5.7 Abnormal Liver Function Tests .................................................. 72 
5.3.5.8 Deaths ....................................................................................... 72 
5.3.5.9 Preexisting Medical Conditions.................................................. 73 
5.3.5.10 Lack of Efficacy or Worsening of Relapsing Remitting Multiple 
Sclerosis .................................................................................................. 73 
5.3.5.11 Hospitalization or Prolonged Hospitalization ............................. 73 

 
 
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5.3.5.12 Adverse Events Associated with an Overdose or Error in Drug 
Administration .......................................................................................... 74 
5.3.5.13 Patient-Reported Outcome Data ............................................... 74 
5.4 
Immediate Reporting Requirements from Investigator to Sponsor ....... 74 
5.4.1 Emergency Medical Contacts ........................................................... 75 
5.4.2 Reporting Requirements for Serious Adverse Events and Adverse 
Events of Special Interest ............................................................................ 75 
5.4.2.1 Events That Occur prior to Study Drug Initiation........................ 75 
5.4.2.2 Events That Occur after Study Drug Initiation ........................... 76 
5.4.3 Reporting Requirements for Pregnancies ......................................... 76 
5.4.3.1 Pregnancies in Female Patients ................................................ 76 
5.4.3.2 Abortions ................................................................................... 77 
5.4.3.3 Congenital Anomalies/Birth Defects .......................................... 77 
5.5 
Follow-Up of Patients after Adverse Events ......................................... 77 
5.5.1 Investigator Follow-Up ...................................................................... 77 
5.5.2 Sponsor Follow-Up ........................................................................... 77 
5.6 
Post-Study Adverse Events .................................................................. 77 
5.7 
Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards, and Ethics Committees ......................................................... 78 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....................... 78 
6.1 
Determination of Sample Size .............................................................. 79 
6.2 
Summaries of Conduct of Study ........................................................... 79 
6.3 
Summaries of Demographic and Baseline Characteristics ................... 80 
6.4 
Efficacy Analyses ................................................................................. 80 
6.4.1 Primary Efficacy Endpoint ................................................................. 80 
6.4.2 Secondary Efficacy Endpoints .......................................................... 80 
6.4.3 Exploratory Efficacy Endpoints ......................................................... 80 
6.4.4 Analysis Methods.............................................................................. 80 
6.5 
Safety Analyses ................................................................................... 82 
6.5.1 Safety Outcome Measures ............................................................... 82 
6.5.2 Safety Analyses ................................................................................ 82 
6.6 
Subgroup Analysis ............................................................................... 82 
6.7 
Handling of Missing Data ..................................................................... 82 
6.8 
Interim Analysis .................................................................................... 83 
7. 
DATA COLLECTION AND MANAGEMENT ................................................ 83 
7.1 
Data Quality Assurance ........................................................................ 83 
7.2 
Electronic Case Report Forms ............................................................. 83 
7.3 
Source Data Documentation ................................................................ 84 
7.4 
Use of Computerized Systems ............................................................. 84 
7.5 
Retention of Records ............................................................................ 85 
8. 
ETHICAL CONSIDERATIONS .................................................................... 85 
8.1 
Compliance with Laws and Regulations ............................................... 85 
8.2 
Informed Consent ................................................................................. 85 
8.3 
Institutional Review Board or Ethics Committee ................................... 86 
8.4 
Confidentiality ....................................................................................... 87 
8.5 
Financial Disclosure ............................................................................. 87 

 
 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
15/Protocol MA30005, Version 5 
9. 
STUDY DOCUMENTATION, MONITORING, AND ADMINISTRATION ..... 87 
9.1 
Study Documentation ........................................................................... 87 
9.2 
Protocol Deviations .............................................................................. 87 
9.3 
Site Inspections .................................................................................... 88 
9.4 
Administrative Structure ....................................................................... 88 
9.5 
Publication of Data and Protection of Trade Secrets ............................ 88 
9.6 
Protocol Amendments .......................................................................... 89 
10. 
REFERENCES ........................................................................................ 90 
 
 
LIST OF TABLES 
Table 1 
Overview of Ocrelizumab Dosing ................................................ 49 
Table 2 
Guidelines for Management of Specific Adverse Events ............ 64 
Table 3 
Adverse Event Severity Grading Scale for IRRs and Other 
Events Not Specifically Listed in NCI CTCAE ............................. 68 
Table 4 
Causal Attribution Guidance ....................................................... 69 
Table 5 
MRI Lesion Characteristics Typical of PML and MS ................. 115 
 
 
LIST OF FIGURES 
Figure 1 
Gd-enhancing lesions by week in each study group in Phase 
II study of ocrelizumab ................................................................ 33 
Figure 2 
Overview of Study Procedures .................................................... 38 
Figure 3 
Overview of End of Treatment Period ......................................... 40 
Figure 4 
Follow-up:  Variable B-Cell Monitoring Period............................. 41 
Figure 5 
Diagnostic Algorithm for PML .................................................... 114 
 
 
LIST OF APPENDICES 
Appendix 1: Schedule of Assessments: Screening through the End of 
Treatment Period ........................................................................ 94 
Appendix 2: Follow-up Schedule of Assessments .............................................. 99 
Appendix 3: Expanded Disability Status Scale (EDSS) .................................... 101 
Appendix 4: Telephone Interviews .................................................................... 103 
Appendix 5: Patient Reported Outcomes ......................................................... 105 
Appendix 6: Guidance for Diagnosis of Progressive Multifocal 
Leukoencephalopathy ............................................................... 113 
Appendix 7: Patient Diary ................................................................................. 117 
Appendix 8: Summary of Product Characteristics (SmPC) for Disease 
Modifying Therapies for EMEA Countries ................................. 118 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
16/Protocol MA30005, Version 5 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
AN OPEN-LABEL STUDY TO EVALUATE THE 
EFFICACY AND SAFETY OF OCRELIZUMAB IN 
PATIENTS WITH RELAPSING REMITTING MULTIPLE 
SCLEROSIS WHO HAVE A SUBOPTIMAL RESPONSE 
TO AN ADEQUATE COURSE OF DISEASE-MODIFYING 
TREATMENT 
PROTOCOL NUMBER: MA30005 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
2015-005597-38 
IND NUMBER: 
Not applicable 
TEST PRODUCT: 
Ocrelizumab (RO4964913) 
MEDICAL MONITOR: 
TBC 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy as 
instructed by the CRO. 
 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
17/Protocol MA30005, Version 5 
PROTOCOL SYNOPSIS 
TITLE: 
AN OPEN-LABEL STUDY TO EVALUATE THE EFFICACY 
AND SAFETY OF OCRELIZUMAB IN PATIENTS WITH 
RELAPSING REMITTING MULTIPLE SCLEROSIS WHO 
HAVE A SUBOPTIMAL RESPONSE TO AN ADEQUATE 
COURSE OF DISEASE-MODIFYING TREATMENT 
PROTOCOL NUMBER: 
MA30005 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
2015-005597-38  
IND NUMBER: 
Not applicable 
TEST PRODUCT: 
Ocrelizumab (RO4964913) 
PHASE: 
Phase IIIb 
INDICATION: 
Relapsing remitting multiple sclerosis 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives and Endpoints 
This study will evaluate the efficacy and safety of ocrelizumab in patients with relapsing 
remitting multiple sclerosis (RRMS) who have a suboptimal response to an adequate course of 
a disease modifying treatment (DMT). Specific objectives and corresponding endpoints for the 
study are outlined below. 
 
Efficacy Objective 
The primary objective for this study is to assess the efficacy of ocrelizumab 600 mg intravenous 
(IV) given every 24 weeks on the basis of the following endpoint: 
• 
Proportion of patients who have no evidence of disease activity (NEDA, as per protocol 
defined events) during a 96-week period. The magnetic resonance imaging (MRI) activity will 
be calculated on the events starting from week 8 (baseline reset) when drug is fully active. 
The definition of a protocol-defined event of disease activity is the occurrence of at least one of 
the following while on treatment with ocrelizumab: 
− 
A protocol-defined relapse as defined below 
− 
24 weeks confirmed disability progression based on increases in Expanded 
Disability Status Scale (EDSS) while on treatment with ocrelizumab 
− 
A T1 gadolinium (Gd)-enhanced lesion after Week 8 
− 
A new and/or enlarging T2 hyperintense lesion on MRI after Week 8 compared to 
the Week 8 MRI scan 
A protocol-defined multiple sclerosis (MS) relapse is an occurrence of new or worsening 
neurological symptoms attributable to MS that meets the following criteria: 
• 
Symptoms must persist for >24 hours and should not be attributable to confounding clinical 
factors (e.g., fever, infection, injury, adverse reactions to medications) 
• 
Symptoms should be preceded by neurological stability for at least 30 days 
• 
Symptoms should be accompanied by new objective neurological worsening determined 
with a timely EDSS/ Functional Systems Score (FSS) assessment, consistent with an 
increase of at least:  
− 
≥ 0.5 points on EDSS scale 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
18/Protocol MA30005, Version 5 
− 
or ≥ 2 points on one of the following FSS scales: pyramidal, ambulation, cerebellar, 
brainstem, sensory, or visual 
− 
 or ≥ 1 point on two or more of the following FSS scales: pyramidal, ambulation, 
cerebellar, brainstem, sensory, or visual 
Episodic spasms, sexual dysfunction, fatigue, mood change or bladder or bowel urgency or 
incontinence will not suffice to establish a relapse (Please note:  Sexual dysfunction and fatigue 
need not be scored). 
 
The secondary objective for this study is to evaluate the efficacy of ocrelizumab 600 mg IV given 
every 24 weeks on the basis of the following endpoints: 
• 
The proportions of patients free from a protocol-defined event of disease activity during a 24-
week period and a 48-week period 
• 
Time to first protocol-defined event of disease activity 
• 
Change in EDSS from baseline to Week 96 
• 
Proportion of patients who, over a 96-week period, have Confirmed Disability Improvement 
(CDI), Confirmed Disability Progression (CDP) or stable disability (i.e. neither CDI nor CDP) 
• 
Annualized rate of protocol-defined relapses at Week 96 
• 
Time to onset of first protocol-defined relapse 
• 
Time to onset of 24 weeks CDP  
• 
Time to onset of first new and/or enlarging T2 lesion 
• 
Total number of T1 Gd-enhanced lesions detected by brain MRI at Weeks 24, 48 and 96 
• 
Change in total T2 lesion volume detected by brain MRI from baseline to Week 96 
• 
Volume and number of new and/or enlarging T2 hyperintense lesions from baseline to 
Weeks 24, 48 and 96 
• 
Change in T1 hypointense lesion volume from baseline to Weeks 48 and 96   
• 
Change in brain volume from baseline measured at Weeks 24, 48 and 96 
• 
Change from baseline in cognitive performance at Week 48 and Week 96 as measured by 
the BICAMS (Brief International Cognitive Assessment for Multiple Sclerosis) 
 
Safety Objective 
The safety objective for this study is to evaluate the safety and tolerability of ocrelizumab 600 mg 
IV given every 24 weeks on the basis of the following endpoints:  
• 
Rate and nature of adverse events 
• 
Changes in vital signs, physical and neurological examinations, clinical laboratory results, 
locally reviewed MRI for safety (non-MS central nervous system [CNS] pathology) and 
concomitant medications (including pre-medications and medications used during and 
following ocrelizumab administration). 
 
Exploratory Objectives 
The exploratory efficacy objective for this study is to further assess the efficacy of ocrelizumab 
600 mg IV given every 24 weeks by monitoring patient-reported outcomes (PROs) related to 
quality of life (QoL), treatment satisfaction and other endpoints and analyses as follows: 
• 
Multiple Sclerosis Impact Scale (MSIS)-29 (MS-specific QoL questionnaire) 
• 
Treatment satisfaction questionnaire for medication (TSQM II) 
• 
Patient reported outcome: SymptoMScreen  
• 
MRI and clinical outcomes at 6 months and 1 year 
• 
Predictors of NEDA and association between NEDA and disability or other efficacy 
parameters 
• 
Severity of relapses (hospitalization for MS relapse, use of corticosteroids, residual disability) 
• 
Employment status (WPAI) 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
19/Protocol MA30005, Version 5 
• 
Proportion of patients who have no evidence of disease activity (NEDA, as per protocol 
defined events) during a 96-week period and starting from baseline. 
 
Study Design 
Description of Study 
This study is a prospective, multicenter, open-label, efficacy, and safety study in patients with 
RRMS who have a suboptimal response to an adequate course of a DMT.  An adequate course 
of prior DMT is defined as a stable dose of the same DMT administered for at least 6 months. 
The first dose of ocrelizumab will be administered as an initial dose of two 300-mg infusions 
(600 mg total) in 250 mL 0.9% sodium chloride each separated by 14 days (i.e., Days 1 and 15) 
followed by one 600-mg infusion in 500 mL 0.9% sodium chloride every 24 weeks for the study 
duration.   
Patients will be assessed for efficacy and safety every 24 weeks.  The study will consist of the 
following periods: 
• 
Screening period:  Up to 4 weeks 
• 
Treatment period:  Open-label treatment period of 96 weeks (last dose administered at 
Week 72) 
• 
A follow-up period of at least 2 years, which is independent of the DMT administered 
 
Follow-up Period:  Patients who discontinue treatment early will be followed up for at least 96 
weeks after the Early Treatment Discontinuation Visit. Patients who complete the 96 weeks 
Treatment Period and, in agreement with their treating neurologist, decide not to continue in a 
separate long-term extension (LTE) study, will be followed up for at least 96 weeks after the 
end of the Treatment Period. Patients who decide to leave the study and switch to 
commercially marketed Ocrelizumab, either after completion of the 96 weeks Treatment 
Period or after early discontinuation of the 96 weeks Treatment Period, will not enter the safety 
Follow-up Period. 
 
Patients whose B-cells have not been repleted after 96 weeks of Follow-up Period will continue 
with visits every 24 weeks, and telephone contacts every 8 weeks, until B-cell repletion 
(Prolonged B-cell monitoring). If the patients are receiving other B-cell targeted therapies, then 
the Follow-up Period will be stopped at 96 weeks regardless of their B-cell count. 
 
A structured telephone interview will be conducted by site personnel every 8 weeks between the 
study visits during the treatment period and follow-up to identify and collect information on any 
changes in the patient’s health status that warrant an unscheduled visit (including new or 
worsening neurological symptoms) and possible events or infections. 
 
Number of Patients 
This study will enroll 750 patients with RRMS who have had a suboptimal response to an 
adequate course of a DMT.   
 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Signed informed consent form 
• 
Able to comply with the study protocol, in the investigator’s judgment 
• 
Age 18 − 55 years, inclusive 
• 
Have a definite diagnosis of RRMS, confirmed as per the revised McDonald 2010 criteria 
(Polman et al. 2011) 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
20/Protocol MA30005, Version 5 
• 
Have a length of disease duration, from first symptom, of < 10 years. If the date of first 
symptom is unknown, then the diagnosis of RRMS should be of ≤ 5 years 
• 
Have received no more than two prior DMTs, and the discontinuation of the most recent 
DMT was due to lack of efficacy 
• 
Suboptimal disease control while on a DMT; a suboptimal response is defined by having at 
least one of the following events while being on a stable dose of the same DMT for at least 6 
months: 
− 
One or more clinically reported relapse(s) 
− 
OR one or more T1 Gd-enhanced lesion(s) 
− 
OR two or more new and/or enlarging T2 lesions on MRI 
In addition, in patients receiving stable doses of the same approved DMT for more than a 
year, at least one of the above events must have occurred within the last 12 months of 
treatment with this DMT. 
• 
EDSS of 0.0 to 4.0, inclusive, at screening 
• 
For women of childbearing potential:  agreement to use an acceptable birth control method 
during the treatment period and for at least 6 months after the last dose of study drug. 
A woman is considered to be of childbearing potential if she is postmenarcheal, has not 
reached a postmenopausal state ( 12 continuous months of amenorrhea with no identified 
cause other than menopause), and has not undergone surgical sterilization (removal of 
ovaries and/or uterus). 
The following are acceptable contraceptive methods: progestogen-only oral hormonal 
contraception, where inhibition of ovulation is not the primary mode of action, male or female 
condom with or without spermicide, and cap, diaphragm, or sponge with spermicide.  A 
combination of male condom with cap, diaphragm, or sponge with spermicide (double-barrier 
methods) is considered acceptable 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Secondary progressive multiple sclerosis (SPMS) or history of primary progressive or 
progressive relapsing MS 
• 
Inability to complete an MRI (contraindications for MRI include but are not restricted to 
pacemaker, cochlear implants, presence of foreign substances in the eye, intracranial 
vascular clips, surgery within 6 weeks of entry into the study, coronary stent implanted within 
8 weeks prior to the time of the intended MRI, inability to tolerate Gadolinium-based contrast 
agents etc.) 
 
• 
Known presence of other neurological disorders, including but not limited to, the following: 
− 
History of ischemic cerebrovascular disorders (e.g., stroke, transient ischemic attack) or 
ischemia of the spinal cord 
− 
History or known presence of CNS or spinal cord tumor (e.g., meningioma, glioma) 
− 
History or known presence of potential metabolic causes of myelopathy (e.g., untreated 
vitamin B12 deficiency) 
− 
History or known presence of infectious causes of myelopathy (e.g., syphilis, Lyme 
disease, human T-lymphotropic virus 1 (HTLV-1), herpes zoster myelopathy) 
− 
History of genetically inherited progressive CNS degenerative disorder (e.g., hereditary 
paraparesis; MELAS [mitochondrial myopathy, encephalopathy, lactic acidosis, stroke] 
syndrome) 
− 
Neuromyelitis optica 
− 
History or known presence of systemic autoimmune disorders potentially causing 
progressive neurologic disease (e.g., lupus, anti-phospholipid antibody syndrome, 
Sjogren’s syndrome, Behçet’s disease) 
− 
History or known presence of sarcoidosis 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
21/Protocol MA30005, Version 5 
− 
History of severe, clinically significant brain or spinal cord trauma (e.g., cerebral 
contusion, spinal cord compression) 
 
Exclusions Related to General Health 
• 
Pregnancy or lactation 
• 
Any concomitant disease that may require chronic treatment with systemic corticosteroids or 
immunosuppressants during the course of the study 
• 
History or currently active primary or secondary immunodeficiency 
• 
Lack of peripheral venous access 
• 
History of severe allergic or anaphylactic reactions to humanized or murine monoclonal 
antibodies 
• 
Significant or uncontrolled somatic disease or any other significant disease that may preclude 
patient from participating in the study 
• 
Congestive heart failure (New York Heart Association [NYHA] III or IV functional severity) 
• 
Known active bacterial, viral, fungal, mycobacterial infection or other infection, excluding 
fungal infection of nail beds 
Note: Active infections should be treated and effectively controlled before possible inclusion 
in the study 
• 
History of major opportunistic infections (i.e. cryptococcosis, Pneumocystis pneumonia, 
progressive multifocal leukoencephalopathy [PML]) 
• 
History or known presence of recurrent or chronic infection (e.g., hepatitis B or C, human 
immunodeficiency virus [HIV], syphilis, tuberculosis [TB]) 
• 
History of malignancy, including solid tumors and hematological malignancies, except basal 
cell carcinoma, in situ squamous cell carcinoma of the skin, and in situ carcinoma of the 
cervix of the uterus that have been previously completely excised with documented, clear 
margins 
• 
History of alcohol or drug abuse within 24 weeks prior to baseline 
• 
History or laboratory evidence of coagulation disorders 
 
Exclusions Related to Medications* 
• 
Receipt of a live vaccine or attenuated live vaccine within 6 weeks prior to the baseline visit. 
In rare cases when patient requires vaccination with a live vaccine, the screening period may 
be extended but cannot exceed 8 weeks 
• 
Treatment with any investigational agent within 24 weeks of screening (Visit 1) or five half-
lives of the investigational drug (whichever is longer) or treatment with any experimental 
procedures for MS (e.g., treatment for chronic cerebrospinal venous insufficiency) 
• 
Contraindications to or intolerance of oral or IV corticosteroids, according to the country 
label, including: 
a) Psychosis not yet controlled by a treatment; 
b) Hypersensitivity to any of the constituents 
• 
Previous treatment with B-cell targeted therapies (i.e., rituximab, ocrelizumab, atacicept, 
belimumab, or ofatumumab) 
• 
Systemic corticosteroid therapy within 4 weeks prior to screening 
• 
Any previous treatment with alemtuzumab (Campath/Mabcampath/Lemtrada), cladribine, 
mitoxantrone, daclizumab, laquinimod, total body irradiation, or bone marrow transplantation. 
• 
Treatment with cyclophosphamide, azathioprine, mycophenolate mofetil, cyclosporine or 
methotrexate 
• 
Previous treatment with natalizumab unless natalizumab was discontinued because of 
persistent anti-natalizumab antibodies 
• 
Treatment with IV immunoglobulin (Ig) within 12 weeks prior to baseline 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
22/Protocol MA30005, Version 5 
• 
Any previous treatment with an investigational MS DMT not yet approved at time of 
screening. 
• 
History of recurrent aspiration pneumonia requiring antibiotic therapy 
• 
Patients previously treated with teriflunomide, unless an accelerated elimination procedure is 
implemented before screening visit 
Accelerated elimination procedure after stopping treatment with teriflunomide: 
o 
cholestyramine 8g is administered 3 times daily for a period of 11 days, or 
cholestyramine 4g three times a day can be used, if cholestyramine 8g three times a 
day is not well tolerated, 
o 
alternatively, 50g of activated powdered charcoal is administered every 12 hours for 
a period of 11 days 
In cases where no pregnancy is expected teriflunomide plasma concentrations of 0.03-0.04 
mg/ml are accepted to include the patient in study. 
• 
Previous treatment with fingolimod or dimethyl fumarate if at baseline the lymphocyte count 
is below lower limit of normal (LLN). The provisions for stopping therapy as described in the 
respective SmPCs should be followed.  
• 
Treatment with fampridine/dalfamipridine (Fampyra®)/Ampyra®) unless on stable dose for   
≥ 30 days prior to screening. Wherever possible, patients should remain on stable doses 
throughout the 96-week treatment period. 
 
* Patients screened for this study should not be withdrawn from therapies for the sole purpose of 
meeting eligibility for the trial.  
 
Exclusions Related to Laboratory Findings* 
• 
Positive serum β human chorionic gonadotropin (hCG) measured at screening 
• 
Positive screening tests for hepatitis B (hepatitis B surface antigen [HBsAg] positive, or 
positive hepatitis B core antibody [total HBcAb] confirmed by a positive viral DNA 
polymerase chain reaction [PCR]) or hepatitis C (HepCAb) 
• 
Lymphocyte count below LLN 
• 
CD4 count<250/μL. 
• 
Aspartate aminotransferase (AST)/ serum glutamic oxaloacetic transaminase (SGOT) or 
alanine aminotransferase (ALT) /serum glutamic pyruvic transaminase (SGPT)≥ 3.0 × the 
upper limit of normal (ULN) 
• 
Platelet count <100,000/μL (<100 × 109/L) 
• 
Absolute neutrophil count <1.0 × 103/μL 
*Re-testing before baseline: any abnormal screening laboratory value that is clinically relevant 
should be retested in order to rule out any progressive or uncontrolled underlying condition. The 
last value before baseline visit must meet study criteria.  
Please note: based on local Ethics Committees or National Competent Authority requirements, 
additional diagnostic testing may be required for selected patients or selected centers to exclude 
tuberculosis, Lyme disease, HTLV-1 associated myelopathy (HAM), acquire immunodeficiency 
syndrome (AIDS), hereditary disorders, connective tissue disorders, or sarcoidosis. Other specific 
diagnostic tests may be requested when deemed necessary by the Investigator. 
 
End of Study 
The end of the study treatment period has been defined as the date on which the last patient 
receiving the full study treatment reached the 96-week visit. Exception will be made for patients 
who have EDSS change at Week 96 and need confirmation of EDSS score after a further 24 
weeks.  
The end of the study is defined as the last patient last visit in the B-cell monitoring of the Follow-
up Period.  

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
23/Protocol MA30005, Version 5 
At the end of the study treatment, patients will be encouraged to be included in a separate LTE 
study to further evaluate the efficacy and safety of their DMT treatment and this is independent of 
the DMT administered. This LTE will also aim to evaluate the relationship between the primary 
endpoint of this study and long-term outcome. 
 
Length of Study 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 5 years. This includes an enrollment period of approximately 12 
months. 
 
Investigational Medicinal Products 
Test Product (Investigational Drug) 
The first dose of ocrelizumab will be administered as two 300-mg IV infusions (600 mg total) in 
250 mL 0.9% sodium chloride each separated by 14 days (i.e., Days 1 and 15), followed by one 
600-mg IV infusion in 500 mL 0.9% sodium chloride every subsequent dose (i.e., every 
24 weeks) for a maximum of 4 doses. 
 
Non-Investigational Medicinal Products 
Premedicate with 100 mg of methylprednisolone (or an equivalent), administered by slow IV 
infusion, to be completed approximately 30 minutes prior to each ocrelizumab infusion, and an 
antihistaminic drug (e.g., diphenhydramine) approximately 30 – 60 minutes before each infusion 
of ocrelizumab to reduce the frequency and severity of infusion-related reactions (IRRs).    The 
addition of an antipyretic (e.g., acetaminophen/ paracetamol) may also be considered. 
 
Statistical Methods 
Primary Analysis 
The primary efficacy analyses will include all enrolled patients who received any dose of 
ocrelizumab (intent-to-treat population). The analysis will be performed after the last CDP and 
CDI confirmation visit. The per-protocol population, defined as all patients who had 96 weeks of 
treatment and who did not have any major protocol violations that are deemed to potentially affect 
the efficacy and safety endpoints, will be used for supportive efficacy analyses of the primary 
endpoint. 
The evaluation of the clinical efficacy of ocrelizumab will be based upon the events in-between 
the baseline visit and week 96 visit. The MRI activity is evaluated from week 8 to week 96. 
The proportion of patients free from protocol-defined events up to Week 96 (i.e. patients with 
NEDA) will be calculated and the corresponding two-sided Clopper-Pearson 95% confidence 
interval (CI) will be presented. Logistic regression models will be used to identify predictors of 
response to treatment (freedom from protocol-defined events of disease activity). Variables that 
will be considered are: region, line of treatment (previous DMTs), gender, and baseline EDSS. In 
addition, specific efficacy endpoints, such as CDP, will be compared between patients with or 
without evidence of disease activity up to Week 96. 
 
Details about the missing data handling, as well as sensitivity analyses, will be specified in the 
statistical analysis plan. 
 
Determination of Sample Size   
With a sample size of 750 patients, an observed NEDA rate of 30% will be estimated with a 
precision (half-width of the 95% CI around the estimate) of 3.3% based on the Clopper-Pearson 
method, i.e. the 95% CI will be (26.7%, 33.4%). Even if the NEDA rate is different from the 
assumed rate of 30%, with the proposed sample size the precision of the estimate will remain 
smaller than 3.6% (value for a NEDA rate of 50%).  
The annualized relapse rate is another relevant outcome measure assessed in this study. Based 
on results from the pivotal Phase III studies WA21092 (OPERA I) and WA21093 (OPERA II), in 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
24/Protocol MA30005, Version 5 
this study the adjusted annualized relapse rate assessed over two years is expected to be 
estimated with a precision of approximately 0.03. 
 
Interim Analyses 
No formal confirmatory efficacy interim analyses are planned. Exploratory analyses of selected 
endpoints may be performed during the course of the study, e.g. after all patients have completed 
the first 6 and 12 months of the treatment phase and the necessary data are available. 
 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
25/Protocol MA30005, Version 5 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
AIDS 
Acquire immunodeficiency syndrome 
ALT 
Alanine aminotransferase 
ARR 
Annual relapse rate 
AST 
Aspartate aminotransferase 
-hCG 
Beta subunit human chorionic gonadotropin 
BICAMS 
Brief International Cognitive Assessment for Multiple Sclerosis 
CDI 
Confirmed disability improvement 
CDP 
Confirmed disability progression 
CI 
Confidence interval 
CNS 
Central nervous system 
CRO 
Contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMT 
Disease modifying treatment 
EC 
Ethics committee 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
EDSS 
Expanded Disability Status Scale 
EU 
European Union 
FDA 
Food and Drug Administration 
FLAIR 
Fluid-attenuated inversion-recovery 
FSH 
Follicle stimulating hormone 
FSS 
Functional Systems Score 
GA 
Glatiramer acetate 
GCP 
Good Clinical Practice 
Gd 
Gadolinium 
GGT 
Gamma-glutamyl transpeptidase 
GPA 
Granulomatosis with polyangiitis 
HAM 
HTLV-1 associated myelopathy 
HBcAb 
Hepatitis B core antibody 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HEENT 
Head, eye, ear, nose, and throat 
HepCAb 
Hepatitis C antibody 
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 
HTLV-1 
Human T-lymphotropic virus 1 
IB 
Investigator’s brochure 

 
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26/Protocol MA30005, Version 5 
Abbreviation 
Definition 
ICH 
International Conference on Harmonisation 
IFN- 
Interferon beta 
Ig 
Immunoglobulin 
IMP 
Investigational medicinal product 
IND 
Investigational New Drug  
IRB 
Institutional Review Board 
IRR 
Infusion-related reaction 
ITT 
intent-to-treat 
IV 
Intravenous 
IxRS 
Interactive voice/Web response system 
JCV 
John Cunningham virus 
LLN 
Lower limit of normal 
LPLV 
Last patient, last visit 
LTE 
Long term extension 
MELAS 
Mitochondrial myopathy, encephalopathy, lactic acidosis, stroke 
MMRM 
Mixed model with repeated measure 
MRI 
Magnetic resonance imaging 
MS 
Multiple sclerosis 
MSIS-29 
Multiple Sclerosis Impact Scale (29-item scale) 
NCI 
National Cancer Institute 
NEDA 
No evidence of disease activity 
NYHA 
New York Heart Association 
OLE 
Open label extension 
PCR 
Polymerase chain reaction 
PML 
Progressive multifocal leukoencephalopathy 
PP 
Per-protocol 
PPMS 
Primary progressive multiple sclerosis 
PRMS 
Progressive relapsing multiple sclerosis 
PRO 
Patient-reported outcome 
PY 
Patient years 
QOL 
Quality of life 
RA 
Rheumatoid arthritis 
RBC 
Red blood cell 
RMS 
Relapsing multiple sclerosis 
RRMS 
Relapsing remitting multiple sclerosis 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
SGOT 
SGPT 
Standard deviation 
Serum glutamic oxaloacetic transaminase 
Serum glutamic pyruvic transaminase 
SmPC 
Summary of product characteristics 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
27/Protocol MA30005, Version 5 
Abbreviation 
Definition 
SPMS 
Secondary progressive multiple sclerosis 
TB 
Tuberculosis 
TSQM 
Treatment satisfaction questionnaire for medication 
ULN 
Upper limit of normal 
U.S. 
United States 
USP 
United States Pharmacopeia 
WBC 
White blood cell 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
28/Protocol MA30005, Version 5 
1. 
BACKGROUND 
1.1 
BACKGROUND ON MULTIPLE SCLEROSIS 
Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating, and degenerative 
disease of the central nervous system (CNS) that affects approximately 400,000 people 
in the United States (U.S.) and 2.3million worldwide (Tullman et al. 2013).  MS primarily 
affects young adults, with 70% − 80% of patients having an age of onset (i.e., initial visit 
to a physician) between 20 and 40 years (Anderson et al. 1992; Noonan et al. 2002), 
and has a strong gender bias, with approximately 64% − 70% of diagnosed patients 
being women (Goodin 2014).   
MS is clinically subcategorized into four phenotypic disease patterns distinguished by 
the occurrence and timing of relapses relative to disease onset and disability 
progression.  These include relapsing remitting MS (RRMS), primary progressive MS 
(PPMS), progressive relapsing MS (PRMS), and secondary progressive MS (SPMS) 
(Lublin et al. 1996; Lublin et al. 2014).  Approximately 85% of MS patients initially 
present with RRMS (Confavreaux et al. 2000; Leray et al. 2015).  The majority of RRMS 
patients will transition into SPMS within 20-25 years (Trojano et al. 2003).   
The clinical signs in MS can occur in isolation or in combination, and can include 
weakness, spasticity, gait and coordination imbalances, sensory dysfunction, vision loss, 
sexual dysfunction, fatigue, depression, chronic pain, sleep disorders, and cognitive 
impairment (Tanasescu et al. 2015). Current diagnosis of definite MS involves both 
clinical (history and neurological exam) and paraclinical (for example, Magnetic 
Resonance Imaging [MRI], Spinal Tap, Evoked potentials) evidence.  
MS treatments tackle separately the acute exacerbations and their prevention. 
Symptomatic management of relapses involves the use of corticosteroids, while 
disease-modifying treatments (DMTs) aim to decrease the clinical relapse rate and 
concomitant inflammation within the CNS (Tanasescu et al. 2015). DMTs, which include 
immunomodulatory, anti-inflammatory, and immunosuppressive drugs, are used to slow 
the development of MS-related neurological damage and disability progression.  By 
providing a more effective approach to MS treatment, DMTs may improve quality of life 
for individuals with MS (Weinstock-Guttman 2013). 
MS therapeutic landscape is changing rapidly. After several years in which first-line 
DMTs – glatiramer acetate (GA) and interferon beta (IFNβ) – constituted the principal 
treatment options, a variety of new agents for MS treatment are now approved by 
regulatory authorities or in phase II and III clinical trials (Tanasescu et al. 2015). In 2004 
natalizumab was approved for relapsing forms of MS and in 2014, alemtuzumab and 
peg IFNβ-1a. Fingolimod was the first oral DMT approved by Food and Drug 
Administration (FDA) in 2010 for relapsing forms of MS (RMS) followed by teriflunomide 
in 2012 and dimethyl fumarate in 2013 (wwww.mymsaa.org). 

 
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DMTs like IFNβ and GA are often used early in the course of disease and have a 
favourable benefit-to-risk profile, but they are only partially effective (Freedman 2014; 
Ziemssen et al. 2015) and up to 40% of patients continue to show disease activity on 
these treatments (Tanasescu et al. 2015), indicating the need for an alternative 
therapeutic strategy (Ziemssen et al. 2015). Possible treatment strategies for patients 
who have a suboptimal response to these DMT include switching to either another 
IFNβ/GA or switching to a more effective DMT, namely fingolimod, natalizumab or 
alemtuzumab (Freedman 2014).). Switching patients early to a high-efficacy therapy that 
targets both focal and diffuse damage may impact the course of the disease and achieve 
long-term disease control (Ziemssen et al. 2015).  
Suppression of disease activity and disability progression as early as possible remains 
an important goal of therapy in MS. With the emergence of more efficacious therapies 
and a better understanding of the consequences of subclinical disease activity in recent 
years, physicians have a lower tolerance for allowing disease activity to persist because 
what is lost in MS cannot typically be regained. The potential risk of irreversible disease 
progression is therefore an important factor in the therapeutic decision making of 
patients and their physicians. Although there are now several approved therapies for 
RMS, some lack sufficient efficacy to quell progression of disability, while more effective 
therapies are often reserved for later use because of serious risks. Thus there remains a 
need for highly effective therapies with a benefit-risk profile that supports its expeditious 
use at any time during the course of disease to preserve CNS tissue and neurological 
function, stem accrual of irreversible disability, and improve the quality of life for people 
living with MS.  
1.2 
BACKGROUND ON OCRELIZUMAB 
Ocrelizumab is a recombinant humanized anti-human monoclonal antibody that 
selectively targets CD20-expressing B cells (Klein et al. 2013), which are believed to 
play a critical role in MS.  It then interacts with the body's immune system to eliminate 
CD20-positive B-cells.   
CD20 is a cell surface antigen found on pre-B cells, mature B cells, and memory B cells, 
but it is not expressed on lymphoid stem cells and plasma cells (Stashenko et al. 1980; 
Loken et al. 1987; Tedder and Engel 1994).  While ocrelizumab selectively depletes 
CD20-expressing B cells (Kappos et al. 2011), the capacity of B-cell reconstitution and 
pre-existing humoral immunity are preserved (Martin and Chan 2006; DiLillo et al. 2008).  
In addition, innate immunity and total T-cell numbers are not affected (WA21493 Clinical 
Study Report). 
See the Ocrelizumab Investigator's Brochure (IB) for additional details on nonclinical and 
clinical studies. 
Summary of Clinical Studies of Ocrelizumab in MS 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
30/Protocol MA30005, Version 5 
In two double-blind, double-dummy Phase III global RMS trials (Studies WA21092 and 
WA21093), ocrelizumab 600 mg demonstrated superior efficacy over subcutaneous 
IFNβ-1a 44 g (Hauser et al. 2015).  Efficacy outcomes were consistent between trials 
and across the primary and key clinical and imaging secondary endpoints.  Ocrelizumab 
600 mg demonstrated statistically significant superiority compared with IFNβ-1a on each 
of the following major efficacy endpoints: 
• 
Relative reductions of 46% and 47% (both p  0.0001) in the protocol-defined annual 
relapse rate (ARR) in Studies WA21092 and WA21093, respectively (primary 
endpoint) 
• 
A 40% relative reduction in both the 12-week confirmed disability progression [CDP] 
(Hazards ratio [HR] 0.60 [95% confidence interval [CI]: 0.45, 0.81], p = 0.0006) and 
24-week CDP (HR 0.60 [95% CI: 0.43, 0.84], p=0.0025) in the pooled analysis of 
Studies WA21092 and WA21093.  Each individual trial also demonstrated a 
significant relative risk reduction of 12-week CDP and 24-week CDP (43% reduction 
for both 12- and 24-week CDP in Study WA21092 and 37% reduction for both 12- 
and 24-week CDP in Study WA21093) 
• 
Relative reductions of 94% and 95% (both p<0.0001) in the number of 
T1- gadolinium (Gd)-enhancing lesions per scan at Weeks 24, 48 and 96 in 
Study WA21092 and Study WA21093, respectively 
• 
Relative reductions of 77% and 83% (both p  0.0001) in the total number of new 
and/or enlarging T2 hyperintense lesions per scan at Weeks 24, 48 and 96 in 
Study WA21092 and Study WA21093, respectively 
In a Phase III global PPMS trial (Study WA25046), ocrelizumab 600 mg demonstrated 
statistically significant superiority compared with placebo on each of the following major 
efficacy endpoints (Montalban et al. 2015) 
• 
A 24% relative risk reduction in 12-week CDP, the primary endpoint (HR = 0.76 [95% 
CI: 0.59, 0.98], p = 0.0321) 
• 
A 25% relative risk reduction in 24-week CDP (HR = 0.75 [95% CI: 0.58, 0.98], 
p = 0.0365) 
• 
Relative reduction of 29% in the progression rate of timed 25-foot walk from 
baseline to Week 120 (p = 0.0404) 
• 
A decrease in the volume of T2 lesions by 3.4% over 120 weeks, compared with the 
placebo group in which the T2 lesion volume increased by 7.4% (p  0.0001) 
• 
Relative reduction of 17.5% in whole brain volume loss from Week 24 to Week 120 
(p = 0.0206). 

 
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Clinical Safety 
The safety data included are from the three Phase III studies in RMS (Studies WA21092 
and WA21093) and PPMS (Study WA25046); safety data from the Phase II study in 
RRMS (Study WA21493) is described in the IB. 
All four studies WA21092, WA21093, WA25046, and WA21493 have completed the 
controlled treatment period and are in open-label extension phase. 
In the two double-blind, double-dummy RMS Phase III studies (pooled data of Studies 
WA21092 and WA21093) during the 96-week controlled treatment period, ocrelizumab 
was well tolerated with lower rates of treatment discontinuations for adverse events 
(AEs) in patients treated with ocrelizumab 600 mg (3.5%) than in patients receiving 
IFNβ-1a (6.2%).  The proportion of patients with AEs (83.3% in both groups) as well as 
the total number of AEs were similar in the ocrelizumab and the IFNβ -1a treatment 
groups over the 96-week treatment period.  The proportion of patients reporting 
infections was higher in the ocrelizumab group compared with the IFNβ-1a group, 
(58.4% vs. 52.4%, respectively).  In addition, there were more events of infection in the 
ocrelizumab group (1224 events) compared with the IFNβ -1a group (948 events) and 
the majority of the events were of Grade 1 or 2 intensity. The difference was primarily 
driven by more patients with upper respiratory tract infections in Ocrelizumab group.  
The proportion of patients with serious adverse events (SAEs) was lower in the 
ocrelizumab treatment group than in the IFNβ -1a treatment group (6.9% in the 
ocrelizumab treatment group versus 8.7% in the IFNβ-1a treatment group).  Overall, the 
proportion of patients with serious infections was lower in the ocrelizumab group (1.3%) 
than in the IFNβ-1a group (2.9%).  Two serious infusion-related reactions (IRRs) were 
reported; one in the IFNβ -1a group (Grade 3) and one in the ocrelizumab group (Grade 
4).  As expected, the proportion of patients experiencing IRRs were increased in the 
ocrelizumab group (34.3%) compared with the active control group (9.7%) who received 
dummy infusions.  During the 96-week controlled treatment period, a total of 
6 malignancies were reported, 2 events (1 mantle cell lymphoma and 1 squamous cell 
carcinoma) occurred in 2 patients (0.2%) in the IFNβ -1a treatment group and 4 events 
(2 invasive ductal breast carcinoma, 1 renal cancer and 1 malignant melanoma) 
occurred in 4 patients (0.5%) in the ocrelizumab treatment group.  Three deaths 
occurred in Studies WA21092 and WA21093; 2 patients (suicide and mechanical ileus) 
in the IFNβ -1a treatment group and 1 patient (suicide) in the ocrelizumab treatment 
group.  
In the PPMS Phase III double blind placebo controlled Study WA25046, ocrelizumab 
was well tolerated with a similar proportion of patients with AEs leading to 
discontinuation from treatment (4.1%) compared with the placebo group (3.3%).  The 
proportion of patients who experienced at least one AE was 90% in the placebo group 
compared with 95% in the ocrelizumab group.  Taking into account that twice as many 
patients were randomized to ocrelizumab than placebo, the number of AEs experienced 

 
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by patients with an AE was similar (1762 events in the placebo group and 3690 events in 
the ocrelizumab group).  The proportion of patients who experienced an infection was 
69.8% in the ocrelizumab group compared with 67.8% in the placebo group.  The 
proportion of patients with serious infections was similar in both groups: 5.9% in the 
placebo group compared with 6.2% in the ocrelizumab group.  As expected, the 
proportion of patients who reported IRRs was higher in the ocrelizumab group (39.9%) 
compared with placebo (25.5%).  Overall, 5 patients (1.0%) experienced a serious IRR 
in the ocrelizumab group.  A total of 15 malignancies in 13 patients were reported: 
2 events (basal cell carcinoma and adenocarcinoma of the cervix) occurred in 2 patients 
(0.8%) in the placebo group and 13 events (5 basal cell carcinoma, 2 invasive ductal 
breast carcinoma, 1 anaplastic large-cell lymphoma, 1 breast cancer, 1 endometrial 
cancer, 1 invasive breast carcinoma, 1 malignant fibrous histiocytoma, 1 pancreatic 
carcinoma metastatic) occurred in 11 patients (2.3%) in the ocrelizumab group.  The 
proportion of patients with SAEs (22.2% in the placebo group compared with 20.4% in 
the ocrelizumab group), was similar in both groups.  There were 5 deaths during the 
controlled treatment period, one in the placebo group (road traffic accident) and 4 in the 
ocrelizumab group (pulmonary embolism, pneumonia, pancreatic carcinoma, pneumonia 
aspiration).  
For more detailed information, see IB. 
 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
Over the past two decades, there has been an increase in the number and type of 
available treatments for RMS.  Yet, despite an adequate course of treatment with a 
DMT, a significant proportion of treated patients with RMS will show signs of disease 
activity (Freedman 2014; Ziemssen et al. 2015, Tanasescu et al. 2015).  Suboptimal 
responses defined as relapse, confirmed disability progression, and/or new 
Gd-enhancing or T2 lesion(s) on brain MRI, are reported in approximately one-third of 
patients receiving IFN- therapy  (Bergvall et al. 2014; Durelli et al. 2008; Fernández et 
al. 2005; Waubant et al. 2003).  Disease activity while receiving DMT is associated with 
poorer long-term outcomes (Bermel et al. 2013), thus subsequent treatment with a more 
effective therapy may be warranted in patients with breakthrough disease.  
Consequently, reported rates of treatment switching for suboptimal responses range 
from 20% to 35% of patients (Rio et al. 2012; Gajofatto et al. 2009; Teter et al. 2014).   
While clinical experience and retrospective studies suggest that better disease control is 
obtained by escalating to higher efficacy therapy, few prospective studies have been 
conducted.  In one prospective, observational study, Prosperini and colleagues 
evaluated outcomes of patients who failed first-line treatment with IFN- or GA and 
switched to a different IFN- formulation or GA (switching group) or escalated to 
natalizumab (escalating group) (Prosperini et al. 2012).  At 1 year, no significant 
differences between the two groups were observed in disease activity (i.e., relapse, 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
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disability progression, MRI activity, and combined activity).  However, after 2 years, 
significantly greater proportions of patients who had escalated to natalizumab than those 
who switched between IFN- and GA were free from all disease activity measures.  In 
the Phase III CARE MS II trial, patients with  1 relapse while receiving IFN- or GA 
therapy were randomized to IFN- or alemtuzumab treatment. Significant improvements 
in relapse rate and accumulation of disability were reported with alemtuzumab versus 
IFN- at 1 year (Coles et al. 2012).  
Assessing efficacy and safety in patients who switch to ocrelizumab after a suboptimal 
response to an adequate course of a DMT represents an important question for 
clinicians.  Efficacy and safety data in patients who have switched to ocrelizumab are 
limited.  The Phase II study provided initial evidence that ocrelizumab could be effective 
at further reducing MS disease activity following initial IFN- therapy and demonstrated 
the efficacy in reducing the disease activity as measured by T1 Gd enhancement 
already after 8 weeks as shown in the figure below.   
Figure 1 Gd-enhancing lesions by week in each study group in Phase II study 
of ocrelizumab 
 
Additional data will also be available on previously treated patients in two completed 
Phase III studies (Studies WA21092 [OPERA I], n=106 and WA21093 [OPERA II], 
n=113), but in a limited number of patients. 
It is important to underline that the vast majority of the subjects included in OPERA I and 
OPERA II continue the safety and efficacy follow-up in an open label extension (OLE) 
phase of the study. Patients included in the IFN arm have been given the opportunity to 
be treated with ocrelizumab in the OLE phase of the study. This setting enables efficacy 
and safety data collection on subjects switching from IFN to ocrelizumab. Information on 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
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switching from other DMTs, such as teriflunomide, fingolimod or dimethyl fumarate, is 
currently not available.  
The benefit-risk profile of ocrelizumab appears to be favorable based on the results of 
the pivotal Phase III studies as described in Section 1.2. However, more data from 
patients who switch to higher efficacy therapies from large scale, prospective studies are 
needed. Therefore, a dedicated prospective study to specifically evaluate the efficacy 
and safety of ocrelizumab in patients who have a suboptimal response to an adequate 
course of a DMT is needed to address this important clinical question.  
Based upon the Phase II data, and to allow the real evaluation of the treatment effect, 
the MRI activity should be evaluated starting from week 8. By introducing a MRI 8 weeks 
after baseline visit might also enable exclusion, from a safety point of view, of a possible 
progressive multifocal leukoencephalopathy (PML) infection carried over from a previous 
DMT treatment (i.e. fingolimod, dimethyl fumarate or natalizumab). 
 
2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy and safety of ocrelizumab in patients with RRMS 
who have a suboptimal response to an adequate course of DMT.  
A suboptimal response is defined by having one or more clinically reported MS 
relapse(s), OR one or more T1 Gd-enhanced lesion(s), OR two or more new or 
enlarging T2 lesions on MRI while being on a stable dose of the same DMT for at least 6 
months.  In addition, in patients receiving stable doses of the same approved DMT for 
more than a year, the event of suboptimal response must have occurred within the last 
12 months of treatment with this DMT.  
Patients will be encouraged to enter a long-term follow-up of at least 2 years to allow the 
evaluation and possible contribution of the primary outcome measure of no evidence of 
disease activity (NEDA) or its sub-elements on the longer term evolution of the disease. 
Specific objectives and corresponding endpoints for the study are outlined below. 
 
2.1 
EFFICACY OBJECTIVES 
2.1.1 
Primary Efficacy Objective 
The primary objective for this study is to assess the efficacy of ocrelizumab 600 mg 
intravenous (IV) given every 24 weeks on the basis of the following endpoint: 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
35/Protocol MA30005, Version 5 
• 
Proportion of patients who have NEDA, as per protocol defined events during a 96-
week period. The MRI activity will be calculated on the events starting from week 8 
(baseline reset) when drug is fully active. 
The definition of a protocol-defined event of disease activity is the occurrence of at least 
one of the following while on treatment with ocrelizumab: 
− 
A protocol-defined relapse as defined in Section 4.5.4 
− 
24 weeks confirmed disability progression based on increases in EDSS 
while on treatment with ocrelizumab 
− 
A T1 Gd-enhanced lesion after Week 8 
− A new and/or enlarging T2 hyperintense lesion on MRI after Week 8 
compared to the Week 8 MRI scan 
 
 
2.1.2 
Secondary Efficacy Objectives 
The secondary objective for this study is to evaluate the efficacy of ocrelizumab 600 mg 
IV given every 24 weeks on the basis of the following endpoints: 
• 
The proportions of patients free from a protocol-defined event of disease activity 
during a 24-week period and a 48-week period 
• 
Time to first protocol-defined event of disease activity 
• 
Change in EDSS from baseline to Week 96 
• 
Proportion of patients who, over a 96-week period, have Confirmed Disability 
Improvement (CDI) Confirmed Disability Progression (CDP) or stable disability (i.e. 
neither CDI nor CDP). 
• 
Annualized rate of protocol-defined relapses at Week 96 
• 
Time to onset of first protocol-defined relapse 
• 
Time to onset of 24 weeks CDP  
• 
Time to onset of first new and/or enlarging T2 lesion 
• 
Total number of T1 Gd-enhanced lesions detected by brain MRI at Weeks 24, 48 
and 96 
• 
Change in total T2 lesion volume detected by brain MRI from baseline to Week 96 
• 
Volume and number of new and/or enlarging T2 hyperintense lesions from baseline 
to Weeks 24, 48 and 96 
• 
Change in T1 hypointense lesion volume from baseline to Weeks 48 and 96   
• 
Change in brain volume from baseline measured at Weeks 24, 48 and 96 
• 
Change from baseline in cognitive performance at Week 48 and Week 96 as 
measured by the BICAMS (Brief International Cognitive Assessment for Multiple 
Sclerosis) 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
36/Protocol MA30005, Version 5 
 
2.1.3 
Exploratory Efficacy Objective 
The exploratory efficacy objective for this study is to further assess the efficacy of 
ocrelizumab 600 mg IV given every 24 weeks by monitoring patient-reported outcomes 
(PROs) related to quality of life (QoL), treatment satisfaction and other endpoints or 
analyses as follows: 
• 
Multiple Sclerosis Impact Scale (MSIS)-29 (MS-specific QoL questionnaire) 
• 
Treatment satisfaction questionnaire for medication (TSQM II) 
• 
Patient reported outcome: SymptoMScreen  
• 
MRI and clinical outcomes at 6 months and 1 year 
• 
Predictors of NEDA and association between NEDA and disability or other efficacy 
parameters 
• 
Severity of relapses (hospitalization for MS relapse, use of corticosteroids, residual 
disability) 
• 
Employment status (WPAI) 
• 
Proportion of patients who have NEDA, as per protocol defined events during a 96-
week period and starting from baseline 
 
2.2 
SAFETY OBJECTIVE 
The safety objective for this study is to evaluate the safety and tolerability of ocrelizumab 
600 mg IV given every 24 weeks on the basis of the following endpoints:  
• 
Rate and nature of adverse events 
• 
Changes in vital signs, physical and neurological examinations, clinical laboratory 
results, locally reviewed MRI for safety (non-MS CNS pathology) and concomitant 
medications (including pre-medications and medications used during and following 
ocrelizumab administration). 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This study is a prospective, multicenter, open-label, efficacy and safety study in patients 
with RRMS who have had a suboptimal response to an adequate course of a DMT.  An 
adequate course of prior DMT is defined as a stable dose of the same DMT 
administered for at least 6 months. The first dose of ocrelizumab will be administered as 
an initial dose of two 300-mg infusions (600 mg total) in 250 mL 0.9% sodium chloride 

 
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each separated by 14 days (i.e., Days 1 and 15) followed by one 600-mg infusion in 500 
mL 0.9% sodium chloride every 24 weeks for the remainder of the study duration.   
This study will enroll 750 patients. Patients will be assessed for efficacy and safety every 
24 weeks as described in the Schedule of Assessments presented in Appendix 1.  
The study will consist of the following periods: 
• 
Screening period:  Up to 4 weeks 
• 
Treatment period:  Open-label treatment period of 96 weeks (last dose administered 
at Week 72) 
• 
A follow-up period of at least 2 years, which is independent of the DMT administered 
Follow-up Period:  Patients who discontinue treatment early will be followed up for at 
least 96 weeks after the Early Treatment Discontinuation Visit. Patients who complete 
the 96 weeks Treatment Period and, in agreement with their treating neurologist, decide 
not to continue in a separate long-term extension (LTE) study, will be followed up for at 
least 96 weeks after the end of the Treatment Period. Patients who decide to leave the 
study and switch to commercially marketed Ocrelizumab, either after completion of the 
96 weeks Treatment Period or after early discontinuation of the 96 weeks Treatment 
Period, will not enter the safety Follow-up Period. 
Patients whose B-cells have not been repleted after 96 weeks of Follow-up Period will 
continue with visits every 24 weeks, and telephone contacts every 8 weeks, until B-cell 
repletion (Prolonged B-cell monitoring). If the patients are receiving other B-cell targeted 
therapies, then the Follow-up Period will be stopped at 96 weeks regardless of their B-
cell count.  
A structured telephone interview will be conducted by site personnel every 8 weeks 
between the study visits during the treatment period and follow-up to identify and collect 
information on any changes in the patient’s health status that warrant an unscheduled 
visit (including new or worsening neurological symptoms) and possible events or 
infections.  

 
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3.1.1 
Overview of Study Design 
Figure 2 presents an overview of the study procedures.  A schedule of assessments is 
provided in Appendix 1.  
Figure 2 Overview of Study Procedures 
 
DMTs = disease modifying treatments; IV = intravenous; RRMS = relapsing remitting multiple 
sclerosis. 
 
3.1.2 
Screening 
Patients screened for this study should not be withdrawn from DMT therapies for the 
sole purpose of meeting eligibility for the trial.  Patients who discontinue their current 
therapy for non-medical reasons should be informed of treatment options before 
deciding to enroll in the study. Investigators should refer to the local label for 
discontinuation/wash out of previous DMTs. The summary of product characteristics 
(SmPCs) of DMTs for EMEA countries are provided in Appendix 8.  
After providing written informed consent, patients will enter a screening period (up to 4-
weeks) to be evaluated for eligibility.  
Re-screening of patients is allowed in this protocol. In case a patient needs to be re-
screened there is no need to sign a new ICF if the re-screening is done within 2 months 
after signing the ICF; the patients should only be asked to re-sign and re-date the 
previously signed ICF to confirm that they are still willing to participate in the study. 

 
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3.1.3 
Treatment Period 
Eligible patients will be treated with an initial dose of two 300-mg infusions (600 mg total) 
in 250 mL 0.9% sodium chloride each separated by 14 days (i.e., Days 1 and 15) 
followed by one 600-mg infusion in 500 mL 0.9% sodium chloride every 24 weeks for the 
remainder of study duration. 
Laboratory samples can be taken up to 2 weeks prior to the scheduled study visit. Results 
should be available prior dosing, except for John Cunningham virus (JCV) and 
immunoglobulins (Ig) (plasma samples collected and stored centrally), which will be 
analyzed upon request and CD8 and CD19 (no interference with re-treatment). 
For patients presenting with EDSS change at Week 96, the EDSS score will be confirmed 
after a further 24 weeks. 
Criteria for Re-Treatment with Ocrelizumab 
Prior to re-treatment with ocrelizumab, patients will be evaluated for the following 
conditions and laboratory abnormalities. If any of these are present prior to re-dosing, 
further administration of ocrelizumab should be suspended until these are resolved or 
held indefinitely: 
• Life threatening (Common Terminology Criteria for Adverse Events [CTCAE] Grade 4) 
infusion-related event that occurred during a previous ocrelizumab infusion 
• Any significant or uncontrolled medical condition or treatment-emergent, clinically 
significant laboratory abnormality 
• Active infection other than a fungal nailbed infection. The re-treatment should be delayed 
until the active infection is treated, and patient fully recovered 
• CD4 cell count < 250/μL 
• Ongoing pregnancy 
 
At the end of the study treatment the patients will be encouraged to be included in a 
separate LTE study to further evaluate the efficacy and safety of their DMT treatment 
and this is independent of the DMT. This LTE will also aim to evaluate the relationship 
between the primary endpoint of this study and long-term outcome.  
Patients who discontinue treatment early will be followed up for at least 96 weeks after 
the Early Treatment Discontinuation Visit. Patients who complete the 96 weeks 
Treatment Period and, in agreement with their treating neurologist, decide not to 
continue in a separate LTE study, will be followed up for at least 96 weeks after the end 
of the Treatment Period (see Section 3.1.4). Patients who decide to leave the study and 
switch to commercially marketed Ocrelizumab, either after completion of the 96 weeks 
Treatment Period or after early discontinuation of the 96 weeks Treatment Period, will 
not enter the safety Follow-up Period. 

 
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Figure 3 Overview of End of Treatment Period 
 
 
Patient 
discontinued 
treatment early 
 
Follow-up period 
96 weeks after the 
Early Treatment 
Discontinuation 
Visit 
 
End of 
Treatment 
 
 
 
 
 
 
 
Patient 
completed 
Treatment 
Period 
 
Roll over to a 
separate LTE study  
 
 
 
 
 
 
 
 
 
Follow-up period 
96 weeks after the 
end of the 
Treatment Period 
 
 
 
3.1.4 
Follow-up Period 
Patients who discontinue treatment early will be followed up for at least 96 weeks after 
the Early Treatment Discontinuation Visit. Patients who complete the 96 weeks 
Treatment Period and, in agreement with their treating neurologist, decide not to 
continue in a separate LTE study, will be followed up for at least 96 weeks after the end 
of the Treatment Period.  
Patients who decide to leave the study and switch to commercially marketed 
Ocrelizumab, either after completion of the 96 weeks Treatment Period or after early 
discontinuation of the 96 weeks Treatment Period, will not enter the safety Follow-up 
Period.  
Any patient whose peripheral blood B-cell count remains depleted after this period will 
continue to be monitored at 24-week intervals until the B-cell count has returned to the 
baseline value or to lower limit of normal (LLN) range, whichever is lower.   
Figure 4 provides an overview of the Follow-up Period, which is the variable B-cell 
monitoring period.  A schedule of assessments for the Follow-up Period is presented in 
Appendix 2.  

 
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visit (including new or worsening neurological symptoms) and possible events or 
infections.  
3.1.5 
Planned Total Sample Size 
This study will enroll approximately 750 patients.  Please refer to the Section 6.1 for 
more details. 
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of the study treatment period has been defined as the date on which the last 
patient receiving the full study treatment reached the 96-week visit. Exception will be 
made for patients that have EDSS change at Week 96 and need confirmation of EDSS 
score after a further 24 weeks.  
The end of the study is defined as the last patient last visit in the B-cell monitoring of the 
Follow-Up period. At the end of the study treatment, patients will be encouraged to be 
included in a separate LTE study to further evaluate the efficacy and safety of their DMT 
treatment, and this is independent of the DMT. This LTE will also aim to evaluate the 
relationship between the primary endpoint of this study and long-term outcome. 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 5 years. This includes an enrollment period of 
approximately 12 months. 
3.3 
RATIONALE FOR STUDY DESIGN 
This is a Phase IIIb, prospective, multicenter, open-label, study to assess the efficacy 
and safety of ocrelizumab in patients with RRMS who have a suboptimal response to an 
adequate course of a DMT. The efficacy and safety of ocrelizumab has been studied in 
three randomized, double-blind, parallel group, controlled Phase III studies (WA21092 
and WA21093 in relapsing MS and WA25046 in PPMS) with further follow-up ongoing in 
OLE phase. As there are limited data in patients who have switched to ocrelizumab after 
a suboptimal response to an adequate course of a DMT, a single-arm study is 
considered appropriate given the aims of this study.  As the aim of the study is to 
evaluate the efficacy of ocrelizumab in this setting, the MRI results will be evaluated 
starting from week 8, as demonstrated in the Phase II clinical trial.  
3.3.1 
Rationale for Ocrelizumab Dose and Schedule 
The dose level of ocrelizumab administered in this study is 600 mg.  The first dose will 
be administered as two 300-mg IV infusions in 250 mL 0.9% sodium chloride each 
separated by 14 days in order to lower the amount of ocrelizumab administered upon 
first exposure.  The remaining doses will be administered as single 600-mg infusion in 
500 mL 0.9% sodium chloride every 24 weeks to assess the tolerability of the intended 
administration regimen. 

 
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This dosing regimen is anticipated to be well-tolerated and is consistent with the dosing 
regimen used in Studies WA21092 and WA21093 in patients with RMS. 
3.3.2 
Rationale for Patient Population 
This study will be conducted in RRMS patients who show a suboptimal response to an 
adequate course of a DMT. RRMS is the most common type of MS, approximately 85% 
of MS patients present initially with RRMS (Confavreaux et al. 2000; Leray et al. 2015).   
Despite an adequate course of treatment with a DMT, a significant proportion of treated 
patients with RRMS will show signs of disease activity (Freedman 2014; Ziemssen et al. 
2015; Tanasescu et al. 2015). Suboptimal responses are reported in approximately one-
third of patients receiving DMT and therefore this population is considered to be 
appropriate to study the efficacy and safety of ocrelizumab. 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Approximately 750 patients with RRMS who fulfill the eligibility criteria listed below will 
be enrolled in the study. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Signed informed consent form 
• 
Able to comply with the study protocol, in the investigator’s judgment 
• 
Age 18 − 55 years, inclusive 
• 
Have a definite diagnosis of RRMS, confirmed as per the revised McDonald 2010 
criteria (Polman et al. 2011)   
• 
Have a length of disease duration, from first symptom, of < 10 years. If the date of 
first symptom is unknown, then the diagnosis of RRMS should be of ≤ 5 years 
• 
Have received no more than two prior DMTs, and the discontinuation of the most 
recent DMT was due to lack of efficacy 
• 
Suboptimal disease control while on a DMT; a suboptimal response is defined by 
having at least one of the following events while being on a stable dose of the same 
DMT for at least 6 months: 
− 
One or more clinically reported relapse(s) 
− 
OR one or more T1 Gd-enhanced lesion(s) 
− 
OR two or more new and/or enlarging T2 lesions on MRI 
 
In addition, in patients receiving stable doses of the same approved DMT for more 
than a year, at least one of the above events must have occurred within the last 12 
months of treatment with this DMT. 
• 
EDSS of 0.0 to 4.0, inclusive, at screening 

 
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• 
For women of childbearing potential:  agreement to use an acceptable birth control 
method during the treatment period and for at least 6 months after the last dose of 
study drug. 
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state ( 12 continuous months of amenorrhea with 
no identified cause other than menopause), and has not undergone surgical 
sterilization (removal of ovaries and/or uterus). 
The following are acceptable contraceptive methods: progestogen-only oral 
hormonal contraception, where inhibition of ovulation is not the primary mode of 
action, male or female condom with or without spermicide, and cap, diaphragm, or 
sponge with spermicide.  A combination of male condom with cap, diaphragm, or 
sponge with spermicide (double-barrier methods) is considered acceptable 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
SPMS or history of primary progressive or progressive relapsing MS 
• 
Inability to complete an MRI (contraindications for MRI include but are not restricted 
to pacemaker, cochlear implants, presence of foreign substances in the eye, 
intracranial vascular clips, surgery within 6 weeks of entry into the study, coronary 
stent implanted within 8 weeks prior to the time of the intended MRI, inability to 
tolerate Gadolinium-based contrast agents etc.) 
• 
Known presence of other neurological disorders, including but not limited to, the 
following: 
− 
History of ischemic cerebrovascular disorders (e.g., stroke, transient ischemic 
attack) or ischemia of the spinal cord 
− 
History or known presence of CNS or spinal cord tumor (e.g., meningioma, 
glioma) 
− 
History or known presence of potential metabolic causes of myelopathy (e.g., 
untreated vitamin B12 deficiency) 
− 
History or known presence of infectious causes of myelopathy (e.g., syphilis, 
Lyme disease, human T-lymphotropic virus 1 (HTLV-1), herpes zoster 
myelopathy) 
− 
History of genetically inherited progressive CNS degenerative disorder (e.g., 
hereditary paraparesis; MELAS [mitochondrial myopathy, encephalopathy, lactic 
acidosis, stroke] syndrome) 
− 
Neuromyelitis optica 
− 
History or known presence of systemic autoimmune disorders potentially causing 
progressive neurologic disease (e.g., lupus, anti-phospholipid antibody 
syndrome, Sjogren’s syndrome, Behçet’s disease) 
− 
History or known presence of sarcoidosis 

 
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− 
History of severe, clinically significant brain or spinal cord trauma (e.g., cerebral 
contusion, spinal cord compression) 
 
Exclusions Related to General Health 
• 
Pregnancy or lactation. 
• 
Any concomitant disease that may require chronic treatment with systemic 
corticosteroids or immunosuppressants during the course of the study. 
• 
History or currently active primary or secondary immunodeficiency. 
• 
Lack of peripheral venous access. 
• 
History of severe allergic or anaphylactic reactions to humanized or murine 
monoclonal antibodies. 
• 
Significant or uncontrolled somatic disease or any other significant disease that may 
preclude patient from participating in the study. 
• 
Congestive heart failure (New York Heart Association [NYHA] III or IV functional 
severity). 
• 
Known active bacterial, viral, fungal, mycobacterial infection or other infection, 
excluding fungal infection of nail beds. 
Note: Active infections must be treated and effectively controlled before possible 
inclusion in the study 
• 
History of major opportunistic infections (i.e. cryptococcosis, Pneumocystis 
pneumonia, PML) 
• 
History or known presence of recurrent or chronic infection (e.g., hepatitis B or C, 
human immunodeficiency virus [HIV], syphilis, tuberculosis [TB]) 
• 
History of malignancy, including solid tumors and hematological malignancies, 
except basal cell carcinoma, in situ squamous cell carcinoma of the skin, and in situ 
carcinoma of the cervix of the uterus that have been previously completely excised 
with documented, clear margins. 
• 
History of alcohol or drug abuse within 24 weeks prior to baseline. 
• 
History or laboratory evidence of coagulation disorders. 
 
Exclusions Related to Medications* 
• 
Receipt of a live vaccine or attenuated live vaccine within 6 weeks prior to the 
baseline visit. 
In rare cases when patient requires vaccination with a live vaccine, the screening 
period may be extended but cannot exceed 8 weeks. 
• 
Treatment with any investigational agent within 24 weeks of screening (Visit 1) or 
five half-lives of the investigational drug (whichever is longer) or treatment with any 
experimental procedures for MS (e.g., treatment for chronic cerebrospinal venous 
insufficiency). 

 
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• 
Contraindications to or intolerance of oral or IV corticosteroids, according to the 
country label, including: 
a) Psychosis not yet controlled by a treatment; 
b) Hypersensitivity to any of the constituents. 
• 
Previous treatment with B-cell targeted therapies (i.e., rituximab, ocrelizumab, 
atacicept, belimumab, or ofatumumab). 
• 
Systemic corticosteroid therapy within 4 weeks prior to screening. 
• 
Any previous treatment with alemtuzumab (Campath/Mabcampath/Lemtrada), 
cladribine, mitoxantrone, daclizumab, laquinimod, total body irradiation, or bone 
marrow transplantation. 
• 
Treatment with cyclophosphamide, azathioprine, mycophenolate mofetil, 
cyclosporine or methotrexate. 
• 
Previous treatment with natalizumab unless natalizumab was discontinued because 
of persistent anti-natalizumab antibodies. 
• 
Treatment with IV Ig within 12 weeks prior to baseline. 
• 
Any previous treatment with an investigational MS DMT not yet approved at time of 
screening. 
• 
History of recurrent aspiration pneumonia requiring antibiotic therapy. 
• 
Patients previously treated with teriflunomide, unless an accelerated elimination 
procedure is implemented before screening visit. 
Accelerated elimination procedure after stopping treatment with teriflunomide: 
o cholestyramine 8g is administered 3 times daily for a period of 11 days, or 
cholestyramine 4g three times a day can be used, if cholestyramine 8g three 
times a day is not well tolerated, 
o alternatively, 50g of activated powdered charcoal is administered every 12 
hours for a period of 11 days. 
• 
Previous treatment with fingolimod or dimethyl fumarate if at baseline the 
lymphocyte count is below lower limit of normal (LLN). The provisions for stopping 
therapy as described in the respective SmPCs should be followed.  
• 
Treatment with fampridine/dalfamipridine (Fampyra®)/Ampyra®) unless on stable 
dose for ≥ 30 days prior to screening. Wherever possible, patients should remain 
on stable doses throughout the 96-week treatment period. 
* Patients screened for this study should not be withdrawn from therapies for the sole 
purpose of meeting eligibility for the trial.  
 
Exclusions Related to Laboratory Findings* 
• 
Positive serum β human chorionic gonadotropin (hCG) measured at screening. 

 
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• 
Positive screening tests for hepatitis B (hepatitis B surface antigen [HBsAg] positive, 
or positive hepatitis B core antibody [total HBcAb] confirmed by a positive viral DNA 
polymerase chain reaction [PCR]) or hepatitis C (HepCAb). 
• 
Lymphocyte count below LLN 
• 
CD4 count<250/μL. 
• 
Aspartate aminotransferase (AST)/ serum glutamic oxaloacetic transaminase 
(SGOT) or alanine aminotransferase (ALT) /serum glutamic pyruvic transaminase 
(SGPT)≥ 3.0 × ULN 
• 
Platelet count <100,000/μL (<100 × 109/L). 
• 
Absolute neutrophil count <1.0 × 103/μL. 
*Re-testing before baseline: any abnormal screening laboratory value that is clinically 
relevant should be retested in order to rule out any progressive or uncontrolled 
underlying condition. The last value before baseline visit must meet study criteria.  
Please note: based on local Ethics Committees or National Competent Authority 
requirements, additional diagnostic testing may be required for selected patients or 
selected centers to exclude tuberculosis, Lyme disease, HTLV-1 associated myelopathy 
(HAM), acquire immunodeficiency syndrome (AIDS), hereditary disorders, connective 
tissue disorders, or sarcoidosis. Other specific diagnostic tests may be requested when 
deemed necessary by the Investigator. 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
This is an open-label study in which all patients will receive the 600-mg dose of 
ocrelizumab following the 24-week regimen.  Therefore, no randomization or blinding will 
be used in this study.   
4.3 
STUDY TREATMENT  
The investigational medicinal product (IMP) for this study is ocrelizumab. 
4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
Ocrelizumab 
Ocrelizumab will be supplied by the Sponsor as a liquid formulation containing 
30-mg/mL ocrelizumab in 20 mM sodium acetate at pH 5.3, with 106 mM trehalose 
dihydrate and 0.02% polysorbate 20.  The drug product is provided as a single-use liquid 
formulation in a 15-cc, type I USP, glass vial fitted with a 20-mm, fluoro-resin, laminated 
stopper and an aluminum seal with a flip-off plastic cap.  The vial contains 300 mg 
ocrelizumab.  No preservative is used as each vial is designed for single use. 
The ocrelizumab drug product must be diluted before administration.  Solutions of 
ocrelizumab for IV administration are prepared by dilution of the drug product into an 

 
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infusion bag containing 0.9% sodium chloride to a final drug concentration of 1 to 
2 mg/mL.  
Ocrelizumab may contain fine translucent and/or reflective particles associated with 
enhanced opalescence.  Do not use the solution if discolored or if the solution contains 
discrete foreign particulate matter. The infusion solution must be administered using an 
infusion set with an in-line, sterile, non-pyrogenic, low-protein-binding filter (pore size of 
up to 0.2 μm). 
For information on the formulation and handling of ocrelizumab, see the Ocrelizumab IB 
and Drug Preparation Guidelines. 
4.3.2 
Dosage, Administration, and Compliance 
4.3.2.1 
Ocrelizumab 
The first dose of ocrelizumab will be administered as two 300-mg infusions (600 mg 
total) in 250 mL 0.9% sodium chloride each separated by 14 days (i.e., Days 1 and 15), 
followed by one 600-mg infusion in 500 mL 0.9% sodium chloride every subsequent 
dose (i.e., every 24 weeks) for a maximum of 4 doses. 
It is anticipated that the patient will need to stay at the hospital or clinic for a full day for 
the infusion visits.  Ocrelizumab infusions should be initiated and supervised by an 
experienced professional with access to appropriate medical support to manage severe 
reactions such as serious IRRs. Each ocrelizumab infusion should be given as a slow IV 
infusion over approximately 150 minutes (2.5 hours) for the 300 mg dose and 
approximately 215 minutes (3.6 hours) for the 600 mg dose.  To reduce potential IRRs, 
all patients will receive prophylactic treatment with 100 mg of methylprednisolone, or 
equivalent, administered by slow IV infusion, to be completed approximately 30 minutes 
before the start of each ocrelizumab infusion, and an antihistaminic drug (e.g., 
diphenhydramine) approximately 30 − 60 minutes before each infusion of ocrelizumab.  
Additional premedication is recommended, see Section 4.3.3. 
Hypotension, as a symptom of IRR, may occur during ocrelizumab IV infusions. 
Therefore, withholding antihypertensive treatments should be considered for 12 hours 
prior to and throughout each ocrelizumab infusion.   
Ocrelizumab must not be administered as an IV push or bolus.  Well-adjusted infusion 
pumps should be used to control the infusion rate, and ocrelizumab should be infused 
through a dedicated line.  It is important not to use evacuated glass containers, which 
require vented administration sets, to prepare the infusion because this causes foaming 
as air bubbles pass through the solution.  
The patient will need to remain at the clinic at every visit for at least 1 hour after the 
completion of the infusion for observation. After completion of the infusion, the IV 
cannula should remain in situ for at least 1 hour to allow for administration of drugs 

 
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intravenously, if necessary, in the event of a delayed reaction. If no adverse events 
occur during this period of time, the IV cannula may be removed, and the patient may be 
discharged.  
See the Ocrelizumab IB and Drug Preparation Guidelines for detailed instructions on 
drug preparation, storage, and administration. 
An overview of the ocrelizumab dosing is presented in Table 1.   
Table 1 
Overview of Ocrelizumab Dosing  
Group 
1st Dose a,c 
2nd Dose b,c 
3rd Dose b,c 
4th Dose b,c 
(Weeks 1 − 24) 
(Weeks 24 − 48) 
(Weeks 48 − 72) 
(Weeks 72 − 96) 
Day 1 
Infusion 
Day 15 
Infusion 
Week 24 
Infusion 
Week 48 
Infusion 
Week 72 
Infusion 
Ocrelizumab  300 mg IV 
in 250 mL 
0.9%  
sodium 
chloride 
300 mg IV 
in 250 mL 
0.9% 
sodium 
chloride 
600 mg IV 
in 500 mL 0.9%  
sodium chloride 
600 mg IV 
in 500 mL 0.9% 
sodium chloride 
600 mg IV 
in 500 mL 0.9%  
sodium chloride 
IV = intravenous. 
Note:  Before each infusion of ocrelizumab, 100 mg of methylprednisolone IV and an 
antihistaminic drug will be administered to reduce the potential for infusion-related reactions.  
Each dose has a duration of 24 weeks.  The open-label treatment period consists of 96 weeks of 
treatment; patients will receive a maximum of 4 doses.   
a The first dosing will consist of two IV infusions separated by 14 days (i.e., Days 1 and 15). 
b Beginning with the second dose, a single infusion of ocrelizumab will be administered. 
c Prior to the next infusion, a clinical evaluation will be performed to ensure that the patient 
remains eligible for retreatment. 
 
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.4. 
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  AEs associated with 
an overdose or incorrect administration of study drug should be recorded on the AE 
eCRF. 
4.3.3 
Prophylactic Treatment  
Premedicate with 100 mg of methylprednisolone (or an equivalent), administered by 
slow IV infusion, to be completed approximately 30 minutes prior to each ocrelizumab 
infusion and an antihistaminic drug (e.g., diphenhydramine) approximately 30 – 60 
minutes before each ocrelizumab infusion to reduce the frequency and severity of IRRs. 
The addition of an antipyretic (e.g., acetaminophen/paracetamol) may also be 
considered.  

 
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Any overdose or incorrect administration of methylprednisolone should be noted on the 
Pre-Infusion Prophylactic Treatment eCRF.  Adverse events associated with an 
overdose or incorrect administration of methylprednisolone and antihistaminic drug 
should be recorded on the Adverse Event eCRF. 
Patients administered a sedating antihistamine for the treatment or prevention of IRRs 
should be given appropriate warnings concerning drowsiness and potential impairment 
of ability to drive or operate machinery. 
4.3.4 
Investigational Medicinal Product Accountability 
The IMP required for completion of this study (ocrelizumab) will be provided by the 
Sponsor where required by local health authority regulations.  The study site will 
acknowledge receipt of IMP, using the interactive voice/Web response system (IxRS) to 
confirm the shipment condition and content.  Any damaged shipments will be replaced.  
The IMP will either be disposed of at the study site according to the study site’s 
institutional standard operating procedure or returned to the Sponsor with the 
appropriate documentation.  The site's method of IMP destruction must be agreed to by 
the Sponsor.  The site must obtain written authorization from the Sponsor before any 
unused IMP is destroyed, and IMP destruction must be documented on the appropriate 
form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log. 
4.3.5 
Post-Trial Access to Ocrelizumab 
Patients who completed the study and decided, in agreement with their treating 
neurologist, to continue on ocrelizumab treatment can be rolled-over in a separate 
ocrelizumab LTE study.  
4.4 
CONCOMITANT THERAPY 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient within 6 weeks prior to the screening visit to the study completion/ discontinuation 
visit.  All such medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF.  
4.4.1 
Permitted Therapy  
Patients who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use. 

 
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4.4.2 
Prohibited Therapy 
No formal drug-drug interaction studies have been conducted with ocrelizumab, as no 
drug-drug interactions are expected via the Cytochromes P450, other metabolizing 
enzymes or transporters. 
Ocrelizumab is a monotherapy and has not been studied in combination with other 
DMTs. As with other immunomodulatory therapies, exercise caution when initiating 
ocrelizumab after an immunosuppressive therapy, and when initiating another therapy 
after ocrelizumab, taking into consideration the potential for overlapping 
pharmacodynamic effects.  
Immunosuppressants, lymphocyte-depleting agents, or lymphocyte-trafficking blockers 
should NOT be administered while patient is B-cell depleted.  
Hypotension, as a symptom of IRR, may occur during ocrelizumab IV infusions. 
Therefore, withholding antihypertensive treatments should be considered for 12 hours 
prior to and throughout each ocrelizumab infusion.   
See the Ocrelizumab IB for a more detailed safety profile. In addition, the investigator 
should contact the Medical Monitor if questions arise regarding medications not listed 
above.  
4.5 
STUDY ASSESSMENTS  
Please see Appendix 1 for the schedule of assessments to be performed during the 
study. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures.  Informed Consent Forms for enrolled patients 
and for patients who are not subsequently enrolled will be maintained at the study site. 
All screening evaluations must be completed and reviewed by the investigator to confirm 
that patients meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
4.5.2 
Medical History and Demographic Data 
Patients’ demographics (age, gender, self-reported race) and neurological examination 
will be collected. Medical History will include clinically significant diseases, surgeries, 
reproductive status, smoking history, and all medications (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, and nutritional 
supplements) used by the patient within 6 weeks prior to the screening visit:  

 
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MS disease history:  
First MS symptom: date, symptoms, severity, MRI.  
Diagnosis of MS: Date, disease status, (EDSS, relapses, MRI) and, when available, 
criteria on which the diagnosis is based.  
Baseline disease status:  
EDSS, Number of relapses in the previous year, MRI lesions 
Treatment history: 
DMT: name, dose, start date (EDSS, relapses), stop date with disease status and 
reasons for discontinuation 
4.5.3 
Physical Examinations 
A complete physical examination should include an evaluation of head, eye, ear, nose, 
and throat (HEENT), cardiovascular, dermatological, musculoskeletal, respiratory, and 
gastrointestinal systems.  The following assessments will also be conducted:  
neurological examination (see Section 4.5.4), relapse description, EDSS (see 
Section 4.5.6), and MRI (see Section 4.5.7).  Changes from baseline abnormalities 
should be recorded in patient notes.  New or worsened clinically significant abnormalities 
not related to MS should be recorded as adverse events on the Adverse Event eCRF. 
Height and weight will be measured at screening only. See Appendix 1 (Schedule of 
Assessments) for the timing of these assessments. 
4.5.4 
Neurological Examinations 
Neurological examinations will be used to distinguish relapse in MS from another 
neurological (non-MS) disorder.  MS relapses should be recorded throughout the 
treatment period on a dedicated MS relapse eCRF page.  See Appendix 1 (Schedule of 
Assessments) for the timing of these assessments. 
A protocol-defined MS relapse is an occurrence of new or worsening neurological 
symptoms attributable to MS that meets the following criteria: 
• 
Symptoms must persist for >24 hours and should not be attributable to 
confounding clinical factors (e.g., fever, infection, injury, adverse reactions to 
medications) 
• 
Symptoms should be preceded by neurological stability for at least 30 days 
• 
Symptoms should be accompanied by new objective neurological worsening 
determined with a timely EDSS/ Functional Systems Score (FSS) assessment, 
consistent with an increase of at least:  
− 
≥ 0.5 points on EDSS scale 
− 
or ≥ 2 points on one of the following FSS scales: pyramidal, ambulation, 
cerebellar, brainstem, sensory, or visual 
− 
 or ≥ 1 point on two or more of the following FSS scales: pyramidal, 
ambulation, cerebellar, brainstem, sensory, or visual 

 
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Episodic spasms, sexual dysfunction, fatigue, mood change or bladder or bowel urgency 
or incontinence will not suffice to establish a relapse (Please note:  Sexual dysfunction 
and fatigue need not be scored).  
All patients with new neurological symptoms suggestive of a relapse should have an 
EDSS/FSS assessment performed as soon as possible, ideally within 7 days of the 
onset of symptoms. EDSS/FSS data is needed to allow the Sponsor to confirm 
whether the reported clinical relapse meets the criteria for a Protocol-defined relapse. 
Please note: All MS relapses (i.e., regardless of whether they may meet criteria for a 
protocol-defined relapse which will be adjudicated by the Sponsor based on the above 
criteria) will be recorded on a pre-specified eCRF “MS relapse” form.  
As infection is a potentially serious complication of B cell-depleting therapy, investigators 
will also screen patients for signs and symptoms of PML by evaluating neurological 
deficits localized to the cerebral cortex, such as cortical symptoms/signs, behavioral and 
neuropsychological alteration, retrochiasmal visual defects, hemiparesis, cerebellar 
symptoms/signs (e.g., gait abnormalities, limb incoordination).  Patients with suspected 
PML should be withheld from ocrelizumab treatment until PML is ruled out by complete 
clinical evaluation and appropriate diagnostic testing.  A patient with confirmed PML 
should be withdrawn from the study.  PML should be reported as a serious adverse 
event (with all available information) with immediate notification of the Medical Monitor. 
Please refer to Appendix 6 for guidance for diagnosis of PML. 
Cognitive status: The cognitive status of the patient will be evaluated at baseline, and 
further yearly for the full duration of the trial with the use of BICAMS components. 
4.5.5 
Vital Signs 
Vital signs will include measurements of heart rate, systolic and diastolic blood 
pressures, and oral or auricular temperature while the patient is in a seated position. 
Vital signs should be taken within 45 minutes prior to the premedication 
methylprednisolone (or an equivalent) infusion.  In addition, vital signs should be 
obtained prior to the ocrelizumab infusion then every 15 minutes ( 5 minutes) for the 
first hour, followed by every 30 minutes (± 10 minutes) until 1 hour after the end of the 
infusion.   
Vital sign measurements will be performed as outlined in the schedule of assessments 
(see Appendix 1). Record abnormalities observed before enrollment on the General 
Medical History and Baseline Conditions eCRF. At subsequent visits, record new or 
worsened clinically significant abnormalities on the Adverse Event eCRF (as presented 
in Section 5.3.5.6). 

 
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4.5.6 
Assessment of Disability 
Disability in MS will be measured by the EDSS.  See Appendix 1 (Schedule of 
Assessments) for the timing of these assessments. 
The EDSS is based on a standard neurological examination, incorporating seven 
functional systems (pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, 
and cerebral [or mental], plus “other”) rated and scored as FSSs.  Each FSS is an 
ordinal clinical rating scale ranging from 0 to 5 or 6.  These ratings are then used in 
conjunction with observations and information concerning ambulation and use of 
assistive devices to determine the EDSS score.  The EDSS is a disability scale that 
ranges in 0.5-point steps from 0 (normal) to 10 (death) (see Appendix 3). 
4.5.7 
Brain Magnetic Resonance Imaging 
MRI will be used to monitor CNS lesions and potentially other pathophysiology, such as 
inflammation and neurodegeneration.  Brain MRI scans will be obtained at study visits as 
shown in the Schedule of Assessments (see Appendix 1).  All efforts should be made to 
obtain the brain MRI scans before the next ocrelizumab infusion and the scans should 
be reviewed locally for the presence of any non-MS pathology, including PML, before the 
next infusion is administered.  
If patients receive corticosteroids for a treatment of an MS relapse, every effort should 
be made to obtain the scan prior to the first steroid dose if the pre-steroid scan is within 
1 week of the scheduled visit. In patients already receiving corticosteroids for an MS 
relapse, there should be an interval of at least 3 weeks between the last dose of 
corticosteroids and the scan, to allow for normalization of blood-brain barrier. 
MRI scans will be read by a centralized reading center for efficacy endpoints.  Further 
details on scanning acquisition sequences, methods, handling, transmission of the 
scans, and certification of site MRI radiologist/technicians are described in a separate 
MRI technical manual. 
Assessments will include T1-weighted scans before and after injection of gadolinium 
contrast, and may also include, but may not be limited to:  fluid-attenuated 
inversion-recovery (FLAIR), proton density-weighted, and T2-weighted scans. The MRI 
activity will be based upon the MRI scan taken on week 8 when the drug has reached its 
anti-inflammatory activity.  
The total brain volume and the different white and grey matter structures will be 
measured over the full duration of the study and follow-up period. 
4.5.8 
Laboratory, Biomarker, and Other Biological Samples  
Laboratory samples can be taken up to 2 weeks prior to the scheduled study visit. Results 
should be available prior to dosing, except for anti-JCV antibodies (plasma samples 

 
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collected and stored centrally), which will be analyzed upon request, and CD8 and CD19 
(no interference with re-treatment). 
Pre-infusion laboratory samples should be drawn so that routine laboratory test results are 
available for review before the infusion, unless otherwise specified.   
Routine laboratory assessments (performed in local laboratory) will include the following: 
• 
Hematology (hemoglobin, hematocrit, platelet count, red blood cell [RBC] count, 
white blood cell [WBC] count, percent and absolute differential count [neutrophils, 
bands, eosinophils, lymphocytes, monocytes, basophils, other cells]). 
• 
Serum chemistries (AST, ALT, gamma-glutamyl transpeptidase [GGT], total 
bilirubin, creatinine, random glucose, potassium, sodium) 
• 
Urine dipstick at site 
• 
Pregnancy test:  All women of childbearing potential (including those who have had 
a tubal ligation) will have a serum pregnancy test at screening.  A urine pregnancy 
test should be performed prior to methylprednisolone infusion in subsequent doses.  
If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
The follicle-stimulating hormone (FSH) test is only applicable to confirm 
postmenopausal status in female patients. 
• 
Viral serology and detection: 
− 
Hepatitis B (HBsAg and HBcAb confirmed, if positive, by positive viral DNA PCR) 
− 
For enrolled patients with negative HBsAg and positive total HBcAb, Hepatitis B 
virus (HBV) DNA (by PCR) must be repeated every 24 weeks 
− 
Hepatitis C virus (HCV) antibody 
• 
Lymphocytes subtypes 
− 
Whole-blood samples will be collected to determine the duration of B-cell 
depletion and recovery (CD19+) and T-cell counts (CD4+, CD8+) 
Additional laboratory samples will be collected: 
• 
Plasma samples for anti-JCV antibody assessments at baseline, 1 year and end of 
study. Samples will be stored in a central laboratory until one year after last patient 
last visit (LPLV) for further analysis upon request. 
 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Per local Institutional Review Board (IRB)/Ethics Committee (EC) requirements, 
additional testing may be required for selected patients or selected centers to exclude 
tuberculosis, Lyme disease, HAM, AIDS, hereditary disorders, connective tissue 
disorders, or sarcoidosis. 

 
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4.5.9 
Patient-Reported Outcomes 
PRO data will be elicited from patients in this study to better characterize patient quality 
of life and treatment satisfaction while on ocrelizumab. 
MSIS-29 is a 29-item questionnaire designed to measure the physical and psychological 
impact of MS from the patient’s perspective.   
TSQM II is a 14-item subject assessed evaluation of treatment medication using a 7-
point Likert-type scale rated as follows: 1=Extremely Dissatisfied to 7= Extremely 
Satisfied. Domain scores range from 0–100, with higher scores representing higher 
satisfaction. TSQM has been validated using a national panel study of chronic disease 
(Atkinson et al. 2004). 
SymptoMScreen: composite score based upon a battery of seven-point Likert scales for 
11 distinct domains commonly affected by MS: mobility, dexterity, vision, fatigue, 
cognition, bladder function, sensation, spasticity, body pain, depression and anxiety. 
Total score and subscale scores are assessed over the study duration (Green et al. 
2015). 
Employment Status WPAI: questionnaire that assesses the effect of MS on ability to 
work and perform regular activities. 
Please refer to Appendix 5 for detailed information on the PROs.  
The PRO instruments, translated as required in the local language, will be distributed by 
the investigator staff and completed in their entirety by the patient. To ensure instrument 
validity and that data standards meet health authority requirements, PRO questionnaires 
should be self-administered at the investigator site prior to the completion of other study 
assessments and the administration of study drug. Patients must complete these 
measures prior to the patient having any tests and prior to any discussion of the patient’s 
progress with their physician or any other healthcare personnel at the site. PRO 
assessments will be performed as outlined in the schedule of assessments (see 
Appendix 1)  
4.5.10 
BICAMS 
The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) battery 
includes the following tests of mental processing speed and memory: 
• 
Symbol Digit Modalities Test (SDMT) 
• 
California Verbal Learning Test 2 (CVLT-II) 
• 
Brief Visuospatial Memory Test Revised (BVMT-R) 

 
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Since CVLT-II is not yet available in all the languages of the countries participating in 
this study, the patients will not be assessed with this portion of the BICAMS. The 
patients will only need to complete the two components of the BICAMS test battery 
(Symbol Digit Modalities Test and Brief Visuospatial Memory Test Revised). 
Please note that the BICAMS should be administered only after the patient has 
completed all the PRO assessments. The recommended order of administration is first 
the SDMT, followed by the BVMT-R. The BICAMS will be scored centrally by a global 
reader and the results will be provided to the sites to be recorded in the eCRF.  
4.5.11 
Telephone Interviews 
The telephone interview will be conducted by site personnel familiar with the patient(s) 
every 8 weeks (± 3 days) between the study visits during the treatment period and 
follow-up. The purpose of this semi-structured interview is to identify new or worsening 
neurological symptoms that warrant an unscheduled visit and collect information on 
possible events of infections. The site will record in the eCRF the telephone interview as 
“Done” or “Not Done” and documentation of the interview will be maintained in the 
patient’s study file. Please refer to Appendix 4 for detailed information. 
4.5.12 
Patient Diary (optional) 
Due to the low frequency of study visits (every 6 months) and the structured telephone 
interviews (every 8 weeks between the study visits), patient diaries are proposed as an 
additional optional tool to help further improve the collection and documentation of 
Adverse Events and concomitant medications. The decision to use the patient diary is 
left to the discretion of each investigator. The investigator must ensure that required 
EC/IRB approval was obtained before implementing the patient diary at his/her site. 
Additional instructions around the use of an optional Patient Diary are provided in 
Appendix 7. 
 
 
4.6 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Patient Discontinuation 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following: 
• 
Patient withdrawal of consent at any time 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study 
• 
Investigator or Sponsor determines it is in the best interest of the patient 

 
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• 
Patient non-compliance, defined as failure to follow dosing instructions or to 
complete study visits 
 
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw from the study will not be replaced. 
4.6.2 
Study Treatment Discontinuation 
Patients must discontinue study treatment if they experience any of the following: 
• 
Ongoing pregnancy or breastfeeding (in case of pregnancy, treatment should be 
interrupted, and the patient should be monitored for safety; however, the patient  
can be re-started with the treatment after the pregnancy and breastfeeding period. 
During pregnancy and breastfeeding, the patient will continue to come for the 
regular schedule visits as per protocol and will perform all assessments except 
MRI). 
• 
Life-threating IRR or serious hypersensitivity reaction 
• 
Active hepatitis B infection 
• 
PML 
• 
Active tuberculosis, either new onset or reactivation 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF. Patient discontinuing the study treatment prematurely will be further 
monitored in a safety follow-up (see Section 3.1.4). 
Patients who discontinue study treatment prematurely will not be replaced. 
4.6.3 
Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
• 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients. 
• 
Patient enrollment is unsatisfactory. 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.   
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 

 
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• 
Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice (GCP) 
• 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 
4.6.4 
End of study treatment 
At the end of the study treatment the patients will be encouraged to be included in a 
separate LTE study to further evaluate the efficacy and safety of their DMT treatment, 
and this is independent of the DMT. This LTE will also aim to evaluate the relationship 
between the primary endpoint of this study and long-term outcome. 
Patients who discontinue treatment early will be followed up for at least 96 weeks after 
the Early Treatment Discontinuation Visit . Patients who complete the 96 weeks 
Treatment Period and, in agreement with their treating neurologist, decide not to 
continue in a separate LTE study, will be followed up for at least 96 weeks after the end 
of the Treatment Period. (see Section 3.1.4). Patients who decide to leave the study and 
switch to commercially marketed Ocrelizumab, either after completion of the 96 weeks 
Treatment Period or after early discontinuation of the 96 weeks Treatment Period, will 
not enter the safety Follow-up Period. 
 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
Ocrelizumab is currently in clinical development for the treatment of MS.  Identified and 
potential risks associated with ocrelizumab treatment will continue to be closely 
monitored throughout the clinical program.  Patient safety during the ocrelizumab 
program is ensured by targeting the most appropriate patient population, stringent safety 
monitoring by the Sponsor, and protocol-specified ocrelizumab treatment interruption 
criteria.  Patients will be evaluated clinically and with standard laboratory tests before 
and at regular intervals during their participation in this study.  Safety evaluations will 
consist of medical interviews, recording of adverse events, physical examinations, and 
standard laboratory measurements.  Adverse events will be graded according to the 
National Cancer Institute (NCI) CTCAE v4.0. 
Administration of ocrelizumab will be performed in a hospital, clinic environment or 
doctor’s office/practice under close supervision of the investigator or a medically 
qualified staff member with immediate availability of full resuscitation facilities.  All 
adverse events and serious adverse events will be recorded during the study and until 
96 weeks after the end of the Treatment Period as provided through this study.  Safety 
assessments will include the incidence, nature, and severity of (serious) adverse events 
graded per the NCI CTCAE v4.0.  Safety assessments will be conducted per the 
schedule of assessments in Appendix 1.  

 
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The potential safety issues anticipated in this study, as well as measures intended to 
avoid or minimize these issues, are outlined in the following sections. 
 
5.1.1 
Risks Associated with Ocrelizumab 
 
5.1.1.1 
Identified Risks and Adverse Drug Reactions 
 
Infusion-Related Reactions (IRRs) 
All CD20 depleting agents administered via the intravenous route, including ocrelizumab 
have been associated with acute IRRs. Following the approved administration regimen 
(which includes the use of premedication prior to treatment with ocrelizumab in order to 
reduce frequency and severity of IRRs), symptoms of IRRs may occur during any 
ocrelizumab infusion but have been more frequently reported during the first infusion. 
Physicians should alert patients that IRRs can occur within 24 hours of the infusion. 
Across the RMS and PPMS trials, symptoms associated with IRRs included, but were 
not limited to: pruritus, rash, urticaria, erythema, throat irritation, oropharyngeal pain, 
dyspnoea, pharyngeal or laryngeal edema, flushing, hypotension, pyrexia, fatigue, 
headache, dizziness, nausea and tachycardia. 
Patients should be observed for at least one hour after the completion of the infusion for 
any symptom of IRR. They will be informed about the possibility of delayed post-infusion 
symptoms and instructed to contact their study physician if they develop such 
symptoms. 
Hypotension, as a symptom of IRR, may occur during ocrelizumab infusions. Therefore, 
withholding of antihypertensive treatments should be considered for 12 hours prior to 
and throughout each ocrelizumab infusion.  
Infections   
Infection is an identified risk associated with ocrelizumab treatment, predominantly 
involving mild to moderate respiratory tract infections. Non-disseminated herpes virus-
associated infections, mostly mild to moderate, were also reported more frequently with 
ocrelizumab (approximately 5 to 6%, simplex and zoster) than with comparators 
(approximately 3%).   
During the controlled period of the pivotal trials, the proportion of patients with serious 
infections in RMS was lower in the ocrelizumab group (1.3%) than in the interferon beta-
1a group (2.9%); in PPMS, the proportion of patients with serious infections, was similar 
in both groups: 6.7% in the placebo group compared with 6.2% in the ocrelizumab group 
Serious, opportunistic and fatal infections have occurred in patients with lupus and 
rheumatoid arthritis (RA) treated with ocrelizumab in Phase III clinical trials. Data from 
completed studies regarding infection risks with ocrelizumab treatment in these patient 
populations are provided in the Ocrelizumab IB.  

 
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No opportunistic infections were reported by any MS patient treated with ocrelizumab 
during the controlled period of the pivotal trials. 
In interventional clinical studies there were no reports of hepatitis B reactivation in MS 
patients treated with ocrelizumab, but it had been reported in one RA patient treated with 
ocrelizumab. HBV screening should be performed in all patients before initiation of 
treatment with ocrelizumab as per local guidelines. Patients with active Hepatitis B Virus 
should not be treated with ocrelizumab. Patients with positive serology should consult 
liver disease experts before start of treatment and should be monitored and managed 
following local medical standards to prevent Hepatitis B reactivation. 
Delay ocrelizumab administration in patients with an active infection until the infection is 
resolved. 
For PML see “Potential risks” below. 
Decrease in immunoglobulins 
Treatment with ocrelizumab resulted in a decrease in total immunoglobulins (Ig) over the 
controlled period of the studies, mainly driven by reduction in IgM, with no observed 
association with serious infections during the controlled periods. The proportion of 
patients with decrease in Igs below LLN increased over time and with successive 
dosing. Based on additional patient exposure, in cases of continuous decrease over 
time, a higher risk of serious infection cannot be ruled out (see below in potential risks 
section).  
 
Delayed return of peripheral B cells 
Treatment with ocrelizumab leads to rapid depletion of CD19+ B cells in blood by 14 
days post treatment (first time-point of assessment) as an expected pharmacologic 
effect. This was sustained throughout the treatment period. The longest follow up time 
after the last ocrelizumab infusion from Phase II Study WA21493 in 51 patients, 
indicates that the median time to repletion (returned to baseline/LLN whichever occurred 
first of B cells was 72 weeks (range 27 − 175 weeks). Patients with prolonged B-cell 
depletion should be monitored until their B-cells have repleted.  
 
Impaired Response to Vaccination 
After treatment with ocrelizumab over 2 years in pivotal clinical trials, the proportion of 
patients with positive antibody titers against streptococcus pneumoniae, mumps, rubella, 
and varicella were generally similar to the proportions at baseline. 
The results of the randomized, open-label Phase IIIb study (BN29739) that assessed if 
ocrelizumab recipients with RMS raise adequate humoral responses to selected 
vaccines indicate that patients treated with ocrelizumab were able to mount humoral 
responses, albeit decreased, to tetanus toxoid, 23-valent pneumococcal polysaccharide, 

 
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keyhole limpet hemocyanin neoantigen, and seasonal influenza vaccines. The results 
are summarized in the current version of the IB.  
Physicians should review the immunization status of patients being considered for 
treatment with ocrelizumab. Patients who require vaccination should complete it at least 
6 weeks prior to initiation of ocrelizumab. For seasonal influenza vaccines, it is still 
recommended to vaccinate patients on ocrelizumab. Vaccination with live or live-
attenuated vaccines are not recommended during the treatment with ocrelizumab and 
until B cells have returned to normal levels.  
Due to the potential depletion of B-cells in neonates and infants of mothers, who have 
been exposed to ocrelizumab during pregnancy, it is recommended that vaccination with 
live or live-attenuated vaccines should be delayed until B-cells have recovered; 
therefore, measuring CD19-positive B cell level, in neonates and infants, prior to 
vaccination is recommended.  
It is recommended that all vaccinations other than live or live-attenuated should follow 
the local immunization schedule and measurement of vaccine-induced response titers 
should be considered to check whether individuals can mount a protective immune 
response because the efficacy of the vaccination may be decreased.   
 
5.1.1.2 
Potential Risks 
 
PML  
PML is an important potential risk for ocrelizumab and it has only been reported with 
ocrelizumab where the risk for PML was preexisting, specifically from prior 
immunosuppressive treatment (e.g. natalizumab or fingolimod treatment). In all of these 
PML cases, the causality with ocrelizumab was not considered plausible. Based on the 
available information, it is reasonable to consider that the PML started before the first 
administration of ocrelizumab, given new symptom onset and/or MRI changes had 
already occurred on the previous therapy or during the wash out period, and was related 
to prior immunosuppressive treatment. Physicians should be vigilant for early signs and 
symptoms of PML, which can include any new onset, or worsening of neurological signs 
or symptoms as these can be similar to an MS relapse. If PML is suspected, dosing with 
ocrelizumab must be withheld. Evaluation of PML, including MRI, confirmatory CSF 
testing for JC Viral DNA and repeat neurological assessments, should be considered. If 
PML is confirmed, ocrelizumab must be discontinued permanently. Please refer to 
Appendix 6 for guidance for diagnosis of PML. Please see the IB for more details. 
Serious infections related to decrease in immunoglobulins (particularly in 
patients previously exposed to immunosuppressive/ immunomodulatory 
drugs or with pre-existing hypogammaglobulinaemia) 
Based on additional patient exposure an apparent association between decrease in 
immunoglobulins (IgA, IgG, IgM) and serious infections with ocrelizumab treatment was 
observed.  There was no difference in the pattern (type, latency, duration, outcome) of 

 
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the serious infections reported in this subset of patients compared to the overall serious 
infections profile. In addition, risk factors for a subset of patients at higher risk of serious 
infections could not be identified. 
 
Hypersensitivity reactions  
No hypersensitivity reactions to ocrelizumab were reported in the controlled clinical trials.  
Hypersensitivity may be difficult to distinguish from IRRs in terms of symptoms.  A 
hypersensitivity reaction may present during any infusion, although typically would not 
present during the first infusion.  For subsequent infusions, more severe symptoms than 
previously experienced, or new severe symptoms, should prompt consideration of a 
potential hypersensitivity reaction. If a hypersensitivity reaction is suspected during 
infusion, the infusion must be stopped immediately and permanently. Patients with 
known IgE-mediated hypersensitivity to ocrelizumab must not be treated.   
Malignancies including Breast Cancer 
Patients should follow standard breast cancer screening guidelines.  
Please see the IB for more details.  
Neutropenia 
In the controlled treatment period, decreased neutrophils were observed in 12 to 15% of 
MS patients treated with ocrelizumab, in PPMS and RMS respectively. Most were mild to 
moderate in severity, and approximately 1% of the patients had Grade 3 or 4 
neutropenia; no temporal association with infections was identified. Based on additional 
patient exposure, an association between neutropenia and serious infections with 
ocrelizumab treatment was not observed. 
Additional information can be found in the current IB.  
5.1.2 
Risks Associated with Corticosteroids 
The adverse reactions of corticosteroids may result from unwanted glucocorticoid 
actions, or from inhibition of the hypothalamic-pituitary-adrenal axis. Please refer to local 
Prescribing Information.  
 
5.1.3 
Risks Associated with Antihistamines 
The adverse reactions depend on the sedating properties of the antihistamine and 
include but are not limited to nausea, drowsiness, headaches, dry mouth, and allergic 
reactions such as rash. Please refer to local Prescribing Information.  
 

 
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5.1.4 
Management of Patients Who Experience Specific Adverse 
Events 
Guidelines for management of specific adverse events are outlined in Table 2.  
Additional guidelines are provided in the subsections below. 
Table 2 
Guidelines for Management of Specific Adverse Events 
Event 
Action to Be Taken 
Mild to moderate IRR 
• 
If the event that a patient experiences is a mild to moderate 
IRR (e.g. headache), the infusion rate should be reduced to half 
the rate at the time of the event.  
• 
This reduced rate should be maintained for at least 30 minutes. 
If tolerated, the infusion rate may then be increased according 
to the patient’s initial infusion schedule. 
 
Severe IRR (or complex of 
flushing, fever, and throat 
pain) 
• 
If a patient experiences a severe IRR or a complex of flushing, 
fever, and throat pain symptoms, the infusion should be 
interrupted immediately, and the patient should receive 
symptomatic treatment.  
• 
The infusion should be re-started only after all symptoms have 
resolved.  
• 
The initial infusion rate at restart should be half of the infusion 
rate at the time of onset of the reaction. 
 
Life-threatening or 
disabling IRR (e.g., 
anaphylaxis) 
• 
Immediately stop ocrelizumab if there are signs of a life-
threatening or disabling IRR during an infusion, such as acute 
hypersensitivity or acute respiratory distress syndrome. 
• 
The patient should receive appropriate treatment.  
• 
Permanently discontinue ocrelizumab in these patients. 
 
hr = hour; IRR = infusion-related reaction 
 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4 

 
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5.2.1 
Adverse Events 
According to the ICH guideline for GCP, an adverse event is any untoward medical 
occurrence in a clinical investigation subject administered a pharmaceutical product, 
regardless of causal attribution.  An adverse event can therefore be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.10 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
• 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
• 
Is fatal (i.e., the adverse event actually causes or leads to death) 
• 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
This does not include any adverse event that had it occurred in a more severe 
form or was allowed to continue might have caused death. 
• 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.11) 
• 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions) 
• 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
• 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings). 

 
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Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
include the following: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s 
law (see Section 5.3.5.7). 
• 
Suspected transmission of an infectious agent by the study drug, as defined below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible 
spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious 
agent.  A transmission of an infectious agent may be suspected from clinical symptoms 
or laboratory findings that indicate an infection in a patient exposed to a medicinal 
product.  This term applies only when a contamination of the study drug is suspected. 
 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Section 5.4, Section 5.5 
and Section 5.6. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).   
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 

 
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procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events). 
After initiation of study drug, all adverse events will be reported until 96 weeks after 
the end of the Treatment Period, but may be extended in patients whose B-cells take 
longer to replete.  
Related SAEs must be collected and reported regardless of the time elapsed from the 
last study drug administration, even if the study has been closed. 
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6. 
 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation time points.  Examples of 
non-directive questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
 
5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity.  Table 3 will be used for assessing severity for 
infusion related reactions and adverse events that are not specifically listed in the NCI 
CTCAE. 

 
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Table 3 
Adverse Event Severity Grading Scale for IRRs and Other Events 
Not Specifically Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v4.0), which can be found at:   
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are not 
bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration (see also 
Table 4): 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event. 
 

 
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Table 4 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified below.   
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug). 
  
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Infusion-Related Reactions 
Adverse events that occur during or within 24 hours after study drug administration and 
are judged to be related to study drug infusion should be captured as a diagnosis (e.g., 
"infusion-related reaction" or "anaphylactic reaction") on the Adverse Event eCRF.  If 
possible, avoid ambiguous terms such as "systemic reaction."  Associated signs and 
symptoms should be recorded on the dedicated Infusion-Related Reaction eCRF.   
Investigators should consider a local IRR for any symptoms affecting the skin and 
localized to only one place. Any other IRR should be considered as systemic. 
If a patient experiences both a local and systemic reaction to the same dose of study 
drug, each reaction should be recorded separately on the Adverse Event eCRF, with 
signs and symptoms also recorded separately on the dedicated Infusion-Related 
Reaction eCRF. 
5.3.5.2 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 

 
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and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 
5.3.5.3 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
• 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
• 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.4 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation time points.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events. 
A recurrent adverse event is one that resolves between patient evaluation time points 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 

 
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5.3.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment  
 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5  ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.6 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment  
 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 

 
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If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.7 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST ( 3  ULN) in combination with either an elevated 
total bilirubin ( 2  ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
• 
Treatment-emergent ALT or AST  3  ULN in combination with total bilirubin 
 2  ULN 
• 
Treatment-emergent ALT or AST  3  ULN in combination with clinical jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2). 
5.3.5.8 
Deaths 
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  This 
includes death attributed to progression of RRMS. 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  The term "sudden death" should be used only for the occurrence of an 
abrupt and unexpected death due to presumed cardiac causes in a patient with or 
without preexisting heart disease, within 1 hour after the onset of acute symptoms or, in 
the case of an unwitnessed death, within 24 hours after the patient was last seen alive 
and stable.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death. 
If the death is attributed to progression of RRMS, "RRMS progression" should be 
recorded on the Adverse Event eCRF.  

 
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5.3.5.9 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 
5.3.5.10 
Lack of Efficacy or Worsening of Relapsing Remitting Multiple 
Sclerosis 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease, such as MS relapses or disability worsening should not be recorded 
as adverse events.  These data will be captured as efficacy assessment data only.  In 
most cases, the expected pattern of progression will be based on EDSS score.  In rare 
cases, the determination of clinical progression will be based on symptomatic 
deterioration.  However, every effort should be made to document progression through 
use of objective criteria.  If there is any uncertainty as to whether an event is due to 
disease progression, it should be reported as an adverse event.  
Occasional isolated symptoms that according to the investigator are caused by MS, but 
do not constitute a full MS relapse, should be reported as an AE, with the causality 
“Disease under study" (see Section 5.3.4). 
5.3.5.11 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., in-patient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.   
The following hospitalization scenarios are not considered to be adverse events: 
• 
Hospitalization for respite care 
• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
− 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected normal 
progression of the disease 
− 
The patient has not experienced an adverse event 
 

 
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The following hospitalization scenarios are not considered to be serious adverse events, 
but should be reported as adverse events instead: 
• 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours. 
• 
Elective hospitalizations or surgical procedures that are a result of a patient’s pre-
existing condition(s) that have not worsened since receiving trial medication. 
Examples may include, but are not limited to, cholecystectomy for gallstones, and 
diagnostic testing. Such events should still be recorded as medical procedures in 
the “Surgeries and therapies” eCRF. 
• 
Hospitalization to receive trial medication such as infusions of ocrelizumab unless 
this is prolonged (more than 24 hours). 
• 
Hospitalization following an MS relapse as long as the reason for hospitalization is 
to receive standard treatment with i.v. methylprednisolone. 
 
For a list of serious ADRs that are considered expected, kindly refer to the current IB. 
 
5.3.5.12 
Adverse Events Associated with an Overdose or Error in Drug 
Administration 
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2). 
Adverse events associated with an overdose of ocrelizumab in previous clinical studies 
include IRRs and infection. 
5.3.5.13 
Patient-Reported Outcome Data 
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data.  However, if any PRO responses 
suggestive of a possible adverse event are identified during site review of the PRO data, 
the investigator will determine whether the criteria for an adverse event have been met 
and, if so, will report the event on the Adverse Event eCRF. 
 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 

 
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such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
• 
Serious adverse events (see Section 5.4.2 for further details) 
• 
Adverse events of special interest (see Section 5.4.2 for further details) 
• 
Pregnancies (see Section 5.4.3 for further details) 
 
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
 
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators.  
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to investigators should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the event), either by faxing or 
by scanning and emailing the form using the fax number or email address provided to 
investigators. 

 
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5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events will be reported until 96 weeks after 
the end of the Treatment Period.  Investigators should record all case details that can be 
gathered immediately (i.e., within 24 hours after learning of the event) on the 
Adverse Event eCRF and submit the report via the electronic data capture (EDC) 
system.  A report will be generated and sent to Roche Safety Risk Management by the 
EDC system  
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the event), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.   
Related SAEs must be collected and reported regardless of the time elapsed from the 
last study drug administration, even if the study has been closed. 
Instructions for reporting post-study adverse events are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 24 weeks after the last 
dose of study drug.  A Clinical Trial Pregnancy Reporting Form should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the pregnancy), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  Pregnancy should not be 
recorded on the Adverse Event eCRF.  The investigator should discontinue study drug 
and counsel the patient, discussing the risks of the pregnancy and the possible effects 
on the fetus.  Monitoring of the patient should continue until conclusion of the pregnancy.  
Any serious adverse events associated with the pregnancy (e.g., an event in the fetus, 
an event in the mother during or after the pregnancy, or a congenital anomaly/birth 
defect in the child) should be reported on the Adverse Event eCRF.  In addition, the 
investigator will submit a Clinical Trial Pregnancy Reporting Form when updated 
information on the course and outcome of the pregnancy becomes available.  
For pregnancies occurring in female patients who have been exposed to Ocrelizumab at 
any time during pregnancy or within six months prior to conception, pregnancy outcome 
and the health status of the child will be followed until the child is one year of age. Data 
collection is voluntary only; it does not include any interventions or invasive procedures. 
A Pregnancy Outcome and Infant Health Information on First Year of Life questionnaire 
will be submitted to Health Authorities and IRB/IECs for their approval, along with the 
infant data release consent form. The data will be reported on dedicated pregnancy 

 
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outcome and infant health information paper form, hence will not be entered in the 
eCRF. 
5.4.3.2 
Abortions 
Any abortion should be classified as a serious adverse event (as the Sponsor considers 
abortions to be medically significant), recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2). Any abortion should be reported in the same fashion (as the 
Sponsor considers abortions to be medically significant). 
5.4.3.3 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug should be classified as a serious adverse event, recorded on the Adverse Event 
eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2).   
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification. 
All pregnancies reported in patients during the study should be followed with a 
Pregnancy Outcome and Infant Health Information on First Year of life questionnaire. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, and pregnancies, the Sponsor or a designee may follow up 
by telephone, fax, electronic mail, and/or a monitoring visit to obtain additional case 
details and outcome information (e.g., from hospital discharge summaries, consultant 
reports, autopsy reports) in order to perform an independent medical assessment of the 
reported case. 
5.6 
POST-STUDY ADVERSE EVENTS 
The Sponsor should be notified if the investigator becomes aware of any serious and 
non-serious adverse event that occurs after the end of the adverse event reporting 
period (defined as 96 weeks after the end of the Treatment Period), if the event is 
believed to be related to prior study drug treatment.   

 
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The investigator should report these events directly to the Sponsor or its designee, either 
by faxing or by scanning and emailing the Serious Adverse Event/Adverse Event of 
Special Interest Reporting Form using the fax number or email address provided to 
investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, and applicable health 
authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document: 
• 
Ocrelizumab IB 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
Certain adverse events are anticipated to occur in the study population at some 
frequency independent of study drug exposure and will be excluded from expedited 
reporting.  These anticipated events include, but are not limited to, the following: 
• 
Infection 
• 
Infusion related reactions 
 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The analysis of this single-arm non-comparative study will be exploratory and primarily 
based on descriptive statistical methods. Unless otherwise specified, statistical tests will 
be two-sided and the statistical significance level will be 5%. Corresponding 95% CIs will 
be presented as appropriate. Although multiple statistical tests may be conducted, no 
adjustments to the Type 1 error rate will be made. 
For continuous variables, descriptive statistics (e.g., mean, median, standard deviation 
[SD], n, 25th and 75th percentiles, minimum, and maximum) will be calculated and 
summarized.  For categorical variables, the number and percentage in each category 
will be displayed.  Full details of all statistical issues and planned statistical analyses will 
be specified in a separate Statistical Analysis Plan (SAP), which will be finalized prior to 
the locking of the study database and may include further exploratory analyses not 

 
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explicitly described in this section, as well as analyses of data from the study phase 
beyond the main 96-week study period. 
Analysis populations 
The efficacy and safety analyses will be performed using the intent-to-treat (ITT) 
population. The per-protocol (PP) population will be used for supportive efficacy 
analyses of the primary endpoint and selected secondary endpoints in order to evaluate 
the influence of major protocol violators on key efficacy endpoints.Intent-to-Treat 
Population 
All enrolled patients who received any dose of ocrelizumab will be included in the ITT 
population. Patients who prematurely withdrew from the study for any reason and who 
did not perform any assessment for any reason will still be included in the ITT 
population.  
Per-Protocol Population 
The per-protocol population will consist of the subset of the ITT population defined as all 
patients who had 96 weeks of treatment and who did not have any major protocol 
violations that are deemed to potentially affect the efficacy and safety endpoints. The list 
of criteria leading to exclusion from the per-protocol population will be finalized prior to 
database closure and documented in the SAP.  
 
6.1 
DETERMINATION OF SAMPLE SIZE 
With a sample size of 750 patients, an observed NEDA rate of 30% will be estimated 
with a precision (half-width of the 95% CI around the estimate) of 3.3% based on the 
Clopper-Pearson method, i.e. the 95% CI will be (26.7%, 33.4%). Even if the NEDA rate 
is different from the assumed rate of 30%, with the proposed sample size the precision 
of the estimate will remain better than 3.6% (value for a NEDA rate of 50%).  
The annualized relapse rate is another relevant outcome measure assessed in this 
study. Based on results from the pivotal Phase III studies WA21092 (Opera I) and 
WA21093 (Opera II), in this study the adjusted annualized relapse rate assessed over 
two years is expected to be estimated with a precision of approximately 0.03. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Enrollment, ocrelizumab administration, and discontinuations from the study will be 
summarized.  Patient disposition and the incidence of treatment discontinuation for 
reasons other than disease progression will be tabulated.  Major protocol violations, 
including violations of inclusion/exclusion criteria, will also be summarized. 

 
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6.3 
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
Patients’ demographics (age, gender, and self-reported race), medical history and 
neurological examination will be summarized. The following will also be summarized: MS 
disease history (duration since first MS symptoms, duration of MS since diagnosis, 
relapses in the past year) and MS treatment history, baseline measures of MRI, EDSS 
and other important variables.  
 
6.4 
EFFICACY ANALYSES 
 
6.4.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint will be the proportion of patients who have no evidence of 
disease activity (NEDA), as per protocol defined events during a 96-week period. The 8 
weeks MRI scan will be the baseline for MRI activity.  
The definition of a protocol-defined event of disease activity is the occurrence of at least 
one of the following while on treatment with ocrelizumab: 
− 
A protocol-defined relapse as defined in Section 4.5.4 
− 
24 weeks confirmed disability progression based on increases in EDSS 
while on treatment with ocrelizumab 
− 
A T1 Gd-enhanced lesion after Week 8 
− 
A new and/or enlarging T2 hyperintense lesion on MRI after Week 8 
compared to the Week 8 MRI scan. 
 
6.4.2 
Secondary Efficacy Endpoints 
The secondary objective for this study is to evaluate the efficacy of ocrelizumab 600 mg 
IV given every 24 weeks on the basis of the endpoints and analyses listed in Section 
2.1.2. 
 
6.4.3 
Exploratory Efficacy Endpoints 
The exploratory efficacy objective for this study is to further assess the efficacy of 
ocrelizumab 600 mg IV given every 24 weeks by monitoring PROs related to QoL, 
treatment satisfaction, and other endpoints and analyses as listed in Section 2.1.3. 
 
6.4.4 
Analysis Methods 
The analysis will be performed after the last CDP and CDI confirmation visit. The per-
protocol population will be used for supportive efficacy analyses of the primary endpoint. 
The evaluation of the clinical efficacy of ocrelizumab will be based upon the events in-
between baseline visit and week 96. The MRI activity is evaluated from week 8 to week 

 
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96. The proportion of patients free from protocol-defined events up to Week 96 (i.e. 
patients with NEDA) will be calculated and the corresponding two-sided Clopper-
Pearson 95% CI will be presented. Logistic regression models will be used to identify 
predictors of response to treatment (freedom from events). Variables that will be 
considered include: region, line of treatment (previous DMTs), gender, and baseline 
EDSS. In addition, specific efficacy endpoints, such as CDP, will be compared between 
patients with or without evidence of disease activity up to Week 96. 
Details about the missing data handling, as well as sensitivity analyses, will be specified 
in the statistical analysis plan. 
The proportion of patients free from a protocol-defined event up to Week 24, 48, and 96 
will be calculated and the corresponding two-sided Clopper-Pearson 95% CI will be 
presented. Logistic regression models will be used to identify predictors of response to 
treatment (freedom from events). Variables that will be considered include: region, line of 
treatment (previous DMTs), gender, and baseline EDSS. 
The annualized relapse rate by Week 96 will be analyzed using regression based on a 
negative binomial model, adjusting for factors that may include region, baseline EDSS 
( 4.0 vs  4.0), line of treatment (previous DMTs), with the log-transformed drug 
exposure time in years as an “offset” variable.  The adjusted annualized relapse rate will 
be presented.  
EDSS and its change from baseline, as well as other continuous variables such as the 
change in total T2 lesion volume and the key PROs, will be summarized descriptively at 
each assessment visit. The time course of these variables will be described using 
techniques such as linear mixed models for repeated measures (MMRM) adjusting for 
covariates such as the respective baseline score, geographical region, and baseline 
EDSS. 
The Kaplan–Meier method will be used to estimate the survival function for time-to-event 
data (e.g., time to onset of first relapse; time to onset of sustained disability progression 
for at least 12 weeks) and Cox proportional hazards regression will be used to identify 
predictors of survival. Variables to be included in the regression model will be the same 
as those used in the logistic regression described above. Further details will be specified 
in the SAP. 
The total number of T1 Gd-enhanced lesions will be calculated as the sum of the 
individual number of T1 Gd-enhanced lesions at Weeks 24, 48 and 96.  Data from 
unscheduled assessments will not be included in this summary or analysis.  A negative 
binomial model will be used to estimate the rate of lesion occurrence. 
 

 
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6.5 
SAFETY ANALYSES 
6.5.1 
Safety Outcome Measures 
The safety outcome measures comprise the following:  the incidence and nature of all 
adverse events, including findings on vital sign measurements, physical and neurological 
examinations, clinical laboratory tests, locally reviewed MRI for safety (non-MS CNS 
pathology), and concomitant medications. 
6.5.2 
Safety Analyses 
Safety will be assessed through summaries of adverse events (including rates/incidence 
rates and corresponding 95% CIs) and clinical laboratory abnormalities.   
All adverse events occurring on or after treatment on Day 1 will be coded, summarized 
by NCI CTCAE v4.0 grade, and tabulated by body system and Preferred Term for 
individual adverse events within each body system.  Grade 3 to 5 adverse events, 
serious adverse events, adverse events leading to treatment discontinuation, time to 
withdrawal from the study due to an adverse event, first adverse event leading to 
infusion adjustment, and time to first selected treatment-related adverse event will be 
summarized.  In addition, all serious adverse events and deaths will be listed. 
Associated laboratory parameters, such as hepatic function, renal function, and 
hematology values, will be grouped and presented together.   
Ocrelizumab exposure will be summarized, including duration and dosage.  
6.6 
SUBGROUP ANALYSIS 
Subgroup analysis will be done based upon 
• 
First or second switch 
• 
Previous treatments 
• 
Age of subjects (≤ 40 years, > 40 years) 
• 
Disease severity at inclusion and in disease history: 
o EDSS at baseline (< EDSS 2.5, ≥ EDSS 2.5) 
o Number of relapses over the year prior to inclusion (≤ 1, >1) 
o MRI activity at baseline (number of T1 Gd+, ≤ 2, > 2) 
 
6.7 
HANDLING OF MISSING DATA 
Details about the missing data handling will be specified in statistical analysis plan 

 
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6.8 
INTERIM ANALYSIS 
No formal confirmatory efficacy interim analyses are planned. Exploratory analyses of 
selected endpoints may be performed during the course of the study, e.g. after all 
patients have completed the first 6 and 12 months of the treatment phase and the 
necessary data are available. 
 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
A contract research organization (CRO) will be responsible for data management of this 
study, including quality checking of the data.  Data entered manually will be collected via 
EDC through use of eCRFs.  Sites will be responsible for data entry into the EDC 
system.  In the event of discrepant data, the CRO will request data clarification from the 
sites, which the sites will resolve electronically in the EDC system. 
The CRO will produce a Data Quality Plan that describes the quality checking to be 
performed on the data.   
The Sponsor will perform oversight of the data management of this study, including 
approval of the CRO’s data management plans and specifications.  Data will be 
periodically transferred electronically from the CRO to the Sponsor, and the Sponsor’s 
standard procedures will be used to handle and process the electronic transfer of these 
data. Central imaging review data will be sent directly to the Sponsor, using the 
Sponsor’s standard procedures to handle and process the electronic transfer of these 
data. 
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored at the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures. 
PRO data will be collected on paper questionnaires. The data from the PRO 
questionnaires as well as the BICAMS scoring data received from the central reader will 
be entered into the EDC system by site staff. 
 
7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the CRO. 

 
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All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5. 
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 

 
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7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, PRO data, Informed Consent Forms, laboratory test results, and 
medication inventory records, must be retained by the Principal Investigator for at least 
15 years after completion or discontinuation of the study, or for the length of time 
required by relevant national or local health authorities, whichever is longer.  After that 
period of time, the documents may be destroyed, subject to local regulations.   
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for GCP and 
the principles of the Declaration of Helsinki, or the laws and regulations of the country in 
which the research is conducted, whichever affords the greater protection to the 
individual.  The study will comply with the requirements of the ICH E2A guideline 
(Clinical Safety Data Management:  Definitions and Standards for Expedited Reporting).  
Studies conducted in the United States (U.S.) or under a U.S. Investigational New Drug 
(IND) application will comply with U.S. FDA regulations and applicable local, state, and 
federal laws.  Studies conducted in the European Union (E.U.) or European Economic 
Area will comply with the E.U. Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Home Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 
or any alternate consent forms proposed by the site (collectively, the "Consent Forms") 
before IRB/EC submission.  The final IRB/EC−approved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature. 

 
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The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 9.6). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file.  

 
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8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., last patient, last visit 
[LPLV]). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures. 

 
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9.3 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored by Roche and will be managed by Roche and CROs.  CROs 
will provide clinical operations management, data management, biostatistics, and 
medical monitoring.  
An IxRS will be used to assign patient numbers, monitor enrollment and patient status, 
and to manage study treatment requests and study drug shipments.   
Patient data will be recorded via an EDC system using eCRFs. 
9.5 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals.  The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site: 
http://www.rochetrials.com/pdf/RocheGlobalDataSharingPolicy.pdf 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective clinical study report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 

 
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Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 

 
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10. 
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APPENDICES 

 
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Appendix 1: Schedule of Assessments: Screening through the End of Treatment Period 

 
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e Vital signs will include the measurements of heart rate, systolic and diastolic blood pressures, and oral or auricular temperature while the patient is in a seated 
position.  Vital signs should be taken within 45 minutes prior to the premedication methylprednisolone infusion.  In addition, vital signs should be obtained prior to 
the ocrelizumab infusion then every 15 minutes ( 5 minutes) for the first hour, followed by every 30 minutes (± 10 minutes) until 1 hour after the end of the 
infusion. Record abnormalities observed before enrollment on the General Medical History and Baseline Conditions eCRF. At subsequent visits, record new or 
worsened clinically significant abnormalities on the Adverse Event eCRF.  
f Hematology will include hemoglobin, hematocrit, RBCs, WBC absolute and differential, ANC, and quantitative platelet count.  Chemistry will include AST, ALT, 
GGT, creatinine, total bilirubin, random glucose, potassium and sodium. Urine dipstick will be done at site locally. 
g Serum b-hCG must be performed at screening in women of childbearing potential.  Subsequently, urine β-hCG (sensitivity  25 mIU/mL) must be collected.  On 
infusion visits, the urine pregnancy test should be performed prior to methylprednisolone infusion in all women of childbearing potential.  If positive, ocrelizumab 
should be withheld.  The FSH test is only applicable to confirm postmenopausal status in female patients. 
h All patients must have negative HBsAg result and negative HepCAb screening tests prior to enrollment.  If total HBcAb is positive at screening, HBV DNA 
measured by PCR must be negative in order for a patient to be eligible for the study.  For enrolled patients with negative HBsAg and positive total HBcAb, HBV 
DNA (by PCR) must be repeated every 24 weeks.  
i Lymphocytes subtypes samples should be collected prior to ocrelizumab infusion to screen for CD19+ and T-cell counts (CD4+, CD8+) at a local laboratory. 
j 
Plasma samples for anti-JCV antibodies should be taken at baseline and repeated yearly and end of study for storage in a central laboratory. Samples will be 
analyzed upon request. 
k Patients must have an EDSS score of 0.0 to 4.0 points, inclusive at screening to be eligible. EDSS needs to be confirmed after 24 weeks if EDSS changes from 
baseline to Week 96 
l Neurological examinations will be used to distinguish relapse in MS from another neurological (non-MS) disorder.  Potential relapses should be recorded 
throughout the treatment period.  Investigators will also screen patients for signs and symptoms of PML by evaluating neurological deficits localized to the 
cerebral cortex, such as cortical symptoms/signs, behavioral and neuropsychological alteration, retrochiasmal visual defects, hemiparesis, cerebellar 
symptoms/signs (e.g., gait abnormalities, limb incoordination).  Patients with suspected PML should be withheld from ocrelizumab treatment until PML is ruled 
out by complete clinical evaluation and appropriate diagnostic testing.  A patient with confirmed PML should be withdrawn from the study.   
m After initiation of study drug, all adverse events should be reported until 96 weeks after the end of the Treatment Period but may be extended in patients whose 
B-cells take longer to replete.  After this period, the investigator should report any serious and non-serious adverse events that are believed to be related to prior 
study drug treatment (see Sections 5.3.1 and 5.6).  
n All patients must receive prophylactic treatment with 100 mg methylprednisolone, administered by slow IV infusion, to be completed approximately 30 minutes 
before the start of each ocrelizumab infusion, and an antihistaminic drug (e.g., diphenhydramine) approximately 30 – 60 minutes before each infusion of 
ocrelizumab. 
o Ocrelizumab will be administered as two 300-mg IV infusions in 250 mL 0.9% sodium chloride each on Days 1 and 15 and one 600-mg infusion in 500 mL 0.9% 
sodium chloride every subsequent dose (i.e., every 24 weeks) for a maximum of 72 weeks. It is anticipated that the patient will need to stay at the hospital or 
clinic for a full day for the infusion visits. 

 
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p A structured telephone interview will be conducted by site personnel every 8 weeks (± 3 days) to identify and collect information on any changes in the patient’s 
health status that warrant an unscheduled visit (including new or worsening neurological symptoms) and possible events or infections. No telephone contact is 
needed in weeks where patient is performing on-site visits (week 24, 48, 72 and 96).  
q If the subject discontinues treatment early, all efforts should be made to perform the Early study treatment discontinuation evaluation visit as soon as possible 
after discontinuation from treatment period. Otherwise, reasons for discontinuation will be captured via telephone call. 
r All efforts should be made to obtain the brain MRI scans before the next ocrelizumab infusion and the scans should be reviewed locally for the presence of any 
non-MS pathology, including PML, before the next infusion is administered. 
s 
In case of re-screening, MRI does not need to be repeated if the MRI scan obtained at first screening is not older than 3 months. 
t 
Since CVLT-II is not yet available in all the languages of the countries participating in this study, the patients will not be assessed with this portion of the 
BICAMS. The patients will only need to complete the two components of the BICAMS test battery (Symbol Digit Modalities Test and Brief Visuospatial Memory 
Test Revised). 
 
Note: Lab samples can be taken up to 2 weeks prior to the scheduled study visit. Results should be available prior dosing, except for anti-JCV antibodies (plasma 
samples collected and stored centrally) which will be analyzed upon request, and CD8 and CD19 (no interference with re-treatment) 
 

 
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Appendix 2: Follow-up Schedule of Assessments 
(Including Additional B-Cell Monitoring, if required) 
Patients who decide to leave the study and switch to commercially marketed Ocrelizumab, either 
after completion of the 96 weeks Treatment Period or after early discontinuation of the 96 weeks 
Treatment Period, will not enter the safety Follow-up Period. 
 
 
Follow Up 
Prolonged B-Cell Monitoring a 
Assessment 
Visits Every 24 Weeks 
( 14 days) b 
Visits Every 24 Weeks  
( 14 days) 
Routine safety laboratory tests c 
X 
X 
Lymphocytes subtypes d 
X 
X 
Plasma  anti-JCV antibodies sample e 
X 
X 
Vital signs 
X 
X 
EDSS score f 
X 
 
Potential relapses recorded 
X 
X 
Adverse events g 
X 
X 
BICAMS assessment h 
X 
X 
Concomitant medication 
X 
X 
MRI i 
X 
X 
Telephone contact every 8 weeksj  
X 
X 
BICAMS= Brief International Cognitive Assessment for Multiple Sclerosis; EDSS = Expanded 
Disability Status Scale; JCV = John Cunningham virus; MRI = Magnetic resonance imaging; MS 
= Multiple sclerosis 
a Patients whose B-cells have not been repleted after 96 weeks of Follow-up Period will continue 
with visits every 24 weeks ( 14 days) and telephone contacts every 8  weeks until B-cell 
repletion (Prolonged B-cell monitoring). If the patients are receiving other B-cell targeted 
therapies, then the Follow-up Period is only 96 weeks regardless of their B-cell count.  
b Visits will be performed at 24-week intervals following the Early Treatment Discontinuation Visit 
(if discontinued early) or after the end of the Treatment Period 
c Routine safety lab: hematology, chemistry and urinalysis. 
d  Lymphocytes subtypes samples for CD19+ and T-cell counts (CD4+, CD8+) 
e Plasma sampling for anti-JCV antibodies will be repeated yearly. Samples will be analyzed 
upon request. 
f EDSS assessment needs to be performed only once, at the first follow-up visit 
g After initiation of study drug, all adverse events must be reported until 96 weeks after the end 
of the Treatment Period, but may be extended in patients whose B-cells take longer to replete. 
Related SAEs must be collected and reported regardless of the time elapsed from the last 
study drug administration, even if the study has been closed (see Sections 5.3.1 and 5.6). 
h BICAMS will be assessed yearly. Since CVLT-II is not yet available in all the languages of the 
countries participating in this study, the patients will not be assessed with this portion of the 
BICAMS. The patients will only need to complete the other two components of the BICAMS 
test battery (Symbol Digit Modalities Test and Brief Visuospatial Memory Test Revised). 

 
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I MRIs will be performed yearly 
j A structured telephone interview will be conducted by site personnel every 8 weeks (± 3 days) 
to identify and collect information on any changes in the patient’s health status that warrant an 
unscheduled visit (including new or worsening neurological symptoms) and possible events or 
infections. No telephone contact is needed in weeks where patient is performing on-site visits.  
 
Patients who receive alternative MS therapies that may decrease B-cell levels will not be entered 
into the prolonged B-cell Monitoring period thereafter. 
 
A dedicated (scheduled or unscheduled) follow-up visit directly prior to the start of an alternative 
MS treatment is required for patients who begin an alternative treatment for MS while in follow-up 
in order to assess the patient’s clinical status and safety parameters (assessments to be 
performed as per schedule of assessments: follow-up or prolonged B-cell monitoring visits, 
depending on the study period in which the patient was in when the alternative treatment began). 

 
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Appendix 3: Expanded Disability Status Scale (EDSS) 

 
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Source: http://www.nationalmssociety.org/For-Professionals/Researchers/Resources-for-
Researchers/Clinical-Study-Measures/Functional-Systems-Scores-(FSS)-and-Expanded-Disab 
 

 
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Appendix 4: Telephone Interviews 
The purpose of this interview is to identify and collect information on any changes in the 
patient’s health status that warrant an unscheduled visit (including new or worsening 
neurological symptoms). Telephone interviews should be performed by study personnel 
every 8 weeks between clinic visits (see also Section 4.5.11) 
 
Please ask the following questions and record patient’s answers during the 
Telephone Interview: 
 
Questions 
No 
Yes 
1.  Since your last visit or telephone interview, have you had any 
new or worsening medical problems (such as sudden 
changes in your thinking, alterations in your behavior, visual 
disturbances, 
extremity 
weakness, 
limb 
coordination 
problems, or gait abnormalities) that have persisted over 
more than one day? 
 
 
2.  Since your last visit or telephone interview, have you had any 
signs of an infection? 
3.  Since your last visit or telephone interview, have you had any 
other new or worsening medical problems or conditions 
(including pregnancy)? 
4.  Since your last visit or telephone interview, have you taken 
any new medicines (including medicines to treat cancer or 
MS, any other new medicines that weaken your immune 
system, or steroid medicines other than for the treatment of 
a recent relapse)? 
 
 
 
If the patient answered YES to any question, contact the Treating Investigator and 
review the patient’s answers.  The Investigator can determine if an unscheduled 
visit is required. 
Please report all relevant information in the eCRF as well. 
 
Record any pertinent comments made by the patient during the interview: 
________________________________________________________________
________ 
________________________________________________________________
________ 
NAME:______________________________ Date:______________________________ 
Name of person completing the telephone interview 
 

 
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APPENDIX 4: TELEPHONE INTERVIEWS  (cont.) 
 
Below is a sample list of medications that can weaken the immune system.  
This list does not include all drugs that can suppress the immune system.   
Approved MS Therapies: 
Glatiramer acetate (Copaxone®) 
Interferon -1a (Rebif®, AVONEX®) 
Interferon -1b (Betaseron®) 
Mitoxantrone (Novantrone®) 
Natalizumab (Tysabri®) 
Fingolimod (Gilenya®) – if relevant 
Immunosuppressants/Antineoplastics: 
Azathioprine (Imuran®, Azasan®) 
Cladribine (Leustatin®) 
Cyclophosphamide (Cytoxan®, Neosar®) 
Cyclosporine (Sandimmune®, Neoral®) 
Fludarabine phosphate (Fludara®) 
Leflunomide (Arava®) 
Mercaptopurine (Purinethol®) 
Methotrexate (Methotrex®, Rheumatrex®, Trexall®) 
Mycophenolate mofetil (CellCept®) 
Pemetrexed (Alimta®) 
Additional Immunomodulators and Immunosuppressants: 
Other interferons (Actimmune®, Infergen®, Intron® A, 
Pegasys®, PEG-Intron®, Rebetron®, Roferon®-A) 
Adalimumab (Humira®) 
Alefacept (Amevive®) 
Alemtuzumab (Campath®) 
Anakinra (Kineret®) 
Daclizumab (Zenapax®) 
Etanercept (Enbrel®) 
Infliximab (Remicade®) 
Intravenous immunoglobulin (IVIG) 
Ofatumumab (Arzerra®) 
Rituximab (Rituxan/MabThera®) 
Trastuzumab (Herceptin®) 
 

 
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Appendix 6: Guidance for Diagnosis of Progressive Multifocal 
Leukoencephalopathy 
 
Action Steps if Progressive Multifocal Leukoencephalopathy (PML) is 
Suspected 
• If the clinical presentation is suggestive of PML, further investigations should 
include brain MRI evaluation as soon as possible.  If MRI evaluation reveals 
lesions suspicious for PML (see Figure 5), a lumbar puncture with evaluation 
of the cerebrospinal fluid (CSF) for the detection of JC virus (JCV) DNA 
using a validated sensitive assay should be undertaken.  A diagnosis of PML 
can potentially be made by evaluating clinical and MRI findings plus the 
identification of JCV in the CSF. 
• There is no known treatment or cure for PML. Treatment considerations are 
discussed in the medical literature (Calabrese et al. 2007) 
 
MRI Assessment 
• Although there are no pathognomonic findings that differentiate PML from 
MS, a brain MRI scan that includes fluid-attenuated inversion recovery 
(FLAIR) and T2-weighted and T1-weighted sequences, with and without 
gadolinium, should be performed to assess patients with neurological 
changes suggestive of PML (see Figure 5). 
• Comparison with a baseline scan may assist with interpretation of the findings 
on the newly acquired MRI (see Table 5 for differences in lesion 
characteristics that may help differentiate between PML and MS). 
 
CSF Assessment 
• The detection of JCV DNA in the CSF of a patient with clinical and MRI 
features suggestive of PML establishes the diagnosis of PML. 
• If JCV DNA is not detected in CSF and if clinical suspicion of PML remains 
high, a repeat lumbar puncture should be performed. 
• 
If diagnosis remains uncertain and suspicion of PML remains high, a brain 
biopsy may be considered to establish a definitive diagnosis. 
 

 
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APPENDIX 6: 
GUIDANCE FOR DIAGNOSIS OF PROGRESSIVE MULTIFOCAL 
LEUKOENCEPHALOPATHY (Cont.)  
 
Table 5 
MRI Lesion Characteristics Typical of PML and MS 
Feature 
MS (relapse) 
PML 
Location of new 
lesions 
Mostly focal; affect entire brain 
and spinal chord, in white and 
possibly gray matter 
Diffuse lesions, mainly subcortical 
and rarely periventricular, located 
almost exclusively in white matter, 
although occasional extension to 
gray matter has been seen; 
posterior fossa frequently involved 
(cerebellum) 
Borders 
Sharp edges; mostly round or 
finger-like in shape (especially 
periventricular lesions), confluent 
with other lesions; U-fibers may 
be involved 
Ill-defined edges; irregular in shape; 
confined to white matter; sparing 
gray matter; pushing against the 
cerebral cortex; U-fibers destroyed. 
Mode of extension 
Initially focal; lesions enlarge 
within days or weeks and later 
decrease in size within months 
Lesions are diffuse and asymmetric, 
extending homogeneously; no 
confluence with other lesions; 
confined to white-matter tracks, 
sparing the cortex; continuous 
progression 
Mass effect 
Acute lesions show some mass 
effect 
No mass effect even in large 
lesions (but lesion slightly abuts 
cerebral cortex) 
On T2-weighted 
sequence 
- Acute lesions: hyperintense 
center, isointense ring, discrete 
hyperintensity outside the ring 
structure 
- Subacute and chronic lesions: 
hyperintense with no ring 
structure 
Diffuse hyperintensity, slightly 
increased intensity of newly 
involved areas compared with old 
areas, little irregular signal intensity 
of lesions. 
On T1-weighted 
sequence 
Acute lesions: densely 
hypointense (large lesions) or 
isointense (small lesions); 
increasing signal intensity over 
time in 80%; decreasing signal 
intensity (axonal loss) in about 
20%  
Slightly hypointense at onset, with 
signal intensity decreasing over 
time and along the affected area; 
no reversion of signal intensity 
On FLAIR sequence 
Hyperintense, sharply delineated 
Hyperintensity more obvious; true 
extension of abnormality more 
clearly visible than in T2-weighted 
images 
With enhancement 
- Acute lesions: dense 
homogeneous enhancement, 
sharp edges 
- Subacute lesions: ring 
enhancement 
- Chronic lesions: no 
enhancement 
Usually no enhancement, even in 
large lesions; in patients with HIV, 
some peripheral enhancement is 
possible, especially under therapy. 

 
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Atrophy 
Focal atrophy possible due to 
focal white-matter degeneration; 
no progression 
No focal atrophy 
Adapted from Yousry TA et al. 2006   

 
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Appendix 7: Patient Diary 
Accurate AE reporting is essential to ensure patient safety, early detection of safety 
signals, assess molecule benefit profile, regulatory compliance. In this study protocol the 
patient visits will occur every 6 months, site staff will conduct a phone interview every 8 
week in between the visits at site.  
Due to the low visit frequency patient diaries have been proposed as an optional tool to 
mitigate the risk related to AEs / concomitant medication low reporting.  
The decision to use the patient diary is left to the discretion of each PI. The PI must 
ensure that required EC/IRB approval was obtained before implementing the patient 
diary at his/her site.  
If you are using the patient diary, this is to be considered as patient source 
documentation. Please ensure the following process is followed at your site:  
 
• 
The patient diary will be provided to the patient at the Baseline Visit.  
• 
You or your site staff will explain to the patient when/how to complete it and 
remind him/her to bring it back at each visit at your site.  
• 
Dispensing at Baseline and re-dispensing of patient diary at subsequent on-site 
visits should be documented in patient notes.  
• 
Completed patient diaries should never be mailed to/ by patients.  
• 
You or your site staff must review the completed patient diary at each visit and 
discuss the reported data with the patient.  
• 
In between of the visit, you or your site staff should discuss the patient diary and 
any updates made during the 8-weeks telephone interviews.  
• 
During each visit you or your site staff should make a copy of the completed 
patient diary, document your review and assessment, sign and date all pages 
and file it with the medical records  
• 
In case you or your site staff cannot copy the patient diary, you would need to 
check the original during each patient study visits at site for any new adverse 
events / any new concomitant medication which occurred since last patient visit 
at site and document this in the patient notes (Source Data).  
• 
When the patient early terminated or has completed the study, originals should 
be filed in the patient notes.  
• 
To increase the patient compliance, please thank the patients for their time and 
effort and emphasize the importance of their contribution to the study to them.  
 

 
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Appendix 8: Summary of Product Characteristics (SmPC) for 
Disease Modifying Therapies for EMEA Countries 
 

 
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SmPC for Aubagio 
 
 
1. 
NAME OF THE MEDICINAL PRODUCT 
 
AUBAGIO 14 mg film-coated tablets 
 
 
2. 
QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 14 mg of teriflunomide. 
 
Excipient with known effect: Each tablet contains 72 mg of lactose (as monohydrate). 
 
For the full list of excipients, see section 6.1. 
 
 
3. 
PHARMACEUTICAL  FORM 
 
Film-coated tablet (tablet). 
 
Pale blue to pastel blue, pentagonal film-coated tablets with imprint on one side (‘14’) and engraved with 
a corporate logo on the other side. 
 
 
4. 
CLINICAL  PARTICULARS 
 
4.1 
Therapeutic  indications 
 
AUBAGIO is indicated for the treatment of adult patients with relapsing remitting multiple sclerosis (MS). 
(please refer to section 5.1 for important information on the population for which efficacy has been 
established). 
 
4.2 Posology and method of administration 
 
The treatment should be initiated and supervised by a physician experienced in the management of 
multiple sclerosis. 
 
Posology 
The recommended dose of AUBAGIO is 14 mg once daily.  
 
Special populations 
Elderly population 
AUBAGIO should be used with caution in patients aged 65 years and over due to insufficient data on 
safety and efficacy. 
 
Renal impairment 
No dosage adjustment is necessary for patients with mild, moderate or severe renal impairment not 
undergoing dialysis. 
Patients with severe renal impairment undergoing dialysis were not evaluated. Teriflunomide is 
contraindicated in this population (see section 4.3). 
 
Hepatic impairment 
No dosage adjustment is necessary for patients with mild and moderate hepatic impairment. 
Teriflunomide is contraindicated in patients with severe hepatic impairment (see section 4.3). 
 
Paediatric population 
The safety and efficacy of AUBAGIO in children aged from 10 to less than 18 years has not yet been 
established. There is no relevant use of teriflunomide in children aged from birth to less than 10 years 
for the treatment of multiple sclerosis. 
No data are available. 

 
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Method of administration 
The film-coated tablets are for oral use. The tablets should be swallowed whole with some water. 
AUBAGIO can be taken with or without food. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
Patients with severe hepatic impairment (Child-Pugh class C). 
Pregnant women, or women of childbearing potential who are not using reliable contraception during 
treatment with teriflunomide and thereafter as long as its plasma levels are above 0.02 mg/l (see 
section 4.6). Pregnancy must be excluded before start of treatment (see section 4.6). 
 
Breast-feeding women (see section 4.6). 
 
Patients with severe immunodeficiency states, e.g. AIDS. 
 
Patients with significantly impaired bone marrow function or significant anaemia, leucopenia, 
neutropenia or thrombocytopenia. 
 
Patients with severe active infection until resolution (see section 4.4). 
 
Patients with severe renal impairment undergoing dialysis, because insufficient clinical experience is 
available in this patient group. 
 
Patients with severe hypoproteinaemia, e.g. in nephrotic syndrome. 
 
4.4 Special warnings and precautions for use 
 
Monitoring 
Before treatment 
Before starting treatment with teriflunomide the following should be assessed: 
• 
Blood pressure 
• 
Alanine aminotransferase (ALT/SGPT) 
• 
Complete blood cell count including differential white blood cell and platelet count. 
 
During treatment 
During treatment with teriflunomide the following should be monitored: 
• 
Blood pressure 
• 
Alanine aminotransferase (ALT/SGPT) 
• 
Complete blood cell counts should be performed based on signs and symptoms (e.g. 
infections) during t reatment. 
 
Accelerated elimination procedure 
Teriflunomide is eliminated slowly from the plasma. Without an accelerated elimination procedure, it 
takes an average of 8 months to reach plasma concentrations less than 0.02 mg/l, although due to 
individual variation in substance clearance it may take up to 2 years. An accelerated elimination 
procedure can be used at any time after discontinuation of teriflunomide (see section 4.6 and 5.2 for 
procedural details). 
 
Hepatic effects 
Elevations of liver enzymes have been observed in patients receiving teriflunomide (see section 4.8). 
These elevations occurred mostly within the first 6 months of treatment. 
Liver enzymes should be assessed before initiation of teriflunomide therapy - every two weeks during 
the first 6 months of treatment, and every 8 weeks thereafter or as indicated by clinical signs and 
symptoms such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice 
and/or dark urine. For ALT (SGPT) elevations between 2- and 3-fold the upper limit of normal, 
monitoring must be performed weekly. Teriflunomide therapy should be discontinued if liver injury is 
suspected; consider discontinuing teriflunomide therapy if elevated liver enzymes (greater than 3-fold 
ULN) are confirmed. Patients with pre- existing liver disease may be at increased risk of developing 
elevated liver enzymes when taking teriflunomide and should be closely monitored for signals of liver 
disease. 

 
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The medicinal product should be used with caution in patients who consume substantial quantities of 
alcohol. 
 
Since teriflunomide is highly protein bound and as the binding is dependent upon the concentrations of 
albumin, unbound plasma teriflunomide concentrations are expected to be increased in patients with 
hypoproteinaemia, e.g. in nephrotic syndrome. Teriflunomide should not be used in patients with 
conditions of severe hypoproteinaemia. 
 
Blood pressure 
Elevation of blood pressure may occur during treatment with teriflunomide (see section 4.8). Blood 
pressure must be checked before the start of teriflunomide treatment and periodically thereafter. Blood 
pressure elevation should be appropriately managed before and during treatment with teriflunomide. 
 
Infections 
Initiation of treatment with teriflunomide should be delayed in patients with severe active infection until 
resolution. 
In placebo-controlled studies, no increase in serious infections was observed with teriflunomide (see 
section 4.8). However, based on the immunomodulatory effect of AUBAGIO, if a patient develops a 
serious infection, suspending treatment with AUBAGIO should be considered and the benefits and 
risks should be reassessed prior to re-initiation of therapy. Due to the prolonged half-life, accelerated 
elimination with cholestyramine or charcoal may be considered. 
Patients receiving AUBAGIO should be instructed to report symptoms of infections to a physician. 
Patients with active acute or chronic infections should not start treatment with AUBAGIO until the 
infection(s) is resolved. 
The safety of AUBAGIO in individuals with latent tuberculosis infection is unknown, as tuberculosis 
screening was not systematically performed in clinical studies. For patients testing positive in 
tuberculosis screening, treat by standard medical practice prior to therapy with AUBAGIO. 
 
Respiratory reactions 
No cases of interstitial lung diseases (ILD) have been reported with teriflunomide in the clinical trials. 
However, ILD, which is a potentially fatal disorder, has been reported during treatment with leflunomide, 
the parent compound. ILD may occur acutely during therapy; the risk is increased in patients who had 
a history of ILD when treated with leflunomide. 
Pulmonary symptoms, such as persistent cough and dyspnoea, may be a reason for discontinuation of 
the therapy and for further investigation, as appropriate. 
 
Haematological  effects 
A mean decrease less than 15% from baseline affecting white blood cell count has been observed (see 
section 4.8). As a precaution, a recent complete blood cell count, including differential white blood cell 
count and platelets, should be available before the initiation of treatment with AUBAGIO and the 
complete blood cell count should be assessed during AUBAGIO therapy as indicated by clinical signs 
and symptoms (e.g., infections). 
 
In patients with pre-existing anaemia, leucopenia, and /or thrombocytopenia as well as in patients with 
impaired bone marrow function or those at risk of bone marrow suppression, the risk of haematological 
disorders is increased. If such effects occur, the accelerated elimination procedure (see above) to 
reduce plasma levels of teriflunomide should be considered. 
In cases of severe haematological reactions, including pancytopenia, AUBAGIO and any concomitant 
myelosuppressive treatment must be discontinued and a teriflunomide accelerated elimination 
procedure should be considered. 
 
Skin reactions 
Cases of severe skin reactions have been reported postmarketing (including Stevens-Johnson 
syndrome and toxic epidermal necrolysis). 
 
In patients treated with leflunomide, the parent compound, very rare cases of Drug Reaction with 
Eosinophilia and Systemic Symptoms (DRESS) have also been reported. 
 
In case of ulcerative stomatitis, teriflunomide administration should be discontinued. If skin and /or 
mucosal reactions are observed which raise the suspicion of severe generalised major skin reactions 
(Stevens-Johnson syndrome, or toxic epidermal necrolysis-Lyell’s syndrome), teriflunomide and any 

 
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other possibly associated treatment must be discontinued, and an accelerated procedure initiated 
immediately. In such cases patients should not be re-exposed to teriflunomide (see section 4.3). 
 
Peripheral neuropathy 
Cases of peripheral neuropathy have been reported in patients receiving AUBAGIO (see section 4.8). 
Most patients improved after discontinuation of AUBAGIO. However, there was a wide variability in 
final outcome, i.e. in some patients the neuropathy resolved and some patients had persistent 
symptoms. If a patient taking AUBAGIO develops a confirmed peripheral neuropathy, consider 
discontinuing AUBAGIO therapy and performing the accelerated elimination procedure. 
 
Vaccination 
Two clinical studies have shown that vaccinations to inactivated neoantigen (first vaccination), or recall 
antigen (reexposure) were safe and effective during AUBAGIO treatment. The use of live attenuated 
vaccines may carry a risk of infections and should therefore be avoided. 
 
Immunosuppressive or immunomodulating therapies 
As leflunomide is the parent compound of teriflunomide, co-administration of teriflunomide with 
leflunomide is not recommended. 
Co-administration with antineoplastic or immunosuppressive therapies used for treatment of MS has 
not been evaluated. Safety studies, in which teriflunomide was concomitantly administered with 
interferon beta or with glatiramer acetate for up to one year did not reveal any specific safety 
concerns, but a higher adverse reaction rate as compared to teriflunomide monotherapy was 
observed. The long term safety of these combinations in the treatment of multiple sclerosis has not 
been established. 
 
Switching to or from AUBAGIO 
Based on the clinical data related to concomitant administration of teriflunomide with interferon beta or 
with glatiramer acetate, no waiting period is required when initiating teriflunomide after interferon beta 
or glatiramer acetate or when starting interferon beta or glatiramer acetate, after teriflunomide. 
 
Due to the long half-life of natalizumab, concomitant exposure, and thus concomitant immune effects, 
could occur for up to 2-3 months following discontinuation of natalizumab if AUBAGIO was immediately 
started. Therefore, caution is required when switching patients from natalizumab to AUBAGIO. 
 
Based on the half-life of fingolimod, a 6-week interval without therapy is needed for clearance from the 
circulation and a 1 to 2 month period is needed for lymphocytes to return to normal range following 
discontinuation of fingolimod. Starting AUBAGIO during this interval will result in concomitant exposure 
to fingolimod. This may lead to an additive effect on the immune system and caution is, therefore, 
indicated. 
 
In MS patients, the median t1/2z was approximately 19 days after repeated doses of 14 mg. If a 
decision is made to stop treatment with AUBAGIO, during the interval of 5 half-lives (approximately 3.5 
months although may be longer in some patients), starting other therapies will result in concomitant 
exposure to AUBAGIO. This may lead to an additive effect on the immune system and caution is, 
therefore, indicated. 
 
Lactose 
Since AUBAGIO tablets contain lactose, patients with rare hereditary problems of galactose 
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption, should not take this 
medicinal product. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Pharmacokinetic interactions of other substances on teriflunomide 
The primary biotransformation pathway for teriflunomide is hydrolysis, with oxidation being a minor 
pathway. 
Potent cytochrome P450 (CYP) and transporter inducers: Co-administration of repeated doses (600 mg 
once daily for 22 days) of rifampicin (a CYP2B6, 2C8, 2C9, 2C19, 3A inducer), as well as an inducer of 
the efflux transporters P-glycoprotein [P-gp] and breast cancer resistant protein [BCRP] with 
teriflunomide (70 mg single dose) resulted in an approximately 40% decrease in teriflunomide 
exposure. Rifampicin and other known potent CYP and transporter inducers such as carbamazepine, 

 
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phenobarbital, phenytoin and St John’s Wort should be used with caution during the treatment with 
teriflunomide. 
 
Cholestyramine or activated charcoal 
It is recommended that patients receiving teriflunomide are not treated with cholestyramine or activated 
charcoal because this leads to a rapid and significant decrease in plasma concentration unless an 
accelerated elimination is desired. The mechanism is thought to be by interruption of enterohepatic 
recycling and/or gastrointestinal dialysis of teriflunomide. 
 
Pharmacokinetic interactions of teriflunomide on other substances 
Effect of teriflunomide on CYP2C8 substrate: repaglinide 
There was an increase in mean repaglinide Cmax and AUC (1.7- and 2.4-fold, respectively), following 
repeated doses of teriflunomide, suggesting that teriflunomide is an inhibitor of CYP2C8 in vivo. 
Therefore, medicinal products metabolised by CYP2C8, such as repaglinide, paclitaxel, pioglitazone 
or rosiglitazone, should be used with caution during treatment with teriflunomide. 
 
Effect of teriflunomide on oral contraceptive: 0.03 mg ethinylestradiol and 0.15 mg levonorgestrel 
There was an increase in mean ethinylestradiol Cmax and AUC0-24 (1.58- and 1.54-fold, 
respectively) and levonorgestrel Cmax and AUC0-24 (1.33- and 1.41-fold, respectively) following 
repeated doses of 
teriflunomide. While this interaction of teriflunomide is not expected to adversely impact the efficacy of 
oral contraceptives, it should be considered when selecting or adjusting oral contraceptive treatment 
used in combination with teriflunomide. 
 
Effect of teriflunomide on CYP1A2 substrate: caffeine 
Repeated doses of teriflunomide decreased mean Cmax and AUC of caffeine (CYP1A2 substrate) by 
18% and 55%, respectively, suggesting that teriflunomide may be a weak inducer of CYP1A2 in vivo. 
Therefore, medicinal products metabolised by CYP1A2 (such as duloxetin, alosetron, theophylline and 
tizanidine) should be used with caution during treatment with teriflunomide, as it could lead to the 
reduction of the efficacy of these products. 
 
Effect of teriflunomide on warfarin 
Repeated doses of teriflunomide had no effect on the pharmacokinetics of S-warfarin, indicating that 
teriflunomide is not an inhibitor or an inducer of CYP2C9. However, a 25% decrease in peak 
international normalised ratio (INR) was observed when teriflunomide was coadministered with 
warfarin as compared with warfarin alone. Therefore, when warfarin is co-administered with 
teriflunomide, close INR follow-up and monitoring is recommended. 
 
Effect of teriflunomide on organic anion transporter 3 (OAT3) substrates: 
There was an increase in mean cefaclor Cmax and AUC (1.43- and 1.54-fold, respectively), following 
repeated doses of teriflunomide, suggesting that teriflunomide is an inhibitor of OAT3 in vivo. 
Therefore, when teriflunomide is coadministered with substrates of OAT3, such as cefaclor, 
benzylpenicillin, ciprofloxacin, indometacin, ketoprofen, furosemide, cimetidine, methotrexate, 
zidovudine, caution is recommended. 
 
Effect of teriflunomide on BCRP and /or organic anion transporting polypeptide B1 and B3 (OATP1B1/B3) 
substrates: 
There was an increase in mean rosuvastatin Cmax and AUC (2.65- and 2.51-fold, respectively), 
following repeated doses of teriflunomide. However, there was no apparent impact of this increase in 
plasma rosuvastatin exposure on the HMG-CoA reductase activity. For rosuvastatin, a dose reduction 
by 50% is recommended for coadministration with teriflunomide. For other substrates of BCRP (e.g., 
methotrexate, topotecan, sulfasalazine, daunorubicin, doxorubicin) and the OATP family especially 
HMG-Co reductase inhibitors (e.g., simvastatin, atorvastatin, pravastatin, methotrexate, nateglinide, 
repaglinide, rifampicin) concomitant administration of teriflunomide should also be undertaken with 
caution. Patients should be closely monitored for signs and symptoms of excessive exposure to the 
medicinal products and reduction of the dose of these medicinal products should be considered. 
 
4.6 Fertility, pregnancy and lactation 
 
Use in males 
The risk of male-mediated embryo-foetal toxicity through teriflunomide treatment is considered low 
(see section 5.3). 

 
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Pregnancy 
There are limited amount of data from the use of teriflunomide in pregnant women. Studies in animals 
have shown reproductive toxicity (see section 5.3). 
Teriflunomide may cause serious birth defects when administered during pregnancy. Teriflunomide is 
contraindicated in pregnancy (see section 4.3). 
 
Women of childbearing potential have to use effective contraception during treatment and after 
treatment as long as teriflunomide plasma concentration is above 0.02 mg/l. During this period women 
should discuss any plans to stop or change contraception with the treating physician. 
 
The patient must be advised that if there is any delay in onset of menses or any other reason to 
suspect pregnancy, they must notify the physician immediately for pregnancy testing, and if positive, 
the physician and patient must discuss the risk to the pregnancy. It is possible that rapidly lowering 
the blood level of teriflunomide, by instituting the accelerated elimination procedure described below, 
at the first delay of menses, may decrease the risk to the foetus. 
For women receiving teriflunomide treatment, who wish to become pregnant, the medicine should be 
stopped and an accelerated elimination procedure is recommended in order to more rapidly achieve 
concentration below 0.02 mg/l (see below): 
 
If an accelerated elimination procedure is not used, teriflunomide plasma levels can be expected to be 
above 
0.02 mg/l for an average of 8 months, however, in some patients it may take up to 2 years to reach 
plasma concentration below 0.02 mg/l. Therefore, teriflunomide plasma concentrations should be 
measured before a woman begins to attempt to become pregnant. Once the teriflunomide plasma 
concentration is determined to be below 0.02 mg/l, the plasma concentration must be determined 
again after an interval of at least 14 days. If both plasma concentrations are below 0.02 mg/l, no risk 
to the foetus is to be expected. 
For further information on the sample testing please contact the Marketing Authorisation Holder or its 
local representative (see section 7). 
 
Accelerated elimination procedure 
 
After stopping treatment with teriflunomide: 
• 
cholestyramine 8 g is administered 3 times daily for a period of 11 days, or cholestyramine 4 
g three times a day can be used, if cholestyramine 8 g three times a day is not well 
tolerated, 
• 
alternatively, 50 g of activated powdered charcoal is administered every 12 hours for a 
period of 11 d ays. 
 
However, also following either of the accelerated elimination procedures, verification by 2 separate 
tests at an interval of at least 14 days and a waiting period of one-and-a-half months between the first 
occurrence of a plasma concentration below 0.02 mg/l and fertilisation is required. 
Both cholestyramine and activated powdered charcoal may influence the absorption of oestrogens and 
progestogens such that reliable contraception with oral contraceptives may not be guaranteed during 
the accelerated elimination procedure with cholestyramine or activated powdered charcoal. Use of 
alternative contraceptive methods is recommended. 
 
Breast-feeding 
Animal studies have shown excretion of teriflunomide in breast milk. Breast-feeding women must, 
therefore, not receive teriflunomide. 
 
Fertility 
Results of studies in animals have not shown an effect on fertility (see section 5.3). Although human 
data are lacking, no effect on male and female fertility is anticipated. 
 
4.7 Effects on ability to drive and use machines 
 
AUBAGIO has no or negligible influence on the ability to drive and use machines. 
In the case of adverse reactions such as dizziness, which has been reported with leflunomide, the 
parent compound, the patient’s ability to concentrate and to react properly may be impaired. In such 
cases, patients should refrain from driving cars and using machines. 

 
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complete hair loss reported) and occurred most often during the first 6 months and with resolution 
in 121 of 139 (87.1%) patients treated with teriflunomide 14 mg. Discontinuation because of 
alopecia was 1.3% in the teriflunomide 14 mg teriflunomide group, versus 0.1% in the placebo 
group. 
 
Hepatic effects 
During placebo-controlled studies the following was detected: 
 
ALT increase (based on laboratory data) according to baseline status - Safety population in 
placebo- controlled studies 
Placebo 
Teriflunomide 14 mg 
(N=997) 
(N=1002) 
>3 ULN 
66/994 (6.6%) 
80/999 (8.0%) 
>5 ULN 
37/994 (3.7%) 
31/999 (3.1%) 
>10 ULN 
16/994 (1.6%) 
9/999 (0.9%) 
>20 ULN 
4/994 (0.4%) 
3/999 (0.3%) 
ALT >3 ULN and TBILI >2 ULN 
5/994 (0.5%) 
3/999 (0.3%) 
 
Mild increases in transaminase, ALT below or equal to 3-fold ULN were more frequently seen in 
teriflunomide-treated groups as compared to placebo. The frequency of elevations above 3-fold 
ULN and higher was balanced across treatment groups. These elevations in transaminase 
occurred mostly within the first 6 months of treatment and were reversible after treatment 
cessation. The recovery time varied between months and years. 
 
Blood pressure effects 
In placebo-controlled studies the following was established: 
- 
systolic blood pressure was >140 mm Hg in 19.9% of patients receiving 14 mg/day 
teriflunomide as compared to 15.5% receiving placebo; 
- 
systolic blood pressure was >160 mm Hg in 3.8% of patients receiving 14 mg/day 
teriflunomide as compared to 2.0% receiving placebo; 
diastolic blood pressure was >90 mm Hg in 21.4% of patients receiving 14 mg/day teriflunomide 
as c ompared to 13.6% receiving placebo. 
 
Infections 
In placebo-controlled studies, no increase in serious infections was observed with teriflunomide 14 
mg (2.7%) as compared to placebo (2.2%). Serious opportunistic infections occurred in 0.2% of 
each group. Severe infections including sepsis, sometimes fatal have been reported 
postmarketing. 
 
Haematological effects 
A mean decrease affecting white blood cell (WBC) count (<15% from baseline levels, mainly 
neutrophil and lymphocytes decrease) was observed in placebo-controlled trials with AUBAGIO, 
although a greater decrease was observed in some patients. The decrease in mean count from 
baseline occurred during the first 6 weeks then stabilised over time while on-treatment but at 
decreased levels (less than a 15% decrease from baseline). The effect on red blood cell (RBC) 
(<2%) and platelet counts (<10%) was less pronounced. 
 
Peripheral neuropathy 
In placebo-controlled studies, peripheral neuropathy, including both polyneuropathy and 
mononeuropathy (e.g., carpal tunnel syndrome), was reported more frequently in patients taking 
teriflunomide than in patients taking placebo. In the pivotal, placebo-controlled studies, the 
incidence of peripheral neuropathy confirmed by nerve conduction studies was 1.9% (17 patients 
out of 898) on 14 mg of teriflunomide, compared with 0.4% (4 patients out of 898) on placebo. 
Treatment was discontinued in 5 patients with peripheral neuropathy on teriflunomide 14 mg. 
Recovery following treatment discontinuation was reported in 4 of these patients. 
 
Neoplasms benign, malignant and unspecified (incl. cysts and polyps) 
There does not appear to be an increased risk of malignancy with teriflunomide in the clinical trial 
experience. The risk of malignancy, particularly lymphoproliferative disorders, is increased with use 
of some other agents that affect the immune system (class effect). 
 

 
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Severe skin reactions 
Cases of severe skin reactions have been reported with teriflunomide post-marketing (see section 4.4). 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows 
continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are 
asked to report any suspected adverse reactions via the national reporting system listed in Appendix 
V. 
 
4.9 Overdose 
 
Symptoms 
There is no experience regarding teriflunomide overdose or intoxication in humans. Teriflunomide 70 
mg daily was administered up to 14 days in healthy subjects. The adverse reactions were consistent 
with the safety profile for teriflunomide in MS patients. 
 
Management 
In the event of relevant overdose or toxicity, cholestyramine or activated charcoal is recommended to 
accelerate elimination. The recommended elimination procedure is cholestyramine 8 g three times a 
day for 11 days. If this is not well tolerated, cholestyramine 4 g three times a day for 11 days can be 
used. 
Alternatively, when cholestyramine is not available, activated charcoal 50 g twice a day for 11 days may 
also be used. In addition, if required for tolerability reasons, administration of cholestyramine or 
activated charcoal does not need to occur on consecutive days (see section 5.2). 
 
 
5. 
PHARMACOLOGICAL   PROPERTIES 
 
5.1 
Pharmacodynamic properties 
 
Pharmacotherapeutic group: Selective immunosuppressants, ATC Code: L04AA31. 
Mechanism of action 
Teriflunomide is an immunomodulatory agent with anti-inflammatory properties that selectively and 
reversibly inhibits the mitochondrial enzyme dihydroorotate dehydrogenase (DHO-DH), required for the 
de novo pyrimidine synthesis. As a consequence teriflunomide reduces the proliferation of dividing 
cells that need de novo synthesis of pyrimidine to expand. The exact mechanism by which 
teriflunomide exerts its therapeutic effect in MS is not fully understood, but this is mediated by a 
reduced number of lymphocytes. 
 
Pharmacodynamic effects 
 
Immune system 
Effects on immune cell numbers in the blood: In the placebo-controlled studies, teriflunomide 14 mg once 
a day led to a mild mean reduction in lymphocyte count, of less than 0.3 x 109/l, which occurred over 
the first 3 months of treatment and levels were maintained until the end of the treatment. 
 
Potential to prolong the QT interval 
In a placebo-controlled thorough QT study performed in healthy subjects, teriflunomide at mean steady-
state concentrations did not show any potential for prolonging the QTcF interval compared with 
placebo: the largest time matched mean difference between teriflunomide and placebo was 3.45 ms 
with the upper bound of the 90% CI being 6.45 ms. 
 
Effect on renal tubular functions 
In the placebo-controlled studies, mean decreases in serum uric acid at a range of 20 to 30% were 
observed in patients treated with teriflunomide compared to placebo. Mean decrease in serum 
phosphorus was around 10% in the teriflunomide group compared to placebo. These effects are 
considered to be related to increase in renal tubular excretion and not related to changes in 
glomerular functions. 
 
Clinical efficacy and safety 
 

 
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The efficacy of AUBAGIO was demonstrated in two placebo-controlled studies, the TEMSO and the 
TOWER study, that evaluated once daily doses of teriflunomide 7 mg and 14 mg in patients with RMS. 
 
A total of 1088 patients with RMS were randomised in TEMSO to receive 7 mg (n=366) or 14 mg 
(n=359) of teriflunomide or placebo (n= 363) for 108 weeks duration. All patients had a definite 
diagnosis of MS (based on McDonald criteria (2001)), exhibited a relapsing clinical course, with or 
without progression, and experienced at least 1 relapse over the year preceding the trial or at least 2 
relapses over the 2 years preceding the trial. At entry, patients had an Expanded Disability Status 
Scale (EDSS) score ≤5.5. 
The mean age of the study population was 37.9 years. The majority of patients had relapsing–remitting 
multiple sclerosis (91.5%), but a subgroup of patients had secondary progressive (4.7%) or progressive 
relapsing multiple sclerosis (3.9%). The mean number of relapses within the year before study inclusion 
was 
1.4 with 36.2% of patients having gadolinium-enhancing lesions at baseline. The median EDSS score 
at baseline was 2.50; 249 patients (22.9%) had an EDSS score › 3.5 at baseline. The mean duration 
of disease, since first symptoms, was 8.7 years. A majority of patients (73%) had not received disease-
modifying therapy during the 2 years before study entry. The study results are shown in Table 1. 
 
A total of 1169 patients with RMS were randomised in TOWER to receive 7 mg (n=408) or 14 mg 
(n=372) of teriflunomide or placebo (n= 389) for a variable treatment duration ending at 48 weeks after 
last patient randomised. All patients had a definite diagnosis of MS (based on McDonald criteria 
(2005)), exhibited a relapsing clinical course, with or without progression, and experienced at least 1 
relapse over the year preceding the trial or at least 2 relapses over the 2 years preceding the trial. At 
entry, patients had an Expanded Disability Status Scale (EDSS) score ≤5.5. 
The mean age of the study population was 37.9 years. The majority of patients had relapsing–remitting 
multiple sclerosis (97.5%), but a subgroup of patients had secondary progressive (0.8%) or progressive 
relapsing multiple sclerosis (1.7%). The mean number of relapses within the year before study inclusion 
was 
1.4. Gadolinium-enhancing lesions at baseline: no data. The median EDSS score at baseline was 2.50; 
298 patients (25.5%) had an EDSS score › 3.5 at baseline. The mean duration of disease, since first 
symptoms, was 8.0 years. A majority of patients (67.2%) had not received disease-modifying therapy 
during the 2 years before study entry. The study results are shown in Table 1. 
 
Table 1 - Main Results (for the approved dose, ITT population) 
 
N 
Clinical Outcomes 
Annualised relapse rate 
Risk difference (CI95%) 
Relapse-free week 108 
Hazard ratio (CI95%) 
3-month Sustained 
Disability Progression 
week 108 
Hazard ratio 
(CI95%) 6-month 
Sustained Disability 
Progression week 108 
Hazard ratio 
(CI95%) MRI endpoints    
Change in BOD week 10  
(1) 
8 
Change relative to 
placebo 
Mean Number of Gd- 
enhancing lesions at week 
108 
TEMSO-study 
Teriflunomide 
    Placebo 
14 mg 
358 
         363 
 
0.37 
0.54 
-0.17 (-0.26, -0.08) 
56.5% 
45.6% 
0.72, (0.58, 0.89) 
20.2% 
          27.3% 
0.70 (0.51, 0.97) 
 
13.8% 
18.7% 
 
0.75 (0.50, 1.11) 
 
0.72 
2.21 
67% 
0.38 
            1.18 
TOWER-study 
Teriflunomide 
Placebo 
14 mg 
 
370 
388 
0.32 
0.50 
-0.18 (-0.27, -0.09) 
57.1% 
46.8% 
0.63, (0.50, 0.79) 
15.8% 
19.7% 
0.68 (0.47, 1.00) 
11.7% 
11.9% 
0.84 (0.53, 1.33) 
Not measured 

 
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Change relative to 
placebo 
(CI95%) 
Number of unique active 
lesions /scan 
Change relative to 
placebo 
(CI95%) 
-0.80 (-1.20, -0.39) 
0.75 
           2.46 
69%, (59%; 77%) 
 
   p<0.0001    p<0.001  p<0.01  p<0.05 compared to placebo 
(1) BOD: burden of disease: total lesion volume (T2 and T1 hypointense) in ml 
 
Efficacy in patients with high disease activity: 
A consistent treatment effect on relapses and time to 3-month sustained disability progression in a 
subgroup of patients in TEMSO (n= 127) with high disease activity was observed. Due to the design of 
the study, high disease activity was defined as 2 or more relapses in one year, and with one or more Gd-
enhancing lesion on brain MRI. No similar subgroup analysis was performed in TOWER as no MRI data 
were obtained. 
No data are available in patients who have failed to respond to a full and adequate course (normally at 
least one year of treatment) of beta-interferon, having had at least 1 relapse in the previous year while 
on therapy, and at least 9 T2-hyperintense lesions in cranial MRI or at least 1 Gd-enhancing lesion, or 
patients having an unchanged or increased relapse rate in the prior year as compared to the previous 
2 years. 
 
TOPIC was a double-blind, placebo-controlled study that evaluated once daily doses of teriflunomide 7 
mg and 14 mg for up to 108 weeks in patients with first clinical demyelinating event (mean age 32.1 
years). The primary endpoint was time to a second clinical episode (relapse). A total of 618 patients 
were randomized to receive 7 mg (n=205) or 14 mg (n=216) of teriflunomide or placebo (n=197). The 
risk of a second clinical attack over 2 years was 35.9% in the placebo group and 24.0% in the 
teriflunomide 14 mg treatment group (hazard ratio: 0.57, 95% confidence interval: 0.38 to 0.87, 
p=0.0087). The results from the TOPIC study confirmed the efficacy of teriflunomide in RRMS 
(including early RRMS with first clinical demyelinating event and MRI lesions disseminated in time and 
space). 
 
Teriflunomide effectiveness was compared to that of a subcutaneous interferon beta-1a (at the 
recommended dose of 44 µg three times a week) in 324 randomised patients in a study (TENERE) 
with minimum treatment duration of 48 weeks (maximum 114 weeks). The risk of failure (confirmed 
relapse or permanent treatment discontinuation whichever came first) was the primary endpoint. The 
number of patients with permanent treatment discontinuation in the teriflunomide 14 mg group was 22 
out of 111 (19.8%), the reasons being adverse events (10.8%), lack of efficacy (3.6%), other reason 
(4.5%) and lost to follow-up (0.9%). The number of patients with permanent treatment discontinuation 
in the subcutaneous interferon beta-1a group was 30 out of 104 (28 .8%), the reasons being adverse 
events (21.2%), lack of efficacy (1.9%), other reason (4.8%) and poor compliance to protocol (1%). 
Teriflunomide 14 mg/day was not superior to interferon beta- 1a on the primary endpoint: the estimated 
percentage of patients with treatment failure at 96 weeks using the Kaplan-Meier method was 41.1% 
versus 44.4% (teriflunomide 14 mg versus interferon beta-1a group, p=0.595). 
 
Paediatric population 
The European Medicines Agency has waived the obligation to submit the results of studies with 
AUBAGIO in children from birth to less than 10 years in treatment of multiple sclerosis (see section 4.2 
for information on paediatric use). 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
AUBAGIO in one or more subsets of the paediatric population in multiple sclerosis (see section 4.2 for 
information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Absorption 
Median time to reach maximum plasma concentrations occurs between 1 to 4 hours post-dose 
following repeated oral administration of teriflunomide, with high bioavailability (approximately 100%). 
 
Food does not have a clinically relevant effect on teriflunomide pharmacokinetics. 

 
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From the mean predicted pharmacokinetic parameters calculated from the population pharmacokinetic 
(PopPK) analysis using data from healthy volunteers and MS patients, there is a slow approach to 
steady- state concentration (i.e., approximately 100 days (3.5 months) to attain 95% of steady-state 
concentrations) and the estimated AUC accumulation ratio is approximately 34-fold. 
 
Distribution 
Teriflunomide is extensively bound to plasma protein (>99%), probably albumin and is mainly 
distributed in plasma. The volume of distribution is 11 l after a single intravenous (IV) administration. 
However, this is most likely an underestimation since extensive organ distribution was observed in 
rats. 
 
Biotransformation 
Teriflunomide is moderately metabolised and is the only component detected in plasma. The primary 
biotransformation pathway for teriflunomide is hydrolysis with oxidation being a minor pathway. 
Secondary pathways involve oxidation, N-acetylation and sulfate conjugation. 
 
Elimination 
Teriflunomide is excreted in the gastrointestinal tract mainly through the bile as unchanged medicinal 
product and most likely by direct secretion. Teriflunomide is a substrate of the efflux transporter BCRP, 
which could be involved in direct secretion. Over 21 days, 60.1% of the administered dose is excreted 
via feces (37.5%) and urine (22.6%). After the rapid elimination procedure with cholestyramine, an 
additional 23.1% was recovered (mostly in feces). Based on individual prediction of pharmacokinetic 
parameters using the PopPK model of teriflunomide in healthy volunteers and MS patients, median 
t1/2z was approximately   19 days after repeated doses of 14 mg. After a single IV administration, the 
total body clearance of teriflunomide is 30.5 ml/h. 
 
Accelerated Elimination Procedure: Cholestyramine and activated charcoal 
The elimination of teriflunomide from the circulation can be accelerated by administration of 
cholestyramine or activated charcoal, presumably by interrupting the reabsorption processes at the 
intestinal level. 
Teriflunomide concentrations measured during an 11-day procedure to accelerate teriflunomide 
elimination with either 8 g cholestyramine three times a day, 4 g cholestyramine three times a day or 
50 g activated charcoal twice a day following cessation of teriflunomide treatment have shown that 
these regimens were effective in accelerating teriflunomide elimination, leading to more than 98% 
decrease in teriflunomide plasma concentrations, with cholestyramine being faster than charcoal. 
Following discontinuation of teriflunomide and the administration of cholestyramine 8 g three times a 
day, the plasma concentration of teriflunomide is reduced 52% at the end of day 1, 91% at the end of 
day 3, 99.2% at the end of day 7, and 99.9% at the completion of day 11. The choice between the 3 
elimination procedures should depend on the patient’s tolerability. If cholestyramine 8 g three times a 
day is not well-tolerated, cholestyramine 4 g three times a day can be used. Alternatively, activated 
charcoal may also be used (the 11 days do not need to be consecutive unless there is a need to lower 
teriflunomide plasma concentration rapidly). 
 
Linearity/non-linearity 
Systemic exposure increases in a dose proportional manner after oral administration teriflunomide from 
7 to 14 mg. 
 
Characteristics in specific groups of patients 
Gender, Elderly, Paediatric patients 
Several sources of intrinsic variability were identified in healthy subjects and MS patients based on the 
PopPK analysis: age, body weight, gender, race, and albumin and bilirubin levels. Nevertheless, their 
impact remains limited (31%). 
 
Hepatic impairment 
Mild and moderate hepatic impairment had no impact on the pharmacokinetic of teriflunomide. 
Therefore no dose adjustment is anticipated in mild and moderate hepatic-impaired patients. 
However, teriflunomide is contraindicated in patients with severe hepatic impairment (see sections 4.2 
and 4.3). 
 
Renal impairment 

 
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Severe renal impairment had no impact on the pharmacokinetic of teriflunomide. Therefore no dose 
adjustment is anticipated in mild, moderate and severe renal-impaired patients. 
 
5.3 Preclinical safety data 
 
Repeated oral administration of teriflunomide to mice, rats and dogs for up to 3, 6, and 12 months, 
respectively, revealed that the major targets of toxicity were the bone marrow, lymphoid organs, oral 
cavity/ gastro intestinal tract, reproductive organs, and pancreas. Evidence of an oxidative effect on 
red blood cells was also observed. Anemia, decreased platelet counts and effects on the immune 
system, including leukopenia, lymphopenia and secondary infections, were related to the effects on the 
bone marrow and/or lymphoid organs. The majority of effects reflect the basic mode of action of the 
compound (inhibition of dividing cells). Animals are more sensitive to the pharmacology, and therefore 
toxicity, of teriflunomide than humans. As a result, toxicity in animals was found at exposures 
equivalent or below human therapeutic levels. 
 
Teriflunomide was not mutagenic in vitro or clastogenic in vivo. Clastogenicity observed in vitro was 
considered to be an indirect effect related to nucleotide pool imbalance resulting from the 
pharmacology of DHO-DH inhibition. The minor metabolite TFMA (4-trifluoromethylaniline) caused 
mutagenicity and clastogenicity in vitro but not in vivo. 
 
No evidence of carcinogenicity was observed in rats and mice. 
 
Fertility was unaffected in rats despite adverse effects of teriflunomide on male reproductive organs, 
including reduced sperm count. There were no external malformations in the offspring of male rats 
administered teriflunomide prior to mating with untreated female rats. Teriflunomide was embryotoxic 
and teratogenic in rats and rabbits at doses in the human therapeutic range. Adverse effects on the 
offspring were also seen when teriflunomide was administered to pregnant rats during gestation and 
lactation. The risk of male-mediated embryo-fetal toxicity through teriflunomide treatment is considered 
low. The estimated female plasma exposure via the semen of a treated patient is expected to be 100 
times lower than the plasma exposure after 14 mg of oral teriflunomide. 
 
6. 
PHARMACEUTICAL   PARTICULARS 
 
6.1 
List of excipients 
 
Tablet core 
lactose monohydrate  
maize starch 
microcrystalline  cellulose 
sodium starch glycolate (Type A)  
hydroxypropylcellulose  
magnesium stearate 
 
Tablet coating  
hypromellose  
 titanium dioxide (E171)  
talc 
macrogol 8000 
indigo carmine aluminum lake (E132)  
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
133/Protocol MA30005, Version 5 
 
Aluminium-aluminium blisters inserted in wallets (14 and 28 film-coated tablets) and packed in cartons 
containing 14, 28, 84 (3 wallets of 28), and 98 (7 wallets of 14) film-coated tablets. 
Each wallet is placed in a protective sleeve. 
 
Aluminium-aluminium perforated unit-dose blister packs in cartons containing 10x1 film-coated tablets. 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. 
MARKETING  AUTHORISATION  HOLDER 
 
sanofi-aventis groupe 
54, rue La Boétie 
F-75008 Paris  
France 
 
8. 
MARKETING  AUTHORISATION  NUMBER(S) 
 
EU/1/13/838/001 
EU/1/13/838/002 
EU/1/13/838/003 
EU/1/13/838/004 
EU/1/13/838/005 
 
 
9. 
 
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 26 August 2013 
 
 
10.  
DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency  http://www.ema.europa.eu.. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
134/Protocol MA30005, Version 5 
SmPC for Copaxone 
 
 
Copaxone 20mg/ml, Solution For Injection, Pre-Filled Syringe 
 
Summary of Product Characteristics Updated 21-Apr-2016 | Teva Pharmaceuticals Ltd 
1. 
Name of the medicinal product 
Copaxone ® 20 mg/ml Solution for Injection, Pre-filled Syringe 
 
2. 
Qualitative and quantitative composition 
1 ml of solution for injection contains 20 mg glatiramer acetate *, equivalent to 18 mg of glatiramer 
base per pre-filled syringe 
* The average molecular weight of glatiramer acetate mixture is in the range of 5,000-9,000 daltons. 
Due to its compositional complexity, no specified polypeptide can be fully characterized in terms of 
amino acid sequence, although the final glatiramer acetate composition is not entirely random. 
For full list of excipients, see section 6.1. 
 
3. 
Pharmaceutical form 
Solution for Injection, Pre-filled 
Syringe Clear solution free of 
visible particles 
The solution for injection has a pH of 5.5 - 7.0 and an osmolarity of about 265 mOsmol/L. 
 
4. 
Clinical particulars 
4.1 Therapeutic  indications 
 
Copaxone is indicated for the treatment of relapsing forms of multiple sclerosis (MS) (see section 
5.1 for important information on the population for which efficacy has been established). 
Copaxone is not indicated in primary or secondary progressive MS. 
4.2 Posology and method of administration Posology 
The recommended dosage in adults is 20 mg of glatiramer acetate (one pre-filled syringe), 
administered as a subcutaneous injection once daily. 
At the present time, it is not known for how long the patient should be treated. 
A decision concerning long term treatment should be made on an individual basis by the treating 
physician. 
Paediatric population 
Children and adolescents: No prospective, randomized, controlled clinical trials or pharmacokinetic 
studies have been conducted in children or adolescents. However, limited published data suggest 
that the safety profile in adolescents from 12 to 18 years of age receiving Copaxone 20 mg 
subcutaneously every day is similar to that seen in adults. 
There is not enough information available on the use of Copaxone in children below 12 years of age 
to make any recommendation for its use. Therefore, Copaxone should not be used in this 
population. 
Elderly patients 
Copaxone has not been specifically studied in the elderly. 
Patients with renal impairment 
Copaxone has not been specifically studied in patients with renal impairment (see section 4.4). 
Method of administration 
Patients should be instructed in self-injection techniques and should be supervised by a health-care 
professional the first time they self-inject and for 30 minutes after. 
A different site for injection should be chosen every day, so this will reduce the chances of any 
irritation or pain at the site of the injection. Sites for self-injection include the abdomen, arms, hips 
and thighs. 
 
4.3 Contraindications 
 
Copaxone is contraindicated under the following conditions: 
• Hypersensitivity to glatiramer acetate or mannitol. 
• Pregnant women 
 
4.4 Special warnings and precautions for use 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
135/Protocol MA30005, Version 5 
 
 
Copaxone should only be administered subcutaneously. Copaxone should not be administered by 
intravenous or intramuscular routes. 
The initiation of Copaxone treatment should be supervised by a neurologist or a physician 
experienced in the treatment of MS. 
The treating physician should explain to the patient that a reaction associated with at least one of 
the following symptoms may occur within minutes of a Copaxone injection: vasodilatation 
(flushing), chest pain, dyspnoea, palpitations or tachycardia. The majority of these symptoms is 
short-lived and resolves spontaneously without any sequelae. Should a severe adverse event 
occur, the patient must immediately stop Copaxone treatment and contact his/her physician or any 
emergency doctor. Symptomatic treatment may be instituted at the discretion of the physician. 
There is no evidence to suggest that any particular patient groups are at special risk from these 
reactions. Nevertheless, caution should be exercised when administering Copaxone to patients 
with pre-existing cardiac disorders. These patients should be followed up regularly during 
treatment. 
Convulsions and/or anaphylactoid or allergic reactions have been reported rarely. 
Serious hypersensitivity reactions (e.g. bronchospasm, anaphylaxis or urticaria) may rarely occur. If 
reactions are severe, appropriate treatment should be instituted and Copaxone should be 
discontinued. 
Glatiramer acetate-reactive antibodies were detected in patients' sera during daily chronic treatment 
with Copaxone. Maximal levels were attained after average treatment duration of 3-4 months and, 
thereafter, declined and stabilised at a level slightly higher than baseline. 
There is no evidence to suggest that these glatiramer acetate-reactive antibodies are neutralising or 
that their formation is likely to affect the clinical efficacy of Copaxone. 
In patients with renal impairment, renal function should be monitored while they are treated with 
Copaxone. Whilst there is no evidence of glomerular deposition of immune complexes in patients, 
the possibility cannot be excluded. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Interaction between Copaxone and other medicinal products have not been formally evaluated. 
Observations from existing clinical trials and post-marketing experience do not suggest any 
significant interactions of Copaxone with therapies commonly used in MS patients, including the 
concurrent use of corticosteroids for up to 28 days. 
In vitro work suggests that glatiramer acetate in blood is highly bound to plasma proteins but that it is 
not displaced by, and does not itself displace, phenytoin or carbamazepine. Nevertheless, as 
Copaxone has, theoretically, the potential to affect the distribution of protein bound substances, 
concomitant use of such medicinal products should be monitored carefully. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
There are no adequate data from the use of glatiramer acetate in pregnant women. Animal studies 
are insufficient with respect to effects on pregnancy, embryonal/foetal development, parturition 
and postnatal development (see section 5.3). The potential risk for humans is unknown. Copaxone 
is contraindicated during pregnancy. 
A contraceptive cover should be considered whilst using this medicinal product. 
Breastfeeding 
Data regarding excretion of glatiramer acetate, its metabolites or antibodies in human milk are 
unavailable. Caution should be exercised when Copaxone is administered to a nursing mother. 
The relative risk and benefit to the mother and child should be taken into consideration. 
 
4.7 Effects on ability to drive and use machines 
 
No studies on the effects on the ability to drive and use machines have been performed. 
 
4.8 Undesirable effects 
 
In all clinical trials, injection-site reactions were seen to be the most frequent adverse reactions and 
were reported by the majority of patients receiving Copaxone. In controlled studies, the proportion 
of patients reporting these reactions, at least once, was higher following treatment with Copaxone 
(70%) than placebo injections (37%). The most commonly reported injection-site reactions, in 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
136/Protocol MA30005, Version 5 
clinical trials and in post marketing experience, were erythema, pain, mass, pruritus, oedema, 
inflammation and hypersensitivity, and rare occurrences of lipoatrophy and skin necrosis. 
A reaction, associated with at least one or more of the following symptoms, has been described as 
the Immediate Post-Injection Reaction: vasodilatation(flushing), chest pain, dyspnoea, palpitation 
or tachycardia. This reaction may 
 
 
 
occur within minutes of a Copaxone injection. At least one component of this Immediate Post-
Injection Reaction was reported at least once by 31% of patients receiving Copaxone compared to 
13% of patients receiving placebo. 
All adverse reactions, which were more frequently reported in Copaxone vs. placebo-treated patients, 
are presented in the table below. This data was derived from four pivotal, double-blind, placebo-
controlled clinical trials with a total of 512 patients treated with Copaxone and 509 patients treated 
with placebo for up to 36 months. Three trials in relapsing-remitting MS (RRMS) included a total of 
269 patients treated with Copaxone and 271 patients treated with placebo for up to 35 months. The 
fourth trial in patients who have experienced a first clinical episode and were determined to be at 
high risk of developing clinically definite MS included 243 patients treated with Copaxone and 238 
patients treated with placebo for up to 36 months. 
 
System Organ Class 
(SOC) 
Very Common 
(≥1/10) 
Common (≥1/100 to <1/10) Uncommon (≥1/1,000 to 
<1/100) 
Infections and infestations 
Infection, 
Influenza 
Bronchitis,  Gastroenteritis, 
Herpes Simplex, Otitis 
Media, Rhinitis, Tooth 
Abscess, Vaginal 
Candidiasis* 
Abscess, Cellulitis, Furuncle, 
Herpes Zoster, Pyelonephritis 
Neoplasms benign, 
malignant and unspecified 
(incl cysts and polyps) 
Benign Neoplasm Of Skin, 
Neoplasm 
Skin Cancer 
Blood and lymphatic system 
disorders 
Lymphadenopathy* 
Leukocytosis,  Leukopenia, 
Splenomegaly 
Thrombocytopenia, Lymphocyte  
Morphology Abnormal 
Immune system disorders 
Hypersensitivity 
Endocrine disorders 
Goitre,  Hyperthyroidism 
Metabolism and nutrition 
disorders 
Anorexia, Weight 
Increased* 
Alcohol Intolerance, Gout, 
Hyperlipidaemia,  Blood Sodium 
Increased, Serum Ferritin 
Decreased 
Psychiatric disorders 
Anxiety*, 
Depression 
Nervousness 
Abnormal Dreams, Confusional 
State, Euphoric Mood, 
Hallucination, Hostility, Mania, 
Personality Disorder, Suicide 
Attempt 
Nervous system disorders 
Headache, 
Dysgeusia,  Hypertonia, 
Migraine, Speech Disorder, 
Syncope, Tremor* 
Carpal Tunnel Syndrome, 
Cognitive Disorder, Convulsion,  
Dysgraphia, Dyslexia, Dystonia, 
Motor Dysfunction,  Myoclonus, 
Neuritis,  Neuromuscular 
Blockade,  Nystagmus, Paralysis, 
Peroneal Nerve Palsy, Stupor, 
Visual Field Defect 
Eye disorders 
Diplopia, Eye Disorder* 
Cataract, Corneal Lesion, Dry Eye, 
Eye Haemorrhage, Eyelid Ptosis, 
Mydriasis, Optic Atrophy 
Ear and labyrinth disorders 
Ear Disorder 
Cardiac disorders 
Palpitations*,  Tachycardia* 
Extrasystoles, Sinus 
Bradycardia,  Tachycardia 
Paroxysmal 
Vascular disorders 
Vasodilatation* 
Varicose Vein 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
137/Protocol MA30005, Version 5 
System Organ Class 
(SOC) 
Very Common 
(≥1/10) 
Common (≥1/100 to <1/10) Uncommon (≥1/1,000 to 
<1/100) 
Respiratory, thoracic and 
mediastinal disorders 
Dyspnoea* 
Cough, Rhinitis Seasonal 
Apnoea, Epistaxis, 
Hyperventilation, 
Laryngospasm, Lung 
Disorder, Choking 
Sensation 
Gastrointestinal  disorders 
Nausea* 
Anorectal Disorder, 
Constipation, Dental Caries, 
Dyspepsia,  Dysphagia, 
Faecal Incontinence, 
Vomiting* 
Colitis, Colonic Polyp, 
Enterocolitis,  Eructation, 
Oesophageal Ulcer, 
Periodontitis Rectal 
Haemorrhage,  Salivary Gland 
Enlargement 
Hepatobiliary  disorders 
Liver Function Test 
Abnormal 
Cholelithiasis, 
Hepatomegaly 
Skin and subcutaneous 
tissue disorders 
Rash* 
Ecchymosis,  Hyperhidrosis, 
Pruritus, Skin Disorder*, 
Urticaria 
Angioedema,  Dermatitis 
Contact, Erythema Nodosum, 
Skin Nodule 
Musculoskeletal and 
connective tissue disorders 
Arthralgia, Back 
Pain* 
Neck Pain 
Arthritis, Bursitis, Flank Pain, 
Muscle Atrophy, 
Osteoarthritis 
Renal and urinary disorders 
Micturition Urgency, 
Pollakiuria, Urinary 
Retention 
Haematuria, Nephrolithiasis,  
Urinary Tract Disorder, Urine 
Abnormality 
Pregnancy, puerperium and 
perinatal Conditions 
Abortion 
Reproductive system and 
breast disorders 
Breast Engorgement, Erectile 
Dysfunction, Pelvic Prolapse, 
Priapism, Prostatic Disorder, 
Smear Cervix Abnormal, 
Testicular Disorder, Vaginal 
Haemorrhage,  Vulvovaginal 
Disorder 
General disorders and 
administration site 
conditions 
Asthenia, 
Chest Pain*, 
Injection Site 
Reactions*§, 
Pain* 
Chills*, Face Oedema*, 
Injection Site Atrophy♣, 
Local Reaction*, Oedema 
Peripheral, Oedema, 
Pyrexia 
Cyst, Hangover, Hypothermia,  
Immediate Post-Injection  
Reaction, Inflammation, Injection 
Site Necrosis, Mucous 
Membrane Disorder 
Injury, poisoning and 
procedural  complications 
Post Vaccination Syndrome 
* More than 2% (>2/100) higher incidence in the Copaxone treatment group than in the placebo 
group. Adverse reaction without the * symbol represents a difference of less than or equal to 2%. 
§ The term 'Injection site reactions' (various kinds) comprises all adverse events occurring at the 
injection site excluding injection site atrophy and injection site necrosis, which are presented 
separately within the table. 
♣ Includes terms which relate to localized lipoatrophy at the injection sites. 
In the fourth trial noted above, an open-label treatment phase followed the placebo-controlled 
period (see section 5.1). No change in the known risk profile of Copaxone was observed during 
the open-label follow-up period of up to 5 years. 
The following adverse reaction reports were collected from MS patients treated with Copaxone in 
uncontrolled clinical trials and from post-marketing experience with Copaxone: hypersensitivity 
reactions (including rare occurrence of anaphylaxis, >1/10000, < 1/1000. 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: 
www.mhra.gov.uk/yellowcard. 
 
4.9 Overdose 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
138/Protocol MA30005, Version 5 
A few cases of overdose with Copaxone (up to 300 mg glatiramer acetate) have been reported. 
These cases were not associated with any adverse reactions other than those mentioned in section 
4.8. 
In case of overdose, patients should be monitored and the appropriate symptomatic and supportive 
therapy instituted. 
 
5. 
Pharmacological properties 
5.1 Pharmacodynamic  properties 
 
Pharmacotherapeutic group: Antineoplastic and immunomodulating agents, Other 
Immunostimulants ATC code: L03AX13 
The mechanism(s) by which glatiramer acetate exerts its effects in patients with MS is (are) not fully 
elucidated. However, it is thought to act by modifying immune processes that are currently 
believed to be responsible for the pathogenesis of MS. This hypothesis is supported by findings of 
studies that have been carried out to explore the pathogenesis of experimental allergic 
encephalomyelitis (EAE), a condition induced in several animal species through immunisation 
against central nervous system derived material containing myelin and often used as an 
experimental animal model of MS. Studies in animals and in MS patients suggest that upon its 
administration, glatiramer acetate- specific suppressor T cells are induced and activated in the 
periphery. 
 
RRMS: 
A total of 269 patients have been treated with Copaxone in three controlled trials. The first was a 
two-year study involving 50 patients (Copaxone n=25, placebo n=25) who were diagnosed with 
relapsing-remitting MS by the then- applicable standard criteria, and who had at least two attacks 
of neurological dysfunction (exacerbations) during the preceding two years. The second study 
applied the same inclusion criteria and included 251 patients treated for up to 35 months 
(Copaxone n=125, placebo n=126). The third study was a nine-month study involving 239 patients 
(Copaxone n=119, placebo n=120) where inclusion criteria were similar to those in the first and 
second studies with the additional criterion that patients had to have at least one gadolinium-
enhancing lesion on the screening MRI. 
In clinical trials in MS patients receiving Copaxone, a significant reduction in the number of relapses, 
compared with placebo, was seen. 
In the largest controlled study, the relapse rate was reduced by 32% from 1.98 under placebo to 1.34 
under glatiramer acetate. 
Exposure data are available for up to twelve years in 103 patients treated with Copaxone. 
Copaxone has also demonstrated beneficial effects over placebo on MRI parameters relevant to 
relapsing-remitting MS. 
Copaxone had, however, no beneficial effect on progression of disability in relapsing-remitting 
MS patients. There is no evidence that Copaxone treatment has an effect on relapse duration 
or severity. 
There is currently no evidence for the use of Copaxone in patients with primary or secondary progressive 
disease. 
 
Single clinical event suggestive of MS: 
One placebo-controlled study involving 481 patients (Copaxone n=243, placebo n=238) was 
performed in patients with a well-defined, single, unifocal neurological manifestation and MRI 
features highly suggestive of MS (at least two cerebral lesions on the T2-weighted MRI above 6 
mm diameter). Any disease other than MS that could better explain signs and symptoms of the 
patient had to be excluded. The placebo-controlled period was followed by an open label 
treatment: Patients who either presented with MS symptoms or were asymptomatic for three years, 
whichever came first, were assigned to active drug treatment in an open-label phase for an 
additional period of two years, not exceeding a maximal total treatment duration of 5 years. Of the 
243 patients initially randomized to Copaxone, 198 continued Copaxone treatment in the open-
label phase. Of the 238 patients initially randomized to placebo, 211 switched to Copaxone 
treatment in the open-label phase. 
During the placebo-controlled period of up to three years, Copaxone delayed the progression from 
the first clinical event to clinically definite multiple sclerosis (CDMS) according to Poser criteria in a 
statistically significant and clinically meaningful manner, corresponding to a risk reduction of 45% 
(Hazard Ratio = 0.55; 95% CI [0.40; 0.77], 
p-value=0.0005). The proportion of patients who converted to CDMS was 43% for the placebo 
group and 25% in the Copaxone group. 

 
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The favourable effect of treatment with Copaxone over placebo was also demonstrated in two 
secondary MRI endpoints, i.e. number of new T2 lesions and T2 lesion volume. 
Post-hoc subgroup analyses were performed in patients with various baseline characteristics to 
identify a population at high risk to develop the second attack. For subjects with baseline MRI with at 
least one T1 Gd-enhancing lesion and 9 or more T2 lesions, conversion to CDMS was evident for 
50% of the placebo subjects vs. 28% of the Copaxone subjects in 2.4 years. For subjects with 9 or 
more T2 lesions at baseline, conversion to CDMS was evident for 45% of the placebo subjects vs. 
26% on Copaxone in 2.4 years. However, the impact of early treatment with Copaxone on the long 
term evolution of the disease is unknown even in these high-risk subgroups as the study was mainly 
designed to assess the time to the second event. In any case, treatment should only be considered 
for patients classified at high risk. 
 
The effect shown in the placebo-controlled phase was sustained in the long-term follow-up period of 
up to 5 years. The time progression from the first clinical event to CDMS was prolonged with 
earlier Copaxone treatment as compared to delayed treatment, reflecting a 41% risk reduction 
with earlier versus later treatment (Hazard Ratio = 0.59; 95% CI [0.44; 0.80], p-value=0.0005). 
The proportion of subjects in the Delayed Start group who progressed was higher (49.6%) 
compared to those in the Early Start group (32.9%). 
A consistent effect in favour of early treatment over delayed treatment across time was shown for 
the annualized number of lesions over the entire study period in new T1 Gd-enhancing lesions 
(reduced by 54%; p<0.0001), new T2 lesions (reduced by 42%; p<0.0001) and new T1 
hypointense lesions (reduced by 52%; p<0.0001). An effect in reductions in favour of early versus 
delayed treatment was also observed for the total number of new T1 Gd- enhancing lesions 
(reduced by 46%; p=0.001), T1 Gd-enhancing lesion volume (a mean difference of -0.06 ml; 
p<0.001), as well as the total number of new T1 hypointense lesions (reduced by 46%; p<0.001) 
measured over the entire study period. 
No appreciable differences between the Early Start and Delayed Start cohorts were observed for 
either hypointense T1 lesion volume or brain atrophy over 5 years. However, analysis of brain 
atrophy at last observed value (adjusted to treatment exposure) showed a reduction in favour of 
early treatment with GA (the mean difference of percent change in brain volume was 0.28%; 
p=0.0209). 
 
5.2 Pharmacokinetic  properties 
 
Pharmacokinetic studies in patients have not been performed. In vitro data and limited data from 
healthy volunteers indicate that with subcutaneous administration of glatiramer acetate, the active 
substance is readily absorbed and that a large part of the dose is rapidly degraded to smaller 
fragments already in subcutaneous tissue. 
 
5.3 Preclinical safety data 
 
Preclinical data reveal no special hazard for humans based on studies of safety pharmacology, 
repeated dose toxicity, toxicity to reproduction, genotoxicity or carcinogenicity, beyond the 
information included in other sections of the    SPC. Due to the lack of pharmacokinetic data in 
humans, margins of exposure between humans and animals can not be established. 
Immune complex deposition in the glomeruli of the kidney was reported in a small number of rats and 
monkeys treated for at least 6 months. In a 2 years rat study, no indication of immune complex 
deposition in the glomeruli of the kidney was seen. 
Anaphylaxis after administration to sensitised animals (guinea pigs or mice) was reported. The 
relevance of these data for humans is unknown. 
Toxicity at the injection site was a common finding after repeated administration in animals. 
 
6. 
Pharmaceutical particulars 
6.1 List of excipients 
 
Mannitol 
Water for Injections 
 
6.2 Incompatibilities 
 
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products. 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
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6.3 Shelf life 
 
2 years 
 
6.4 Special precautions for storage 
 
Keep the pre-filled syringes in the outer carton, in order to protect 
from light. Store in a refrigerator (2°C – 8°C). 
Do not freeze. 
If the pre-filled syringes cannot be stored in a refrigerator, they can be stored between 15°C and 
25°C, once for up to one month. 
After this one month period, if the Copaxone 20 mg/ml pre-filled syringes have not been used 
and are still in their original packaging, they must be returned to storage in a refrigerator (2°C to 
8°C). 
 
6.5 Nature and contents of container 
 
A pre-filled syringe containing Copaxone solution for injection consists of a 1 ml long colourless type 
I glass syringe barrel with staked needle, a polypropylene (optional polystyrene) plunger rod, a 
rubber plunger stopper and a needle shield. 
Copaxone is available in packs containing 7, 28 or 30 pre-filled syringes of 1 ml solution for injection 
or a multipack containing 90 (3 packs of 30) pre-filled syringes of 1 ml solution for injection. 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
For single use only. Any unused product or waste material must be discarded. 
 
7. 
Marketing authorisation holder 
Teva Pharmaceuticals Ltd.  
Ridings Point 
Whistler Drive  
Castleford  
West Yorkshire 
WF10 5HX United Kingdom 
 
8. 
Marketing authorisation number(s) 
PL 10921/0023 
 
9. 
Date of first authorisation/renewal of the authorisation 
Date of first authorization: 7 April 2003 
 
10. Date of revision of the text 
17/03/2016 
 
Company Contact Details 
Teva Pharmaceuticals Ltd 
Address 
Teva UK Limited, Field House, Station Approach, Harlow, Essex, CM20 2FB, UK 
 
Fax 
+44 (0) 207 4507349 
 
Telephone 
+44 (0) 207 5407117 
 
Medical Information e-mail 
medinfo@tevauk.com 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
141/Protocol MA30005, Version 5 
SmPC for Gilenya 
 
 
1. 
NAME OF THE MEDICINAL PRODUCT 
 
GILENYA 0.5 mg hard capsules 
 
 
2. 
QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each capsule contains 0.5 mg fingolimod (as hydrochloride). For 
the full list of excipients, see section 6.1. 
 
3. 
PHARMACEUTICAL FORM 
 
Hard capsule 
 
Capsule of 16 mm with bright yellow opaque cap and white opaque body; imprint with black ink, “FTY0.5 
mg” on cap and two radial bands imprinted on the body with yellow ink. 
 
 
4. 
CLINICAL PARTICULARS 
 
4.1 
Therapeutic indications 
 
Gilenya is indicated as single disease modifying therapy in highly active relapsing remitting multiple 
sclerosis for the following adult patient groups: 
 
- 
Patients with highly active disease despite a full and adequate course of treatment with at least 
one disease modifying therapy (for exceptions and information about washout periods see 
sections 4.4 and 5.1). 
or 
- 
Patients with rapidly evolving severe relapsing remitting multiple sclerosis defined by 2 or more 
disabling relapses in one year, and with 1 or more Gadolinium enhancing lesions on brain MRI or 
a significant increase in T2 lesion load as compared to a previous recent MRI. 
 
4.2 Posology and method of administration 
The treatment should be initiated and supervised by a physician experienced in multiple sclerosis. Posology 
The recommended dose of Gilenya is one 0.5 mg capsule taken orally once daily. Gilenya can be 
taken with or without food. 
 
The same first dose monitoring as for treatment initiation is recommended when treatment is interrupted for: 
• 
1 day or more during the first 2 weeks of treatment. 
• 
more than 7 days during weeks 3 and 4 of treatment. 
• 
more than 2 weeks after one month of treatment. 
If the treatment interruption is of shorter duration than the above, the treatment should be continued with 
the next dose as planned (see section 4.4). 
 
Special populations 
Elderly population 
Gilenya should be used with caution in patients aged 65 years and over due to insufficient data on safety 
and efficacy (see section 5.2). 
 
Renal impairment 
Gilenya was not studied in patients with renal impairment in the multiple sclerosis pivotal studies. Based 
on clinical pharmacology studies, no dose adjustments are needed in patients with mild to severe renal 
impairment. 
 
Hepatic impairment 

 
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Gilenya must not be used in patients with severe hepatic impairment (Child-Pugh class C) (see section 
4.3). Although no dose adjustments are needed in patients with mild or moderate hepatic impairment, 
caution should be exercised when initiating treatment in these patients (see sections 4.4 and 5.2). 
 
Diabetic patients 
Gilenya has not been studied in multiple sclerosis patients with concomitant diabetes mellitus.  Gilenya 
should be used with caution in these patients due to a potential increase in the risk of macular oedema 
(see sections 4.4 and 4.8). Regular ophthalmological examinations should be conducted in these patients 
to detect macular oedema. 
 
Paediatric population 
The safety and efficacy of Gilenya in children aged 0 to 18 years have not yet been established. Currently 
available data are described in section 5.2 but no recommendation on a posology can be made. 
 
4.3 Contraindications 
 
Known immunodeficiency syndrome. 
Patients with increased risk for opportunistic infections, including immunocompromised patients 
(including those currently receiving immunosuppressive therapies or those immunocompromised by prior 
therapies). 
Severe active infections, active chronic infections (hepatitis, tuberculosis). Known 
active malignancies. 
Severe liver impairment (Child-Pugh class C). 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
4.4 Special warnings and precautions for use 
 
Bradyarrhythmia 
Initiation of Gilenya treatment results in a transient decrease in heart rate and may also be associated with 
atrioventricular conduction delays, including the occurrence of isolated reports of transient, spontaneously 
resolving complete AV block (see sections 4.8 and 5.1). 
 
After the first dose, the decline in heart rate starts within one hour, and is maximal within 6 hours. This 
post-dose effect persists over the following days, although usually to a milder extent, and usually abates 
over the next weeks. With continued administration, the average heart rate returns towards baseline within 
one month. However individual patients may not return to baseline heart rate by the end of the first month. 
Conduction abnormalities were typically transient and asymptomatic. They usually did not require 
treatment and resolved within the first 24 hours on treatment. If necessary, the decrease in heart rate 
induced by fingolimod can be reversed by parenteral doses of atropine or isoprenaline. 
 
All patients should have an ECG and blood pressure measurement performed prior to and 6 hours after 
the first dose of Gilenya. All patients should be monitored for a period of 6 hours for signs and symptoms 
of bradycardia with hourly heart rate and blood pressure measurement. Continuous (real time) ECG 
monitoring during this 6 hour period is recommended. 
 
Should post-dose bradyarrhythmia-related symptoms occur, appropriate clinical management should be 
initiated and monitoring should be continued until the symptoms have resolved. Should a patient require 
pharmacological intervention during the first-dose monitoring, overnight monitoring in a medical facility 
should be instituted and the first-dose monitoring should be repeated after the second dose of Gilenya. 
 
If the heart rate at 6 hours is the lowest since the first dose was administered (suggesting that the 
maximum pharmacodynamic effect on the heart may not yet be manifest), monitoring should be extended 
by at least 2 hours and until heart rate increases again. Additionally, if after 6 hours, the heart rate is <45 
bpm, or the ECG shows new onset second degree or higher grade AV block or a QTc interval ≥500 msec, 
extended monitoring (at least overnight monitoring), should be performed, and until the findings have 
resolved. The occurrence at any time of third degree AV block should also lead to extended monitoring (at 
least overnight monitoring). 
 
Very rare cases of T-wave inversion have been reported in patients treated with fingolimod. In case of T-
wave inversion, the prescriber should ensure that there are no associated myocardial ischaemia signs or 
symptoms. If myocardial ischaemia is suspected, it is recommended to seek advice from a cardiologist. 
 

 
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Due to the risk of serious rhythm disturbances, Gilenya should not be used in patients with second 
degree Mobitz type II or higher AV block, sick-sinus syndrome, or sino-atrial heart block, a history of 
symptomatic bradycardia or recurrent syncope, or in patients with significant QT prolongation 
(QTc>470msec (female) or >450msec (male)). Since significant bradycardia may be poorly tolerated in 
patients with known ischaemic heart disease (including angina pectoris), cerebrovascular disease, 
history of myocardial infarction, congestive heart failure, history of cardiac arrest, uncontrolled 
hypertension or severe sleep apnoea, Gilenya should not be used in these patients. In such patients, 
treatment with Gilenya should be considered only if the anticipated benefits outweigh the potential risks. 
If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in 
order to determine the most appropriate monitoring, at least overnight extended monitoring is 
recommended for treatment initiation (see also section 4.5). 
 
Gilenya has not been studied in patients with arrhythmias requiring treatment with class Ia (e.g. quinidine, 
disopyramide) or class III (e.g. amiodarone, sotalol) antiarrhythmic medicinal products. Class Ia and class 
III antiarrhythmic medicinal products have been associated with cases of torsades de pointes in patients 
with bradycardia. Since initiation of Gilenya treatment results in decreased heart rate, Gilenya should not 
be used concomitantly with these medicinal products. 
 
Experience with Gilenya is limited in patients receiving concurrent therapy with beta blockers, heart- rate-
lowering calcium channel blockers (such as verapamil, diltiazem or ivabradine), or other substances 
which may decrease heart rate (e.g. digoxin, anticholinesteratic agents or pilocarpine). 
Since the initiation of Gilenya treatment is also associated with slowing of the heart rate (see also section 
4.8, Bradyarrhythmia), concomitant use of these substances during Gilenya initiation may be associated 
with severe bradycardia and heart block. Because of the potential additive effect on heart rate treatment 
with Gilenya should not be initiated in patients who are concurrently treated with these substances (see 
also section 4.5). In such patients, treatment with Gilenya should be considered only if the anticipated 
benefits outweigh the potential risks. If treatment with Gilenya is considered, advice from a cardiologist 
should be sought regarding the switch to non heart-rate lowering medicinal products prior to initiation of 
treatment. If the heart-rate-lowering medication cannot be stopped, cardiologist’s advice should be sought 
to determine appropriate first dose monitoring, at least overnight extended monitoring is recommended 
(see also section 4.5). 
 
The effects on heart rate and atrioventricular conduction may recur on re-introduction of Gilenya 
treatment depending on duration of the interruption and time since start of Gilenya treatment. The same 
first dose monitoring as for treatment initiation is recommended when treatment is interrupted for: 
• 
1 day or more during the first 2 weeks of treatment. 
• 
more than 7 days during weeks 3 and 4 of treatment. 
• 
more than 2 weeks after one month of treatment. 
If the treatment interruption is of shorter duration than the above, the treatment should be continued with 
the next dose as planned. 
 
QT interval 
In a thorough QT interval study of doses of 1.25 or 2.5 mg fingolimod at steady-state, when a negative 
chronotropic effect of fingolimod was still present, fingolimod treatment resulted in a prolongation of QTcI, 
with the upper limit of the 90% CI ≤13.0 ms. There is no dose- or exposure-response relationship of 
fingolimod and QTcI prolongation. There is no consistent signal of increased incidence of QTcI outliers, 
either absolute or change from baseline, associated with fingolimod treatment. 
 
The clinical relevance of this finding is unknown. In the multiple sclerosis studies, clinically relevant effects 
on prolongation of the QTc-interval have not been observed but patients at risk for QT prolongation were 
not included in clinical studies. 
 
Medicinal products that may prolong QTc interval are best avoided in patients with relevant risk factors, 
for example, hypokalaemia or congenital QT prolongation. 
 
Infections 
A core pharmacodynamic effect of Gilenya is a dose-dependent reduction of the peripheral 
lymphocyte count to 20-30% of baseline values. This is due to the reversible sequestration of 
lymphocytes in lymphoid tissues (see section 5.1). 
 
Before initiating treatment with Gilenya, a recent complete blood count (CBC) (i.e. within 6 months or 
after discontinuation of prior therapy) should be available. Assessments of CBC are also recommended 

 
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periodically during treatment, at month 3 and at least yearly thereafter, and in case of signs of infection. 
Absolute lymphocyte count <0.2x109/l, if confirmed, should lead to treatment interruption until recovery, 
because in clinical studies, fingolimod treatment was interrupted in patients with absolute lymphocyte 
count <0.2x109/l. 
 
Initiation of treatment with Gilenya should be delayed in patients with severe active infection until 
resolution. 
 
Patients need to be assessed for their immunity to varicella (chickenpox) prior to Gilenya treatment. It is 
recommended that patients without a health care professional confirmed history of chickenpox or 
documentation of a full course of vaccination with varicella vaccine undergo antibody testing to varicella 
zoster virus (VZV) before initiating Gilenya therapy. A full course of vaccination for antibody-negative 
patients with varicella vaccine is recommended prior to commencing treatment  with Gilenya (see section 
4.8). Initiation of treatment with Gilenya should be postponed for 1 month to allow full effect of vaccination 
to occur. 
 
The immune system effects of Gilenya may increase the risk of infections, including opportunistic 
infections (see section 4.8). Effective diagnostic and therapeutic strategies should be employed in patients 
with symptoms of infection while on therapy. During treatment, patients receiving Gilenya should be 
instructed to report symptoms of infection to their physician. 
 
Suspension of Gilenya should be considered if a patient develops a serious infection and consideration 
of benefit-risk should be undertaken prior to re-initiation of therapy. 
 
Isolated cases of cryptococcal meningitis (a fungal infection) have been reported in the post- marketing 
setting (see section 4.8). Patients with symptoms and signs consistent with cryptococcal meningitis (e.g. 
headache accompanied by mental changes such as confusion, hallucinations, and/or personality 
changes) should undergo prompt diagnostic evaluation. If cryptococcal meningitis is diagnosed, 
fingolimod should be suspended and appropriate treatment should be initiated. A multidisciplinary 
consultation (i.e. infectious disease specialist) should be undertaken if re-initiation of fingolimod is 
warranted. 
 
Progressive multifocal leukoencephalopathy (PML) has been reported under fingolimod treatment since 
marketing authorisation (see section 4.8). PML is an opportunistic infection caused by John Cunningham 
virus (JCV), which may be fatal or result in severe disability. PML can only occur in the presence of a JCV 
infection. If JCV testing is undertaken, it should be considered that the influence of lymphopenia on the 
accuracy of anti-JCV antibody testing has not been studied in fingolimod-treated patients. It should also 
be noted that a negative anti-JCV antibody test does not preclude the possibility of subsequent JCV 
infection. Before initiating treatment with fingolimod, a baseline MRI should be available (usually within 3 
months) as a reference. During routine MRI (in accordance with national and local recommendations), 
physicians should pay attention to PML suggestive lesions. 
MRI may be considered as part of increased vigilance in patients considered at increased risk of PML. If 
PML is suspected, MRI should be performed immediately for diagnostic purposes and treatment with 
fingolimod should be suspended until PML has been excluded. 
 
Elimination of fingolimod following discontinuation of therapy may take up to two months and 
vigilance for infection should therefore be continued throughout this period. Patients should be 
instructed to report symptoms of infection up to 2 months after discontinuation of fingolimod. 
 
Macular oedema 
Macular oedema with or without visual symptoms has been reported in 0.5% of patients treated with 
fingolimod 0.5 mg, occurring predominantly in the first 3-4 months of therapy (see section 4.8). An 
ophthalmological evaluation is therefore recommended at 3-4 months after treatment initiation. If patients 
report visual disturbances at any time while on therapy, evaluation of the fundus, including the macula, 
should be carried out. 
 
Patients with history of uveitis and patients with diabetes mellitus are at increased risk of macular oedema 
(see section 4.8). Gilenya has not been studied in multiple sclerosis patients with concomitant diabetes 
mellitus. It is recommended that multiple sclerosis patients with diabetes mellitus or a history of uveitis 
undergo an ophthalmological evaluation prior to initiating therapy and have follow-up evaluations while 
receiving therapy. 
 

 
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Continuation of Gilenya in patients with macular oedema has not been evaluated. It is recommended that 
Gilenya be discontinued if a patient develops macular oedema. A decision on whether or not Gilenya 
therapy should be re-initiated after resolution of macular oedema needs to take into account the potential 
benefits and risks for the individual patient. 
 
Liver function 
Increased hepatic enzymes, in particular alanine aminotransaminase (ALT) but also gamma 
glutamyltransferase (GGT) and aspartate transaminase (AST) have been reported in multiple sclerosis 
patients treated with Gilenya. In clinical trials, elevations 3-fold the upper limit of normal (ULN) or greater in 
ALT occurred in 8.0% of patients treated with fingolimod 0.5 mg compared to 1.9% of placebo patients. 
Elevations 5-fold the ULN occurred in 1.8% of patients on fingolimod and 0.9% of patients on placebo. In 
clinical trials, fingolimod was discontinued if the elevation exceeded 5 times the ULN. Recurrence of liver 
transaminase elevations occurred with rechallenge in some patients, supporting a relationship to 
fingolimod. In clinical studies, transaminase elevations occurred at any time during treatment although the 
majority occurred within the first 12 months. Serum transaminase levels returned to normal within 
approximately 2 months after discontinuation of fingolimod. 
 
Gilenya has not been studied in patients with severe pre-existing hepatic injury (Child-Pugh class C) and 
should not be used in these patients (see section 4.3). 
 
Due to the immunosuppressive properties of fingolimod, initiation of treatment should be delayed in 
patients with active viral hepatitis until resolution. 
 
Recent (i.e. within last 6 months) transaminase and bilirubin levels should be available before initiation of 
treatment with Gilenya. In the absence of clinical symptoms, liver transaminases should be monitored at 
Months 1, 3, 6, 9 and 12 on therapy and periodically thereafter. If liver transaminases rise above 5 times 
the ULN, more frequent monitoring should be instituted, including serum bilirubin and alkaline 
phosphatase (ALP) measurement. With repeated confirmation of liver transaminases above 5 times the 
ULN, treatment with Gilenya should be interrupted and only re-commenced once liver transaminase 
values have normalised. 
 
Patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, 
abdominal pain, fatigue, anorexia, or jaundice and/or dark urine, should have liver enzymes checked and 
Gilenya should be discontinued if significant liver injury is confirmed (for example liver transaminase levels 
greater than 5-fold the ULN and/or serum bilirubin elevations). Resumption of therapy will be dependent 
on whether or not another cause of liver injury is determined and on the benefits to patient of resuming 
therapy versus the risks of recurrence of liver dysfunction. 
 
Although there are no data to establish that patients with pre-existing liver disease are at increased risk 
of developing elevated liver function tests when taking Gilenya, caution in the use of Gilenya should be 
exercised in patients with a history of significant liver disease. 
 
Interference with serological testing 
Since fingolimod reduces blood lymphocyte counts via re-distribution in secondary lymphoid organs, 
peripheral blood lymphocyte counts cannot be utilised to evaluate the lymphocyte subset status of a 
patient treated with Gilenya. Laboratory tests involving the use of circulating mononuclear cells require 
larger blood volumes due to reduction in the number of circulating lymphocytes. 
 
Blood pressure effects 
Patients with hypertension uncontrolled by medication were excluded from participation in premarketing 
clinical trials and special care is indicated if patients with uncontrolled hypertension are treated with 
Gilenya. 
 
In MS clinical trials, patients treated with fingolimod 0.5 mg had an average increase of approximately 3 
mmHg in systolic pressure, and approximately 1 mmHg in diastolic pressure, first detected approximately 
1 month after treatment initiation, and persisting with continued treatment. In the two-year placebo-
controlled study, hypertension was reported as an adverse event in 6.5% of patients on fingolimod 0.5 
mg and in 3.3% of patients on placebo. Therefore, blood pressure should be regularly monitored during 
treatment with Gilenya. 
 
Respiratory effects 

 
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Minor dose-dependent reductions in values for forced expiratory volume (FEV1) and diffusion capacity for 
carbon monoxide (DLCO) were observed with Gilenya treatment starting at Month 1 and remaining stable 
thereafter. Gilenya should be used with caution in patients with severe respiratory disease, pulmonary 
fibrosis and chronic obstructive pulmonary disease (see also section 4.8). 
 
Posterior reversible encephalopathy syndrome 
Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported at the 0.5 mg 
dose in clinical trials and in the post-marketing setting (see section 4.8). Symptoms reported included 
sudden onset of severe headache, nausea, vomiting, altered mental status, visual disturbances and 
seizure. Symptoms of PRES are usually reversible but may evolve into ischaemic stroke or cerebral 
haemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is 
suspected, Gilenya should be discontinued. 
 
Prior treatment with immunosuppressive or immunomodulatory therapies 
There have been no studies performed to evaluate the efficacy and safety of Gilenya when switching 
patients from teriflunomide, dimethyl fumarate or alemtuzumab treatment to Gilenya. When switching 
patients from another disease modifying therapy to Gilenya, the half-life and mode of action of the other 
therapy must be considered in order to avoid an additive immune effect whilst at the same time minimising 
the risk of disease reactivation. A CBC is recommended prior to initiating Gilenya to ensure that immune 
effects of the previous therapy (i.e. cytopenia) have resolved. 
 
Gilenya can generally be started immediately after discontinuation of interferon or glatiramer acetate. 
 
For dimethyl fumarate, the washout period should be sufficient for CBC to recover before treatment with 
Gilenya is started. 
 
Due to the long half-life of natalizumab, elimination usually takes up to 2-3 months following 
discontinuation. Teriflunomide is also eliminated slowly from the plasma. Without an accelerated 
elimination procedure, clearance of teriflunomide from plasma can take from several months up to 2 
years. An accelerated elimination procedure as defined in the teriflunomide summary of product 
characteristics is recommended or alternatively washout period should not be shorter than 3.5 months. 
Caution regarding potential concomitant immune effects is required when switching patients from 
natalizumab or teriflunomide to Gilenya. 
 
Alemtuzumab has profound and prolonged immunosuppressive effects. As the actual duration of these 
effects is unknown, initiating treatment with Gilenya after alemtuzumab is not recommended unless the 
benefits of such treatment clearly outweigh the risks for the individual patient. 
 
A decision to use prolonged concomitant treatment with corticosteroids should be taken after careful 
consideration. 
 
Co-administration with potent CYP450 inducers 
The combination of fingolimod with potent CYP450 inducers should be used with caution. Concomitant 
administration with St John’s wort is not recommended (see section 4.5). 
 
Basal cell carcinoma 
Basal cell carcinoma (BCC) has been reported in patients receiving Gilenya (see section 4.8). Vigilance 
for skin lesions is warranted and a medical evaluation of the skin is recommended at initiation, after at 
least one year and then at least yearly taking into consideration clinical judgement. The patient should be 
referred to a dermatologist in case suspicious lesions are detected. 
 
Stopping therapy 
If a decision is made to stop treatment with Gilenya a 6 week interval without therapy is needed, based 
on half-life, to clear fingolimod from the circulation (see section 5.2). Lymphocyte counts progressively 
return to normal range within 1-2 months of stopping therapy (see section 5.1). Starting other therapies 
during this interval will result in concomitant exposure to fingolimod. Use of immunosuppressants soon 
after the discontinuation of Gilenya may lead to an additive effect on the immune system and caution is 
therefore indicated. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Anti-neoplastic, immunomodulatory or immunosuppressive therapies 

 
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Anti-neoplastic, immunomodulatory or immunosuppressive therapies should not be co-administered due to 
the risk of additive immune system effects (see sections 4.3 and 4.4). 
 
Caution should also be exercised when switching patients from long-acting therapies with immune effects 
such as natalizumab, teriflunomide or mitoxantrone (see section 4.4). In multiple sclerosis clinical studies 
the concomitant treatment of relapses with a short course of corticosteroids was not associated with an 
increased rate of infection. 
 
Vaccination 
During and for up to two months after treatment with Gilenya vaccination may be less effective. The use of 
live attenuated vaccines may carry a risk of infections and should therefore be avoided (see sections 4.4 
and 4.8). 
 
Bradycardia-inducing substances 
Fingolimod has been studied in combination with atenolol and diltiazem. When fingolimod was used with 
atenolol in an interaction study in healthy volunteers, there was an additional 15% reduction of heart rate 
at fingolimod treatment initiation, an effect not seen with diltiazem. Treatment with Gilenya should not be 
initiated in patients receiving beta blockers, or other substances which may decrease heart rate, such as 
class Ia and III antiarrhythmics, calcium channel blockers (such as ivabradine, verapamil or diltiazem), 
digoxin, anticholinesteratic agents or pilocarpine because of the potential additive effects on heart rate 
(see sections 4.4 and 4.8). If treatment with Gilenya is considered in  such patients, advice from a 
cardiologist should be sought regarding the switch to non heart-rate lowering medicinal products or 
appropriate monitoring for treatment initiation, at least overnight monitoring is recommended, if the heart-
rate-lowering medication cannot be stopped. 
 
Pharmacokinetic interactions of other substances on fingolimod 
Fingolimod is metabolised mainly by CYP4F2. Other enzymes like CYP3A4 may also contribute to its 
metabolism, notably in the case of strong induction of CYP3A4. Potent inhibitors of transporter proteins 
are not expected to influence fingolimod disposition. Co-administration of fingolimod with ketoconazole 
resulted in a 1.7-fold increase in fingolimod and fingolimod phosphate exposure (AUC) by inhibition of 
CYP4F2. Caution should be exercised with substances that may inhibit CYP3A4 (protease inhibitors, 
azole antifungals, some macrolides such as clarithromycin or telithromycin). 
 
Co-administration of carbamazepine 600 mg twice daily at steady-state and a single dose of fingolimod 2 
mg reduced the AUC of fingolimod and its metabolite by approximately 40%. Other strong CYP3A4 
enzyme inducers, for example rifampicin, phenobarbital, phenytoin, efavirenz and St. John’s Wort, may 
reduce the AUC of fingolimod and its metabolite at least to this extent. As this could potentially impair the 
efficacy, their co-administration should be used with caution. 
Concomitant administration with St. John’s Wort is however not recommended (see section 4.4). 
 
Pharmacokinetic interactions of fingolimod on other substances 
Fingolimod is unlikely to interact with substances mainly cleared by the CYP450 enzymes or by 
substrates of the main transporter proteins. 
 
Co-administration of fingolimod with ciclosporin did not elicit any change in the ciclosporin or fingolimod 
exposure. Therefore, fingolimod is not expected to alter the pharmacokinetics of medicinal products that 
are CYP3A4 substrates. 
 
Co-administration of fingolimod with oral contraceptives (ethinylestradiol and levonorgestrel) did not elicit 
any change in oral contraceptive exposure. No interaction studies have been performed with oral 
contraceptives containing other progestagens, however an effect of fingolimod on their exposure is not 
expected.  
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential / Contraception in females 
Before initiation of Gilenya treatment, women of childbearing potential should be counselled regarding the 
potential for serious risk to the foetus and the need for effective contraception during treatment with 
Gilenya. Since it takes approximately two months to eliminate fingolimod from the body on stopping 
treatment (see section 4.4), the potential risk to the foetus may persist and contraception should be 
continued during that period. 
 
Pregnancy 

 
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Before initiation of treatment in women of childbearing potential a negative pregnancy test result needs to 
be available. While on treatment, women should not become pregnant and active contraception is 
recommended. If a woman becomes pregnant while taking Gilenya, discontinuation of Gilenya is 
recommended. 
 
Animal studies have shown reproductive toxicity including foetal loss and organ defects, notably 
persistent truncus arteriosus and ventricular septal defect (see section 5.3). Furthermore, the receptor 
affected by fingolimod (sphingosine 1-phosphate receptor) is known to be involved in vascular formation 
during embryogenesis. There are very limited data from the use of fingolimod in pregnant women. 
There are no data on the effects of fingolimod on labour and delivery. 
Breast-feeding 
Fingolimod is excreted in milk of treated animals during lactation at concentrations 2-3-fold higher 
than that found in maternal plasma (see section 5.3). Due to the potential for serious adverse reactions to 
fingolimod in nursing infants, women receiving Gilenya should not breastfeed. 
 
Fertility 
Data from preclinical studies do not suggest that fingolimod would be associated with an increased risk of 
reduced fertility (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
Gilenya has no or negligible influence on the ability to drive and use machines. 
 
However, dizziness or drowsiness may occasionally occur when initiating therapy with Gilenya. On 
initiation of Gilenya treatment it is recommended that patients be observed for a period of 6 hours (see 
section 4.4, Bradyarrhythmia). 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
The safety population of Gilenya is derived from two Phase III placebo-controlled clinical studies and 
one Phase III active-controlled clinical study in patients with relapsing remitting multiple sclerosis. It 
includes a total of 2,431 patients on Gilenya (0.5 or 1.25 mg). Study D2301 (FREEDOMS) was a 2- year 
placebo-controlled clinical study in 854 patients treated with fingolimod (placebo: 418). Study D2309 
(FREEDOMS II) was a 2-year placebo-controlled clinical study in 728 multiple sclerosis patients treated 
with fingolimod (placebo: 355). In the pooled data from these two studies the most serious adverse 
reactions on Gilenya 0.5 mg were infections, macular oedema and transient atrioventricular block at 
treatment initiation. The most frequent adverse reactions (incidence ≥10%) 
on Gilenya 0.5 mg were influenza, sinusitis, headache, diarrhoea, back pain, hepatic enzyme increased 
and cough. The most frequent adverse reaction reported for Gilenya 0.5 mg leading to treatment 
interruption was ALT elevations (2.2%). The adverse reactions in Study D2302 (TRANSFORMS), a 1-
year study in 849 patients treated with fingolimod which used interferon beta-1a as comparator, were 
generally similar to placebo-controlled studies, taking into account the differences in study duration. 
 
Adverse reactions reported with Gilenya 0.5 mg in Studies D2301 (FREEDOMS) and D2309 
(FREEDOMS II) are shown below. Frequencies were defined using the following convention: very 
common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to 
<1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Tabulated 
list of adverse reactions 
Infections and infestations 
Very common: 
Influenza 
Sinusitis 
Common: 
Herpes viral infections 
Bronchitis Tinea 
versicolor 
Uncommon: 
Pneumonia 
Not known**: 
Progressive multifocal leukoencephalopathy (PML) 
Cryptococcal infections 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) 

 
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Common: 
Basal cell carcinoma 
Rare***: 
Lymphoma 
Blood and lymphatic system disorders 
Common: 
Lymphopenia 
Leucopenia 
Not known***: 
Peripheral oedema 
Immune system disorders 
Not known***: 
Hypersensitivity reactions, including rash, urticaria and angioedema 
upon treatment initiation 
Psychiatric disorders 
Common: 
Depression 
Uncommon: 
Depressed mood 
Nervous system disorders 
Very common: 
Headache 
Common: 
Dizziness 
Migraine 
Rare*: 
Posterior reversible encephalopathy syndrome (PRES) 
Eye disorders 
Common: 
Vision blurred 
Uncommon: 
Macular oedema 
Cardiac disorders 
Common: 
Bradycardia 
Atrioventricular block 
Very rare***: 
T-wave inversion 
Vascular disorders 
Common: 
Hypertension 
Respiratory, thoracic and mediastinal disorders 
Very common: 
Cough 
Common: 
Dyspnoea 
Gastrointestinal disorders 
Very common: 
Diarrhoea 
Uncommon***: 
Nausea 
Skin and subcutaneous tissue disorders 
Common: 
Eczema 
Alopecia 
Pruritus 
Musculoskeletal and connective tissue disorders 
Very common: 
Back pain 
General disorders and administration site conditions 
Common: 
Asthenia 
Investigations 
Very common: 
Hepatic enzyme increased (increased ALT, Gamma 
glutamyltransferase, Aspartate transaminase) 
Common: 
Blood triglycerides increased 
Uncommon: 
Neutrophil count decreased 
 
* 
Not reported in Studies FREEDOMS, FREEDOMS II and TRANSFORMS. The frequency 
category was based on an estimated exposure of approximately 10, 000 patients to fingolimod 
in all clinical trials. 
** 
PML and cryptococcal infections (including isolated cases of cryptococcal meningitis) have 
been reported in the post-marketing setting (see section 4.4). 

 
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*** 
Adverse drug reactions from spontaneous reports and literature 
 
Description of selected adverse reactions 
Infections 
In multiple sclerosis clinical studies the overall rate of infections (65.1%) at the 0.5 mg dose was similar 
to placebo. However, lower respiratory tract infections, primarily bronchitis and to a lesser extent 
herpes infection and pneumonia were more common in Gilenya-treated patients. 
 
Some cases of disseminated herpes infection, including fatal cases, have been reported even at the 
0.5 mg dose. 
 
In the post-marketing setting, cases of infections with opportunistic pathogens, such as viral (e.g. 
varicella zoster virus [VZV], John Cunningham virus [JCV] causing Progressive Multifocal 
Leukoencephalopathy, herpes simplex virus [HSV]), fungal (e.g. cryptococci including cryptococcal 
meningitis) or bacterial (e.g. atypical mycobacterium), have been reported (see section 4.4). 
 
Macular oedema 
In multiple sclerosis clinical studies macular oedema occurred in 0.5% of patients treated with the 
recommended dose of 0.5 mg and 1.1% of patients treated with the higher dose of 1.25 mg. The 
majority of cases occurred within the first 3-4 months of therapy. Some patients presented with blurred 
vision or decreased visual acuity, but others were asymptomatic and diagnosed on routine 
ophthalmological examination. The macular oedema generally improved or resolved spontaneously 
after discontinuation of Gilenya. The risk of recurrence after re-challenge has not been evaluated. 
 
Macular oedema incidence is increased in multiple sclerosis patients with a history of uveitis (17% with a 
history of uveitis vs. 0.6% without a history of uveitis). Gilenya has not been studied in multiple sclerosis 
patients with diabetes mellitus, a disease which is associated with an increased risk for macular oedema 
(see section 4.4). In renal transplant clinical studies in which patients with diabetes mellitus were 
included, therapy with fingolimod 2.5 mg and 5 mg resulted in a 2-fold increase in the incidence of 
macular oedema. 
 
Bradyarrhythmia 
Initiation of Gilenya treatment results in a transient decrease in heart rate and may also be associated with 
atrioventricular conduction delays. In multiple sclerosis clinical studies the maximal decline in heart rate 
was seen within 6 hours after treatment initiation, with declines in mean heart rate of 
12-13 beats per minute for Gilenya 0.5 mg. Heart rate below 40 beats per minute was rarely observed in 
patients on Gilenya 0.5 mg. The average heart rate returned towards baseline within 1 month of chronic 
treatment. Bradycardia was generally asymptomatic but some patients experienced mild to moderate 
symptoms, including hypotension, dizziness, fatigue and/or palpitations, which resolved within the first 24 
hours after treatment initiation (see also sections 4.4 and 5.1). 
 
In multiple sclerosis clinical studies first-degree atrioventricular block (prolonged PR interval on ECG) was 
detected after treatment initiation in 4.7% of patients on fingolimod 0.5 mg, in 2.8% of patients on 
intramuscular interferon beta-1a, and in 1.6% of patients on placebo. Second-degree atrioventricular block 
was detected in less than 0.2% patients on Gilenya 0.5 mg. In the post- marketing setting, isolated reports 
of transient, spontaneously resolving complete AV block have been observed during the six hour 
monitoring period following the first dose of Gilenya. The patients recovered spontaneously. The 
conduction abnormalities observed both in clinical trials and post- marketing were typically transient, 
asymptomatic and resolved within the first 24 hours after treatment initiation. Although most patients did 
not require medical intervention, one patient on Gilenya 0.5 mg received isoprenaline for asymptomatic 
second-degree Mobitz I atrioventricular block. 
 
In the post-marketing setting, isolated delayed onset events, including transient asystole and unexplained 
death, have occurred within 24 hours of the first dose. These cases have been confounded by concomitant 
medicinal products and/or pre-existing disease. The relationship of such events to Gilenya is uncertain. 
 
Blood pressure 
In multiple sclerosis clinical studies Gilenya 0.5 mg was associated with an average increase of 
approximately 3 mmHg in systolic pressure and approximately 1 mmHg in diastolic pressure, manifesting 
approximately 1 month after treatment initiation. This increase persisted with continued treatment. 
Hypertension was reported in 6.5% of patients on fingolimod 0.5 mg and in 3.3% of patients on placebo. 
In the post-marketing setting, cases of hypertension have been reported within the first month of treatment 

 
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initiation and on the first day of treatment that may require treatment with antihypertensive agents or 
discontinuation of Gilenya (see also section 4.4, Blood pressure effects). 
 
Liver function 
Increased hepatic enzymes have been reported in multiple sclerosis patients treated with Gilenya. In 
clinical studies 8.0% and 1.8% of patients treated with Gilenya 0.5 mg experienced an asymptomatic 
elevation in serum levels of ALT of ≥3x ULN (upper limit of normal) and ≥5x ULN, respectively. 
Recurrence of liver transaminase elevations has occurred upon re-challenge in some patients, supporting 
a relationship to the medicinal product. In clinical studies, transaminase elevations occurred at any time 
during treatment although the majority occurred within the first 12 months. ALT levels returned to normal 
within approximately 2 months after discontinuation of Gilenya. In a small number of patients (N=10 on 
1.25 mg, N=2 on 0.5 mg) who experienced ALT elevations ≥5x ULN and who continued on Gilenya 
therapy, the ALT levels returned to normal within approximately 
5 months (see also section 4.4, Liver function). 
 
Nervous system disorders 
In clinical studies, rare events involving the nervous system occurred in patients treated with fingolimod at 
higher doses (1.25 or 5.0 mg) including ischaemic and haemorrhagic strokes and neurological atypical 
disorders, such as acute disseminated encephalomyelitis (ADEM)-like events. 
 
Vascular disorders 
Rare cases of peripheral arterial occlusive disease occurred in patients treated with fingolimod at higher 
doses (1.25 mg). 
 
Respiratory system 
Minor dose-dependent reductions in values for forced expiratory volume (FEV1) and diffusion capacity for 
carbon monoxide (DLCO) were observed with Gilenya treatment starting at Month 1 and remaining stable 
thereafter. At Month 24, the reduction from baseline values in percentage of predicted FEV1 was 2.7% for 
fingolimod 0.5 mg and 1.2% for placebo, a difference that resolved after treatment discontinuation. For 
DLCO the reductions at Month 24 were 3.3% for fingolimod 0.5 mg and 2.7% for placebo. 
 
Lymphomas 
There have been cases of lymphoma of different varieties, in both clinical studies and the post- marketing 
setting, including a fatal case of Epstein-Barr virus (EBV) positive B-cell lymphoma. The incidence of 
lymphoma (B-cell and T-cell) cases was higher in clinical trials than expected in the general population. 
 
Haemophagocytic syndrome 
Very rare cases of haemophagocytic syndrome (HPS) with fatal outcome have been reported in patients 
treated with fingolimod in the context of an infection. HPS is a rare condition that has been described in 
association with infections, immunosuppression and a variety of autoimmune diseases. 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows 
continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are 
asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 
 
4.9 Overdose 
 
Single doses up to 80 times the recommended dose (0.5 mg) were well tolerated in healthy volunteers. At 
40 mg, 5 of 6 subjects reported mild chest tightness or discomfort which was clinically consistent with 
small airway reactivity. 
 
Fingolimod can induce bradycardia upon treatment initiation. The decline in heart rate usually starts within 
one hour of the first dose, and is steepest within 6 hours. The negative chronotropic effect of Gilenya 
persists beyond 6 hours and progressively attenuates over subsequent days of treatment (see section 4.4 
for details). There have been reports of slow atrioventricular conduction, with isolated reports of transient, 
spontaneously resolving complete AV block (see sections 4.4 and 4.8). 
 
If the overdose constitutes first exposure to Gilenya, it is important to monitor patients with a continuous 
(real time) ECG and hourly measurement of heart rate and blood pressure, at least during the first 6 
hours (see section 4.4). 
 

 
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Additionally, if after 6 hours the heart rate is <45 bpm or if the ECG at 6 hours after the first dose shows 
second degree or higher AV block, or if it shows a QTc interval ≥500 msec, monitoring should be 
extended at least for overnight and until the findings have resolved. The occurrence at any time of third 
degree AV block should also lead to extended monitoring including overnight monitoring. 
 
Neither dialysis nor plasma exchange results in removal of fingolimod from the body. 
 
5. 
PHARMACOLOGICAL PROPERTIES 
 
5.1 
Pharmacodynamic properties 
Pharmacotherapeutic group: Selective immunosuppressants, ATC code: L04AA27 Mechanism 
of action 
Fingolimod is a sphingosine 1-phosphate receptor modulator. Fingolimod is metabolised by 
sphingosine kinase to the active metabolite fingolimod phosphate. Fingolimod phosphate binds at low 
nanomolar concentrations to sphingosine 1-phosphate (S1P) receptor 1 located on lymphocytes, and 
readily crosses the blood-brain barrier to bind to S1P receptor 1 located on neural cells in the central 
nervous system (CNS). By acting as a functional antagonist of S1P receptors on lymphocytes, fingolimod 
phosphate blocks the capacity of lymphocytes to egress from lymph nodes, causing a redistribution, rather 
than depletion, of lymphocytes. Animal studies have shown that this redistribution reduces the infiltration 
of pathogenic lymphocytes, including pro-inflammatory Th17 cells, into the CNS, where they would be 
involved in nerve inflammation and nervous tissue damage. Animal studies and in vitro experiments 
indicate that fingolimod may also act via interaction with S1P receptors on neural cells. 
 
Pharmacodynamic effects 
Within 4-6 hours after the first dose of fingolimod 0.5 mg, the lymphocyte count decreases to 
approximately 75% of baseline in peripheral blood. With continued daily dosing, the lymphocyte count 
continues to decrease over a two-week period, reaching a minimal count of approximately 
500 cells/microlitre or approximately 30% of baseline. Eighteen percent of patients reached a minimal 
count below 200 cells/microlitre on at least one occasion. Low lymphocyte counts are maintained  with 
chronic daily dosing. The majority of T and B lymphocytes regularly traffic through lymphoid organs and 
these are the cells mainly affected by fingolimod. Approximately 15-20% of T lymphocytes have an effector 
memory phenotype, cells that are important for peripheral immune surveillance. Since this lymphocyte 
subset typically does not traffic to lymphoid organs it is not affected by fingolimod. Peripheral lymphocyte 
count increases are evident within days of stopping fingolimod treatment and typically normal counts are 
reached within one to two months. Chronic fingolimod dosing leads to a mild decrease in the neutrophil 
count to approximately 80% of baseline. Monocytes are unaffected by fingolimod. 
 
Fingolimod causes a transient reduction in heart rate and decrease in atrioventricular conduction at 
treatment initiation (see sections 4.4 and 4.8). The maximal decline in heart rate is seen within 6 hours 
post dose, with 70% of the negative chronotropic effect achieved on the first day. With continued 
administration heart rate returns to baseline within one month. The decrease in heart rate induced by 
fingolimod can be reversed by parenteral doses of atropine or isoprenaline. Inhaled salmeterol has also 
been shown to have a modest positive chronotropic effect. With initiation of fingolimod treatment there is 
an increase in atrial premature contractions, but there is no increased rate of atrial fibrillation/flutter or 
ventricular arrhythmias or ectopy. Fingolimod treatment is not associated with a decrease in cardiac 
output. Autonomic responses of the heart, including diurnal variation of heart rate and response to 
exercise are not affected by fingolimod treatment. 
 
Fingolimod treatment with single or multiple doses of 0.5 and 1.25 mg for two weeks is not associated with 
a detectable increase in airway resistance as measured by FEV1 and forced expiratory flow rate (FEF) 
25-75. However, single fingolimod doses ≥5 mg (10-fold the recommended dose) are associated with a 
dose-dependent increase in airway resistance. Fingolimod treatment with multiple doses of   0.5, 1.25, or 
5 mg is not associated with impaired oxygenation or oxygen desaturation with exercise or an increase in 
airway responsiveness to methacholine. Subjects on fingolimod treatment have a normal bronchodilator 
response to inhaled beta-agonists. 
 
Clinical efficacy and safety 
The efficacy of Gilenya has been demonstrated in two studies which evaluated once-daily doses of 
fingolimod 0.5 mg and 1.25 mg in patients with relapsing-remitting multiple sclerosis (RRMS). Both 
studies included patients who had experienced ≥2 relapses in the prior 2 years or ≥1 relapse during 
the prior year. Expanded Disability Status Score (EDSS) was between 0 and 5.5. A third study targeting 
the same patient population was completed after registration of Gilenya. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
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Study D2301 (FREEDOMS) was a 2-year randomised, double-blind, placebo-controlled Phase III study 
of 1,272 patients (n=425 on 0.5 mg, 429 on 1.25 mg, 418 on placebo). Median values for baseline 
characteristics were: age 37 years, disease duration 6.7 years, and EDSS score 2.0. Outcome results 
are shown in Table 1. There were no significant differences between the 0.5 mg and the 
1.25 mg doses as regards either endpoint. 
 
Table 1: Study D2301 (FREEDOMS): Main results 
 
Fingolimod 
0.5 mg 
Placebo 
Clinical endpoints 
Annualised relapse rate (primary endpoint) 
0.18** 
0.40 
Percentage of patients remaining relapse-free at 24 
months 
70%** 
46% 
Proportion with 3-month Confirmed Disability 
Progression† 
17% 
24% 
Hazard ratio (95% CI) 
0.70 (0.52, 0.96)* 
MRI endpoints 
Median (mean) number of new or enlarging T2 
lesions over 24 months 
0.0 (2.5)** 
5.0 (9.8) 
Median (mean) number of Gd-enhancing lesions at 
Month 24 
0.0 (0.2)** 
0.0 (1.1) 
Median (mean) % change in brain volume over 24 
months 
-0.7 (-0.8)** 
-1.0 (-1.3) 
† 
Disability progression defined as 1-point increase in EDSS confirmed 3 months later 
** 
p<0.001, *p<0.05 compared to placebo 
All analyses of clinical endpoints were intent-to-treat. MRI analyses used evaluable dataset. 
 
Patients who completed the 24-month core FREEDOMS study could enter a dose-blinded extension 
study (D2301E1) and receive fingolimod. In total, 920 patients entered (n=331 continued on 0.5 mg, 
289 continued on 1.25 mg, 155 switched from placebo to 0.5 mg and 145 switched from placebo to 
1.25 mg). After 12 months (month 36), 856 patients (93%) were still enrolled. Between months 24 and 
36, the annualised relapse rate (ARR) for patients on fingolimod 0.5 mg in the core study who remained 
on 0.5 mg was 0.17 (0.21 in the core study). The ARR for patients who switched from placebo to 
fingolimod 0.5 mg was 0.22 (0.42 in the core study). 
 
Comparable results were shown in a replicate 2-year randomised, double-blind, placebo-controlled 
Phase III study on fingolimod in 1,083 patients (n=358 on 0.5 mg, 370 on 1.25 mg, 355 on placebo) 
with RRMS (D2309; FREEDOMS 2). Median values for baseline characteristics were: age 41 years, 
disease duration 8.9 years, EDSS score 2.5. 
 
Table 2: Study D2309 (FREEDOMS 2): Main results 
 
Fingolimod 
0.5 mg 
Placebo 
Clinical endpoints 
Annualised relapse rate (primary endpoint) 
0.21** 
0.40 
Percentage of patients remaining relapse-free at 24 
months 
71.5%** 
52.7% 
Proportion with 3-month Confirmed Disability 
Progression† 
25% 
29% 
Hazard ratio (95% CI) 
0.83 (0.61, 1.12) 
MRI endpoints 

 
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Median (mean) number of new or enlarging T2 
lesions over 24 months 
0.0 (2.3)** 
4.0 (8.9) 
Median (mean) number of Gd-enhancing 
lesions at Month 24 
0.0 (0.4)** 
0.0 (1.2) 
Median (mean) % change in brain volume over 24 
months 
-0.71 (-0.86)** 
-1.02 (-1.28) 
† 
Disability progression defined as 1-point increase in EDSS confirmed 3 months later 
** 
p<0.001 compared to placebo 
All analyses of clinical endpoints were intent-to-treat. MRI analyses used evaluable dataset. 
 
Study D2302 (TRANSFORMS) was a 1-year randomised, double-blind, double-dummy, active 
(interferon beta-1a)-controlled Phase III study of 1,280 patients (n=429 on 0.5 mg, 420 on 1.25 mg, 431 
on interferon beta-1a, 30 µg by intramuscular injection once weekly). Median values for baseline 
characteristics were: age 36 years, disease duration 5.9 years, and EDSS score 2.0. Outcome results 
are shown in Table 3. There were no significant differences between the 0.5 mg and the 1.25 mg doses 
as regards study endpoints. 
 
Table 3: Study D2302 (TRANSFORMS): Main results 
 
Fingolimod 
0.5 mg 
Interferon beta- 
1a, 30 μg 
Clinical endpoints 
Annualised relapse rate (primary endpoint) 
0.16** 
0.33 
Percentage of patients remaining relapse-free at 12 
months 
83%** 
71% 
Proportion with 3-month Confirmed Disability 
Progression† 
6% 
8% 
Hazard ratio (95% CI) 
0.71 (0.42, 1.21) 
MRI endpoints 
Median (mean) number of new or enlarging T2 
lesions over 12 months 
0.0 (1.7)* 
1.0 (2.6) 
Median (mean) number of Gd-enhancing lesions at 
12 months 
0.0 (0.2)** 
0.0 (0.5) 
Median (mean) % change in brain volume over 12 
months 
-0.2 (-0.3)** 
-0.4 (-0.5) 
† 
Disability progression defined as 1-point increase in EDSS confirmed 3 months later. 
* 
p<0.01,** p<0.001, compared to interferon beta-1a 
All analyses of clinical endpoints were intent-to-treat. MRI analyses used evaluable dataset. 
 
Patients who completed the 12-month core TRANSFORMS study could enter a dose-blinded extension 
(D2302E1) and receive fingolimod. In total, 1,030 patients entered, however, 3 of these patients did not 
receive treatment (n=356 continued on 0.5 mg, 330 continued on 1.25 mg, 167 switched from interferon 
beta-1a to 0.5 mg and 174 from interferon beta-1a to 1.25 mg). After 
12 months (month 24), 882 patients (86%) were still enrolled. Between months 12 and 24, the ARR for 
patients on fingolimod 0.5 mg in the core study who remained on 0.5 mg was 0.20 (0.19 in the core 
study). The ARR for patients who switched from interferon beta-1a to fingolimod 0.5 mg was 
0.33 (0.48 in the core study). 
 
Pooled results of Studies D2301 and D2302 showed a consistent and statistically significant reduction in 
annualised relapse rate compared to comparator in subgroups defined by gender, age, prior multiple 
sclerosis therapy, disease activity or disability levels at baseline. 
 
Further analyses of clinical trial data demonstrate consistent treatment effects in highly active subgroups 
of relapsing remitting multiple sclerosis patients. 
 

 
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The European Medicines Agency has deferred the obligation to submit the results of studies with Gilenya 
in one or more subsets of the paediatric population in multiple sclerosis (see section 4.2 for information 
on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Pharmacokinetic data were obtained in healthy volunteers, in renal transplant patients and in multiple 
sclerosis patients. 
The pharmacologically active metabolite responsible for efficacy is fingolimod phosphate. Absorption 
Fingolimod absorption is slow (tmax of 12-16 hours) and extensive (≥85%). The apparent absolute oral 
bioavailability is 93% (95% confidence interval: 79-111%). Steady-state-blood concentrations are 
reached within 1 to 2 months following once-daily administration and steady-state levels are 
approximately 10-fold greater than with the initial dose. 
 
Food intake does not alter Cmax or exposure (AUC) of fingolimod. Fingolimod phosphate Cmax was 
slightly increased by 34% but AUC was unchanged. Therefore, Gilenya may be taken without regard to 
meals (see section 4.2). 
 
Distribution 
Fingolimod highly distributes in red blood cells, with the fraction in blood cells of 86%. Fingolimod 
phosphate has a smaller uptake in blood cells of <17%. Fingolimod and fingolimod phosphate are highly 
protein bound (>99%). 
 
Fingolimod is extensively distributed to body tissues with a volume of distribution of about 1,200260 
litres. A study in four healthy subjects who received a single intravenous dose of a radioiodolabelled 
analogue of fingolimod demonstrated that fingolimod penetrates into the brain. In a study in 13 male 
multiple sclerosis patients who received Gilenya 0.5 mg/day, the mean amount of fingolimod (and 
fingolimod phosphate) in seminal ejaculate, at steady-state, was approximately 10,000 times lower than 
the oral dose administered (0.5 mg). 
 
Biotransformation 
Fingolimod is transformed in humans by reversible stereoselective phosphorylation to the 
pharmacologically active (S)-enantiomer of fingolimod phosphate. Fingolimod is eliminated by oxidative 
biotransformation catalysed mainly via CYP4F2 and possibly other isoenzymes and subsequent fatty 
acid-like degradation to inactive metabolites. Formation of pharmacologically inactive non-polar ceramide 
analogues of fingolimod was also observed. The main enzyme involved in the metabolism of fingolimod 
is partially identified and may be either CYP4F2 or CYP3A4. 
 
Following single oral administration of [14C] fingolimod, the major fingolimod-related components in blood, 
as judged from their contribution to the AUC up to 34 days post dose of total radiolabelled components, 
are fingolimod itself (23%), fingolimod phosphate (10%), and inactive metabolites (M3 carboxylic acid 
metabolite (8%), M29 ceramide metabolite (9%) and M30 ceramide metabolite (7%)). 
 
Elimination 
Fingolimod blood clearance is 6.32.3 l/h, and the average apparent terminal half-life (t1/2) is 
6-9 days. Blood levels of fingolimod and fingolimod phosphate decline in parallel in the terminal phase, 
leading to similar half-lives for both. 
 
After oral administration, about 81% of the dose is slowly excreted in the urine as inactive metabolites. 
Fingolimod and fingolimod phosphate are not excreted intact in urine but are the major components in 
the faeces, with amounts representing less than 2.5% of the dose each. After 34 days, the recovery of 
the administered dose is 89%. 
 
Linearity 
Fingolimod and fingolimod phosphate concentrations increase in an apparently dose proportional manner 
after multiple once-daily doses of 0.5 mg or 1.25 mg. 
 
Characteristics in specific groups of patients 
The pharmacokinetics of fingolimod and fingolimod phosphate do not differ in males and females, in 
patients of different ethnic origin, or in patients with mild to severe renal impairment. 
 

 
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In subjects with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, and C), no change 
in fingolimod Cmax was observed, but fingolimod AUC was increased respectively by 12%, 44%, and 
103%. In patients with severe hepatic impairment (Child-Pugh class C), fingolimod- phosphate Cmax was 
decreased by 22% and AUC was not substantially changed. The pharmacokinetics of fingolimod-
phosphate were not evaluated in patients with mild or moderate hepatic impairment. 
The apparent elimination half-life of fingolimod is unchanged in subjects with mild hepatic impairment, but 
is prolonged by about 50% in patients with moderate or severe hepatic impairment. 
 
Fingolimod should not be used in patients with severe hepatic impairment (Child-Pugh class C) (see 
section 4.3). Fingolimod should be introduced cautiously in mild and moderate hepatic impaired patients 
(see section 4.2). 
 
Clinical experience and pharmacokinetic information in patients aged above 65 years are limited. Gilenya 
should be used with caution in patients aged 65 years and over (see section 4.2). 
 
Paediatric population 
There are limited data available from a renal transplant study that included 7 children above 11 years of 
age (study FTY720A0115). The comparison of these data to those in adult healthy volunteers is of limited 
relevance and no valid conclusions can be drawn regarding the pharmacokinetic properties of fingolimod 
in children. 
 
5.3 Preclinical safety data 
 
The preclinical safety profile of fingolimod was assessed in mice, rats, dogs and monkeys. The major 
target organs were the lymphoid system (lymphopenia and lymphoid atrophy), lungs (increased weight, 
smooth muscle hypertrophy at the bronchio-alveolar junction), and heart (negative chronotropic effect, 
increase in blood pressure, perivascular changes and myocardial degeneration) in several species; blood 
vessels (vasculopathy) in rats only at doses of 0.15 mg/kg and higher in a 2- year study, representing an 
approximate 4-fold margin based on the human systemic exposure (AUC) at a daily dose of 0.5 mg. 
 
No evidence of carcinogenicity was observed in a 2-year bioassay in rats at oral doses of fingolimod up to 
the maximally tolerated dose of 2.5 mg/kg, representing an approximate 50-fold margin based on human 
systemic exposure (AUC) at the 0.5 mg dose. However, in a 2-year mouse study, an increased incidence 
of malignant lymphoma was seen at doses of 0.25 mg/kg and higher, representing an approximate 6-fold 
margin based on the human systemic exposure (AUC) at a daily dose of 
0.5 mg. 
 
Fingolimod was neither mutagenic nor clastogenic in animal studies. 
 
Fingolimod had no effect on sperm count/motility or on fertility in male and female rats up to the highest 
dose tested (10 mg/kg), representing an approximate 150-fold margin based on human systemic 
exposure (AUC) at a daily dose of 0.5 mg. 
 
Fingolimod was teratogenic in the rat when given at doses of 0.1 mg/kg or higher. The most common 
foetal visceral malformations included persistent truncus arteriosus and ventricular septum defect. 
The teratogenic potential in rabbits could not be fully assessed, however an increased embryo-foetal 
mortality was seen at doses of 1.5 mg/kg and higher, and a decrease in viable foetuses as well as foetal 
growth retardation was seen at 5 mg/kg. 
 
In rats, F1 generation pup survival was decreased in the early postpartum period at doses that did not 
cause maternal toxicity. However, F1 body weights, development, behaviour, and fertility were not 
affected by treatment with fingolimod. 
 
Fingolimod was excreted in milk of treated animals during lactation. Fingolimod and its metabolites 
crossed the placental barrier in pregnant rabbits. 
 
Environmental Risk Assessment (ERA) 
A risk for the environment due to use of Gilenya by patients with relapsing multiple sclerosis is not 
expected. 
 
6. 
PHARMACEUTICAL PARTICULARS 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
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6.1 
List of excipients 
 
Capsule core: 
Magnesium stearate 
Mannitol 
 
Capsule shell: 
Yellow iron oxide (E172) 
Titanium dioxide (E171) 
Gelatin 
 
Printing ink:  
Shellac (E904) 
Dehydrated alcohol 
Isopropyl alcohol 
Butyl alcohol 
Propylene glycol 
Purified water 
Strong ammonia solution 
Potassium hydroxide 
Black iron oxide (E172) 
Yellow iron oxide (E172) 
Titanium dioxide (E171) 
Dimethicone 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years 
 
6.4 Special precautions for storage 
 
Do not store above 25°C. 
Store in the original package in order to protect from moisture. 
 
6.5 Nature and contents of container 
 
PVC/PVDC/aluminium blister packs containing 7, 28 or 98 hard capsules or multipacks containing 84 (3 
packs of 28) hard capsules. 
PVC/PVDC/aluminium perforated unit dose blister packs containing 7x 1 hard capsules. Not all 
pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
No special requirements. 
 
 
7. 
MARKETING AUTHORISATION HOLDER 
 
Novartis Europharm 
Limited Frimley Business 
Park Camberley GU16 
7SR United Kingdom 
 
 
8. 
MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/11/677/001-006 
 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
158/Protocol MA30005, Version 5 
9. 
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 17 March 2011 
Date of latest renewal: 23 November 2015 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
159/Protocol MA30005, Version 5 
SmPC for Plegridy 
 
1. 
NAME OF THE MEDICINAL PRODUCT 
 
Plegridy 63 micrograms solution for injection in pre-filled syringe. 
Plegridy 94 micrograms solution for injection in pre-filled syringe. 
 
 
2. 
QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each 63 microgram pre-filled syringe contains 63 micrograms of peginterferon beta-1a* in 0.5 mL solution 
for injection. 
Each 94 microgram pre-filled syringe contains 94 micrograms of peginterferon beta-1a* in 0.5 mL solution 
for injection. 
 
The dose indicates the quantity of the interferon beta-1a moiety of peginterferon beta-1a without 
consideration of the PEG moiety attached. 
*The active substance, peginterferon beta-1a, is a covalent conjugate of interferon beta-1a, produced in 
Chinese Hamster Ovary cells, with 20,000 Dalton (20 kDa) methoxy poly(ethyleneglycol) using an 
O-2-methylpropionaldehyde linker. 
 
The potency of this medicinal product should not be compared to the one of another pegylated 
or non-pegylated protein of the same therapeutic class. For more information see section 5.1. 
 
Excipients with known effect 
 
Each syringe contains 0.13 mg sodium. 
 
For the full list of excipients, see section 6.1. 
 
 
3. 
PHARMACEUTICAL FORM 
 
Solution for injection (injection). 
 
Clear and colourless solution with pH 4.5-5.1. 
 
 
4. 
CLINICAL PARTICULARS 
 
4.1 
Therapeutic indications 
 
Plegridy is indicated in adult patients for the treatment of relapsing remitting multiple sclerosis (see section 
5.1). 
 
4.2 Posology and method of administration 
 
Treatment should be initiated under supervision of a physician experienced in the treatment of multiple 
sclerosis. 
 
Efficacy of Plegridy has been demonstrated over placebo. Direct comparative data for Plegridy versus non- 
pegylated interferon beta or data on efficacy of Plegridy after switching from a non-pegylated interferon 
beta are not available. This should be considered when switching patients between pegylated and non-
pegylated interferons. Please refer also to section 5.1. 
 
Posology 
 
The recommended dosage of Plegridy is 125 micrograms injected subcutaneously every 2 weeks (14 
days). 
 
Treatment initiation 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
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It is generally recommended that patients start treatment with 63 micrograms at dose 1 (on day 0), 
increasing to 94 micrograms at dose 2 (on day 14), reaching the full dose of 125 micrograms by dose 3 
(on day 28) and continuing with the full dose (125 micrograms) every 2 weeks (14 days) thereafter (see 
Table 1). An Initiation Pack is available containing the first 2 doses (63 micrograms and 94 
micrograms). 
 
Table 1: Titration schedule at initiation 
Dose 
Time* 
Amount (micrograms) 
Syringe label 
Dose 1 
Day 0 
63 
Orange 
Dose 2 
Day 14 
94 
Blue 
Dose 3 
Day 28 
125 (full dose) 
Grey 
*Dosed every 2 weeks (14 days) 
 
Dose titration at the initiation of treatment may help to ameliorate flu-like symptoms that can occur at 
treatment initiation with interferons. Prophylactic and concurrent use of anti-inflammatory, analgesic 
and/or antipyretic treatments may prevent or ameliorate flu-like symptoms sometimes experienced 
during interferon treatment (see section 4.8). 
 
If a dose is missed, it should be administered as soon as possible. 
• If 7 days or more to the next planned dose: Patients should administer their missed dose 
immediately. Treatment can then continue with the next scheduled dose as planned. 
• If less than 7 days to the next planned dose: Patients should begin a new 2 week dosing 
schedule starting from when they administer their missed dose. A patient should not 
administer two doses of Plegridy within 7 days of each other. 
 
Special populations 
 
Elderly population 
 
The safety and efficacy of Plegridy in patients over the age of 65 have not been sufficiently studied 
due to the limited number of such patients included in clinical trials. 
 
Renal impairment 
 
No dosage adjustments are necessary in patients with renal impairment based on study data in mild, 
moderate, and severe renal impairment and end stage renal disease (see sections 4.4 and 5.2). 
 
Hepatic impairment 
 
Plegridy has not been studied in patients with hepatic impairment (see section 4.4). 
 
Paediatric population 
 
The safety and efficacy of Plegridy in children and adolescents aged 0 to 18 years have not been 
established in multiple sclerosis. No data are available. 
 
Method of administration 
 
Plegridy is for subcutaneous use. 
 
It is recommended that a healthcare professional trains patients in the proper technique for self-
administering subcutaneous injections using the pre-filled syringe. Patients should be advised to rotate 
sites for subcutaneous injections. The usual sites for subcutaneous injections include abdomen, arm, and 
thigh. 
 
Each Plegridy pre-filled syringe is provided with the needle pre-attached. Pre-filled syringes are for single 
use only and should be discarded after use. 
 
Precautions to be taken before handling or administering the medicinal product 
 

 
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Once removed from the refrigerator, Plegridy should be allowed to warm to room temperature (about 
30 minutes) prior to injection. External heat sources such as hot water must not be used to warm Plegridy. 
 
Plegridy pre-filled syringe must not be used if the liquid is coloured, cloudy, or contains floating particles. 
The liquid in the syringe must be clear and colourless. 
 
4.3 Contraindications 
 
- 
Hypersensitivity to natural or recombinant interferon beta or peginterferon or to any of the 
excipients listed in section 6.1. 
- 
Initiation of treatment in pregnancy (see section 4.6). 
- 
Patients with current severe depression and/or suicidal ideation (see sections 4.4 and 4.8). 
 
4.4 Special warnings and precautions for use 
 
Hepatic injury 
 
Elevated serum hepatic transaminase levels, hepatitis, autoimmune hepatitis and rare cases of severe 
hepatic failure have been reported with interferon beta medicinal products. Elevations in hepatic enzymes 
have been observed with the use of Plegridy. Patients should be monitored for signs of hepatic injury (see 
section 4.8). 
 
Depression 
 
Plegridy should be administered with caution to patients with previous depressive disorders (see section 
4.3). Depression occurs with increased frequency in the multiple sclerosis population and in association 
with interferon use. Patients should be advised to immediately report any symptoms of depression and/or 
suicidal ideation to their prescribing physician. 
 
Patients exhibiting depression should be monitored closely during therapy and treated appropriately. 
Cessation of therapy with Plegridy should be considered (see section 4.8). 
 
Hypersensitivity reactions 
 
Serious hypersensitivity reactions have been reported as a rare complication of treatment with interferon 
beta, including Plegridy. Peginterferon beta-1a should be discontinued if serious hypersensitivity reactions 
occur (see section 4.8). 
 
Injection site reactions 
 
Injection site reactions, including injection site necrosis, have been reported with the use of subcutaneous 
interferon beta. To minimise the risk of injection site reactions patients should be instructed in the use of 
an aseptic injection technique. The procedure for the self-administration by the patient should be 
reviewed periodically especially if injection site reactions have occurred. If the patient experiences any 
break in the skin, which may be accompanied by swelling or drainage of fluid from the injection site, the 
patient should be advised to speak with their doctor. One patient treated with Plegridy in clinical trials 
experienced an injection site necrosis. Whether to discontinue therapy following a single site of necrosis 
is dependent on the extent of necrosis (see section 4.8). 
 
Decreased peripheral blood counts 
 
Decreased peripheral blood counts in all cell lines, including rare pancytopenia and severe 
thrombocytopenia, have been reported in patients receiving interferon beta. Cytopenias, including rare 
severe neutropenia and thrombocytopenia, have been observed in patients treated with Plegridy. Patients 
should be monitored for symptoms or signs of decreased peripheral blood counts (see section 4.8). 
 
Renal and urinary disorders 
 
Nephrotic syndrome 
 
Cases of nephrotic syndrome with different underlying nephropathies including collapsing focal segmental 
glomerulosclerosis (FSGS), minimal change disease (MCD), membranoproliferative glomerulonephritis 
(MPGN) and membranous glomerulopathy (MGN) have been reported during treatment with interferon-beta 

 
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products. Events were reported at various time points during treatment and may occur after several years of 
treatment with interferon beta. Periodic monitoring of early signs or symptoms, e.g. oedema, proteinuria and 
impaired renal function is recommended, especially in patients at higher risk of renal disease. Prompt 
treatment of nephrotic syndrome is required and discontinuation of treatment with Plegridy should be 
considered. 
 
Severe renal impairment 
 
Caution should be used when administering Plegridy to patients with severe renal impairment. 
Thrombotic microangiopathy (TMA) 
Cases of TMA, manifested as thrombotic thrombocytopenic purpura (TTP) or haemolytic uraemic 
syndrome (HUS), including fatal cases, have been reported with interferon beta products. Events were 
reported at various time points during treatment and may occur several weeks to several years after 
starting treatment with interferon beta. Early clinical features include thrombocytopenia, new onset 
hypertension, fever, central nervous system symptoms (e.g. confusion, paresis) and impaired renal 
function. Laboratory findings suggestive of TMA include decreased platelet counts, increased serum 
lactate dehydrogenase (LDH) due to haemolysis and schistocytes (erythrocyte fragmentation) on a blood 
film. Therefore if clinical features of TMA are observed, further testing of blood platelet levels, serum LDH, 
blood films and renal function is recommended. If TMA is diagnosed, prompt treatment is required 
(considering plasma exchange) and immediate discontinuation of Plegridy is recommended. 
 
 
Laboratory abnormalities 
 
Laboratory abnormalities are associated with the use of interferons. In addition to those laboratory tests 
normally required for monitoring patients with multiple sclerosis, complete blood and differential blood cell 
counts, platelet counts, and blood chemistries, including liver function tests (e.g. aspartate 
aminotransferase (AST), alanine aminotransaminase (ALT)), are recommended prior to initiation and at 
regular intervals following introduction of Plegridy therapy and then periodically thereafter in the absence 
of clinical symptoms. 
 
Patients with myelosuppression may require more intensive monitoring of complete blood cell counts, 
with differential and platelet counts. 
 
Hypothyroidism and hyperthyroidism have been observed with the use of interferon beta products. 
Regular thyroid function tests are recommended in patients with a history of thyroid dysfunction or as 
clinically indicated. 
 
Seizure 
 
Plegridy should be administered with caution to patients with a history of seizures, to those receiving 
treatment with anti-epileptics, particularly if their epilepsy is not adequately controlled with anti-epileptics 
(see section 4.8). 
 
Cardiac disease 
 
Worsening of cardiac disease has been reported in patients receiving interferon beta. The incidence of 
cardiovascular events was similar between Plegridy (125 micrograms every 2 weeks) and placebo 
treatment groups (7% in each group). No serious cardiovascular events were reported in patients who 
received Plegridy in the ADVANCE study.  Nevertheless, patients with pre-existing significant cardiac 
disease, such as congestive heart failure, coronary artery disease or arrhythmia should be monitored for 
worsening of their cardiac condition, particularly during initiation of treatment. 
 
Immunogenicity 
 
Patients may develop antibodies to Plegridy. Data from patients treated up to 2 years with Plegridy 
suggests that less than 1% (5/715) developed persistent-neutralising antibodies to the interferon beta-1a 
portion of peginterferon beta-1a. Neutralising antibodies have the potential to reduce clinical efficacy. 
However, the development of antibodies against the interferon moiety of peginterferon beta-1a had no 
discernible impact on safety or clinical efficacy, although the analysis was limited by the low 
immunogenicity incidence. 
 

 
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3% of patients (18/681) developed persistent antibodies to the PEG moiety of peginterferon beta-1a.  In the 
clinical study conducted, the development of antibodies against the PEG moiety of peginterferon beta-1a 
had no discernible impact on safety, or clinical efficacy (including annualised relapse rate, MRI lesions, and 
disability progression). 
 
Hepatic impairment 
 
Caution should be used and close monitoring considered when administering Plegridy to patients with 
severe hepatic impairment. Patients should be monitored for signs of hepatic injury and caution exercised 
when interferons are used concomitantly with other medicinal products associated with hepatic injury (see 
sections 4.8 and 5.2). 
 
Sodium content 
 
Each syringe contains less than 1 mmol (23 mg) sodium and is therefore considered essentially “sodium- 
free”. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed. The clinical studies indicate that multiple sclerosis patients 
can receive Plegridy and corticosteroids during relapses. Interferons have been reported to reduce the 
activity of hepatic cytochrome P450-dependent enzymes in humans and animals. Caution should be 
exercised when Plegridy is administered in combination with medicinal products that have a narrow 
therapeutic index and are largely dependent on the hepatic cytochrome P450 system for clearance, e.g. 
some classes of antiepileptics and antidepressants. 
4.6 Fertility, pregnancy and lactation 
 
Women of child-bearing potential 
 
Women of child-bearing potential have to take appropriate contraceptive measures. If the patient becomes 
pregnant or plans to become pregnant while taking Plegridy she should be informed of the potential 
hazards and discontinuation of therapy should be considered (see section 5.3). In patients with a high 
relapse rate before treatment started, the risk of a severe relapse following discontinuation of Plegridy in 
the event of pregnancy should be weighed against a possible increased risk of spontaneous abortion. 
 
Pregnancy 
 
There is limited information on the use of Plegridy in pregnancy. Available data indicates that there may be 
an increased risk of spontaneous abortion. Initiation of treatment is contraindicated during pregnancy (see 
section 4.3). 
 
Breast-feeding 
 
It is not known whether peginferferon beta-1a is secreted in human milk. Because of the potential for serious 
adverse reactions in breast-feeding infants, a decision should be made either to discontinue breast-feeding or 
Plegridy therapy. 
 
Fertility 
 
There are no data on the effects of peginferferon beta-1a on human fertility.  In animals, anovulatory effects 
were observed at very high doses (see section 5.3).  No information is available on the effects of 
peginterferon beta-1a on male fertility in animals. 
 
4.7 Effects on ability to drive and use machines 
 
Central nervous system-related adverse events associated with the use of interferon beta might influence 
the patient’s ability to drive or use machines (see section 4.8). 
 
4.8 Undesirable effects 
 
Summary of safety profile 
 
The most common adverse drug reactions (ADR) (at a higher incidence than placebo) for Plegridy 

 
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125 micrograms subcutaneously every 2 weeks were injection site erythema, influenza like illness, 
pyrexia, headache, myalgia, chills, injection site pain, asthenia, injection site pruritus, and arthralgia. 
The most commonly reported adverse reaction leading to discontinuation in patients treated with Plegridy 
125 micrograms subcutaneously every 2 weeks was influenza-like illness (<1%). 
 
Tabulated list of adverse reactions 
 
In clinical studies 1468 patients received Plegridy for up to 177 weeks (overall exposure equivalent to 
1932 person-years). 1093 patients received at least 1 year, and 415 patients have received at least 2 
years of treatment with Plegridy. The experience in the randomised, uncontrolled phase (year 2) of the 
ADVANCE study and in the 2 year safety extension study ATTAIN was consistent with the experience in 
the 1 year placebo-controlled phase of the ADVANCE study. 
 
The table summarizes ADRs (incidence above placebo and with a reasonable possibility of causality) from 
512 patients treated with Plegridy 125 micrograms subcutaneously every 2 weeks and 500 patients who 
received placebo for up to 48 weeks. 
 
The ADRs are presented as MedDRA preferred terms under the MedDRA System Organ Class. The 
incidence of the adverse reactions below are expressed according to the following categories: 
 
Very common (≥1/10) 
- 
Common (≥1/100 to <1/10) 
- 
Uncommon (≥1/1, 000 to <1/100) 
- 
Rare (≥1/10, 000 to <1/1,000) 
- 
Very rare (<1/10,000) 
- 
Not known (cannot be estimated from the available data) 
 
MedDRA System Organ Class 
Adverse reaction 
Frequency category 
Blood and lymphatic system 
disorders 
Thrombocytopenia 
Uncommon 
Thrombotic microangiopathy 
including thrombotic 
thrombocytopenic 
purpura/haemolytic uraemic 
syndrome* 
Rare 
Immune system disorders 
Hypersensitivity reaction 
Uncommon 
Nervous system disorders 
Headache 
Very common 
Seizure 
Uncommon 
Respiratory, thoracic and 
mediastinal disorders 
Pulmonary arterial hypertension┼ 
Not known 
Gastrointestinal disorders 
Nausea 
Common 
Vomiting 
Skin and subcutaneous tissue 
disorders 
Pruritus 
Common 
Urticaria 
Uncommon 
Musculoskeletal and connective 
tissue disorders 
Myalgia 
Very common 
Arthralgia 
Renal and urinary disorders 
Nephrotic syndrome, 
glomerulosclerosis 
Rare 
General disorders and 
administration site conditions 
Injection site erythema 
Very common 
Influenza like illness 
Pyrexia 
Chills 
Injection site pain 
Asthenia 
Injection site pruritus 
Hyperthermia 
Common 
Pain 
Injection site oedema 
Injection site warmth 
Injection site haematoma 
Injection site rash 
Injection site swelling 

 
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MedDRA System Organ Class 
Adverse reaction 
Frequency category 
Injection site discolouration 
Injection site inflammation 
Injection site necrosis 
Rare 
Investigations 
Body temperature increased 
Common 
Alanine aminotransferase 
increased 
Aspartate aminotransferase 
increased 
Gamma-glutamyl-transferase 
increased 
Haemoglobin decreased 
Platelet count decreased 
Uncommon 
Decreases in white blood cell counts 
Common 
Psychiatric disorders 
Depression 
Common 
*Class label for interferon beta products (see section 4.4). 
┼ Class label for interferon products, see below Pulmonary arterial hypertension 
 
Description of selected adverse reactions 
 
Flu-like symptoms 
 
Influenza-like illness was experienced by 47% of patients receiving Plegridy 125 micrograms every 2 
weeks and 13% of patients receiving placebo. The incidence of flu-like symptoms (e.g. influenza-like 
illness, chills, hyperpyrexia, musculoskeletal pain, myalgia, pain, pyrexia) was highest at the initiation of 
treatment and generally decreased over the first 6 months. Of the patients who reported flu-like 
symptoms 90% reported them as mild or moderate in severity. None were considered serious in 
nature. Less than 1% of patients who received Plegridy during the placebo controlled phase of the 
ADVANCE study discontinued treatment due to flu-like symptoms. 
 
Injection site reactions 
 
Injection site reactions (e.g. injection site erythema, pain, pruritus, or oedema) were reported by 66% of 
patients who received Plegridy 125 micrograms every 2 weeks compared to 11% of patients receiving 
placebo. Injection site erythema was the most commonly reported injection site reaction. Of the patients 
who experienced injection site reactions 95% reported them as mild or moderate in severity. One 
patient out of 1468 patients who received Plegridy in clinical studies experienced an injection site 
necrosis which resolved with standard medical treatment. 
 
Hepatic transaminase abnormalities 
 
The incidence of hepatic transaminase increases was greater in patients receiving Plegridy compared 
to placebo. The majority of enzyme elevations were <3 times the upper limit of normal (ULN). 
Elevations of alanine aminotransferase and aspartate aminotransferase (>5 times ULN), were 
reported in 1% and <1% of placebo-treated patients and 2% and <1% of patients treated with Plegridy 
respectively. Elevations of serum hepatic transaminases combined with elevated bilirubin were 
observed in two patients who had pre-existing liver test abnormalities prior to receiving Plegridy in the 
clinical trials. Both cases resolved following discontinuation of Plegridy. 
 
Haematological disorders 
 
Decreases in white blood cell counts of <3.0 x 109/L were observed in 7% of patients receiving Plegridy 
and in 1% receiving placebo. Mean white blood cell counts remained within normal limits in patients 
treated with Plegridy. Decreases in white blood cell counts were not associated with an increased risk 
of infections or serious infections. The incidence of potentially clinically significant decreases in 
lymphocyte counts 
(<0.5 x 109/L) (<1%), neutrophil counts (≤1.0 x 109/L) (<1%) and platelet counts (≤100 x 109/L) (≤
1%) was similar in Plegridy-treated patients compared to placebo-treated patients. Two serious cases 
were reported in 
patients treated with Plegridy: one patient (<1%) experienced severe thrombocytopenia (platelet count 

 
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<10 x 109/L), another patient (<1%) experienced severe neutropenia (neutrophil count <0.5 x 109/L). In 
both patients, cell counts recovered after discontinuation of Plegridy. Slight decreases in mean red 
blood cell (RBC) counts were observed in Plegridy treated patients. The incidence of potentially 
clinically significant decreases in RBC counts (<3.3 x 1012/L) was similar in Plegridy-treated patients 
compared to placebo-treated patients. 
 
Hypersensitivity reactions 
 
Hypersensitivity events were reported in 16% of patients treated with Plegridy 125 micrograms every 
2 weeks and 14% of patients who received placebo. Less than 1% of Plegridy treated patients experienced 
a serious hypersensitivity event (e.g. angioedema, urticaria) and they recovered promptly after treatment 
with anti-histamines and/or corticosteroids. 
 
Depression and suicidal ideation 
 
The overall incidence of adverse events related to depression and suicidal ideation was 8% for both 
Plegridy 125 micrograms every 2 weeks and placebo groups. The incidence of serious events related to 
depression and suicidal ideation were similar and low (<1%) in both Plegridy 125 micrograms every 2 
weeks and placebo-treated patients. 
 
Seizure 
 
The incidence of seizure events was low and comparable in patients receiving Plegridy (125 micrograms 
every 2 weeks) and placebo (<1% in each group). 
 
Pulmonary arterial hypertension 
 
Cases of pulmonary arterial hypertension (PAH) have been reported with interferon beta products. 
Events were reported at various time points including up to several years after starting treatment with 
interferon beta. 
 
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows 
continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are 
asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 
 
4.9 Overdose 
 
In case of over-dose, patients may be hospitalized for observation and appropriate supportive treatment 
should be given. 
 
 
5. 
PHARMACOLOGICAL PROPERTIES 
 
5.1 
Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic and immunomodulating agents; immunostimulants; interferons 
ATC code: L03AB13 
 
Plegridy is an interferon beta-1a conjugated with a single, linear molecule of 20,000 Da methoxy 
poly(ethyleneglycol)-O-2-methylpropionaldehyde (20 kDa mPEG-O-2-methylpropionaldehyde) at a degree 
of substitution of 1 mole of polymer/mole of protein. The average molecular mass is approximately 44 kDa 
of which the protein moiety constitutes approximately 23 kDa. 
 
Mechanism of action 
 
A definitive mechanism of action of peginterferon beta-1a in multiple sclerosis (MS) is not known. Plegridy 
binds to the type I interferon receptor on the surface of cells and elicits a cascade of intracellular events 
leading to the regulation of interferon-responsive gene expression. Biological effects that may be mediated 
by Plegridy include up-regulation of anti-inflammatory cytokines (e.g. IL-4, IL-10, IL-27), down-regulation 

 
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of pro-inflammatory cytokines (e.g. IL-2, IL-12, IFN-γ, TNF-α) and inhibiting the migration of activated T 
cells across the blood brain barrier; however additional mechanisms may be involved. Whether the 
mechanism of action of Plegridy in MS is mediated by the same pathway(s) as the biological effects 
described above is not known because the pathophysiology of MS is only partially understood. 
 
Pharmacodynamic effects 
 
Plegridy is interferon beta-1a conjugated to a single, linear 20 kDa methoxy poly(ethyleneglycol) 
molecule at the alpha-amino group of the N-terminal amino acid residue. 
 
Interferons are a family of naturally occurring proteins that are induced by cells in response to biological 
and chemical stimuli, and mediate numerous cellular responses that have been classified as antiviral, 
antiproliferative, and immunomodulatory in nature. The pharmacological properties of Plegridy are 
consistent with those of interferon beta-1a and are believed to be mediated by the protein portion of the 
molecule. 
 
Pharmacodynamic responses were evaluated by measuring the induction of interferon-responsive 
genes including those encoding 2′,5′-oligoadenylate synthetase (2′,5′-OAS), myxovirus 
resistance protein A (MxA), and several chemokines and cytokines, as well as neopterin (D-erythro-
1, 2, 3,- trihydroxypropylpterin), a product of the interferon-inducible enzyme, GTP-cyclohydrolase I. 
Gene induction in healthy human subjects was greater in terms of peak level and exposure (area 
under the effect curve) for Plegridy compared to non-pegylated interferon beta-1a (IM) when both 
were given at the same dose by activity (6 MIU). The duration of this response was sustained and 
prolonged for Plegridy, with elevations detected up to 15 days compared to 4 days for non-pegylated 
interferon beta-1a. Increased concentrations of neopterin were observed in both healthy subjects and 
multiple sclerosis patients treated with Plegridy, with a sustained and prolonged elevation over 10 
days compared to 5 days observed for 
non-pegylated interferon beta-1a. Neopterin concentrations return to baseline after the two week 
dosing interval. 
 
Clinical efficacy and safety 
 
The efficacy and safety of Plegridy was assessed from the placebo-controlled first year of a 2 year 
randomised, double-blind, clinical study in patients with relapsing remitting multiple sclerosis (the 
ADVANCE study). 1512 patients were randomised to and dosed with 125 micrograms Plegridy injected 
subcutaneously every 2 (n=512) or 4 (n=500) weeks versus placebo (n=500). 
 
The primary endpoint was the annualised relapse rate (ARR) over 1 year. The study design and patient 
demographics are presented in Table 2. 
 
No data are available from clinical efficacy/safety studies directly comparing pegylated with non-
pegylated interferon beta-1a, or from patients switching between non-pegylated and pegylated 
interferon. 
 
Table 2: Study design 
Study design 
Disease history 
Patients with RRMS, with at least 2 relapses within the 
prior 3 years, and 1 relapse in the prior year, with an EDSS 
score of ≤5.0 
Follow-up 
1 year 
Study population 
83% treatment-naïve patients  
47% ≥2 relapses in prior year 
38% at least 1 Gd+ lesion at baseline  
92% ≥9 T2 lesions baseline 
16% EDSS ≥4 
17% previously treated 
Baseline characteristics 
Mean age (years) 
37 
Mean/Median disease duration (years) 
3.6/2.0 
Mean number of relapses within the past 3 
years 
2.5 

 
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Mean EDSS score at baseline 
2.5 
EDSS: Expanded Disability Status Scale 
Gd+: Gadolinium-enhancing 
 
Plegridy every 2 weeks significantly reduced the annualized relapse rate (ARR) by 36% compared to 
placebo (p=0.0007) at one year (Table 3) with consistent reductions of the ARR noted in subgroups 
defined by demographic and baseline disease characteristics. Plegridy also significantly reduced the risk of 
relapse by 39% (p=0.0003), the risk of sustained disability progression confirmed at 12 weeks by 38% 
(p=0.0383) and 
at 24 weeks (post-hoc analysis) by 54% (p=0.0069), the number of new or newly enlarging T2 lesions by 
67% (p<0.0001), the number of Gd-enhancing lesions by 86% (p<0.0001) and the number of new T1 
hypointense lesions compared to placebo by 53% (p<0.0001). A treatment effect was observed as early 
as 6 months, with Plegridy 125 micrograms every 2 weeks demonstrating a 61% reduction (p<0.0001) 
in new or newly enlarging T2 lesions as compared with placebo. Across relapse and MRI endpoints 
Plegridy 
125 micrograms every two weeks showed a numerically greater treatment effect over the Plegridy every 
four weeks dosing regimen at year 1. 
 
Results over 2 years confirmed that efficacy was maintained beyond the placebo controlled first year of 
the study. Patients exposed to Plegridy every 2 weeks showed statistically significant reductions 
compared to patients exposed to Plegridy every 4 weeks over 2 years in a post-hoc analysis for 
endpoints including ARR (24%, p=0.0209), the risk of relapse (24%, p=0.0212), the risk of disability 
progression with 24 week confirmation (36%, p=0.0459), and MRI endpoints (new/enlarging T2 60%, 
Gd+ 71%, and new T1 hypointense lesions 53%; p<0.0001 for all). 
 
Results for this study are shown in Table 3. 
 
Table 3: Clinical and MRI results 
Placebo 
Plegridy 
125 micrograms 
every 2 weeks 
Plegridy 
125 micrograms 
every 4 weeks 
Clinical endpoints 
N 
500 
512 
500 
Annualised relapse rate 
0.397 
0.256 
0.288 
Rate ratio 
95% CI 
P-value 
0.64 
0.50 – 0.83 
p=0.0007 
0.72 
0.56 – 0.93 
p=0.0114 
Proportion of subjects relapsed 
0.291 
0.187 
0.222 
HR 
95% CI 
P-value 
0.61 
0.47 – 0.80 
p=0.0003 
0.74 
0.57 – 0.95 
p=0.020 
Proportion with 12 week confirmed 
disability progression* 
0.105 
0.068 
0.068 
HR 
95% CI 
P-value 
0.62 
0.40 – 0.97 
p=0.0383 
0.62 
0.40 – 0.97 
p=0.0380 
Proportion with 24-week confirmed 
disability progression* 
0.084 
0.040 
0.058 
HR 
95% CI 
P-value 
0.46 
(0.26 – 0.81) 
p=0.0069 
0.67 
(0.41 – 1.10) 
p=0.1116 
MRI endpoints 
N 
476 
457 
462 
Mean [Median] no. of new or newly enlarging 
T2 hyperintense lesions (range) 
13.3 [6.0] 
(0 – 148) 
4.1 [1.0] 
(0 – 69) 
9.2 [3.0] 
(0 – 113) 
Lesion mean ratio (95% CI) P-
value 
0.33 (0.27, 0.40) 
p≤0.0001 
0.72 (0.60, 0.87) 
p=0.0008 
Mean [Median] no. of Gd-enhancing 
lesions (range) 
1.4^ [0.0] 
(0 – 39) 
0.2 [0.0] 
(0 – 13) 
0.9 [0.0] 
(0 – 41) 
% reduction vs placebo 
P-value 
86 
p<0.0001 
36 
p=0.0738 

 
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Mean [Median] no. of new T1 hypointense 
lesions (range) 
3.8 [1.0] 
(0 – 56) 
1.8 [0.0] 
(0 – 39) 
3.1 [1.0] 
(0 – 61) 
% reduction vs placebo 
P-value 
53 
p<0.0001 
18 
0.0815 
HR: Hazard ratio 
CI: Confidence interval 
* Sustained disability progression was defined as at least a 1 point increase from baseline EDSS ≥ 1 
or 1.5 point increase for patients with baseline EDSS of 0, sustained for 12 / 24 weeks. 
^n=477 
 
 
Patients who failed previous MS treatment were not included in the study. 
 
Subgroups of patients with higher disease activity were defined by relapse and MRI criteria as 
reported below, with the following efficacy results: 
 
- 
For patients with ≥1 relapse in the previous year and ≥9 T2 lesions or ≥1 Gd+ lesion 
(n=1401), the annual relapse rate at 1 year was 0.39 for placebo, 0.29 for Plegridy every 4 
weeks and 0.25 for Plegridy every 2 weeks. 
 
Results in this subgroup were consistent with those in the overall population. 
 
- 
For patients with ≥2 relapses in the previous year and at least 1 Gd+ lesion (n=273), the 
annual relapse rate at 1 year was 0.47 for placebo, 0.35 for Plegridy every 4 weeks, and 0.33 
for Plegridy every 2 weeks. 
 
Results in this subgroup were numerically consistent with those in the overall population but not 
statistically significant. 
 
Paediatric population 
 
The European Medicines Agency has deferred the obligation to submit the results of studies with Plegridy 
in one or more subsets of the paediatric population in treatment of multiple sclerosis (see section 4.2 for 
information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
The serum half-life of peginterferon beta-1a is prolonged compared with non-pegylated interferon beta-1a. 
Serum concentration of peginterferon beta-1a was dose-proportional in the range of 63 to 188 micrograms 
as observed in a single dose and a multiple dose study in healthy subjects. Pharmacokinetics observed in 
multiple sclerosis patients were consistent with those seen in healthy subjects. 
 
Absorption 
 
Following subcutaneous administration of peginterferon beta-1a in multiple sclerosis patients, the peak 
concentration was reached between 1 to 1.5 days post-dose. The observed Cmax (mean±SE) was 
280 ± 79 pg/mL following repeat dosing of 125 micrograms every two weeks. 
Subcutaneous peginterferon beta-1a resulted in approximately 4-, 9-, and 13-fold higher exposure 
(AUC168h) values and approximately 2-, 3.5- and 5-fold higher Cmax, following single doses of 63 (6 
MIU), 
125 (12 MIU), and 188 (18 MIU) micrograms respectively, compared to intramuscular administration of 
30 (6 MIU) micrograms non-pegylated beta-1a. 
 
Distribution 
 
Following repeat dosing of 125 micrograms doses every two weeks by subcutaneous administration, the 
volume of distribution uncorrected for bioavailability (mean±SE) was 481 ± 105 L. 
 
Biotransformation and elimination 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
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Urinary (renal) clearance is postulated to be a major excretory pathway for Plegridy. The process of 
covalently conjugating a PEG moiety to a protein can alter the in vivo properties of the unmodified protein, 
including decreased renal clearance and decreased proteolysis thus extending the circulating half-life. 
Accordingly, the half-life (t1/2) of peginterferon beta-1a is approximately 2-fold longer than non-pegylated 
interferon beta-1a in healthy volunteers. In multiple sclerosis patients, the t1/2 (mean±SE) of 
peginterferon beta-1a was 78 ± 15 hours at steady state. The mean steady state clearance of 
peginterferon beta-1a was 4.1 ± 0.4 L/hr. 
 
Special populations 
 
Renal impairment 
 
A single-dose study in healthy subjects and subjects with various degrees of renal impairment (mild, 
moderate, and severe renal impairment as well as subjects with end state renal disease) showed a 
fractional increase in AUC (13-62%) and Cmax (42-71%) in subjects with mild (estimated glomerular 
filtration rate 50 to ≤80 mL/min/1.73m2), moderate (estimated glomerular filtration rate 30 to 50 
mL/min/1.73m2), and severe (estimated glomerular filtration rate <30 mL/min/1.73m2) renal impairment, 
compared to subjects with normal renal function (estimated glomerular filtration rate >80 mL/min/1.73m2).  
Subjects with end stage renal disease requiring 2-3 times haemodialysis weekly showed similar AUC and 
Cmax as compared to subjects with normal renal function. Each haemodialysis reduced peginterferon 
beta-1a concentration by approximately 24%, suggesting that haemodialysis partially removes 
peginterferon beta-1a from systemic circulation. 
 
Hepatic function 
 
The pharmacokinetics of peginterferon beta-1a has not been evaluated in patients with hepatic insufficiency. 
 
Elderly patients 
 
Clinical experience in patients aged above 65 years is limited. However, results from a population 
pharmacokinetic analysis (in patients up to 65 years) suggest that age does not impact peginterferon beta-
1a clearance. 
 
Gender 
 
No gender effect on the pharmacokinetics of peginterferon beta-1a was found in a population 
pharmacokinetic analysis. 
 
Race 
 
Race had no effect on the pharmacokinetics of peginterferon beta-1a in a population pharmacokinetic 
analysis. 
 
5.3 Preclinical safety data 
 
Toxicity 
 
Following repeated subcutaneous administration of peginterferon beta-1a in rhesus monkeys at doses up to 
400-fold (based on exposure, AUC) the recommended therapeutic dose; no effects other than the known 
mild pharmacological responses by rhesus monkeys to interferon beta-1a were observed after the first and 
second weekly dose.  Repeated dose toxicology studies were limited to 5 weeks as exposure was greatly 
diminished from 3 weeks onwards, due to the formation of anti-drug antibodies by rhesus monkeys to 
human interferon beta-1a. Therefore, the long-term safety of chronic administration of Plegridy to patients 
cannot be assessed on the basis of these studies. 
 
Mutagenesis 
 
Peginterferon beta-1a was not mutagenic when tested in an in vitro bacterial reverse mutation (Ames) test 
and was not clastogenic in an in vitro assay in human lymphocytes. 
 
Carcinogenesis 

 
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Peginterferon beta-1a has not been tested for carcinogenicity in animals. Based on the known 
pharmacology of interferon beta-1a and clinical experience with interferon beta, the potential for 
carcinogenicity is expected to be low.  
 
Reproductive Toxicity 
Peginterferon beta-1a has not been tested for reproductive toxicity in pregnant animals. Fertility and 
developmental studies in rhesus monkeys have been carried out with non-pegylated interferon beta-1a. At 
very high doses, anovulatory and abortifacient effects were observed in animals. No information is 
available on the potential effects of peginterferon beta-1a on male fertility. Upon repeated dosing with 
peginterferon beta-1a of sexually mature female monkeys, effects on menstrual cycle length and 
progesterone levels were observed. Reversibility of the effects on menstrual cycle length was 
demonstrated. The validity of extrapolating these non-clinical data to humans is unknown. 
 
Data from studies with other interferon beta compounds did not show teratogenic potential. The available 
information on the effects of interferon beta-1a in the peri- and postnatal periods is limited. 
 
 
6. 
PHARMACEUTICAL PARTICULARS 
 
6.1 
List of excipients 
 
Sodium acetate trihydrate 
Acetic acid, glacial 
L-Arginine hydrochloride 
Polysorbate 20 
Water for injections 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years 
 
Plegridy can be stored at room temperature (up to 25°C) for up to 30 days as long as it is stored away 
from light. If Plegridy is at room temperature for a total of 30 days, it should be used or discarded. If it is 
not clear if Plegridy has been stored at room temperature 30 days or more, it should be discarded. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2C 
to 8C). Do not freeze. 
Store in the original package in order to protect from light. 
 
See section 6.3 for additional information on storage at room temperature (up  to 25°C). 
 
6.5 Nature and contents of container 
 
1 mL pre-filled syringe made of glass (Type I) with a bromobutyl rubber stopper and thermoplastic and 
polypropylene rigid needle shield, containing 0.5 mL of solution. 
 
The Plegridy Initiation Pack contains 1x 63 micrograms pre-filled syringe (orange labelled syringe, 1st 
dose) and 1x 94 micrograms pre-filled syringe (blue labelled syringe, 2nd dose) in sealed plastic trays. 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. 
MARKETING AUTHORISATION HOLDER 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
172/Protocol MA30005, Version 5 
 
BIOGEN IDEC LIMITED 
Innovation House 
70 Norden Road 
Maidenhead 
Berkshire 
SL6 4AY 
United Kingdom 
 
 
8. 
MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/14/934/001 
 
 
9. 
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 18 July 2014 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines Agency 
http://www.ema.europa.eu. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
173/Protocol MA30005, Version 5 
SmPC for Rebif 
 
 
1. 
NAME OF THE MEDICINAL PRODUCT 
 
Rebif 22 micrograms solution for injection in pre-filled syringe 
 
 
2. 
QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each pre-filled syringe (0.5 mL) contains 22 micrograms (6 MIU*) of interferon beta-1a**. 
 
* Million International Units, measured by cytopathic effect (CPE) bioassay against the in-house 
interferon beta-1a standard which is calibrated against the current international NIH standard (GB-
23-902-531). 
** produced in Chinese hamster ovary Cells (CHO-K1) by recombinant DNA technology. 
 
Excipient with known effect: 2.5 mg benzyl alcohol 
For the full list of excipients, see section 6.1. 
 
 
3. 
PHARMACEUTICAL FORM 
 
Solution for injection in pre-filled syringe. 
Clear to opalescent solution, with pH 3.5 to 4.5 and osmolarity 250 to 450 mOsm/L. 
 
 
4. 
CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Rebif is indicated for the treatment of relapsing multiple sclerosis. In clinical trials, this was characterised by 
two or more acute exacerbations in the previous two years (see section 5.1). 
 
Efficacy has not been demonstrated in patients with secondary progressive multiple sclerosis without 
ongoing relapse activity (see section 5.1). 
 
4.2 Posology and method of administration 
 
Treatment should be initiated under supervision of a physician experienced in the treatment of the disease. 
 
Rebif is available in three strengths: 8.8 micrograms, 22 micrograms and 44 micrograms. For patients 
initiating treatment with Rebif, Rebif 8.8 micrograms and Rebif 22 micrograms are available in a pack that 
corresponds to the patient needs for the first month of therapy. 
 
Posology 
 
The recommended posology of Rebif is 44 micrograms given three times per week by subcutaneous 
injection. A lower dose of 22 micrograms, also given three times per week by subcutaneous injection, is 
recommended for patients who cannot tolerate the higher dose in view of the treating specialist. 
 
When first starting treatment with Rebif, the dose should be gradually escalated in order to allow 
tachyphylaxis to develop thus reducing adverse reactions. The Rebif initiation package corresponds to the 
patient needs for the first month of treatment. 
 
Paediatric population 
No formal clinical trials or pharmacokinetic studies have been conducted in children or adolescents. 
However, a paediatric retrospective cohort study collected safety data with Rebif from medical records in 
children (n=52) and adolescents (n=255). The results of this study suggest that the safety profile in children 
(2 to 11 years old) and in adolescents (12 to 17 years old) receiving Rebif 22 micrograms or 44 
micrograms subcutaneous three times per week is similar to that seen in adults. 

 
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The safety and efficacy of Rebif in children below 2 years of age have not yet been established. Rebif 
should not be used in this age group. 
 
Method of administration 
 
Rebif is administered by subcutaneous injection. Prior to injection and for an additional 24 hours after each 
injection, an antipyretic analgesic is advised to decrease flu-like symptoms associated with Rebif 
administration. 
 
At the present time, it is not known for how long patients should be treated. Safety and efficacy with Rebif 
have not been demonstrated beyond 4 years of treatment. It is recommended that patients should be 
evaluated at least every second year in the 4-year period after initiation of treatment with Rebif and a 
decision for longer term treatment should then be made on an individual basis by the treating physician. 
 
4.3 Contraindications 
 
• 
Initiation of treatment in pregnancy (see section 4.6). 
• 
Hypersensitivity to natural or recombinant interferon beta or to any of the excipients listed in 
section 6.1. 
• 
Current severe depression and/or suicidal ideation (see sections 4.4 and 4.8). 
 
4.4 Special warnings and precautions for use 
 
Patients should be informed of the most frequent adverse reactions associated with interferon beta 
administration, including symptoms of the flu-like syndrome (see section 4.8). These symptoms tend 
to be most prominent at the initiation of therapy and decrease in frequency and severity with continued 
treatment. 
 
Thrombotic microangiopathy (TMA) 
 
Cases of thrombotic microangiopathy, manifested as thrombotic thrombocytopenic purpura (TTP) or 
haemolytic uraemic syndrome (HUS), including fatal cases, have been reported with interferon beta 
products. Events were reported at various time points during treatment and may occur several weeks to 
several years after starting treatment with interferon beta. Early clinical features include thrombocytopenia, 
new onset hypertension, fever, central nervous system symptoms (e.g. confusion, paresis) and impaired 
renal function. Laboratory findings suggestive of TMA include decreased platelet counts, increased serum 
lactate dehydrogenase (LDH) due to haemolysis and schistocytes (erythrocyte fragmentation) on a blood 
film. Therefore if clinical features of TMA are observed, further           testing of blood platelet levels, serum 
LDH, blood films and renal function is recommended. If       TMA is diagnosed, prompt treatment is required 
(considering plasma exchange) and immediate discontinuation of Rebif is recommended. 
 
Depression and suicidal ideation 
 
Rebif should be administered with caution to patients with previous or current depressive disorders in 
particular to those with antecedents of suicidal ideation (see section 4.3). Depression and suicidal ideation 
are known to occur in increased frequency in the multiple sclerosis population and in association with 
interferon use. Patients treated with Rebif should be advised to immediately report any symptoms of 
depression and/or suicidal ideation to their prescribing physician. Patients exhibiting depression should be 
monitored closely during therapy with Rebif and treated appropriately. Cessation of therapy with Rebif 
should be considered (see sections 4.3 and 4.8). 
 
Seizure disorders 
 
Rebif should be administered with caution to patients with a history of seizures, to those receiving 
treatment with anti-epileptics, particularly if their epilepsy is not adequately controlled with antiepileptics 
(see sections 4.5 and 4.8). 
 
Cardiac disease 
 
Patients with cardiac disease, such as angina, congestive heart failure or arrhythmia, should be closely 
monitored for worsening of their clinical condition during initiation of therapy with interferon beta-1a. 

 
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Symptoms of the flu-like syndrome associated with interferon beta-1a therapy may prove stressful to 
patients with cardiac conditions. 
 
Injection site necrosis 
 
Injection site necrosis (ISN) has been reported in patients using Rebif (see section 4.8). To minimise the 
risk of injection site necrosis patients should be advised to: 
• 
use an aseptic injection technique, 
• 
rotate the injection sites with each dose. 
 
The procedure for the self-administration by the patient should be reviewed periodically especially if 
injection site reactions have occurred. 
 
If the patient experiences any break in the skin, which may be associated with swelling or drainage of fluid 
from the injection site, the patient should be advised to consult with their physician before continuing 
injections with Rebif. If the patient has multiple lesions, Rebif should be discontinued until healing has 
occurred. Patients with single lesions may continue provided that the necrosis is not too extensive. 
 
Hepatic dysfunction 
 
In clinical trials with Rebif, asymptomatic elevations of hepatic transaminases (particularly alanine 
aminotransferase (ALT)) were common and 1-3% of patients developed elevations of hepatic 
transaminases above 5 times the upper limit of normal (ULN). In the absence of clinical symptoms, serum 
ALT levels should be monitored prior to the start of therapy, at months 1, 3 and 6 on therapy and 
periodically thereafter. Dose reduction of Rebif should be considered if ALT rises above 5 times the ULN, 
and gradually re-escalated when enzyme levels have normalized. Rebif should be initiated with caution in 
patients with a history of significant liver disease, clinical evidence of active liver disease, alcohol abuse or 
increased serum ALT (>2.5 times ULN). Treatment with Rebif should be stopped if icterus or other clinical 
symptoms of liver dysfunction appear. 
 
Rebif, like other interferons beta, has a potential for causing severe liver injury including acute hepatic 
failure (see section 4.8). The majority of the cases of severe liver injury occurred within the first six months 
of treatment. The mechanism for the rare symptomatic hepatic dysfunction is not known. No specific risk 
factors have been identified. 
 
Renal and urinary disorders 
 
Nephrotic syndrome 
 
Cases of nephrotic syndrome with different underlying nephropathies including collapsing focal segmental 
glomerulosclerosis (FSGS), minimal change disease (MCD), membranoproliferative glomerulonephritis 
(MPGN) and membranous glomerulopathy (MGN) have been reported during treatment with interferon-
beta products. Events were reported at various time points during treatment and may occur after several 
years of treatment with interferon-beta. Periodic monitoring of early signs or symptoms, e.g. oedema, 
proteinuria and impaired renal function is recommended, especially in patients at higher risk of renal 
disease. Prompt treatment of nephrotic syndrome is required and discontinuation of treatment with Rebif 
should be considered. 
 
Laboratory abnormalities 
 
Laboratory abnormalities are associated with the use of interferons. Therefore, in addition to those 
laboratory tests normally required for monitoring patients with multiple sclerosis, liver enzyme monitoring 
and complete and differential blood cell counts and platelet counts are recommended at regular intervals 
(1, 3 and 6 months) following introduction of Rebif therapy and then periodically thereafter in the absence 
of clinical symptoms. 
 
Thyroid disorders 
 
Patients being treated with Rebif may occasionally develop new or worsening thyroid abnormalities. 
Thyroid function testing is recommended at baseline and if abnormal, every 6-12 months following initiation 
of therapy. If tests are normal at baseline, routine testing is not needed but should be performed if clinical 
findings of thyroid dysfunction appear (see section 4.8). 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
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Severe renal or hepatic failure and severe myelosuppression 
 
Caution should be used, and close monitoring considered when administering interferon beta-1a to 
patients with severe renal and hepatic failure and to patients with severe myelosuppression. 
 
Neutralising antibodies 
 
Serum neutralising antibodies against interferon beta-1a may develop. The precise incidence of 
antibodies is as yet uncertain. Clinical data suggest that after 24 to 48 months of treatment with Rebif 
22 micrograms, approximately 24% of patients develop persistent serum antibodies to interferon 
beta-1a. The presence of antibodies has been shown to attenuate the pharmacodynamic 
response to interferon beta-1a (beta-2 microglobulin and neopterin). Although the clinical significance of the 
induction of antibodies has not been fully elucidated, the development of neutralising antibodies is 
associated with reduced efficacy on clinical and MRI variables. If a patient responds poorly to therapy with 
Rebif, and has neutralising antibodies, the treating physician should reassess the benefit/risk ratio of 
continued Rebif therapy. 
 
The use of various assays to detect serum antibodies and differing definitions of antibody positivity limits 
the ability to compare antigenicity among different products. 
 
Other forms of multiple sclerosis 
 
Only sparse safety and efficacy data are available from non-ambulatory patients with multiple sclerosis. 
Rebif has not yet been investigated in patients with primary progressive multiple sclerosis and should not 
be used in these patients. 
 
Benzyl alcohol 
 
This medicinal product contains 2.5 mg benzyl alcohol per dose. 
It must not be given to premature babies or neonates. It may cause toxic reactions and anaphylactoid 
reactions in infants and children up to 3 years old. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed with interferon beta-1a in humans. 
 
Interferons have been reported to reduce the activity of hepatic cytochrome P450-dependent enzymes in 
humans and animals. Caution should be exercised when administering Rebif in combination with medicinal 
products that have a narrow therapeutic index and are largely dependent on the hepatic cytochrome P450 
system for clearance, e.g. antiepileptics and some classes of antidepressants. 
 
The interaction of Rebif with corticosteroids or adrenocorticotropic hormone (ACTH) has not been studied 
systematically. Clinical studies indicate that multiple sclerosis patients can receive Rebif and 
corticosteroids or ACTH during relapses. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of child-bearing potential 
 
Women of child-bearing potential should take appropriate contraceptive measures. If the patient becomes 
pregnant or plans to become pregnant while taking Rebif she should be informed of the potential hazards 
and discontinuation of therapy should be considered (see section 5.3). In patients with a high relapse rate 
before treatment has started, the risk of a severe relapse following discontinuation of Rebif in the event of 
pregnancy should be weighed against a possible increased risk of spontaneous abortion. 
 
Pregnancy 
 
There is limited information on the use of Rebif in pregnancy. Available data indicates that there may be an 
increased risk of spontaneous abortion. Therefore initiation of treatment is contraindicated during 
pregnancy (see section 4.3). 
 
Breast-feeding 

 
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It is not known whether Rebif is excreted in human milk. Because of the potential for serious adverse 
reactions in breast-fed infants, a decision should be made whether to discontinue breast-feeding or Rebif 
therapy. 
 
Fertility 
 
The effects of Rebif on fertility have not been investigated. 
 
4.7 Effects on ability to drive and use machines 
 
Central nervous system-related adverse events associated with the use of interferon beta 
(e.g. dizziness) might influence the patient's ability to drive or use machines (see section 4.8). 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The highest incidence of adverse reactions associated with Rebif therapy is related to flu-like syndrome. 
Flu-like symptoms tend to be most prominent at the initiation of therapy and decrease in frequency with 
continued treatment. Approximately 70% of patients treated with Rebif can expect to experience the typical 
interferon flu-like syndrome within the first six months after starting treatment. Approximately 30% of 
patients will also experience reactions at the injection site, predominantly mild inflammation or erythema. 
Asymptomatic increases in laboratory parameters of hepatic function and decreases in white blood cells 
are also common. 
 
The majority of adverse reactions observed with interferon beta-1a are usually mild and reversible, and 
respond well to dose reductions. In case of severe or persistent undesirable effects, the dose of Rebif 
may be temporarily lowered or interrupted, at the discretion of the physician. 
 
List of adverse reactions 
 
The adverse reactions presented have been identified from clinical studies as well as from post- marketing 
reports (an asterisk [*] indicates adverse reactions identified during post-marketing surveillance). The 
following definitions apply to the frequency terminology used hereafter: very common (≥1/10), common (≥
1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to 
<1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data). 
 
Blood and the lymphatic system disorders 
Very common: 
Neutropenia, lymphopenia, leukopenia, thrombocytopenia, anaemia 
Rare: 
Thrombotic microangiopathy including thrombotic thrombocytopenic 
purpura/haemolytic uraemic syndrome* (class label for interferon beta 
products, see section 4.4), pancytopenia* 
 
Endocrine disorders 
Uncommon: 
Thyroid dysfunction, most often presenting as hypothyroidism or 
hyperthyroidism 
 
Immune system disorders 
Rare: 
Anaphylactic reactions* 
 
Hepatobiliary disorders 
Very common: 
Asymptomatic transaminase 
increase Common: 
Severe elevations in 
transaminases 
Uncommon: 
Hepatitis with or without icterus* 
Rare: 
Hepatic failure* (see section 4.4), autoimmune hepatitis* 
 
Psychiatric disorders 
Common: 
Depression, insomnia 
Rare: 
Suicide attempt* 
 

 
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Nervous system disorders 
Very common: 
Headache 
Uncommon: 
Seizures* 
Frequency not known: 
Transient neurological symptoms (i.e. hypoesthesia, muscle spasm, 
paraesthesia, difficulty in walking, musculoskeletal stiffness) that may 
mimic multiple sclerosis exacerbations* 
 
Eye disorders 
Uncommon: 
Retinal vascular disorders (i.e. retinopathy, cotton wool spots, obstruction of 
retinal artery or vein)* 
 
Vascular disorders 
Uncommon: 
Thromboembolic events* 
 
Respiratory, thoracic and mediastinal disorders 
Uncommon: 
Dyspnoea* 
Not known: 
Pulmonary arterial hypertension* (class label for interferon beta products, 
see below Pulmonary arterial hypertension) 
 
Gastrointestinal disorders 
Common: 
Diarrhoea, vomiting, nausea 
 
Skin and subcutaneous tissue disorders 
Common: 
Pruritus, rash, erythematous rash, maculo-papular rash, alopecia* 
Uncommon: 
Urticaria* 
Rare: 
Quincke’s oedema (angio-oedema)*, erythema multiforme*, erythema 
multiforme-like skin reactions*, Stevens Johnson syndrome* 
 
Musculoskeletal and connective disorders 
Common: 
Myalgia, arthralgia 
Rare: 
Drug-induced lupus erythematosus* 
 
Renal and urinary disorders 
Rare: 
Nephrotic syndrome*, glomerulosclerosis* (see section 4.4) 
 
General disorders and administration site conditions 
Very common: 
Injection site inflammation, injection site reaction, influenza-like symptoms 
Common: 
Injection site pain, fatigue, rigors, fever 
Uncommon: 
Injection site necrosis, injection site mass, injection site abscess, injection 
site infections*, increased sweating* 
Rare: 
Injection site cellulitis* Paediatric population 
 
No formal clinical trials or pharmacokinetic studies have been conducted in children or adolescents. Limited 
safety data suggest that the safety profile in children and adolescents (2 to 17 years old) receiving Rebif 22 
micrograms or 44 micrograms three times weekly is similar to that seen in adults. 
 
Class effects 
 
The administration of interferons has been associated with anorexia, dizziness, anxiety, arrhythmias, 
vasodilation and palpitation, menorrhagia and metrorrhagia. 
An increased formation of auto-antibodies may occur during treatment with interferon beta. Pulmonary 
arterial hypertension 
Cases of pulmonary arterial hypertension (PAH) have been reported with interferon beta products. Events 
were reported at various time points including up to several years after starting treatment with interferon 
beta. 
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows 
continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are 
asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 
 
4.9 Overdose 

 
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In case of overdose, patients should be hospitalised for observation and appropriate supportive 
treatment should be given. 
 
 
5. 
PHARMACOLOGICAL PROPERTIES 
 
5.1 
Pharmacodynamic properties 
 
Pharmacotherapeutic group: Immunostimulants, Interferons, ATC code: L03AB07 
 
Interferons are a group of endogenous glycoproteins endowed with immunomodulatory, antiviral and 
antiproliferative properties. 
 
Rebif (interferon beta-1a) shares the same amino acid sequence with endogenous human 
interferon beta. It is produced in mammalian cells (Chinese hamster ovary) and is therefore 
glycosylated like the natural protein. 
 
Regardless of the route of dosing, pronounced pharmacodynamic changes are associated with the 
administration of Rebif. After a single dose, intracellular and serum activity of 2’5’OAS synthetase and 
serum concentrations of beta-2 microglobulin and neopterin increase within 24 hours, and start to decline 
within 2 days. Intramuscular and subcutaneous administrations produce fully superimposable responses. 
After repeated subcutaneous administration every 48 hours for 4 doses, these biological responses 
remain elevated, with no signs of tolerance development. 
 
Biological response markers (e.g., 2’,5’-OAS activity, neopterin and beta 2-microglobulin) are induced by 
interferon beta-1a following subcutaneous doses administered to healthy volunteer subjects. Time to 
peak concentrations following a single subcutaneous injection were 24 to 48 hours for neopterin, beta-2-
microglobulin and 2’5’OAS, 12 hours for MX1 and 24 hours for OAS1 and 
OAS2 gene expression. Peaks of similar height and time were observed for most of these markers after 
first and sixth administration. 
 
The precise mechanism of action of Rebif in multiple sclerosis is still under investigation. 
Relapsing-remitting multiple sclerosis 
The safety and efficacy of Rebif has been evaluated in patients with relapsing-remitting multiple sclerosis 
at doses ranging from 11 to 44 micrograms (3-12 million IU), administered subcutaneously three times per 
week. At licensed posology, Rebif 22 micrograms has been demonstrated to decrease the incidence 
(approximately 30% over 2 years) and severity of clinical relapses in patients with at least 2 exacerbations 
in the previous 2 years and with an EDSS of 0-5.0 at entry. The proportion of patients with disability 
progression, as defined by at least one point increase in EDSS confirmed 
three months later, was reduced from 39% (placebo) to 30% (Rebif 22 micrograms). Over 4 years, the 
reduction in the mean exacerbation rate was 22% in patients treated with Rebif 22 micrograms, and 29% in 
patients treated with Rebif 44 micrograms group compared with a group of patients treated with placebo for 
2 years and then either Rebif 22 or Rebif 44 micrograms for 2 years. 
 
Secondary progressive multiple sclerosis 
 
In a 3-year study in patients with secondary progressive multiple sclerosis (EDSS 3-6.5) with evidence of 
clinical progression in the preceding two years and who had not experienced relapses in the preceding 8 
weeks, Rebif had no significant effect on progression of disability, but relapse rate was reduced by 
approximately 30%. If the patient population was divided into 2 subgroups (those with and those without 
relapses in the 2-year period prior to study entry), there was no effect on disability in patients without 
relapses, but in patients with relapses, the proportion with progression in disability at the end of the study 
was reduced from 70% (placebo) to 57% (Rebif 22 micrograms and 
44 micrograms combined). These results obtained in a subgroup of patients a posteriori should be 
interpreted cautiously. 
 
Primary progressive multiple sclerosis 
 
Rebif has not yet been investigated in patients with primary progressive multiple sclerosis, and should not 
be used in these patients. 
 
5.2 Pharmacokinetic properties 

 
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Absorption 
In healthy volunteers after intravenous administration, interferon beta-1a exhibits a sharp 
multi-exponential decline, with serum levels proportional to the dose. Subcutaneous and intramuscular 
administrations of Rebif produce equivalent exposure to interferon beta. 
 
Distribution 
Following repeated subcutaneous injections of 22 and 44 micrograms doses of Rebif maximum 
concentrations were typically observed after 8 hours, but this was highly variable. 
 
Elimination 
After repeated subcutaneous doses in healthy volunteers, the main PK parameters (AUCtau and Cmax) 
increased proportional to the increased in dose from 22 micrograms to 44 micrograms. The estimated 
apparent half-life is 50 to 60 hours, which is in line with the accumulation observed after multiple dosing. 
 
Metabolism 
Interferon beta-1a is mainly metabolised and excreted by the liver and the kidneys. 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, 
repeated-dose toxicity, and genotoxicity. 
 
Rebif has not been investigated for carcinogenicity. 
 
A study on embryo/foetal toxicity in monkeys showed no evidence of reproductive disturbances. Based on 
observations with other alpha and beta interferons, an increased risk of abortions cannot be excluded. No 
information is available on the effects of the interferon beta-1a on male fertility. 
 
 
6. 
PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Mannitol  
Poloxamer 188  
L-methionine  
Benzyl alcohol  
Sodium acetate 
Acetic acid for pH adjustment  
Sodium hydroxide for pH adjustment  
Water for injections 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
18 months. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C – 8°C) away from the cooling element. Do not freeze. Store in the original 
package in order to protect from light. 
 
For the purpose of ambulatory use, the patient may remove Rebif from the refrigerator and store it not above 
25°C for one single period of up to 14 days. Rebif must then be returned to the refrigerator and used before 
the expiry date. 
 
6.5 Nature and contents of container 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
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One mL type 1 glass syringe, with a stainless steel needle, containing 0.5 mL solution. Rebif 
22 micrograms is available as a package of 1, 3 or 12 syringes. 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
The solution for injection in a pre-filled syringe is ready for use. It may also be administered with a suitable 
auto-injector. 
 
For single use only. Only clear to opalescent solution without particles and without visible signs of 
deterioration should be used. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. 
MARKETING AUTHORISATION HOLDER 
 
Merck Serono Europe Limited 
56, Marsh Wall 
London E14 9TP 
United Kingdom 
 
 
8. 
MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/98/063/001 
EU/1/98/063/002 
EU/1/98/063/003 
 
 
9. 
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 04 May 1998 
Date of latest renewal: 04 May 2008 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
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SmPC for Tecfidera 
 
1. 
NAME OF THE MEDICINAL PRODUCT 
 
Tecfidera 120 mg gastro-resistant hard capsules 
Tecfidera 240 mg gastro-resistant hard capsules 
 
 
2. 
QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Tecfidera 120mg capsule 
Each capsule contains 120 mg dimethyl fumarate. 
 
Tecfidera 240mg capsule 
Each capsule contains 240 mg dimethyl fumarate 
For the full list of excipients, see section 6.1. 
 
3. 
PHARMACEUTICAL FORM 
Gastro-resistant hard capsule 
Tecfidera 120mg capsule 
Green and white gastro-resistant hard capsule printed with ‘BG-12 120 mg’. 
 
Tecfidera 240mg capsule 
Green gastro-resistant hard capsule printed with ‘BG-12 240 mg’ 
 
 
4. 
CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Tecfidera is indicated for the treatment of adult patients with relapsing remitting multiple sclerosis (please 
refer to section 5.1 for important information on the populations for which efficacy has been established). 
 
4.2 Posology and method of administration 
 
Treatment should be initiated under supervision of a physician experienced in the treatment of the disease. 
 
Posology 
 
The starting dose is 120 mg twice a day. After 7 days, the dose is increased to the recommended dose of 
240 mg twice a day. 
 
Temporary dose reduction to 120 mg twice a day may reduce the occurrence of flushing and 
gastrointestinal adverse reactions. Within 1 month, the recommended dose of 240 mg twice a day should 
be resumed. 
 
Tecfidera should be taken with food (see section 5.2). For those patients who may experience flushing or 
gastrointestinal adverse reactions, taking Tecfidera with food may improve tolerability (see 
sections 4.4, 4.5 and 4.8). 
 
Elderly 
 
Clinical studies of Tecfidera had limited exposure to patients aged 55 years and above, and did not include 
sufficient numbers of patients aged 65 and over to determine whether they respond differently than 
younger patients (see section 5.2). Based on the mode of action of the active substance there are no 
theoretical reasons for any requirement for dose adjustments in the elderly. 
 
Renal and hepatic impairment 
 

 
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Tecfidera has not been studied in patients with renal or hepatic impairment. Based on clinical 
pharmacology studies, no dose adjustments are needed (see section 5.2). Caution should be used when 
treating patients with severe renal or severe hepatic impairment (see section 4.4). 
 
Paediatric population 
 
The safety and efficacy of Tecfidera in children and adolescents aged 10 to 18 years have not been 
established. No data are available. There is no relevant use of Tecfidera in children aged less than 10 
years for the indication of relapsing remitting multiple sclerosis. 
 
Method of administration 
 
For oral use. 
 
The capsule or its contents should not be crushed, divided, dissolved, sucked or chewed as the enteric- 
coating of the microtablets prevents irritant effects on the gut. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
4.4 Special warnings and precautions for use 
 
Blood/laboratory tests 
 
Changes in renal and hepatic laboratory tests have been seen in clinical trials in subjects treated with 
Tecfidera (see section 4.8). The clinical implications of these changes are unknown. Assessments of renal 
function (e.g. creatinine, blood urea nitrogen and urinalysis) and hepatic function (e.g. ALT and AST) are 
recommended prior to treatment initiation, after 3 and 6 months of treatment, every 6 to 
12 months thereafter and as clinically indicated. 
 
Patients treated with Tecfidera may develop severe prolonged lymphopaenia (see section 4.8). Tecfidera 
has not been studied in patients with pre-existing low lymphocyte counts and caution should be exercised 
when treating these patients. Prior to initiating treatment with Tecfidera, a current complete blood count, 
including lymphocytes, must be performed. If lymphocyte count is found to be below the normal range, 
thorough assessment of possible causes should be completed prior to initiation of treatment with 
Tecfidera. 
 
After starting therapy, complete blood counts, including lymphocytes, must be performed every 3 months. 
Consider interruption of Tecfidera in patients with lymphocyte counts <0.5x109/L persisting for more than 6 
months. The benefit/risk balance of the therapy should be reconsidered in discussion with the patient in the 
context of other therapeutic options available. Clinical factors, evaluation of any laboratory and imaging 
investigations could be included as part of this re-consideration. If treatment is continued despite a 
persistent lymphocyte count < 0.5x109/L, enhanced vigilance is recommended (see also subsection on 
PML). 
 
Lymphocyte counts should be followed until recovery. Upon recovery and in the absence of alternative 
treatment options, decisions about whether or not to restart Tecfidera after treatment discontinuation 
should be based on clinical judgement. 
 
MR imaging 
Before initiating treatment with Tecfidera, a baseline MRI should be available (usually within 3 months) as 
a reference. The need for further MRI scanning should be considered in accordance with national and 
local recommendations. MRI imaging may be considered as part of increased vigilance in patients 
considered at increased risk of PML.  In case of clinical suspicion of PML, MRI should be performed 
immediately for diagnostic purposes. 
 
Progressive Multifocal Leukoencephalopathy (PML) 
 
PML cases have occurred with Tecfidera and other products containing fumarates in the setting of severe 
and prolonged lymphopenia. PML is an opportunistic infection caused by John-Cunningham virus (JCV), 
which may be fatal or result in severe disability. PML can only occur in the presence of a JCV infection. If 

 
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JCV testing is undertaken, it should be considered that the influence of lymphopenia on the accuracy of 
anti-JCV antibody test has not been studied in Tecfidera treated patients. It should also be noted that a 
negative anti JCV antibody test (in the presence of normal lymphocyte counts) does not preclude the 
possibility of subsequent JCV infection. 
 
Prior treatment with immunosuppressive or immunomodulating therapies 
 
No studies have been performed evaluating the efficacy and safety of Tecfidera when switching patients 
from other disease modifying therapies to Tecfidera. The contribution of prior immunosuppressive therapy 
to the development of PML in Tecfidera treated patients is unknown. When switching patients from 
another disease modifying therapy to Tecfidera, the half-life and mode of action of the other therapy 
should be considered in order to avoid an additive immune effect while at the same time, reducing the risk 
of reactivation of MS. 
 
A complete blood count is recommended prior to initiating Tecfidera and regularly during treatment (see 
Blood/laboratory tests above). 
 
Tecfidera can generally be started immediately after discontinuation of interferon or glatiramer acetate. 
 
Severe renal and hepatic impairment 
 
Tecfidera has not been studied in patients with severe renal or severe hepatic impairment and caution 
should, therefore, be used in these patients (see section 4.2). 
 
Severe active gastrointestinal disease 
 
Tecfidera has not been studied in patients with severe active gastrointestinal disease and caution should, 
therefore, be used in these patients. 
 
Flushing 
 
In clinical trials, 34% of Tecfidera treated patients experienced flushing. In the majority of patients who 
experienced flushing, it was mild or moderate in severity. 
 
In clinical trials, 3 patients out of a total of 2,560 patients treated with Tecfidera experienced serious 
flushing symptoms that were probable hypersensitivity or anaphylactoid reactions. These events were not 
life-threatening, but led to hospitalisation. Prescribers and patients should be alert to this possibility in the 
event of severe flushing reactions (see sections 4.2, 4.5 and 4.8). 
 
Infections 
 
In phase III placebo-controlled studies, the incidence of infections (60% vs 58%) and serious infections 
(2% vs 2%) was similar in patients treated with Tecfidera or placebo, respectively. There was no 
increased incidence of serious infections observed in patients with lymphocyte counts <0.8x109/L or 
<0.5x109/L. During treatment with Tecfidera in the MS placebo controlled trials, mean lymphocyte counts 
decreased by approximately 30% from baseline at one year and then plateaued (see section 4.8). Mean 
lymphocyte counts remained within normal limits. Patients with lymphocyte counts <0.5x109/L were 
observed in <1% of patients treated with placebo and 6% of patients treated with Tecfidera.  In clinical 
studies (both controlled and uncontrolled), 2% of patients experienced lymphocyte counts <0.5 x 109/L for 
at least six months. In these patients, the majority of lymphocyte counts remained <0.5 x 109/L with 
continued therapy. 
 
If therapy is continued in the presence of severe prolonged lymphopenia, the risk of an opportunistic 
infection, including Progressive Multifocal Leukoencephalopathy (PML) cannot be ruled out (please refer 
to subsection PML above for further details). 
 
If a patient develops a serious infection, suspending treatment with Tecfidera should be considered and 
the benefits and risks should be reassessed prior to re-initiation of therapy. Patients receiving Tecfidera 
should be instructed to report symptoms of infections to a physician. Patients with serious infections 
should not start treatment with Tecfidera until the infection(s) is resolved. 

 
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4.5 Interaction with other medicinal products and other forms of interaction 
 
Tecfidera has not been studied in combination with anti-neoplastic or immunosuppressive therapies and 
caution should, therefore, be used during concomitant administration. In multiple sclerosis clinical studies, 
the concomitant treatment of relapses with a short course of intravenous corticosteroids was not 
associated with a clinically relevant increase of infection. 
 
Vaccination during treatment with Tecfidera has not been studied. It is not known whether treatment with 
Tecfidera might reduce the effectiveness of some vaccines. Live vaccines might carry an increased risk of 
clinical infection and should not be given to patients treated with Tecfidera unless, in exceptional cases, 
this potential risk is considered to be outweighed by the risk to the individual of not vaccinating. 
 
During treatment with Tecfidera, simultaneous use of other fumaric acid derivatives (topical or systemic) 
should be avoided. 
 
In humans, dimethyl fumarate is extensively metabolised by esterases before it reaches the systemic 
circulation and further metabolism occurs through the tricarboxylic acid cycle, with no involvement of the 
cytochrome P450 (CYP) system. Potential drug interaction risks were not identified from in vitro CYP-
inhibition and induction studies, a p-glycoprotein study, or studies of the protein binding of dimethyl 
fumarate and monomethyl fumarate (a primary metabolite of dimethyl fumarate). 
 
Commonly used medicinal products in patients with multiple sclerosis, intramuscular interferon 
beta-1a and glatiramer acetate, were clinically tested for potential interactions with dimethyl fumarate and 
did not alter the pharmacokinetic profile of dimethyl fumarate. 
 
Administration of 325 mg (or equivalent) non-enteric coated acetylsalicylic acid, 30 minutes prior to 
Tecfidera, over 4 days of dosing, did not alter the pharmacokinetic profile of Tecfidera and reduced the 
occurrence and severity of flushing in a healthy volunteer study. However, long term use of acetylsalicylic 
acid is not recommended for the management of flushing. Potential risks associated with acetylsalicylic 
acid therapy should be considered prior to co-administration with Tecfidera. (see sections 4.2, 4.4 and 
4.8). 
 
Concurrent therapy with nephrotoxic medicinal products (such as aminoglycosides, diuretics, NSAIDs or 
lithium) may increase the potential of renal adverse reactions (e.g. proteinuria) in patients taking Tecfidera 
(see section 4.8). 
 
Consumption of moderate amounts of alcohol did not alter exposure to Tecfidera and was not associated 
with an increase in adverse reactions. Consumption of large quantities of undiluted strong alcoholic drinks 
(more than 30% alcohol by volume) may lead to increased dissolution rates of Tecfidera and, therefore, 
may increase the frequency of gastrointestinal adverse reactions. 
 
In vitro CYP induction studies did not demonstrate an interaction between Tecfidera and oral 
contraceptives. In vivo interaction studies have not been performed with oral contraceptives. Even 
though an interaction is not expected, non-hormonal contraceptive measures should be considered 
with Tecfidera (see section 4.6). 
 
Paediatric population 
 
Interaction studies have only been performed in adults. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
There are no or limited amount of data from the use of dimethyl fumarate in pregnant women. Animal 
studies have shown reproductive toxicity (see section 5.3). Tecfidera is not recommended during 
pregnancy and in women of childbearing potential not using appropriate contraception (see 
section 4.5). Tecfidera should be used during pregnancy only if clearly needed and if the potential benefit 
justifies the potential risk to the foetus. 
 
Breast-feeding 
 

 
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It is unknown whether dimethyl fumarate or its metabolites are excreted in human milk. A risk to the 
newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or 
to discontinue Tecfidera therapy. The benefit of breast-feeding for the child and the benefit of therapy for 
the woman should be taken into account. 
 
Fertility 
 
There are no data on the effects of Tecfidera on human fertility. Data from preclinical studies do not 
suggest that dimethyl fumarate would be associated with an increased risk of reduced fertility (see section 
5.3). 
 
4.7 Effects on ability to drive and use machines 
 
No studies on the ability to drive and use machines have been conducted. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The most common adverse reactions (incidence ≥10%) for patients treated with Tecfidera were flushing 
and gastrointestinal events (i.e. diarrhoea, nausea, abdominal pain, abdominal pain upper). Flushing and 
gastrointestinal events tend to begin early in the course of treatment (primarily during the first month) and 
in patients who experience flushing and gastrointestinal events, these events may continue to occur 
intermittently throughout treatment with Tecfidera. The most commonly reported adverse reactions leading 
to discontinuation (incidence >1%) in patients treated with Tecfidera were flushing (3%) and 
gastrointestinal events (4%). 
 
In placebo-controlled and uncontrolled clinical studies, a total of 2,468 patients have received Tecfidera 
and been followed for periods up to 4 years with an overall exposure equivalent to 3,588 person-years. 
Approximately 1,056 patients have received more than 2 years of treatment with Tecfidera. The 
experience in uncontrolled clinical trials is consistent with the experience in the placebo-controlled clinical 
trials. 
 
Tabulated summary of adverse reactions 
 
Adverse reactions, which were more frequently reported in Tecfidera versus placebo-treated patients, are 
presented in the table below. These data were derived from 2 pivotal Phase 3 placebo-controlled, double-
blind clinical trials with a total of 1,529 patients treated with Tecfidera and for up to 24 months with an 
overall exposure of 2,371 person-years (see section 5.1). The frequencies described in the table below are 
based on 769 patients treated with Tecfidera 240 mg twice a day and 771 patients treated with placebo. 
 
The adverse reactions are presented as MedDRA preferred terms under the MedDRA System Organ 
Class. The incidence of the adverse reactions below are expressed according to the following categories: 
- 
Very common (≥1/10) 
- 
Common (≥1/100 to <1/10) 
- 
Uncommon (≥1/1, 000 to <1/100) 
- 
Rare (≥1/10, 000 to <1/1,000) 
- 
Very rare (<1/10,000) 
- 
Not known (cannot be estimated from the available data) 
 
MedDRA System Organ Class 
Adverse reaction 
Frequency category 
Infections and infestations 
Gastroenteritis 
Common 
Progressive multifocal 
leukoencephalopathy 
(PML) 
Not known 
Blood and lymphatic system 
disorders 
Lymphopenia 
Common 
Leucopenia 
Common 
Immune system disorders 
Hypersensitivity 
Uncommon 
Nervous system disorders 
Burning sensation 
Common 
Vascular disorders 
Flushing 
Very common 
Hot flush 
Common 

 
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MedDRA System Organ Class 
Adverse reaction 
Frequency category 
Gastrointestinal disorders 
Diarrhoea 
Very common 
Nausea 
Very common 
Abdominal pain upper 
Very common 
Abdominal pain 
Very common 
Vomiting 
Common 
Dyspepsia 
Common 
Gastritis 
Common 
Gastrointestinal disorder 
Common 
Skin and subcutaneous tissue 
disorders 
Pruritus 
Common 
Rash 
Common 
Erythema 
Common 
Renal and urinary disorders 
Proteinuria 
Common 
General disorders and 
administration site conditions 
Feeling hot 
Common 
Investigations 
Ketones measured in urine 
Very common 
Albumin urine present 
Common 
Aspartate aminotransferase increased Common 
Alanine aminotransferase increased 
Common 
White blood cell count decreased 
Common 
 
 
Description of selected adverse reactions 
 
Flushing 
 
In the placebo-controlled studies, the incidence of flushing (34% versus 4%) and hot flush 
(7% versus 2%) was increased in patients treated with Tecfidera compared to placebo, respectively. 
 
Flushing is usually described as flushing or hot flush, but can include other events (e.g. warmth, redness, 
itching, and burning sensation). Flushing events tend to begin early in the course of treatment (primarily 
during the first month) and in patients who experience flushing, these events may continue to occur 
intermittently throughout treatment with Tecfidera. In patients with flushing, the majority had flushing 
events that were mild or moderate in severity. Overall, 3% of patients treated with Tecfidera discontinued 
due to flushing. The incidence of serious flushing, which may be characterised by generalised erythema, 
rash and/or pruritus, was seen in less than 1% of patients treated with Tecfidera (see sections 4.2, 4.4 and 
4.5). 
 
Gastrointestinal 
 
The incidence of gastrointestinal events (e.g. diarrhoea [14% versus 10%], nausea [12% versus 9%], 
upper abdominal pain [10% versus 6%], abdominal pain [9% versus 4%], vomiting [8% versus 5%] and 
dyspepsia [5% versus 3%]) was increased in patients treated with Tecfidera compared to placebo, 
respectively. Gastrointestinal events tend to begin early in the course of treatment (primarily during the 
first month) and in patients who experience gastrointestinal events, these events may continue to occur 
intermittently throughout treatment with Tecfidera. In the majority of patients who experienced 
gastrointestinal events, it was mild or moderate in severity. Four per cent (4%) of patients treated with 
Tecfidera discontinued due to gastrointestinal events. The incidence of serious gastrointestinal events, 
including gastroenteritis and gastritis, was seen in 1% of patients treated with Tecfidera (see 
section 4.2). 
 
Hepatic transaminases 
 
In placebo-controlled studies, elevations of hepatic transaminases were observed. The majority of 
patients with elevations had hepatic transaminases that were <3 times the upper limit of normal (ULN). 
The increased incidence of elevations of hepatic transaminases in patients treated with Tecfidera relative 
to placebo was primarily seen during the first 6 months of treatment. Elevations of alanine 
aminotransferase and aspartate aminotransferase ≥3 times ULN, respectively, were seen in 5% and 2% 
of patients treated with placebo and 6% and 2% of patients treated with Tecfidera. There were no 
elevations in transaminases ≥3 times ULN with concomitant elevations in total bilirubin 

 
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>2 times ULN. Discontinuations due to elevated hepatic transaminases were <1% and similar in patients 
treated with Tecfidera or placebo. 
 
Renal 
 
In placebo-controlled studies, the incidence of proteinuria was higher in patients treated with Tecfidera (9%) 
compared to placebo (7%). The overall incidence of renal and urinary adverse events was similar for 
Tecfidera and placebo-treated patients. There were no reports of serious renal failure. On 
urinalysis, the percentage of patients with protein values of 1+ or greater was similar for Tecfidera (43%) 
and placebo-treated patients (40%). Typically, laboratory observations of proteinuria were not progressive. 
Compared to patients treated with placebo, estimated glomerular filtration rate (eGFR) was observed to 
increase in patients treated with Tecfidera, including those patients with 2 consecutive occurrences of 
proteinuria (≥1+). 
 
Haematological 
 
In the placebo-controlled studies, most patients (>98%) had normal lymphocyte values prior to initiating 
treatment. Upon treatment with Tecfidera, mean lymphocyte counts decreased over the first year with a 
subsequent plateau. On average, lymphocyte counts decreased by approximately 30% of baseline value. 
Mean and median lymphocyte counts remained within normal limits. Lymphocyte counts <0.5x109/l were 
observed in <1% of patients treated with placebo and 6% of patients treated with Tecfidera. A lymphocyte 
count <0.2x109/l was observed in 1 patient treated with Tecfidera and in no patients treated with 
placebo.The incidence of infections (58% versus 60%) and serious infections (2% versus 2%) was similar 
in patients treated with placebo or Tecfidera. An increased incidence of infections and serious infections 
was not observed in patients with lymphocyte counts <0.8x109/l or 
<0.5x109/l. PML has occurred in the setting of severe and prolonged lymphopenia (please refer to section 
4.4). A transient increase in mean eosinophil counts was seen during the first 2 months of therapy. 
 
 
Laboratory abnormalities 
 
In the placebo-controlled studies, measurement of urinary ketones (1+ or greater) was higher in patients 
treated with Tecfidera (45%) compared to placebo (10%). No untoward clinical consequences were 
observed in clinical trials. 
 
Levels of 1,25-dihydroxyvitamin D decreased in Tecfidera treated patients relative to placebo (median 
percentage decrease from baseline at 2 years of 25% versus 15%, respectively) and levels of parathyroid 
hormone (PTH) increased in Tecfidera treated patients relative to placebo (median percentage increase 
from baseline at 2 years of 29% versus 15%, respectively). Mean values for both parameters remained 
within normal range. 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows 
continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are 
asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 
 
4.9 Overdose 
 
No cases of overdose have been reported. 
 
 
5. 
PHARMACOLOGICAL PROPERTIES 
 
5.1 
Pharmacodynamic properties 
 
Pharmacotherapeutic group: Other nervous system drugs, ATC code: N07XX09 
 
Mechanism of action 
The mechanism by which dimethyl fumarate exerts therapeutic effects in multiple sclerosis is not fully 
understood. Preclinical studies indicate that dimethyl fumarate pharmacodynamic responses appear to be 
primarily mediated through activation of the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) transcriptional 

 
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pathway. Dimethyl fumarate has been shown to up regulate Nrf2-dependent antioxidant genes in patients 
(e.g. NAD(P)H dehydrogenase, quinone 1; [NQO1]). 
 
Pharmacodynamic effects 
 
Effects on the immune system 
 
In preclinical and clinical studies, Tecfidera demonstrated anti-inflammatory and immunomodulatory 
properties. Dimethyl fumarate and monomethyl fumarate, the primary metabolite of dimethyl fumarate, 
significantly reduced immune cell activation and subsequent release of pro-inflammatory cytokines in 
response to inflammatory stimuli in preclinical models. In clinical studies with psoriasis patients, dimethyl 
fumarate affected lymphocyte phenotypes through a down-regulation of pro- inflammatory cytokine 
profiles (TH1, TH17), and biased towards anti-inflammatory production (TH2). Dimethyl fumarate 
demonstrated therapeutic activity in multiple models of inflammatory and neuroinflammatory injury. In 
Phase 3 studies, upon treatment with Tecfidera mean lymphocyte counts decreased on average by 
approximately 30% of their baseline value over the first year with a subsequent plateau. 
 
Effect on cardiovascular system 
 
Single doses of 240 mg or 360 mg Tecfidera did not have any effect on the QTc interval when compared to 
placebo in a QTc study. 
 
Clinical efficacy and safety 
 
Two, 2-year, randomised, double-blind, placebo controlled studies [Study 1 (DEFINE) with 1234 
subjects and Study 2 (CONFIRM) with 1417 subjects] of subjects with relapsing-remitting multiple 
sclerosis (RRMS) were performed. Subjects with progressive forms of MS were not included in 
these studies. Efficacy (see table below) and safety were demonstrated in subjects with Expanded 
Disability Status Scale (EDSS) scores ranging from 0 to 5 inclusive, who had experienced at least 1 
relapse during the year prior to randomisation, or, within 6 weeks of randomisation had a brain 
Magnetic Resonance Imaging (MRI) demonstrating at least one gadolinium-enhancing (Gd+) lesion. 
Study 2 contained a rater-blinded (i.e. study physician/ investigator assessing the response to study 
treatment was blinded) reference comparator of glatiramer acetate. 
 
In Study 1, patients had the following median baseline characteristics: age 39 years, disease duration 7.0 
years, EDSS score 2.0. In addition, 16% of patients had an EDSS score >3.5, 28% had ≥2 relapses in the 
prior year and 42% had previously received other approved MS treatments. In the MRI cohort 36% of 
patients entering the study had Gd+ lesions at baseline (mean number of Gd+ lesions 1.4). 
 
In Study 2, patients had the following median baseline characteristics: age 37 years, disease duration 
6.0 years, EDSS score 2.5. In addition, 17% of patients had an EDSS score >3.5, 32% had 
≥2 relapses in the prior year and 30% had previously received other approved MS treatments. In the MRI 
cohort 45% of patients entering the study had Gd+ lesions at baseline (mean number of Gd+ lesions 2.4). 
 
Compared to placebo, subjects treated with Tecfidera had a clinically meaningful and statistically significant 
reduction on: the primary endpoint in Study 1, proportion of subjects relapsed at 2 years; and the primary 
endpoint in Study 2, annualised relapse rate at 2 years. 
 
The annualised relapse rate for glatiramer acetate and placebo was 0.286 and 0.401 respectively in 
Study 2, corresponding to a reduction of 29% (p=0.013), which is consistent with approved prescribing 
information. 
 
 
DEFINE 
CONFIRM 
Placebo 
Tecfidera 
240 mg 
twice a 
day 
Placebo 
Tecfidera 
240 mg 
twice a day 
Glatiramer 
acetate 
Clinical Endpointsa 
No. subjects 
408 
410 
363 
359 
350 
Annualised relapse rate 
0.364 
0.172*** 
0.401 
0.224*** 
0.286* 
Rate ratio 
 
0.47 
0.56 
0.71 

 
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DEFINE 
CONFIRM 
Placebo 
Tecfidera 
240 mg 
twice a 
day 
Placebo 
Tecfidera 
240 mg 
twice a day 
Glatiramer 
acetate 
(95% CI) 
(0.37, 0.61) 
(0.42, 0.74) 
(0.55, 0.93) 
Proportion relapsed 
0.461 
0.270*** 
0.410 
0.291** 
0.321** 
Hazard ratio 
(95% CI) 
 
0.51 
(0.40, 0.66) 
0.66 
(0.51, 0.86) 
0.71 
(0.55, 0.92) 
Proportion with 12-week 
confirmed disability 
progression 
0.271 
0.164** 
0.169 
0.128# 
0.156# 
Hazard ratio 
(95% CI) 
 
0.62 
(0.44, 0.87) 
0.79 
(0.52, 1.19) 
0.93 
(0.63, 1.37) 
Proportion with 24 week 
confirmed disability 
progression 
0.169 
0.128# 
0.125 
0.078# 
0.108# 
Hazard ratio 
(95% CI) 
 
0.77 
(0.52, 1.14) 
0.62 
(0.37, 1.03) 
0.87 
(0.55, 1.38) 
MRI Endpointsb 
No. subjects 
165 
152 
144 
147 
161 
Mean (median) number of 
new or newly enlarging T2 
lesions over 2 years 
16.5 
(7.0) 
3.2 
(1.0)*** 
19.9 
(11.0) 
5.7 
(2.0)*** 
9.6 
(3.0)*** 
Lesion mean ratio 
(95% CI) 
 
0.15 
(0.10, 0.23) 
0.29 
(0.21, 0.41) 
0.46 
(0.33, 0.63) 
Mean (median) number of 
Gd lesions at 2 years 
1.8 
(0) 
0.1 
(0)*** 
2.0 
(0.0) 
0.5 
(0.0)*** 
0.7 
(0.0)** 
Odds ratio 
(95% CI) 
 
0.10 
(0.05, 0.22) 
0.26 
(0.15, 0.46) 
0.39 
(0.24, 0.65) 
Mean (median) number of 
new T1 hypointense lesions 
over 2 years 
5.7 
(2.0) 
2.0 
(1.0)*** 
8.1 
(4.0) 
3.8 
(1.0)*** 
4.5 
(2.0)** 
Lesion mean ratio 
(95% CI) 
 
0.28 
(0.20, 0.39) 
0.43 
(0.30, 0.61) 
0.59 
(0.42, 0.82) 
aAll analyses of clinical endpoints were intent-to-treat; bMRI analysis used MRI cohort 
*P-value < 0.05; **P-value < 0.01; ***P-value < 0.0001; #not statistically significant 
 
Efficacy in patients with high disease activity: 
Consistent treatment effect on relapses in a subgroup of patients with high disease activity was 
observed, whilst the effect on time to 3-month sustained disability progression was not clearly 
established. Due to the design of the studies, high disease activity was defined as follows: 
- 
Patients with 2 or more relapses in one year, and with one or more Gd-enhancing lesions on 
brain MRI (n=42 in DEFINE; n=51 in CONFIRM) or, 
- 
Patients who have failed to respond to a full and adequate course (at least one year of treatment) 
of beta-interferon, having had at least 1 relapse in the previous year while on therapy, and at least 
9 T2-hyperintense lesions in cranial MRI or at least 1 Gd-enhancing lesion, or patients having an 
unchanged or increased relapse rate in the prior year as compared to the previous 2 years (n=177 
in DEFINE; n=141 in CONFIRM). 
 
Paediatric population 
 
The European Medicines Agency has deferred the obligation to submit the results of studies with Tecfidera 
in one or more subsets of the paediatric population in multiple sclerosis (see section 4.2 for information on 
paediatric use). 
 
5.2 Pharmacokinetic properties 

 
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Orally administered Tecfidera (dimethyl fumarate) undergoes rapid presystemic hydrolysis by esterases 
and is converted to its primary metabolite, monomethyl fumarate, which is also active. Dimethyl fumarate is 
not quantifiable in plasma following oral administration of Tecfidera. Therefore, all pharmacokinetic 
analyses related to dimethyl fumarate were performed with plasma monomethyl fumarate concentrations. 
Pharmacokinetic data were obtained in subjects with multiple sclerosis and healthy volunteers. 
 
Absorption 
 
The Tmax of monomethyl fumarate is 2 to 2.5 hours. As Tecfidera gastro-resistant hard capsules contain 
microtablets, which are protected by an enteric coating, absorption does not commence until they leave 
the stomach (generally less than 1 hour). Following 240 mg twice a day administered with food, the median 
peak (Cmax) was 1.72 mg/l and overall (AUC) exposure was 8.02 h.mg/l in subjects with multiple 
sclerosis. Overall, Cmax and AUC increased approximately dose- proportionally in the dose range studied 
(120 mg to 360 mg). In subjects with multiple sclerosis, two 240 mg doses were administered 4 hours 
apart as part of a three times a day dosing regimen. This resulted in a minimal accumulation of exposure 
yielding an increase in the median Cmax of 12% compared to the twice daily dosing (1.72 mg/l for twice 
daily compared to 1.93 mg/l for three times daily) with no safety implications. 
 
Food does not have a clinically significant effect on exposure of dimethyl fumarate. However, Tecfidera 
should be taken with food due to improved tolerability with respect to flushing or gastrointestinal adverse 
events (see section 4.2). 
 
Distribution 
 
The apparent volume of distribution following oral administration of 240 mg Tecfidera varies between 60 L 
and 90 L. Human plasma protein binding of monomethyl fumarate generally ranges between 
27% and 40%. 
Biotransformation 
In humans, dimethyl fumarate is extensively metabolised with less than 0.1% of the dose excreted as 
unchanged dimethyl fumarate in urine. It is initially metabolised by esterases, which are ubiquitous in the 
gastrointestinal tract, blood and tissues, before it reaches the systemic circulation. Further metabolism 
occurs through the tricarboxylic acid cycle, with no involvement of the cytochrome P450 (CYP) system. A 
single 240 mg 14C-dimethyl fumarate dose study identified glucose as the predominant metabolite in 
human plasma. Other circulating metabolites included fumaric acid, citric acid and monomethyl fumarate. 
The downstream metabolism of fumaric acid occurs through the tricarboxylic acid cycle, with exhalation of 
CO2 serving as a primary route of elimination. 
 
Elimination 
 
Exhalation of CO2 is the primary route of dimethyl fumarate elimination accounting for 60% of the dose. 
Renal and faecal elimination are secondary routes of elimination, accounting for 15.5% and 0.9% of the 
dose respectively. 
 
The terminal half-life of monomethyl fumarate is short (approximately 1 hour) and no circulating 
monomethyl fumarate is present at 24 hours in the majority of individuals. Accumulation of parent drug or 
monomethyl fumarate does not occur with multiple doses of dimethyl fumarate at the therapeutic regimen. 
 
Linearity 
 
Dimethyl fumarate exposure increases in an approximately dose proportional manner with single and 
multiple doses in the 120 mg to 360 mg dose range studied. 
 
Pharmacokinetics in special patient groups 
 
Based on the results of Analysis of Variance (ANOVA), body weight is the main covariate of exposure (by 
Cmax and AUC) in relapsing remitting multiple sclerosis (RRMS) subjects, but did not affect safety and 
efficacy measures evaluated in the clinical studies. 
 
Gender and age did not have a clinically significant impact on the pharmacokinetics of dimethyl fumarate. 
The pharmacokinetics in patients aged 65 and over has not been studied. 

 
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Paediatric population 
 
The pharmacokinetics in patients below the age of 18 has not been studied.  
 
Renal impairment 
 
Since the renal pathway is a secondary route of elimination for dimethyl fumarate accounting for less than 
16% of the dose administered, evaluation of pharmacokinetics in individuals with renal impairment was not 
conducted. 
 
Hepatic impairment 
 
As dimethyl fumarate and monomethyl fumarate are metabolised by esterases, without the involvement of 
the CYP450 system, evaluation of phamacokinetics in individuals with hepatic impairment was not 
conducted. 
 
5.3 Preclinical safety data 
 
The adverse reactions described in the Toxicology and Reproduction toxicity sections below were not 
observed in clinical studies, but were seen in animals at exposure levels similar to clinical exposure levels. 
 
Mutagenesis 
 
Dimethyl fumarate and mono-methylfumarate were negative in a battery of in vitro assays (Ames, 
chromosomal aberration in mammalian cells). Dimethyl fumarate was negative in the in vivo micronucleus 
assay in the rat. 
 
Carcinogenesis 
 
Carcinogenicity studies of dimethyl fumarate were conducted for up to 2 years in mice and rats. Dimethyl 
fumarate was administered orally at doses of 25, 75, 200 and 400 mg/kg/day in mice, and at doses of 25, 
50, 100, and 150 mg/kg/day in rats. In mice, the incidence of renal tubular carcinoma was increased at 75 
mg/kg/day, at equivalent exposure (AUC) to the recommended human dose. In rats, the incidence of renal 
tubular carcinoma was increased at 100 mg/kg/day, approximately 3 times higher exposure than the 
recommended human dose. The relevance of these findings to human risk is unknown. 
 
The incidence of squamous cell papilloma and carcinoma in the nonglandular stomach (forestomach) was 
increased at equivalent exposure to the recommended human dose in mice and below exposure to the 
recommended human dose in rats (based on AUC). The forestomach in rodents does not have a human 
counterpart. 
 
Toxicology 
 
Nonclinical studies in rodent, rabbits, and monkeys were conducted with a dimethyl fumarate suspension 
(dimethyl fumarate in 0.8% hydroxypropyl methylcellulose) administered by oral gavage. The chronic dog 
study was conducted with oral administration of the dimethyl fumarate capsule. 
 
Kidney changes were observed after repeated oral administration of dimethyl fumarate in mice, rats, dogs, 
and monkeys. Renal tubule epithelial regeneration, suggestive of injury, was observed in all species. Renal 
tubular hyperplasia was observed in rats with life time dosing (2-year study). Cortical atrophy was 
observed in dogs and monkeys, and single cell necrosis and interstitial fibrosis were observed in monkeys 
that received daily oral doses of dimethyl fumarate for 12 months, at 6 times the recommended dose 
based on AUC. The relevance of these findings to humans is not known. 
 
In the testes, degeneration of the seminiferous epithelium was seen in rats and dogs. The findings were 
observed at approximately the recommended dose in rats and 6 times the recommended dose in dogs 
(AUC basis). The relevance of these findings to humans is not known. 
 
Findings in the forestomach of mice and rats consisted of squamous epithelial hyperplasia and 
hyperkeratosis; inflammation; and squamous cell papilloma and carcinoma in studies of 3 months or 
longer in duration. The forestomach of mice and rats does not have a human counterpart. 
 

 
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Reproduction toxicity 
 
Oral administration of dimethyl fumarate to male rats at 75, 250, and 375 mg/kg/day prior to and during 
mating had no effects on male fertility up to the highest dose tested (at least 2 times the recommended 
dose on an AUC basis). Oral administration of dimethyl fumarate to female rats at 
25, 100, and 250 mg/kg/day prior to and during mating, and continuing to Day 7 of gestation, induced 
reduction in the number of estrous stages per 14 days and increased the number of animals with 
prolonged diestrus at the highest dose tested (11 times the recommended dose on an AUC basis). 
However, these changes did not affect fertility or the number of viable fetuses produced. 
 
Dimethyl fumarate has been shown to cross the placental membrane into fetal blood in rats and rabbits, 
with ratios of fetal to maternal plasma concentrations of 0.48 to 0.64 and 0.1 respectively. No 
malformations were observed at any dose of dimethyl fumarate in rats or rabbits. Administration of 
dimethyl fumarate at oral doses of 25, 100, and 250 mg/kg/day to pregnant rats during the period of 
organogenesis resulted in maternal adverse effects at 4 times the recommended dose on an AUC basis, 
and low fetal weight and delayed ossification (metatarsals and hindlimb phalanges) at 11 times the 
recommended dose on an AUC basis. The lower fetal weight and delayed ossification were considered 
secondary to maternal toxicity (reduced body weight and food consumption). 
 
Oral administration of dimethyl fumarate at 25, 75, and 150 mg/kg/day to pregnant rabbits during 
organogenesis had no effect on embryo-fetal development and resulted in reduced maternal body weight 
at 7 times the recommended dose and increased abortion at 16 times the recommended dose, on an 
AUC basis. 
 
Oral administration of dimethyl fumarate at 25, 100, and 250 mg/kg/day to rats during pregnancy and 
lactation resulted in lower body weights in the F1 offspring, and delays in sexual maturation in F1 males at 
11 times the recommended dose on an AUC basis. There were no effects on fertility in the F1 offspring. 
The lower offspring body weight was considered secondary to maternal toxicity. 
 
 
6. 
PHARMACEUTICAL PARTICULARS 
 
6.1 
List of excipients 
 
Enteric-coated microtablets 
 
Microcrystalline cellulose  
Croscarmellose sodium  
Talc 
Silica, colloidal anhydrous  
Magnesium stearate  
Triethyl citrate 
Methacrylic acid – methyl methacrylate copolymer (1:1)  
Methacrylic acid – ethyl acrylate copolymer (1:1) dispersion 30% 
Simeticone 
Sodium laurilsulfate 
Polysorbate 80 
 
Capsule shell 
 
Gelatin 
Titanium dioxide (E171) 
Brilliant Blue FCF 
(E133) 
Yellow iron oxide (E172)  
 
Capsule print (black ink) 
Shellac 
Potassium hydroxide 
Black iron oxide (E172) 
 
6.2 Incompatibilities 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
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Not applicable. 
 
6.3 Shelf life 
 
120 mg gastro-resistant hard capsules: 4 years 240 
mg gastro-resistant hard capsules: 3 years 
 
 
6.4 Special precautions for storage 
 
Do not store above 30ºC. 
Keep the blisters in the outer carton in order to protect from light. 
 
6.5 Nature and contents of container 
 
120 mg capsules: 14 capsules in PVC/PE/PVDC-PVC aluminium blister packs. 
240 mg capsules: 56 or 168 capsules in PVC/PE/PVDC-PVC aluminium blister packs. Not all 
pack sizes may be marketed. 
6.6 Special precautions for disposal 
 
No special requirements. 
 
 
7. 
MARKETING AUTHORISATION HOLDER 
 
Biogen Idec Ltd 
Innovation House 
70 Norden Road 
Maidenhead 
Berkshire 
SL6 4AY 
United Kingdom 
 
 
8. 
MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/13/837/001 
EU/1/13/837/002 
EU/1/13/837/003 
 
 
9. 
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 30 January 2014 
 
10. DATE OF REVISION OF THE TEXT 
 
{MM/YYYY} 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 

 
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SmPC for Tysabri 
 
 
1. 
NAME OF THE MEDICINAL PRODUCT 
 
TYSABRI 300 mg concentrate for solution for infusion 
 
 
2. 
QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each ml of concentrate contains 20 mg of natalizumab. 
 
When diluted (see section 6.6), the solution for infusion contains approximately 2.6 mg/ml of 
natalizumab. 
 
Natalizumab is a recombinant humanised anti-α4-integrin antibody produced in a murine cell line by 
recombinant DNA technology. 
 
 
Excipient with known effect 
 
Each vial contains 2.3 mmol (or 52 mg) sodium. When diluted in 100 ml sodium chloride 9 mg/ml (0.9) 
the medicinal product contains 17.7 mmol (or 406 mg) sodium. 
 
For the full list of excipients, see section 6.1. 
 
 
3. 
PHARMACEUTICAL FORM  
Concentrate for solution for infusion. 
Colourless, clear to slightly opalescent 
solution. 
 
4. 
CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
TYSABRI is indicated as single disease modifying therapy in highly active relapsing remitting multiple 
sclerosis for the following patient groups: 
 
• 
Adult patients aged 18 years and over with high disease activity despite treatment with a beta- 
interferon or glatiramer acetate. 
 
These patients may be defined as those who have failed to respond to a full and adequate course 
(normally at least one year of treatment) of beta-interferon or glatiramer acetate. Patients should 
have had at least 1 relapse in the previous year while on therapy, and have at least 9 
T2-hyperintense lesions in cranial Magnetic Resonance Image (MRI) or at least 1 
Gadolinium-enhancing lesion. A “non-responder” could also be defined as a patient with an 
unchanged or increased relapse rate or ongoing severe relapses, as compared to the previous 
year. 
 
or 
 
• 
Adult patients aged 18 years and over with rapidly evolving severe relapsing remitting multiple 
sclerosis defined by 2 or more disabling relapses in one year, and with 1 or more Gadolinium 
enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a 
previous recent MRI. 
 
4.2 Posology and method of administration 
 
TYSABRI therapy is to be initiated and continuously supervised by specialised physicians experienced in 
the diagnosis and treatment of neurological conditions, in centres with timely access to MRI. 

 
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Patients treated with TYSABRI must be given the patient alert card and be informed about the risks of the 
medicinal product (see also package leaflet). After 2 years of treatment, patients should be re- informed 
about the risks of TYSABRI, especially the increased risk of Progressive Multifocal Leukoencephalopathy 
(PML), and should be instructed together with their caregivers on early signs and symptoms of PML. 
 
Resources for the management of hypersensitivity reactions and access to MRI should be available. 
 
Patients can switch directly from beta interferon or glatiramer acetate to natalizumab providing there are 
no signs of relevant treatment-related abnormalities e.g. neutropenia. If there are signs of treatment-
related abnormalities these must return to normal before treatment with natalizumab is started. 
 
Some patients may have been exposed to immunosuppressive medicinal products (e.g. mitoxantrone, 
cyclophosphamide, azathioprine). These medicinal products have the potential to cause prolonged 
immunosuppression, even after dosing is discontinued. Therefore the physician must confirm that such 
patients are not immunocompromised before starting treatment with TYSABRI (see also section 4.4). 
 
Posology 
 
TYSABRI 300 mg is administered by intravenous infusion once every 4 weeks. 
 
Continued therapy must be carefully reconsidered in patients who show no evidence of therapeutic 
benefit beyond 6 months 
 
Data on the safety and efficacy of natalizumab at 2 years were generated from controlled, double– blind 
studies. After 2 years continued therapy should be considered only following a reassessment of the 
potential for benefit and risk. Patients should be re-informed about the risk factors for PML, like duration 
of treatment, immunosuppressant use prior to receiving TYSABRI and the presence of anti- John 
Cunningham virus (JCV) antibodies (see section 4.4.). 
 
Readministration 
 
The efficacy of re-administration has not been established, for safety see section 4.4. 
 
Special populations 
 
Elderly 
 
TYSABRI is not recommended for use in patients aged over 65 due to a lack of data in this population. 
 
Renal and hepatic impairment 
 
Studies have not been conducted to examine the effects of renal or hepatic impairment. 
 
The mechanism for elimination and results from population pharmacokinetics suggest that dose 
adjustment would not be necessary in patients with renal or hepatic impairment. 
 
Paediatric population 
 
TYSABRI is contraindicated in children and adolescents below the age of 18 years (see section 4.3).  
 
Method of administration 
TYSABRI is for intravenous use. 
 
For instructions on dilution of the medicinal product before administration, see section 6.6. 
 
After dilution (see section 6.6), the infusion is to be administered over approximately 1 hour and patients are 
to be observed during the infusion and for 1 hour after the completion of the infusion for signs and 
symptoms of hypersensitivity reactions. 
 
TYSABRI must not be administered as a bolus injection. 
 
4.3 Contraindications 

 
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Hypersensitivity to natalizumab or to any of the excipients listed in section 6.1.  
 
Progressive multifocal leukoencephalopathy (PML). 
 
Patients with increased risk for opportunistic infections, including immunocompromised patients (including 
those currently receiving immunosuppressive therapies or those immunocompromised by prior therapies, 
e.g. mitoxantrone or cyclophosphamide, see also sections 4.4 and 4.8). 
 
Combination with beta-interferons or glatiramer acetate. 
 
Known active malignancies, except for patients with cutaneous basal cell carcinoma. 
Children and adolescents below the age of 18 years. 
 
4.4 Special warnings and precautions for use 
 
Progressive Multifocal Leukoencephalopathy (PML) 
 
Use of TYSABRI has been associated with an increased risk of PML, an opportunistic infection caused by 
JC virus, which may be fatal or result in severe disability. Due to this increased risk of developing PML, 
the benefits and risks of TYSABRI treatment should be individually reconsidered by the specialist 
physician and the patient; patients must be monitored at regular intervals throughout and should be 
instructed together with their caregivers on early signs and symptoms of PML. JC virus also causes JCV 
granule cell neuronopathy (GCN) which has been reported in patients treated with TYSABRI.  Symptoms 
of JCV GCN are similar to symptoms of PML (i.e. cerebellar syndrome). 
 
The following risk factors are associated with an increased risk of PML. 
 
• 
The presence of anti-JCV antibodies. 
• 
Treatment duration, especially beyond 2 years. After 2 years all patients should be re-informed 
about the risk of PML with TYSABRI. 
• 
Immunosuppressant use prior to receiving TYSABRI. 
 
Patients who are anti-JCV antibody positive are at an increased risk of developing PML compared to 
patients who are anti-JCV antibody negative. Patients who have all three risk factors for PML (i.e., are 
anti-JCV antibody positive and have received more than 2 years of TYSABRI therapy, and have received 
prior immunosuppressant therapy) have a significantly higher risk of PML. 
 
In anti-JCV antibody positive TYSABRI treated patients who have not used prior immunosuppressants the 
level of anti-JCV antibody response (index) is associated with the level of risk for PML. 
 
In patients considered at high risk treatment with TYSABRI should only be continued if the benefits outweigh 
the risks. For the estimation of PML risk in the different patient subgroups, please refer to the Physician 
Information and Management Guidelines. 
 
Anti-JCV antibody testing 
 
Anti-JCV antibody testing provides supportive information for risk stratification of TYSABRI treatment. 
Testing for serum anti-JCV antibody prior to initiating TYSABRI therapy or in patients receiving the 
medicinal product with an unknown antibody status is recommended. Anti-JCV antibody negative patients 
may still be at risk of PML for reasons such as a new JCV infection, fluctuating antibody status or a false 
negative test result. Re-testing of anti-JCV antibody negative patients every 6 months is recommended. 
Retesting low index patients who have no history of prior immunosuppressant use every 6 months once 
they reach the 2 year treatment point is recommended. 
 
The anti-JCV antibody assay (ELISA) should not be used to diagnose PML. Anti-JCV antibody testing 
should not be performed during, or for at least two weeks following, plasma exchange due to the removal 
of antibodies from the serum. 
 
For further information on anti-JCV antibody testing please see Physician Information and 
Management Guidelines. 
 

 
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MRI screening for PML 
 
Before initiation of treatment with TYSABRI, a recent (usually within 3 months) MRI should be available as 
a reference, and be repeated at least on a yearly basis. More frequent MRIs (e.g. on a 3 to 6 monthly 
basis) using an abbreviated protocol should be considered for patients at higher risk of PML. This 
includes: 
• 
Patients who have all three risk factors for PML (i.e., are anti-JCV antibody positive and 
have received more than 2 years of TYSABRI therapy, and have received prior 
immunosuppressant therapy), 
or 
 
• 
Patients with a high anti-JCV antibody index who have received more than 2 years of 
TYSABRI therapy and without prior history of immunosuppressant therapy. 
 
 
Current evidence suggests that the risk of PML is low at an index equal to or below 0.9 and increases 
substantially above 1.5 for patients who have been on treatment with TYSABRI for longer than 2 years 
(see the Physician Information and Management Guidelines for further information). 
 
PML should be considered as a differential diagnosis in any MS patient taking TYSABRI presenting with 
neurological symptoms and/or new brain lesions in MRI. Cases of asymptomatic PML based on MRI and 
positive JCV DNA in the cerebrospinal fluid have been reported. 
 
Physicians should refer to the Physician Information and Management Guidelines for further information 
on managing the risk of PML in TYSABRI-treated patients. 
 
If PML or JCV GCN is suspected, further dosing must be suspended until PML has been excluded. 
 
The clinician should evaluate the patient to determine if the symptoms are indicative of neurological 
dysfunction and, if so, whether these symptoms are typical of MS or possibly suggestive of PML or JCV 
GCN. If any doubt exists, further evaluation, including MRI scan preferably with contrast (compared with 
pre-treatment baseline MRI), CSF testing for JC Viral DNA and repeat neurological assessments, 
should be considered as described in the Physician Information and Management Guidelines (see 
educational guidance). Once the clinician has excluded PML and/or JCV GCN (if necessary, by 
repeating clinical, imaging and/or laboratory investigations if clinical suspicion remains), dosing of 
TYSABRI may resume. 
 
The physician should be particularly alert to symptoms suggestive of PML or JCV GCN that the patient 
may not notice (e.g. cognitive, psychiatric symptoms or cerebellar syndrome). Patients should also be 
advised to inform their partner or caregivers about their treatment, since they may notice symptoms that 
the patient is not aware of. 
 
PML has been reported following discontinuation of TYSABRI in patients who did not have findings 
suggestive of PML at the time of discontinuation. Patients and physicians should continue to follow the 
same monitoring protocol and be alert for any new signs or symptoms that may be suggestive of PML for 
approximately 6 months following discontinuation of TYSABRI. 
 
If a patient develops PML the dosing of TYSABRI must be permanently discontinued. 
 
Following reconstitution of the immune system in immunocompromised patients with PML improved 
outcome has been seen. 
 
PML and IRIS (Immune Reconstitution Inflammatory Syndrome) 
 
IRIS occurs in almost all TYSABRI PML patients after withdrawal or removal of the medicinal product, e.g. 
by plasma exchange (see section 5.2). IRIS is thought to result from the restoration of immune function in 
patients with PML, which can lead to serious neurological complications and may be fatal. Monitoring for 
development of IRIS, which has occurred within days to several weeks after plasma exchange in TYSABRI 
treated patients with PML, and appropriate treatment of the associated inflammation during recovery from 
PML should be undertaken (see the Physician Information and Management Guidelines for further 
information). 
 

 
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Infections including other opportunistic infections 
 
Other opportunistic infections have been reported with use of TYSABRI, primarily in patients with Crohn’s 
disease who were immunocompromised or where significant co-morbidity existed, however increased risk 
of other opportunistic infections with use of the medicinal product in patients without these co-morbidities 
cannot currently be excluded. Opportunistic infections were also detected in MS patients treated with 
TYSABRI as a monotherapy (see section 4.8). 
 
TYSABRI increases the risk of developing encephalitis and meningitis caused by herpes simplex and 
varicella zoster viruses. Serious, life-threatening, and sometimes fatal cases have been reported in the 
postmarketing setting in multiple sclerosis patients receiving TYSABRI (see section 4.8).  If herpes 
encephalitis or meningitis occurs, the medicinal product should be discontinued, and appropriate treatment 
for herpes encephalitis or meningitis should be administered. 
 
Prescribers should be aware of the possibility that other opportunistic infections may occur during 
TYSABRI therapy and should include them in the differential diagnosis of infections that occur in 
TYSABRI-treated patients. If an opportunistic infection is suspected, dosing with TYSABRI is to be 
suspended until such infections can be excluded through further evaluations. 
 
If a patient receiving TYSABRI develops an opportunistic infection, dosing of the medicinal product must 
be permanently discontinued. 
 
Educational guidance 
 
All physicians who intend to prescribe TYSABRI must ensure they are familiar with the Physician 
Information and Management Guidelines. 
 
Physicians must discuss the benefits and risks of TYSABRI therapy with the patient and provide them with 
a Patient Alert Card. Patients should be instructed that if they develop any infection then they should 
inform their physician that they are being treated with TYSABRI. 
 
Physicians should counsel patients on the importance of uninterrupted dosing, particularly in the early 
months of treatment (see hypersensitivity). 
 
Hypersensitivity 
 
Hypersensitivity reactions have been associated with TYSABRI, including serious systemic reactions (see 
section 4.8). These reactions usually occurred during the infusion or up to 1 hour after completion of the 
infusion. The risk for hypersensitivity was greatest with early infusions and in patients re-exposed to 
TYSABRI following an initial short exposure (one or two infusions) and extended period (three months or 
more) without treatment. However, the risk of hypersensitivity reactions should be considered for every 
infusion administered. 
 
Patients are to be observed during the infusion and for 1 hour after the completion of the infusion (see 
section 4.8). Resources for the management of hypersensitivity reactions should be available. 
 
Discontinue administration of TYSABRI and initiate appropriate therapy at the first symptoms or signs of 
hypersensitivity. 
 
Patients who have experienced a hypersensitivity reaction must be permanently discontinued from 
treatment with TYSABRI. 
 
Concurrent or prior treatment with immunosuppressants 
 
The safety and efficacy of TYSABRI in combination with other immunosuppressive and antineoplastic 
therapies have not been fully established. Concurrent use of these agents with TYSABRI may increase 
the risk of infections, including opportunistic infections, and is contraindicated (see section 4.3). 
 
Patients with a treatment history of immunosuppressant medicinal products are at increased risk for PML. 
Care should be taken with patients who have previously received immunosuppressants to allow sufficient 
time for immune function recovery to occur. Physicians must evaluate each individual case to determine 
whether there is evidence of an immunocompromised state prior to commencing treatment with TYSABRI 
(see section 4.3). 

 
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In Phase 3 MS clinical trials, concomitant treatment of relapses with a short course of corticosteroids was 
not associated with an increased rate of infection. Short courses of corticosteroids can be used in 
combination with TYSABRI. 
 
Immunogenicity 
 
Disease exacerbations or infusion related events may indicate the development of antibodies against 
natalizumab. In these cases the presence of antibodies should be evaluated and if these remain positive 
in a confirmatory test after at least 6 weeks, treatment should be discontinued, as persistent antibodies 
are associated with a substantial decrease in efficacy of TYSABRI and an increased incidence of 
hypersensitivity reactions (see section 4.8). 
 
Since patients who have received an initial short exposure to TYSABRI and then had an extended period 
without treatment are at a higher risk of developing anti-natalizumab antibodies and/or hypersensitivity 
upon redosing, the presence of antibodies should be evaluated and if these remain positive in a 
confirmatory test after at least 6 weeks, the patient should not receive further treatment with TYSABRI. 
 
Hepatic events 
 
Spontaneous serious adverse reactions of liver injury have been reported during the post marketing 
phase. These liver injuries may occur at any time during treatment, even after the first dose. In some 
instances, the reaction reoccurred when TYSABRI was reintroduced. Some patients with a past medical 
history of an abnormal liver test have experienced an exacerbation of abnormal liver test while on 
TYSABRI. Patients should be monitored as appropriate for impaired liver function, and be instructed to 
contact their physician in case signs and symptoms suggestive of liver injury occur, such as jaundice and 
vomiting. In cases of significant liver injury TYSABRI should be discontinued. 
 
Stopping TYSABRI therapy 
 
If a decision is made to stop treatment with natalizumab, the physician needs to be aware that 
natalizumab remains in the blood, and has pharmacodynamic effects (e.g increased lymphocyte counts) 
for approximately 12 weeks following the last dose. Starting other therapies during this interval will result 
in a concomitant exposure to natalizumab. For medicinal products such as interferon and glatiramer 
acetate, concomitant exposure of this duration was not associated with safety risks in clinical trials. No 
data are available in MS patients regarding concomitant exposure with immunosuppressant medication. 
Use of these medicinal products soon after the discontinuation of natalizumab may lead to an additive 
immunosuppressive effect. This should be carefully considered on a case-by-case basis, and a wash-out 
period of natalizumab might be appropriate. Short courses of steroids used to treat relapses were not 
associated with increased infections in clinical trials. 
 
Sodium content in TYSABRI 
 
TYSABRI contains 2.3 mmol (or 52 mg) sodium per vial of medicinal product. When diluted in 100 ml 
sodium chloride 9 mg/ml (0.9) this medicinal product contains 17.7 mmol (or 406 mg) sodium per 
dose. To be taken into consideration by patients on a controlled sodium diet. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
TYSABRI is contraindicated in combination with beta-interferons or glatiramer acetate (see section 4.3). 
 
Immunisations 
 
In a randomised, open label study of 60 patients with relapsing MS there was no significant difference in 
the humoral immune response to a recall antigen (tetanus toxoid) and only slightly slower and reduced 
humoral immune response to a neoantigen (keyhole limpet haemocyanin) was observed in patients who 
were treated with TYSABRI for 6 months compared to an untreated control group. Live vaccines have not 
been studied. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
201/Protocol MA30005, Version 5 
Studies in animals have shown reproductive toxicity (see section 5.3). 
 
Data from clinical trials, a prospective pregnancy registry, post-marketing cases and available literature 
do not suggest an effect of TYSABRI exposure on pregnancy outcomes. 
 
The completed prospective TYSABRI pregnancy registry contained 355 pregnancies with available 
outcomes. There were 316 live births, 29 of which were reported to have birth defects. Sixteen of the 29 
were classified as major defects. The rate of defects corresponds to the defect rates reported in other 
pregnancy registries involving MS patients. There is no evidence of a specific pattern of birth defects with 
TYSABRI. 
 
Cases from published literature reported transient mild to moderate thrombocytopenia and anaemia 
observed in infants born to women exposed to TYSABRI in their third trimester of pregnancy. 
Therefore, it is recommended that newborns of women exposed to the medicinal product during the third 
trimester of pregnancy are monitored for potential haematological abnormalities. 
 
If a woman becomes pregnant while taking TYSABRI, discontinuation of the medicinal product should be 
considered. A benefit-risk evaluation of the use of TYSABRI during pregnancy should take into account 
the patient’s clinical condition and the possible return of disease activity after stopping the medicinal 
product. 
 
Breast-feeding 
 
Natalizumab is excreted in human milk. The effect of natalizumab on newborn/infants is unknown. 
Breast-feeding should be discontinued during treatment with TYSABRI. 
 
Fertility 
 
Reductions in female guinea pig fertility were observed in one study at doses in excess of the human 
dose; natalizumab did not affect male fertility. 
It is considered unlikely that natalizumab will affect fertility performance in humans following the maximum 
recommended dose. 
 
4.7 Effects on ability to drive and use machines 
 
No studies on the effects on the ability to drive and use machines have been performed with TYSABRI. 
However, given that dizziness has been commonly reported, patients who experience this adverse 
reaction should be advised not to drive or use machines until it has resolved. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
In placebo-controlled trials in 1,617 MS patients treated with natalizumab for up to 2 years (placebo: 
1,135), adverse events leading to discontinuation of therapy occurred in 5.8% of patients treated with 
natalizumab (placebo: 4.8%). Over the 2-year duration of the studies, 43.5% of patients treated with 
natalizumab reported adverse reactions (placebo: 39.6%). 
 
The highest incidence of adverse reactions identified from placebo-controlled trials in multiple 
sclerosis patients with natalizumab given at the recommended dose, are reported as dizziness, 
nausea, urticaria and rigors associated with infusions. 
 
Tabulated list of adverse reactions 
 
Adverse reactions reported with natalizumab with an incidence of 0.5% greater than reported with 
placebo are shown below. 
 
The reactions are reported as MedDRA preferred terms under the MedDRA primary system organ 
class. Frequencies were defined as follows: 
 
Common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100). 
 

 
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Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 
 
MedDRA System Organ Class 
Adverse reaction 
Frequency category 
Infections and infestations 
Urinary tract infection 
Common 
Nasopharyngitis 
Common 
Immune system disorders 
Urticaria 
Common 
Hypersensitivity 
Uncommon 
Nervous system disorders 
Headache 
Common 
Dizziness 
Common 
Progressive Multifocal 
Leukoencephalopathy (PML) 
Uncommon 
Gastrointestinal disorders 
Vomiting 
Common 
Nausea 
Common 
Musculoskeletal and connective 
tissue disorders 
Arthralgia 
Common 
General disorders and 
administration site conditions 
Rigors 
Common 
Pyrexia 
Common 
Fatigue 
Common 
 
 
Description of selected adverse reactions 
 
Infusion reactions 
 
In 2-year controlled clinical trials in MS patients, an infusion-related event was defined as an adverse 
event occurring during the infusion or within 1 hour of the completion of the infusion. These occurred in 
23.1% of MS patients treated with natalizumab (placebo: 18.7%). Events reported more commonly with 
natalizumab than with placebo included dizziness, nausea, urticaria and rigors. 
 
Hypersensitivity reactions 
 
In 2-year controlled clinical trials in MS patients, hypersensitivity reactions occurred in up to 4% of 
patients. Anaphylactic/anaphylactoid reactions occurred in less than 1% of patients receiving TYSABRI. 
Hypersensitivity reactions usually occurred during the infusion or within the 1-hour period after the 
completion of the infusion (See section 4.4). In post-marketing experience, there have been reports of 
hypersensitivity reactions which have occurred with one or more of the following associated symptoms: 
hypotension, hypertension, chest pain, chest discomfort, dyspnoea, angioedema, in addition to more usual 
symptoms such as rash and urticaria. 
 
Immunogenicity 
 
In 10% of patients antibodies against natalizumab were detected in 2-year controlled clinical trials in MS 
patients. Persistent anti-natalizumab antibodies (one positive test reproducible on retesting at least 6 
weeks later) developed in approximately 6% of patients. Antibodies were detected on only one occasion 
in an additional 4% of patients. Persistent antibodies were associated with a substantial decrease in the 
effectiveness of TYSABRI and an increased incidence of hypersensitivity reactions. 
Additional infusion-related reactions associated with persistent antibodies included rigors, nausea, 
vomiting and flushing (see section 4.4). 
 
If, after approximately 6 months of therapy, persistent antibodies are suspected, either due to reduced 
efficacy or due to occurrence of infusion-related events, they may be detected and confirmed with a 
subsequent test 6 weeks after the first positive test. Given that efficacy may be reduced or the incidence 
of hypersensitivity or infusion-related reactions may be increased in a patient with persistent antibodies, 
treatment should be discontinued in patients who develop persistent antibodies. 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
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Infections, including PML and opportunistic infections 
 
In 2-year controlled clinical trials in MS patients, the rate of infection was approximately 1.5 per patient-
year in both natalizumab- and placebo-treated patients. The nature of the infections was generally 
similar in natalizumab- and placebo-treated patients. A case of cryptosporidium diarrhoea was reported 
in MS clinical trials. In other clinical trials, cases of additional opportunistic infections have been 
reported, some of which were fatal. The majority of patients did not interrupt natalizumab therapy during 
infections and recovery occurred with appropriate treatment. 
 
In clinical trials, herpes infections (Varicella-Zoster virus, Herpes-simplex virus) occurred slightly more 
frequently in natalizumab-treated patients than in placebo-treated patients. In post marketing 
experience,serious, life-threatening, and sometimes fatal cases of encephalitis and meningitis caused 
by herpes simplex or varicella zoster have been reported in multiple sclerosis patients receiving 
TYSABRI. The duration of treatment with TYSABRI prior to onset ranged from a few months to several 
years (see section 4.4). 
 
Cases of PML have been reported from clinical trials, post-marketing observational studies and post- 
marketing passive surveillance. PML usually leads to severe disability or death (see section 4.4). 
Cases of JCV GCN have also been reported during postmarketing use of TYSABRI. Symptoms of JCV 
GCN are similar to PML. 
 
Hepatic events 
 
Spontaneous cases of serious liver injuries, increased liver enzymes, hyperbilirubinaemia have been 
reported during the post marketing phase (see section 4.4). 
 
Anaemia and haemolytic anaemia 
 
Rare, serious cases of anaemia and haemolytic anaemia have been reported in patients treated with 
TYSABRI in post-marketing observational studies. 
 
Malignancies 
 
No differences in incidence rates or the nature of malignancies between natalizumab- and 
placebo-treated patients were observed over 2 years of treatment. However, observation over longer 
treatment periods is required before any effect of natalizumab on malignancies can be excluded. See 
section 4.3. 
 
Effects on laboratory tests 
 
In 2-year controlled clinical trials in MS patients TYSABRI treatment was associated with increases in 
circulating lymphocytes, monocytes, eosinophils, basophils and nucleated red blood cells. 
Elevations in neutrophils were not seen. Increases from baseline for lymphocytes, monocytes, 
eosinophils and basophils ranged from 35% to 140% for individual cell types but mean cell counts 
remained within normal ranges. During treatment with TYSABRI, small reductions in haemoglobin (mean 
decrease 0.6 g/dl), haematocrit (mean decrease 2%) and red blood cell counts (mean decrease 
0.1 x 106/l) were seen. All changes in haematological variables returned to pre-treatment values, 
usually within 16 weeks of last dose of the medicinal product and the changes were not associated with 
clinical symptoms. In post-marketing experience, there have also been reports of eosinophilia (eosinophil 
count >1,500/mm3) without clinical symptoms. In such cases where TYSABRI therapy was discontinued 
the elevated eosinophil levels resolved. 
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows 
continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are 
asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 
 
4.9 Overdose 
 
No case of overdose has been reported. 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
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5. 
PHARMACOLOGICAL PROPERTIES 
 
5.1 
Pharmacodynamic properties 
 
Pharmacotherapeutic group: Selective immunosuppressive agents, ATC code: L04AA23 
Pharmacodynamic effects 
Natalizumab is a selective adhesion-molecule inhibitor and binds to the α4-subunit of human integrins, 
which is highly expressed on the surface of all leukocytes, with the exception of neutrophils. Specifically, 
natalizumab binds to the α4β1 integrin, blocking the interaction with its cognate receptor, vascular cell 
adhesion molecule-1 (VCAM-1), and ligands osteopontin, and an alternatively spliced domain of 
fibronectin, connecting segment-1 (CS-1). Natalizumab blocks the interaction of α4β7 integrin with the 
mucosal addressin cell adhesion molecule-1 (MadCAM-1). Disruption of these molecular interactions 
prevents transmigration of mononuclear leukocytes across the endothelium into inflamed parenchymal 
tissue. A further mechanism of action of natalizumab may be to suppress ongoing inflammatory reactions 
in diseased tissues by inhibiting the interaction of α4-expressing leukocytes with their ligands in the 
extracellular matrix and on parenchymal cells. As such, natalizumab may act to suppress inflammatory 
activity present at the disease site, and inhibit further recruitment of immune cells into inflamed tissues. 
 
In MS, lesions are believed to occur when activated T-lymphocytes cross the blood-brain barrier (BBB). 
Leukocyte migration across the BBB involves interaction between adhesion molecules on inflammatory 
cells and endothelial cells of the vessel wall. The interaction between α4β1 and its targets is an 
important component of pathological inflammation in the brain and disruption of these interactions leads 
to reduced inflammation. Under normal conditions, VCAM-1 is not expressed in the brain parenchyma. 
However, in the presence of pro-inflammatory cytokines, VCAM-1 is upregulated on endothelial cells 
and possibly on glial cells near the sites of inflammation. In the setting of central nervous system (CNS) 
inflammation in MS, it is the interaction of α4β1 with VCAM-1, CS-1 and osteopontin that mediates the 
firm adhesion and transmigration of leukocytes into the brain parenchyma and may perpetuate the 
inflammatory cascade in CNS tissue. Blockade of the molecular interactions of α4β1 with its targets 
reduces inflammatory activity present in the brain in MS and inhibits further recruitment of immune cells 
into inflamed tissue, thus reducing the formation or enlargement of MS lesions. 
 
Clinical efficacy 
 
Efficacy as monotherapy has been evaluated in one randomised, double-blind, placebo-controlled study 
lasting 2 years (AFFIRM study) in relapsing-remitting MS patients who had experienced at least 1 clinical 
relapse during the year prior to entry and had a Kurtzke Expanded Disability Status Scale (EDSS) score 
between 0 and 5. Median age was 37 years, with a median disease duration of 5 years. 
The patients were randomised with a 2:1 ratio to receive TYSABRI 300 mg (n = 627) or placebo (n = 
315) every 4 weeks for up to 30 infusions. Neurological evaluations were performed every 12 weeks 
and at times of suspected relapse. MRI evaluations for T1-weighted gadolinium (Gd)-enhancing 
lesions and T2-hyperintense lesions were performed annually. Study features and results are 
presented in the table below. 
 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
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AFFIRM study: Main features and results 
Design 
Monotherapy; randomised double-blind placebo-controlled 
parallel-group trial for 120 weeks 
Subjects 
RRMS (McDonald criteria) 
Treatment 
Placebo / Natalizumab 300 mg i.v. every 4 weeks 
One year endpoint 
Relapse rate 
Two year endpoint 
Progression on EDSS 
Secondary endpoints 
Relapse rate derived variables / MRI-derived variables 
Subjects 
Placebo 
Natalizumab 
Randomised 
315 
627 
Completing 1 years 
296 
609 
Completing 2 years 
285 
589 
Age yrs, median (range) 
37 (19-50) 
36 (18-50) 
MS-history yrs, median (range) 
6.0 (0-33) 
5.0 (0-34) 
Time since diagnosis, yrs median 
(range) 
2.0 (0-23) 
2.0 (0-24) 
Relapses in previous 12 months, 
median (range) 
1.0 (0-5) 
1.0 (0-12) 
EDSS-baseline, median (range) 
2 (0-6.0) 
2 (0-6.0) 
RESULTS 
Annual relapse rate 
After one year (primary endpoint) 
0.805 
0.261 
After two years 
0.733 
0.235 
One year 
Rate ratio 0.33 CI95% 0.26 ; 0.41 
Two years 
Rate ratio 0.32 CI95% 0.26 ; 0.40 
Relapse free 
After one year 
53% 
76% 
After two years 
41% 
67% 
Disability 
Proportion progressed1(12-week 
confirmation; primary outcome) 
29% 
17% 
Hazard ratio 0.58, CI95% 0.43; 0.73, p<0.001 
Proportion progressed1(24-week 
confirmation) 
23% 
11% 
Hazard ratio 0.46, CI95% 0.33; 0.64, p<0.001 
MRI (0-2 years) 
Median % change in T2- 
hyperintense lesion volume 
+8.8% 
-9.4% 
(p<0.001) 
Mean number of new or newly- 
enlarging T2-hyperintense lesions 
11.0 
1.9 (p<0.001) 
Mean number of T1-hypointense 
lesions 
4.6 
1.1  
(p<0.001) 
Mean number of Gd-enhancing 
lesions 
1.2 
0.1  
(p<0.001) 
1 Progression of disability was defined as at least a 1.0 point increase on the EDSS from a baseline 
EDSS >=1.0 sustained for 12 or 24 weeks or at least a 1.5 point increase on the EDSS from a baseline 
EDSS =0 sustained for 12 or 24 weeks. 
 
In the sub-group of patients indicated for treatment of rapidly evolving relapsing remitting MS (patients 
with 2 or more relapses and 1 or more Gd+ lesion), the annualised relapse rate was 0.282 in the 
TYSABRI treated group (n = 148) and 1.455 in the placebo group (n = 61) (p <0.001). Hazard ratio for 
disability progression was 0.36 (95% CI: 0.17, 0.76) p = 0.008. These results were obtained from a 
post hoc analysis and should be interpreted cautiously. No information on the severity of the relapses 
before inclusion of patients in the study is available. 
 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
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The European Medicines Agency has deferred the obligation to submit the results of studies with 
TYSABRI in one or more subsets of the paediatric population in multiple sclerosis (see section 4.2 for 
information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Following the repeat intravenous administration of a 300 mg dose of natalizumab to MS patients, the 
mean maximum observed serum concentration was 110 ± 52 μg/ml. Mean average steady-state trough 
natalizumab concentrations over the dosing period ranged from 23 μg/ml to 29 μg/ml. The predicted time 
to steady-state was approximately 36 weeks. 
 
A population pharmacokinetics analysis was conducted on samples from over 1,100 MS patients 
receiving doses ranging from 3 to 6 mg/kg natalizumab. Of these, 581 patients received a fixed 
300 mg dose as monotherapy. The mean ± SD steady-state clearance was 13.1 ± 5.0 ml/h, with a mean 
± SD half-life of 16 ± 4 days. The analysis explored the effects of selected covariates including body 
weight, age, gender, hepatic and renal function, and presence of anti-natalizumab antibodies upon 
pharmacokinetics. Only body weight and the presence of anti-natalizumab antibodies were found to 
influence natalizumab disposition. Body weight was found to influence clearance in a less-than- 
proportional manner, such that a 43% change in body weight resulted in a 31% to 34% change in 
clearance. The change in clearance was not clinically significant. The presence of persistent anti- 
natalizumab antibodies increased natalizumab clearance approximately 3-fold, consistent with reduced 
serum natalizumab concentrations observed in persistently antibody-positive patients, (see section 4.8). 
 
The pharmacokinetics of natalizumab in paediatric MS patients or in patients with renal or hepatic 
insufficiency has not been studied. 
 
The effect of plasma exchange on natalizumab clearance and pharmacodynamics was evaluated in a 
study of 12 MS patients. Estimates of the total natalizumab removal after 3 plasma exchanges (over a 5-8 
day interval) was approximately 70-80%. This compares to approximately 40% seen in earlier studies in 
which measurements occurred after natalizumab discontinuation over a similar period of observation. The 
impact of plasma exchange on the restitution of lymphocyte migration and ultimately its clinical usefulness 
is unknown. 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated dose toxicity and genotoxicity. 
 
Consistent with the pharmacological activity of natalizumab, altered trafficking of lymphocytes was seen 
as white blood cell increases as well as increased spleen weights in most in vivo studies. These changes 
were reversible and did not appear to have any adverse toxicological consequences. 
 
In studies conducted in mice, growth and metastasis of melanoma and lymphoblastic leukaemia tumour 
cells was not increased by the administration of natalizumab. 
 
No clastogenic or mutagenic effects of natalizumab were observed in the Ames or human chromosomal 
aberration assays. Natalizumab showed no effects on in vitro assays of 
α4-integrin-positive tumour line proliferation or cytotoxicity. 
 
Reductions in female guinea pig fertility were observed in one study at doses in excess of the human 
dose; natalizumab did not affect male fertility. 
 
The effect of natalizumab on reproduction was evaluated in 5 studies, 3 in guinea pigs and 2 in 
cynomolgus monkeys. These studies showed no evidence of teratogenic effects or effects on growth of 
offspring. In one study in guinea pigs, a small reduction in pup survival was noted. In a study in monkeys, 
the number of abortions was doubled in the natalizumab 30 mg/kg treatment groups versus matching 
control groups. This was the result of a high incidence of abortions in treated groups in the first cohort that 
was not observed in the second cohort. No effects on abortion rates were noted in any other study. A 
study in pregnant cynomolgus monkeys demonstrated natalizumab-related changes in the foetus that 
included mild anaemia, reduced platelet counts, increased spleen weights and reduced liver and thymus 
weights. These changes were associated with increased splenic extramedullary haematopoiesis, thymic 
atrophy and decreased hepatic haematopoiesis. Platelet counts were also reduced in offspring born to 
mothers treated with natalizumab until parturition, however there was no evidence of anaemia in these 

 
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offspring. All changes were observed at doses in excess of the human dose and were reversed upon 
clearance of natalizumab. 
 
In cynomolgus monkeys treated with natalizumab until parturition, low levels of natalizumab were 
detected in the breast milk of some animals. 
 
 
6. 
PHARMACEUTICAL PARTICULARS 
 
6.1 
List of excipients 
 
Sodium phosphate, monobasic, monohydrate 
Sodium phosphate, dibasic, heptahydrate 
Sodium chloride 
Polysorbate 80 (E433) 
Water for injections 
 
6.2 Incompatibilities 
 
TYSABRI must not be mixed with other medicinal products except those mentioned in section 6.6. 
 
6.3 Shelf life 
 
Unopened vial 4 years 
 
Diluted solution 
 
After dilution with sodium chloride 9 mg/ml (0.9%) solution for injection, immediate use is recommended. If 
not used immediately, the diluted solution must be stored at 2˚C - 8˚C and infused within 8 hours of 
dilution. In-use storage times and conditions prior to use are the responsibility of the user. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2˚C - 8˚C). 
Do not freeze. 
Keep the vial in the outer carton in order to protect from light. 
 
For storage conditions after dilution of the medicinal product see section 6.3. 
 
6.5 Nature and contents of container 
 
15 ml concentrate in a vial (type I glass) with a stopper (bromobutyl rubber) and a seal (aluminium) with a 
flip-off cap. 
Pack size of one vial per carton. 
 
6.6 Special precautions for disposal and other handling 
 
Instructions for use: 
• 
Inspect the TYSABRI vial for particles prior to dilution and administration. If particles are observed 
and/or the liquid in the vial is not colourless, clear to slightly opalescent, the vial must not be 
used. 
• 
Use aseptic technique when preparing TYSABRI solution for intravenous (IV) infusion. Remove 
flip-off cap from the vial. Insert the syringe needle into the vial through the centre of the rubber 
stopper and remove 15 ml concentrate for solution for infusion. 
• 
Add the 15 ml concentrate for solution for infusion to 100 ml sodium chloride 9 mg/ml (0.9) 
solution for injection. Gently invert the TYSABRI solution to mix completely. Do not shake. 
• 
TYSABRI must not be mixed with other medicinal products or diluents. 
• 
Visually inspect the diluted medicinal product for particles or discolouration prior to 
administration. Do not use if it is discoloured or if foreign particles are seen. 

 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
208/Protocol MA30005, Version 5 
• 
The diluted medicinal product is to be used as soon as possible and within 8 hours of dilution. If 
the diluted medicinal product is stored at 2˚C - 8˚C (do not freeze), allow the solution to warm to 
room temperature prior to infusion. 
• 
The diluted solution is to be infused intravenously over 1 hour at a rate of approximately 2 
ml/minute. 
• 
After the infusion is complete, flush the intravenous line with sodium chloride 9 mg/ml (0.9) 
solution for injection. 
• 
Each vial is for single–use only. 
• 
Any unused medicinal product or waste material must be disposed of in accordance with local 
requirements. 
 
 
7. 
MARKETING AUTHORISATION HOLDER 
 
Biogen Idec Limited, 
Innovation House,  
70 Norden Road, 
Maidenhead, 
Berkshire, 
SL6 4AY 
United Kingdom 
 
 
8. 
MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/06/346/001 
 
9. 
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 27th June 2006 
Date of latest renewal: 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.