Ocrevus

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 
 
 
 
 



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This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Ocrevus 300 mg concentrate for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each vial contains 300 mg of ocrelizumab in 10 mL at a concentration of 30 mg/mL. The final drug 
concentration after dilution is approximately 1.2 mg/mL. 
  
Ocrelizumab is a recombinant humanised anti-CD20 monoclonal antibody produced in Chinese 
Hamster Ovary cells by recombinant DNA technology. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Concentrate for solution for infusion.   
 
Clear to slightly opalescent, and colourless to pale brown solution.   
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications  
 
Ocrevus is indicated for the treatment of adult patients with relapsing forms of multiple sclerosis 
(RMS) with active disease defined by clinical or imaging features (see section 5.1).  
 
Ocrevus is indicated for the treatment of adult patients with early primary progressive multiple 
sclerosis (PPMS) in terms of disease duration and level of disability, and with imaging features 
characteristic of inflammatory activity (see section 5.1). 
 
4.2 Posology and method of administration 
  
Ocrevus treatment should be initiated and supervised by specialised physicians experienced in the 
diagnosis and treatment of neurological conditions and who have access to appropriate medical 
support to manage severe reactions such as serious infusion-related reactions (IRRs). 
 
Premedication for infusion-related reactions  
 
The following two premedications must be administered prior to each Ocrevus infusion  to reduce the 
frequency and severity of IRRs (see Infusion-related reactions in section 4.4 for additional steps to 
reduce IRRs): 
• 100 mg intravenous methylprednisolone (or an equivalent) approximately 30 minutes prior to 

each Ocrevus infusion; 
• antihistamine approximately 30-60 minutes prior to each Ocrevus infusion; 
In addition, premedication with an antipyretic (e.g paracetamol) may also be considered approximately 
30-60 minutes prior to each Ocrevus infusion. 
 



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Posology:  
 
Initial Dose 
 
The initial 600 mg dose is administered as two separate intravenous infusions; first as a 300 mg 
infusion, followed 2 weeks later by a second 300 mg infusion (Table 1).   
 
Subsequent Doses   
 
Subsequent doses of Ocrevus thereafter are administered as a single 600 mg intravenous infusion 
every 6 months (Table 1).The first subsequent dose of 600 mg should be administered six months after 
the first infusion of the initial dose.  
 
If patients did not experience a serious infusion-related reaction (IRR) with any previous Ocrevus 
infusion, a shorter (2-hour) infusion can be administered for subsequent doses (Table 1, Option 2). 
 
A minimum interval of 5 months should be maintained between each dose of Ocrevus.   
 
Infusion Adjustments in case of IRRs  
 
In case of IRRs during any infusion, see the following adjustments. Additional information on IRRs 
can be found in section 4.4.   
 
Life-threatening IRRs   
 
If there are signs of a life threatening or disabling IRR during an infusion, such as acute 
hypersensitivity or acute respiratory distress syndrome, the infusion must be stopped immediately and 
the patient should receive appropriate treatment. Ocrevus must be permanently discontinued in these 
patients (see section 4.3). 
 
Severe IRRs 
 
If a patient experiences a severe IRR (such as dyspnea) 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 restarted 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. No infusion 
adjustment is necessary for subsequent new infusions,  unless the patient experiences an IRR. 
 
Mild to Moderate IRRs 
 
If a patient experiences a mild to moderate IRR (e.g. headache), the infusion rate should be reduced to 
half the rate at the onset 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 rate. No 
infusion adjustment is necessary for subsequent new infusions,  unless the patient experiences an IRR. 
 
Dose Modifications during Treatment 
 
The above examples of dose interruption and slowing (for mild/moderate and severe IRRs) will result 
in a change in the infusion rate and increase the total duration of the infusion, but not the total dose. 
No dose reductions of Ocrevus are recommended. 
 
Delayed or Missed Doses 
 
If an infusion of Ocrevus is missed, it should be administered as soon as possible; do not wait until the 
next planned dose. The treatment interval of 6 months (with a minimum of 5 months) for Ocrevus 
should be maintained between doses (see Table 1). 
 



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Special Populations  
 
Adults over 55 years old and elderly population  
 
Based on the limited data available (see section  5.1 and section 5.2), no posology adjustment is 
needed in patients over 55 years of age.  Patients enrolled in the ongoing clinical trials continue to be 
dosed with 600 mg ocrelizumab every six months after they become 55 and older. 
 
Renal Impairment 
 
The safety and efficacy of Ocrevus in patients with renal impairment has not been formally studied.  
Patients with mild renal impairment were included in clinical trials. There is no experience in patients 
with moderate and severe renal impairment. Ocrevus is a monoclonal antibody and cleared via 
catabolism (i.e. breakdown into peptides and amino acids), and a change in dose is not expected to be 
required for patients with renal impairment (see section 5.2).   
 
Hepatic Impairment 
 
The safety and efficacy of Ocrevus in patients with hepatic impairment has not been formally studied.  
Patients with mild hepatic impairment were included in clinical trials. There is no experience in 
patients with moderate and severe hepatic impairment. Ocrevus is a monoclonal antibody and cleared 
via catabolism (rather than hepatic metabolism), and a change in dose is not expected to be required 
for patients with hepatic impairment (see section 5.2).   
 
Paediatric population  
 
The safety and efficacy of Ocrevus in children and adolescents aged 0 to 18 years has not yet been 
established.  No data are available.   
 
Method of Administration  
 
After dilution, Ocrevus is administered as an intravenous infusion through a dedicated line.  Ocrevus 
infusions should not be administered as an intravenous push or bolus. 
 



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Table 1:  Dose and Schedule of Ocrevus 
 

 Amount of 
Ocrevus to be  
administered  

Infusion instructions 

Initial Dose 
(600 mg) 

divided into 2 infusions 

Infusion 1 300 mg in 250 mL • Initiate the infusion at 
a rate of 30 mL/hour 
for 30 minutes 

• The rate can be 
increased in 
30 mL/hour increments 
every 30 minutes to a 
maximum of 
180 mL/hour.   

• Each infusion should 
be given over 
approximately 
2.5 hours 

Infusion 2 
(2 weeks later) 

300 mg in 250 mL 

Subsequent Doses 
(600 mg) 

single infusion 
once every 6 months 

 
 

 Option 1 

Infusion of 
approximately 3.5 

hours duration 

600 mg in 500 mL • Initiate the infusion at 
a rate of 40 mL/hour 
for 30 minutes  

• The rate can be 
increased in 
40 mL/hour increments 
every 30 minutes to a 
maximum of 
200 mL/hour 

• Each infusion should 
be given over 
approximately 
3.5 hours 

OR 

Option 2  

Infusion of 
approximately 2 
hours duration 

600 mg in 500 mL • Initiate the infusion at 
a rate of 100 mL/hour 
for the first 15 minutes 

• Increase the infusion 
rate to 200 mL/hour 
for the next 15 minutes 

• Increase the infusion 
rate to 250 mL/hour 
for the next 30 minutes 



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 Amount of 
Ocrevus to be  
administered  

Infusion instructions 

• Increase the 
infusion rate to 300 
mL/hour for the 
remaining 60 minutes  
• Each infusion 
should be given over 
approximately 2 hours 

 
Solutions of  Ocrevus for intravenous infusion are prepared by dilution of the medicinal product into 
an infusion bag containing 0.9% sodium chloride, to a final concentration of approximately 
1.2 mg/mL.For instructions on dilution of the medicinal product before administration see section 6.6. 
 
Patients should be monitored during the infusion and for at least one hour after the completion of the 
infusion (see section 4.4).   
 
4.3 Contraindications  
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
• Current active infection (see section 4.4) 
• Patients in a severely immunocompromised state (see section 4.4 ). 
• Known active malignancies (see section 4.4)    
 
4.4 Special warnings and precautions for use 
 
Traceability 
 
In order to improve the traceability of biological medicinal products, the name and the batch number 
of the administered product should be clearly recorded. 
 
Infusion-Related Reactions (IRRs)  
 
Ocrevus is associated with IRRs, which may be related to cytokine release and/or other chemical 
mediators.   
 
Symptoms of IRRs may occur during any infusion, but have been more frequently reported during the 
first infusion.  IRRs can occur within 24 hours of the infusion. These reactions may present as pruritus, 
rash, urticaria, erythema, throat irritation, oropharyngeal pain, dyspnoea, pharyngeal or laryngeal 
oedema, flushing, hypotension, pyrexia, fatigue, headache, dizziness, nausea and tachycardia (see 
section 4.8).    
  
Before the infusion: 
• Management of severe reactions: Appropriate resources for the management of severe reactions 

such as serious IRR, hypersensitivity reactions and/or anaphylactic reactions should be 
available. 

• Hypotension: As a symptom of IRR, may occur during Ocrevus infusions. Therefore, 
withholding of antihypertensive treatments should be considered for 12 hours prior to and 
throughout each Ocrevus infusion.  Patients with a history of congestive heart failure (New 
York Heart Association III & IV) were not studied.   

• Premedication: Patients must receive premedication to reduce the frequency and severity of 
IRRs (see section 4.2.). 



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During the infusion:  
• The following measures need to be taken for patients who experience severe pulmonary 

symptoms, such as bronchospasm or asthma exacerbation:  
- their infusion must be interrupted immediately and permanently 
- symptomatic treatment must be administered 
- the patient must be monitored until the pulmonary symptoms have resolved because 

initial improvement of clinical symptoms could be followed by deterioration 
• Hypersensitivity may be difficult to distinguish from an IRR in terms of symptoms. If a 

hypersensitivity reaction is suspected during infusion, the infusion must be stopped immediately 
and permanently (see ‘Hypersensitivity Reactions’ below).    

 
After the infusion:  
• Patients treated with Ocrevus should be observed for at least one hour after the completion of 

the infusion for any symptom of IRR.  
• Physicians should alert patients that an IRR can occur within 24 hours of infusion. 
 
For guidance regarding posology for patients experiencing IRR symptoms see section 4.2. 
 
Hypersensitivity Reactions   
 
A hypersensitivity reaction could also occur (acute allergic reaction to medicinal product).  Type 1 
acute hypersensitivity reactions (IgE-mediated) may be clinically indistinguishable from IRR 
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. Patients with known IgE mediated hypersensitivity to ocrelizumab must not be treated (see 
section 4.3).   
 
Infection  
 
Ocrevus administration must be delayed in patients with an active infection until the infection is 
resolved. 
 
It is recommended to verify the patient’s immune status before dosing since severely 
immunocompromised patients (e.g. with lymphopenia, neutropenia, hypogammaglobulinemia) should 
not be treated (see sections 4.3 and 4.8). 
 
The overall proportion of patients experiencing a serious infection was similar to comparators (see 
section 4.8). The frequency of grade 4 (life-threatening) and grade 5 (fatal) infections was low in all 
treatment groups, but in PPMS it was higher with Ocrevus compared with placebo for life-threatening 
(1.6% vs 0.4%) and fatal (0.6% vs 0%) infections. All life-threatening infections resolved without 
discontinuing ocrelizumab. 
 
In PPMS, patients with swallowing difficulties are at a higher risk of aspiration pneumonia. Ocrevus 
treatment may further increase the risk of severe pneumonia in these patients. Physicians should take 
prompt action for patients presenting with pneumonia.  
 
Progressive multifocal leukoencephalopathy (PML) 
 
A risk of PML cannot be ruled-out since John Cunningham (JC) virus infection resulting in PML has 
been observed in patients treated with anti-CD20 antibodies and other MS therapies, and associated 
with risk factors (e.g. patient population, polytherapy with immunosuppressants).   
 



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Physicians should be vigilant for the 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 MS disease. 
 
If PML is suspected, dosing with Ocrevus must be withheld. Evaluation including Magnetic 
Resonance Imaging (MRI) scan preferably with contrast (compared with pre-treatment MRI), 
confirmatory cerebro-spinal fluid (CSF) testing for John Cunningham (JC) Viral Deoxyribonucleic 
acid (DNA) and repeat neurological assessments, should be considered. If PML is confirmed, 
treatment must be discontinued permanently. 
 
Hepatitis B reactivation 
 
Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure 
and death, has been reported in patients treated with anti-CD20 antibodies.   
 
HBV screening should be performed in all patients before initiation of treatment with Ocrevus as per 
local guidelines. Patients with active HBV (i.e. an active infection confirmed by positive results for 
HBsAg and anti HB testing) should not be treated with Ocrevus.  Patients with positive serology (i.e. 
negative for HBsAg and positive for HB core antibody (HBcAb +); carriers of HBV (positive for 
surface antigen, HBsAg+) should consult liver disease experts before start of treatment and should be 
monitored and managed following local medical standards to prevent hepatitis B reactivation. 
 
Late neutropenia 
 
Cases of late onset of neutropenia have been reported. Although some cases were Grade 3 or 4, the 
majority of the cases were Grade 1 or 2.  Cases of late onset of neutropenia have been reported at least 
4 weeks after the latest Ocrevus infusion. In patients with signs and symptoms of infection, 
measurement of blood neutrophils is recommended (see section 4.8). 
 
Malignancies 
 
An increased number of malignancies (including breast cancers) have been observed in clinical trials 
in patients treated with ocrelizumab, compared to control groups. However, the incidence was within 
the background rate expected for an MS population. Individual benefit risk should be considered in 
patients with known risk factors for malignancies and in patients who are being actively monitored for 
recurrence of malignancy. Patients with a known active malignancy should not be treated with 
Ocrevus (see section 4.3). Patients should follow standard breast cancer screening per local guidelines. 
Please see section 4.2 for populations not studied. 
 
In the controlled period of the clinical trials, the incidence of non-melanoma skin cancers was low and 
there was no imbalance between treatment groups. An increase in incidence was observed between 
years 3 and 4 of treatment due to basal cell carcinoma, which was not observed in subsequent years.  
The incidence remains within the background rate expected for an MS population. 
 
Treatment of severely immunocompromised patients  
 
Patients in a severely immunocompromised state must not be treated until the condition resolves (see 
section 4.3.). 
 
In other auto-immune conditions, use of Ocrevus concomitantly with  immunosuppressive medications 
(e.g. chronic corticosteroids, non-biologic and biologic disease-modifying antirheumatic drugs 
[DMARDS], mycophenolate mofetil, cyclophosphamide, azathioprine) resulted in an increase of 
serious infections, including opportunistic  infections. Infections included and were not limited to 
atypical pneumonia and pneumocystis jirovecii pneumonia, varicella pneumonia, tuberculosis, 
histoplasmosis. In rare cases, some of these infections were fatal.  An exploratory analysis identified 
the following factors associated with risk of serious infections: higher doses of Ocrevus than 
recommended in MS, other comorbidities, and chronic use of immunosuppressants/corticosteroids. 
 



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It is not recommended to use other immunosuppressives concomitantly with Ocrevus except 
corticosteroids for symptomatic treatment of relapses. Knowledge is limited as to whether concomitant 
steroid use for symptomatic treatment of relapses is associated with an increased risk of infections in 
clinical practice. In the ocrelizumab MS pivotal studies the administration of corticosteroids for the 
treatment of relapse was not associated with an increased risk of serious infection. 
 
When initiating Ocrevus after an immunosuppressive therapy or initiating an immunosuppressive 
therapy after Ocrevus, the potential for overlapping pharmacodynamic effects should be taken into 
consideration (see section 5.1 Pharmacodynamic effects). Caution should be exercised when 
prescribing Ocrevus taking into consideration the pharmacodynamics of other disease modifying MS 
therapies.  
 
Vaccinations 
 
The safety of immunisation with live or live-attenuated vaccines, following Ocrevus therapy has not 
been studied and vaccination with live-attenuated or live vaccines is not recommended during 
treatment and not until B-cell repletion (in clinical trials, the median time for B-cell repletion was 
72 weeks). See section 5.1. 
 
In a randomized open-label study, RMS patients were able to mount humoral responses, although 
decreased, to tetanus toxoid, 23-valent pneumococcal polysaccharide with or without a booster 
vaccine, keyhole limpet hemocyanin neoantigen, and seasonal influenza vaccines.  See section 4.5 
and 5.1.   
 
It is recommended to vaccinate patients treated with Ocrevus with seasonal influenza vaccines that are 
inactivated.   
 
Physicians should review the immunisation status of patients being considered for treatment with 
Ocrevus. Patients who require vaccination should complete their immunisation at least 6 weeks prior 
to initiation of Ocrevus.  
 
See section 4.5 and 5.1 for further information about vaccinations. 
 
Exposure in utero to ocrelizumab and vaccination of neonates and infants with live  or live attenuated 
vaccines 
 
Due to the potential depletion of B cells in infants of mothers who have been exposed to Ocrevus  
during pregnancy, it is recommended that vaccination with live or live-attenuated vaccines should be 
delayed until B-cell levels have recovered; therefore, measuring CD19-positive B-cell levels, 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 
immunisation schedule and measurement of vaccine-induced response titers should be considered to 
check whether individuals have mounted a protective immune response because the efficacy of the 
vaccination may be decreased. 
 
The safety and timing of vaccination should be discussed with the infant’s physician (see section 4.6). 
 
Sodium  
 
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. it is essentially 
sodium-free. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No formal drug interaction studies have been performed, as no drug interactions are expected via 
cytochrome P450 enzymes, other metabolising enzymes or transporters.   



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Vaccinations 
 
The safety of immunisation with live or live-attenuated vaccines, following Ocrevus therapy has not 
been studied. 
 
Data are available on the effects of tetanus toxoid, 23-valent pneumococcal polysaccharide, keyhole 
limpet hemocyanin neoantigen, and seasonal influenza vaccines in patients receiving Ocrevus. See 
section 4.4 and 5.1.  
 
After treatment with Ocrevus over 2 years, the proportion of patients with positive antibody titers 
against S. pneumoniae, mumps, rubella and varicella were generally similar to the proportions at 
baseline. 
 
Immunosuppressants  
 
It is not recommended to use other immunosuppressives concomitantly with Ocrevus except 
corticosteroids for symptomatic treatment of relapses. 
 
See section 4.4 ‘Treatment of severely immunocompromised patients’ for information about the use of 
immunosuppressants before, during or after Ocrevus treatment.  
 
4.6 Fertility, pregnancy and lactation 
 
Women of child bearing potential  
 
Women of child bearing potential should use contraception while receiving Ocrevus and for 
12 months after the last infusion of Ocrevus (see below and section 5.1 and 5.2). 
 
Pregnancy  
 
Ocrevus  is a humanised monoclonal antibody of an immunoglobulin G1 subtype and 
immunoglobulins are known to cross the placental barrier.  
 
There is a limited amount of data from the use of Ocrevus in pregnant women.  Postponing 
vaccination with live or live-attenuated vaccines should be considered for neonates and infants born to 
mothers who have been exposed to Ocrevus in utero. No B cell count data have been collected in 
neonates and infants exposed to ocrelizumab and the potential duration of B-cell depletion in neonates 
and infants is unknown (see section 4.4).     
 
Transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to 
mothers exposed to other anti-CD20 antibodies during pregnancy. 
 
Animal studies (embryo-foetal toxicity) do not indicate teratogenic effects.  B-cell depletion in utero 
was detected. Reproductive toxicity was observed in pre and post natal development studies (see 
section 5.3).   
 
Ocrevus should be avoided during pregnancy unless the potential benefit to the mother outweighs the 
potential risk to the foetus. 
 
Breast-feeding  
 
It is unknown whether ocrelizumab/metabolites are excreted in human milk. Available 
pharmacodynamic/toxicological data in animals have shown excretion of ocrelizumab in milk (for 
details see section 5.3). A risk to  neonates and infants cannot be excluded. Women should be advised 
to discontinue breast-feeding during Ocrevus therapy.  
 



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Fertility 
 
Preclinical data reveal no special hazards for humans based on  studies of  male and  female fertility in 
cynomologous monkeys.  
 
4.7 Effects on ability to drive and use machines 
 
Ocrevus has no or negligible influence on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile  
 
The most important and frequently reported adverse drug reactions (ADRs) were IRRs and infections. 
See section 4.4 and section 4.8 (subsection ‘Description of selected adverse reactions’) for further 
details. 
 
Tabulated list of adverse reactions  
 
The overall safety profile of Ocrevus in Multiple Sclerosis is based on data from patients from pivotal 
clinical trials in MS (RMS and PPMS). 
 
The table 2 summarises the ADRs that have been reported in association with the use of Ocrevus in 
1311 patients (3054 patient years) during the controlled treatment periods of MS clinical trials. 
 
Frequencies are defined as 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) and not known (cannot be estimated 
from the available data).  Within each System Organ Class, the adverse reactions are presented in 
order of decreasing frequency.  
 



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Table 2 ADRs reported with Ocrevus (in RMS or PPMS)  
 

 
MedDRA 

 
System Organ Class 

(SOC) 
 

 
Very Common  

 
Common  

 
Not Known2 

Infections and 
infestations 
 

Upper respiratory tract 
infection, 
nasopharyngitis, 
influenza   
 

Sinusitis, bronchitis, 
oral herpes, 
gastroenteritis, 
respiratory tract 
infection, viral 
infection, herpes 
zoster, conjunctivitis, 
cellulitis  

 

Respiratory, thoracic 
and mediastinal 
disorders  

 Cough, catarrh 
 
 

 

Investigations Blood 
immunoglobulin M 
decreased 
 

Blood 
immunoglobulin G 
decreased 
 

 

Blood and lymphatic 
system disorders 

 Neutropenia Late onset of  
neutropenia 

Injury, poisoning and 
procedural 
complications  
 

Infusion-related 
reactions1  

  

1 Symptoms reported as IRRs within 24 hours of the infusion are described below in ‘Infusion-related 
reactions’.  
2 Observed in the postmarketing setting - frequency cannot be estimated from the available data. 
 
Description of selected adverse reactions  
 
Infusion-related reactions 
 
Across the RMS and PPMS trials, symptoms associated with IRRs included, but are not limited to: 
pruritus, rash, urticaria, erythema, flushing, hypotension, pyrexia, fatigue, headache, dizziness, throat 
irritation, oropharyngeal pain, dyspnoea, pharyngeal or laryngeal oedema, nausea, tachycardia.  In 
controlled trials there were no fatal IRRs. 
 
In active-controlled (RMS) clinical trials, IRR was the most common adverse event in patients treated 
with Ocrevus with an overall incidence of 34.3% compared with an incidence of 9.9% in the interferon 
beta-1a treatment group (placebo infusion).  The incidence of IRRs was highest during the Dose 1, 
infusion 1 (27.5%) and decreased over time to <10% at Dose 4.  The majority of IRRs in both 
treatment groups were mild to moderate. 21,7% and 10.1%  of Ocrevus treated patients experienced 
mild and moderate IRRs respectively, 2.4% experienced severe IRRs and 0.1% experienced 
lifethreatening IRRs. See section 4.4.  
 
In the placebo-controlled (PPMS) clinical trial, IRR was the most common adverse event in patients 
treated with Ocrevus with an overall incidence of 40.1% compared with an incidence of 25.5% in the 
placebo group. The incidence of IRRs was highest during Dose 1, infusion 1 (27.4%,) and decreased 
with subsequent doses to <10% at Dose 4. A greater proportion of patients in each group experienced 
IRRs with the first infusion of each dose compared with the second infusion of that dose.  The 
majority of IRRs were mild to moderate. 26.7% and 11.9%  of Ocrevus treated patients experienced 



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mild and moderate IRRs respectively, 1.4% experienced severe IRRs. There were no life-threatening 
IRRs. See section 4.4. 
 
Alternative Shorter Infusion of Subsequent Doses 
 
In a study (MA30143 Shorter Infusion Substudy) designed to characterise the safety profile of shorter 
(2-hour) Ocrevus infusions in patients with Relapsing-Remitting Multiple Sclerosis, the incidence, 
intensity, and types of symptoms of IRRs were consistent with those of infusions administered over 
3.5 hours (see section 5.1 Pharmacodynamic properties). The overall number of interventions needed 
was low in both infusion groups, however, more interventions (slowing down or temporary 
interruptions) were needed to manage IRRs in the shorter (2-hour) infusion group compared to the 3.5-
hour infusion group (8.7% vs. 4.8%, respectively). 
 
Infection 
 
In the active-controlled studies in RMS, infections occurred in 58.5% of patients receiving Ocrevus vs 
52.5% of patients receiving interferon beta 1a. Serious infections occurred in 1.3% of patients 
receiving Ocrevus vs 2.9% of patients receiving interferon beta 1a. In the placebo-controlled study in 
PPMS, infections occurred in 72.2% of patients receiving Ocrevus vs 69.9% of patients receiving 
placebo. Serious infections occurred in 6.2% of patients receiving Ocrevus vs 6.7% of patients 
receiving placebo. An increase in the rate of serious infections was observed in RMS between Years 2 
and 3, but not in subsequent years. No increase was observed in PPMS. 
 
Respiratory Tract Infections 
 
The proportion of respiratory tract infections was higher in Ocrevus treated patients compared to 
interferon beta-1-a and placebo.    
In the RMS clinical trials, 39.9% of Ocrevus treated patients  and 33.2% interferon beta-1-a treated 
patients experienced an upper respiratory tract infection and 7.5% of Ocrevus treated patients and 
5.2% of interferon beta-1-a treated patients experienced a lower respiratory tract infection.   
In the PPMS clinical trial, 48.8% of Ocrevus treated patients and 42.7% of patients who received 
placebo experienced an upper respiratory tract infection, and 9.9% of Ocrevus  treated patients and 
9.2% of patients who received placebo experienced a lower respiratory tract infection.   
The respiratory tract infections reported in patients treated with Ocrevus were predominately mild to 
moderate (80 – 90 %). 
 
Herpes 
 
In active-controlled (RMS) clinical trials, herpes infections were reported more frequently in  
Ocrevus-treated patients than in interferon-beta-1a treated  patients including herpes zoster (2.1% vs 
1.0%), herpes simplex, ( 0.7 % vs 0.1 %) oral herpes (3.0% vs 2.2%), genital herpes (0.1% vs 0%) and 
herpes virus infection (0.1% vs 0%).  Infections were predominantly mild to moderate in severity and 
patients recovered with treatment by standard therapies.  
 
In the placebo-controlled (PPMS) clinical trial, a higher proportion of patients with oral herpes (2.7% 
vs 0.8%) were observed in the Ocrevus treatment arm.  
 
Laboratory Abnormalities 
 
Immunoglobulins  
 
Treatment with Ocrevus resulted in a decrease in total immunoglobulins over the controlled period of 
the studies, mainly driven by reduction in IgM. Clinical trial data have shown an association between  
decreased  levels of  IgG (and less so for  IgM or IgA) and serious infections.  
 



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Lymphocytes 
 
In RMS, a decrease in lymphocyte < LLN was observed in 20.7% of Ocrevus patients compared with 
32.6% of patients treated with interferon beta-1a.  In PPMS, a decrease in lymphocytes <LLN was 
observed in 26.3% of Ocrevus treated patients vs 11.7% of placebo-treated patients. 
  
The majority of these decreases reported in Ocrevus treated patients were Grade 1 (<LLN - 
800 cells/mm3) and 2 (between 500 and 800 cells/mm3) in severity. Approximately 1% of the patients 
in the Ocrevus group had a Grade 3 lymphopenia (between 200 and 500 cells/mm3). None of the 
patients was reported with Grade 4 lymphopenia (< 200 cells/mm3). 
 
An increased rate of serious infections was observed during episodes of confirmed total lymphocytes 
counts decrease in ocrelizumab treated patients. The number of serious infections was too low to draw 
definitive conclusions. 
 
Neutrophils 
 
In the active-controlled (RMS) treatment period, a decrease in  neutrophils < LNN was observed in 
14.7% of Ocrevus patients compared with 40.9% of patients treated with interferon beta-1a.  In the 
placebo-controlled (PPMS) clinical trial, the proportion of Ocrevus patients presenting decreased 
neutrophils was higher (12.9 %) than placebo patients (10.0 %); among these a higher percentage of 
patients (4.3%) in the Ocrevus group had Grade 2 or above neutropenia vs 1.3% in the placebo group; 
approximately 1% of the patients in the Ocrevus group had Grade 4 neutropenia vs 0% in the placebo 
group. 
 
The majority of the neutrophil decreases were transient (only observed once for a given patient treated 
with Ocrevus) and were Grade 1 (between<LLN and 1500 cells/mm3) and 2 (between 1000 and 1500 
cells/mm3) in severity. One patient with grade 3 (between 500 and 1000 cells/mm3) and one patient 
with grade 4 (< 500 cells/mm3) neutropenia required specific treatment with granulocyte-colony 
stimulating factor, and  remained on ocrelizumab after the episode. Neutropenia can occur several 
months after the administration of Ocrevus (see section 4.4). 
 
Other 
 
One patient, who received 2000 mg of Ocrevus, died of systemic inflammatory response syndrome 
(SIRS) of unknown etiology, following a magnetic resonance imaging (MRI) examination 12 weeks 
after the last infusion; an anaphylactoid reaction to the MRI gadolinium-contrast agent could have 
contributed to the SIRS. 
 
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 
 
There is limited clinical trial experience with doses higher than the approved intravenous dose of 
Ocrevus. The highest dose tested to date in MS patients is 2000 mg, administered as two 1000 mg 
intravenous infusions separated by 2 weeks (Phase II dose finding study in RRMS).  The adverse drug 
reactions were consistent with the safety profile for Ocrevus in the pivotal clinical studies. 
 
Please refer to section 4.8 for information about the Systemic Inflammatory Response Syndrome 
(SIRS) that occurred in a patient treated with  Ocrevus 2000 mg.  
 

https://www.ema.europa.eu/documents/template-form/appendix-v-adverse-drug-reaction-reporting-details_en.doc


15 

There is no specific antidote in the event of an overdose; interrupt the infusion immediately and 
observe the patient for IRRs (see section 4.4).   
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: selective immunosuppressants group, ATC code: L04AA36.  
 
Mechanism of Action  
 
Ocrelizumab is a recombinant humanised monoclonal antibody that selectively targets  
CD20-expressing B cells.   
 
CD20 is a cell surface antigen found on pre-B cells, mature and memory B cells but not expressed on 
lymphoid stem cells and plasma cells.    
 
The precise mechanisms through which ocrelizumab exerts its therapeutic clinical effects in MS is not 
fully elucidated but is presumed to involve immunomodulation through the reduction in the number 
and function of CD20-expressing B cells. Following cell surface binding, ocrelizumab selectively 
depletes CD20-expressing B cells through antibody-dependent cellular phagocytosis (ADCP), 
antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and 
apoptosis. The capacity of B-cell reconstitution and preexisting humoral immunity are preserved. In 
addition, innate immunity and total T-cell numbers are not affected. 
 
Pharmacodynamic effects 
 
Treatment with Ocrevus 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. For the B cell counts, CD19 is used, as the presence of Ocrevus interferes with 
the recognition of CD20 by the assay.   
 
In the Phase III studies, between each dose of Ocrevus, up to 5% of patients showed B-cell repletion 
(> lower limit of normal (LLN) or baseline) at least at one time point. The extent and duration of  
B-cell depletion was consistent in the PPMS and RMS trials.   
 
The longest follow up time after the last Ocrevus infusion (Phase II study WA21493, N=51) indicates 
that the median time to B-cell repletion (return to baseline/LLN whichever occurred first) was 
72 weeks (range 27 - 175 weeks). 90% of all patients had their B-cells repleted to LLN or baseline by 
approximately two and a half years after the last infusion. 
 
Clinical efficacy and safety 

 
Relapsing forms of MS 
 
Efficacy and safety of Ocrevus were evaluated in two randomised, double-blind, double-dummy, 
active comparator-controlled clinical trials (WA21092 and WA21093), with identical design, in 
patients with relapsing forms of MS (in accordance with McDonald criteria 2010) and evidence of 
disease activity (as defined by clinical or imaging features) within the previous two years. Study 
design and baseline characteristics of the study population are summarised in Table 3.  
 
Demographic and baseline characteristics were well balanced across the two treatment groups.  
Patients receiving Ocrevus (Group A) were given 600 mg every 6 months (Dose 1 as 2 x 300 mg 
intravenous infusions, administered 2 weeks apart, and subsequent doses were administered as a single 
600 mg intravenous infusion). Patients in Group B were administered Interferon beta-1a (Rebif) 
44 mcg via subcutaneous injection 3 times per week. 



16 

 
Table 3 Study Design, Demographic and Baseline Characteristics 
 

 Study 1 Study 2 
Study name WA21092 (OPERA I)  

(n=821) 
WA21093 (OPERA II) 

(n=835) 

Study design 
Study population Patients with relapsing forms of MS 
Disease history at screening At least two relapses within the prior two years or one relapse 

within the prior year; EDSS* between 0 and 5.5, inclusive 
Study duration 2 years  
Treatment groups Group A: Ocrevus 600 mg 

Group B: interferon beta-1a 44 mcg S.C. (IFN) 
Baseline characteristics Ocrevus  

600 mg  
(n=410) 

IFN  
44 mcg 
(n=411) 

Ocrevus  
600 mg  
 (n=417) 

IFN  
44 mcg 
(n=418) 

Mean age (years) 37.1 36.9 37.2 37.4 
Age range (years) at inclusion 18 - 56 18 - 55 18 - 55 18 - 55 
Gender distribution (% male/% 
female) 

34.1/65.9 33.8/66.2 35.0/65.0 33.0/67.0 

Mean/Median disease duration 
since diagnosis (years) 

3.82/1.53 3.71/1.57 4.15/2.10 4.13/1.84 

Patients naive to previous DMT 
(%)** 

73.4 71.0 72.7 74.9 

Mean number of relapses in the 
last year  

1.31 1.33 1.32 1.34 

Proportion of patients with Gd 
enhancing T1 lesions 

42.5 38.1  39.0 41.4  

Mean EDSS* 2.82 2.71 2.73 2.79 

* Expanded Disability Status Scale 
** Patients who had not been treated with any MS medication in the 2 years prior to randomization. 
 
Key clinical and MRI efficacy results are presented in Table 4 and Figure 1.   
 
The results of these studies show that Ocrevus significantly suppressed relapses, sub-clinical disease 
activity measured by MRI, and disease progression compared with interferon beta-1a 44mcg 
subcutaneous. 
 



17 

Table 4 Key Clinical and MRI Endpoints from Studies WA21092 and WA21093 (RMS) 
 

 
 
Endpoints 

Study 1: WA21092  
(OPERA I)  

Study 2: WA21093  
(OPERA II)  

Ocrevus 
600 mg 
 (n=410) 

IFN  
44 mcg  
(n=411) 

Ocrevus  
600 mg 

 (n=417) 

IFN  
44 mcg  
(n=418) 

Clinical Endpoints   

Annualised Relapse Rate (ARR) (primary endpoint) 0.156  0.292 0.155 0.290 
Relative  Reduction  46 %  (p<0.0001) 47 % (p<0.0001) 

Proportion of patients with 12 week Confirmed Disability 
Progression3 

Risk Reduction (Pooled Analysis1) 
Risk Reduction (Individual Studies2) 

9.8% Ocrevus vs 15.2% IFN 

40% (p=0.0006)7 
43 % (p=0.0139)7 37 % (p=0.0169)7 

Proportion of patients with 24 week Confirmed Disability 
Progression3 

Risk Reduction (Pooled Analysis1) 
Risk Reduction (Individual Studies2) 

7.6% Ocrevus vs  12.0% IFN 
40% (p=0.0025)7 

43 %  (p=0.0278)7 37 % (p=0.0370)7 

Proportion of patients with at least 12 weeks Confirmed Disability 
Improvement4  

20.7% Ocrevus vs 15.6% IFN 

Relative Increase (Pooled Analysis1) 
Relative Increase (Individual Studies2) 
 

33% (p=0.0194) 
61% (p=0.0106) 14% (p=0.4019) 

 
Proportion of patients Relapse free at 96 weeks2 
 
 
 

80.4% 66.7% 78.9% 64.3% 
 
 (p<0.0001) (p<0.0001) 

Proportion of patients with No Evidence of Disease Activity 
(NEDA)5   

48% 29% 48% 25% 

Relative Increase2 64%  (p<0.0001) 89%  (p<0.0001) 

MRI Endpoints  

Mean number of T1 Gd-enhancing lesions per MRI scan 0.016 0.286 0.021 0.416 

Relative reduction 94% (p<0.0001) 95% (p<0.0001) 

Mean number of new and/or enlarging T2 hyperintense lesions per 
MRI scan 

0.323 1.413 0.325 1.904 

Relative reduction 77%  (p<0.0001) 83% (p<0.0001) 

Percentage change in brain volume from Week 24 to week 96  -0.572 -0.741  -0.638 -0.750 

Relative reduction in brain volume loss 22.8%  (p=0.0042)6 14.9%  (p=0.0900) 
 1 Data prospectively pooled from Study 1 and 2 

2 Non-confirmatory p-value analysis; not part of the pre-specified testing hierarchy 
3 Defined as an increase of ≥ 1.0 point from the baseline Expanded Disability Status Scale (EDSS) score for patients 
with baseline score of 5.5 or less, or ≥ 0.5 when the baseline score is > 5.5, Kaplan-Meier estimates at Week 96 
4 Defined as decrease of ≥ 1.0 point from the baseline EDSS score for patients with baseline EDSS score ≥ 2 and 
≤ 5.5, or ≥0.5 when the baseline score is > 5.5. Patients with baseline score < 2 were not included in analysis.  
5 NEDA defined as absence of protocol defined relapses, 12-week Confirmed Disability Progression (CDP), and any 
MRI activity (either Gd-enhancing T1 lesions, or new or enlarging T2 lesions) during the whole 96-week treatment. 
Exploratory result based on complete ITT population.   
6 Non-confirmatory p-value; hierarchical testing procedure terminated before reaching endpoint. 
7 Log-rank test 
 



18 

Figure 1: Kaplan-Meier Plot of Time to Onset of Confirmed Disability Progression Sustained for 
at Least 12 Weeks with the Initial Event of Neurological Worsening Occurring during the 
Double-blind Treatment Period (Pooled WA21092 and WA21093 ITT Population)* 
 

 
*Pre-specified pooled analysis of WA21092 and WA21093 
 
Results of the pre-specified pooled analyses of time to CDP sustained for at least 12 weeks (40% risk 
reduction for Ocrevus compared to interferon beta-1a (p=0.0006) were highly consistent with the 
results sustained for at least 24 weeks (40% risk reduction for Ocrevus compared to interferon beta-1a, 
p=0.0025).    
 
The studies enrolled patients with active disease. These included both active treatment naive and 
previously treated inadequate responders, as defined by clinical or imaging features.  Analysis of 
patient populations with differing baseline levels of disease activity, including active and highly active 
disease, showed that the efficacy of Ocrevus on ARR and 12 week CDP was consistent with the 
overall population.   
 
Primary Progressive MS  
 
Efficacy and safety of Ocrevus were also evaluated in a randomised, double-blind, placebo-controlled 
clinical trial in patients with primary progressive MS (Study WA25046) who were early in their 
disease course according to the main inclusion criteria, i.e. ages 18-55 years, inclusive; EDSS at 
screening from 3.0 to 6.5 points; disease duration from the onset of MS symptoms less than 10 years 
in patients with an EDSS at screening ≤5.0 or less than 15 years in patients with an EDSS at screening 
>5.0. With regard to disease activity, features characteristic of inflammatory activity, even in 
progressive MS, can be imaging-related, (i.e. T1 Gd-enhancing lesions and/or active [new or 
enlarging] T2 lesions). MRI evidence should be used to confirm inflammatory activity in all patients.  
Patients over 55 years of age were not studied. Study design and baseline characteristics of the study 
population are presented in Table 5. 
 
Demographic and baseline characteristics were well balanced across the two treatment groups. Cranial 
MRI showed imaging features characteristic of inflammatory activity either by T1 Gd enhancing 
lesions or T2 lesions.  
 

40% reduction in risk of CDP 
HR (95% CI): 0.60 (0.45, 0.81) 

(p =0.0006) 



19 

During the Phase 3 PPMS study, patients received 600 mg Ocrevus every 6 months as two 300 mg 
infusions, given two weeks apart, throughout the treatment period. The 600 mg infusions in RMS and 
the 2 x 300 mg infusions in PPMS demonstrated consistent PK/PD profiles. IRR profiles per infusion 
were also similar, independent of whether the 600 mg dose was administered as a single 600 mg 
infusion or as two 300 mg infusions separated by two weeks (see sections 4.8 and 5.2), but due to 
overall more infusions with the 2 x 300 mg regimen, the total number of IRRs were higher. Therefore, 
after Dose 1 it is recommended to administer Ocrevus in a 600 mg single infusion (see section 4.2) to 
reduce the total number of infusions (with concurrent exposure to prophylactic methylprednisolone 
and an antihistamine) and the related infusion reactions). 
 
Table 5 Study design, demograhics and baseline characteristics for Study WA25046. 
 

Study name Study WA25046 ORATORIO  (n=732) 
 

Study design 
Study population Patients with primary progressive form of MS 

 
Study duration Event-driven (Minimum 120 weeks and  253 confirmed 

disability progression events)  
(Median follow-up time:  Ocrevus 3.0 years, Placebo 2.8 

years  
Disease history at screening Age 18-55 years, EDSS of 3.0 to 6.5 
Treatment groups Group A: Ocrevus 600 mg 

Group B: Placebo, in 2:1 randomisation 
Baseline characteristics Ocrevus 600 mg (n=488)  Placebo (n=244) 
Mean age (years) 44.7 44.4 
Age range (years) at inclusion 20 - 56  18 - 56 
Gender distribution (% 
male/% female) 

51.4/48.6 49.2/50.8 

Mean/Median disease duration 
since PPMS diagnosis (years) 

2.9/1.6 2.8/1.3 

Mean EDSS 4.7 4.7 
 
Key clinical and MRI efficacy results are presented in Table 6 and Figure 2.   
 
The results of this study show that Ocrevus significantly delays disease progression and reduces 
deterioration in walking speed compared with placebo. 
 



20 

Table 6 Key Clinical and MRI Endpoints from Study WA25046 (PPMS) 
 
 Study 3 

 
 
Endpoints 

WA25046 (Oratorio)  
Ocrevus 600 mg 

(n=488)  
Placebo 
 (n=244) 

Clinical Endpoints 
Primary efficacy endpoint  
Proportion of patients with 12 weeks - Confirmed 
Disability Progression1 (primary endpoint) 
 

Risk reduction 
 

30.2% 34.0% 

24% 
(p=0.0321) 

Proportion of patients with 24 weeks - Confirmed 
Disability Progression1 

28.3% 32.7% 

Risk reduction 
 

25% 
(p=0.0365) 

Percentage change in Timed 25-Foot Walk from 
baseline to Week 120 

38.9  55.1  

Relative reduction in progression rate of walking 
time 
 

29.4%  
 (p=0.0404) 

MRI Endpoints 

Percentage change in T2 hyperintense lesion volume, 
from baseline to Week 120  

-3.4 7.4 

  (p<0.0001) 

Percentage change in brain volume from Week 24 to 
Week 120 

-0.902  -1.093 

Relative reduction in rate of brain volume loss 17.5% 
(p=0.0206) 

1 Defined as an increase of ≥ 1.0 point from the baseline EDSS score for patients with baseline score 
of 5.5 or less, or ≥ 0.5 when the baseline score is > 5.5, Kaplan-Meier estimates at Week 120. 
 



21 

Figure 2: Kaplan-Meier Plot of Time to Onset of Confirmed Disability Progression Sustained for 
at Least 12 Weeks with the Initial Event of Neurological Worsening Occurring during the 
Double-blind Treatment Period (WA25046 ITT Population)*  
 

 
* All patients in this analysis had a minimum of 120 weeks of follow-up.  The primary analysis is 
based on all events accrued.  
  
Pre-specified non-powered subgroup analysis of the the primary endpoint suggests that patients who 
are younger or those with T1 Gd-enhancing lesions at baseline receive a greater treatment benefit than 
patients who are  older or without T1 Gd-enhancing lesions (≤ 45 years: HR 0.64 [0.45, 0.92], 
>45 years: HR 0.88 [0.62, 1.26]; with T1 Gd-enhancing lesions at baseline: HR 0.65 [0.40-1.06], 
without T1 Gd-enhancing lesions at baseline: HR 0.84 [0.62-1.13]).  
Moreover, post-hoc analyses suggested that younger patients with T1 Gd-enhancing lesions at baseline 
have the better treatment effect (≤ 45 years: HR 0.52 [0.27-1.00]; ≤ 46 years [median age of the 
WA25046 study]; HR 0.48 [0.25-0.92]; <51 years: HR 0.53 [0.31-0.89]).   
 
Shorter Infusion Substudy 
 
The safety of the shorter (2-hour) Ocrevus infusion was evaluated in a prospective, multicenter, 
randomised, double-blind, controlled, parallel arm substudy to Study MA30143 (Ensemble) in patients 
with Relapsing-Remitting Multiple Sclerosis that were naïve to other disease modifying treatments.  
The first dose of Ocrevus was administered as two 300 mg infusions (600 mg total) separated by 14 
days. Patients were randomised from their second dose onwards (Dose 2 to 6)  in a 1:1 ratio to either 
the conventional infusion group with Ocrevus infused over approximately 3.5 hours every 24 weeks, 
or the shorter infusion group with Ocrevus infused over approximately 2 hours every 24 weeks. The 
randomisation was stratified by region and the dose at which patients were first randomised. 
 
The primary endpoint was the proportion of patients with IRRs occurring during or within 24 hours 
following the first randomised infusion of Ocrevus. The primary analysis was performed when 580 
patients were randomised. The proportion of patients with IRRs occurring during or within 24 hours 
following the first randomised infusion was 24.6% in the shorter infusion compared to 23.1% in the 
conventional infusion group. The stratified group difference was similar. Overall, in all randomised 

24% reduction in risk of CDP 
HR (95% CI): 0.76 (0.59, 0.98);  

p=0.0321 



22 

doses, the majority of the IRRs were mild or moderate and only two IRRs were severe in intensity, 
with one severe IRR in each group. There were no life-threatening, fatal, or serious IRRs.   
 
Immunogenicity  
 
Patients in MS trials (WA21092, WA21093 and WA25046) were tested at multiple time points 
(baseline and every 6 months post treatment for the duration of the trial) for anti-drug antibodies 
(ADAs).  Out of 1311 patients treated with Ocrevus, 12 (~1%) tested positive for treatment-emergent 
ADAs, of which 2 patients tested positive for neutralising antibodies. The impact of 
treatment-emergent ADAs on safety and efficacy cannot be assessed given the low incidence of ADA 
associated with Ocrevus. 
 
Immunisations 
 
In a randomized open-label study in RMS patients (N=102), the percentage of patients with a positive 
response to tetanus vaccine at 8 weeks after vaccination was 23.9% in the ocrelizumab group 
compared to 54.5% in the control group (no disease-modifying therapy except interferon-beta).  
Geometric mean anti-tetanus toxoid specific antibody titers at 8 weeks were 3.74 and 9.81 IU/ml, 
respectively. Positive response to ≥5 serotypes in 23-PPV at 4 weeks after vaccination was 71.6% in 
the ocrelizumab group and 100% in the control group.  In patients treated with ocrelizumab a booster 
vaccine (13-PCV) given 4 weeks after 23-PPV did not markedly enhance the response to 12 serotypes 
in common with 23-PPV.  The percentage of patients with seroprotective titers against five influenza 
strains ranged from 20.0−60.0% and 16.7−43.8% pre-vaccination and at 4 weeks post vaccination 
from 55.6−80.0% in patients treated with ocrelizumab and 75.0−97.0% in the control group , 
respectively.  See sections 4.4 and 4.5. 
 
Paediatric population 
 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
Ocrevus in one or more subsets of the paediatric population in the treatment of multiple sclerosis. See 
section 4.2 for information on paediatric use. 
 
5.2 Pharmacokinetic properties 
 
The pharmacokinetics of ocrelizumab in the MS studies were described by a two compartment model 
with time-dependent clearance, and with PK parameters typical for an IgG1 monoclonal antibody.  
The overall exposure (AUC over the 24 weeks dosing interval) was identical in the 2 x 300 mg in 
PPMS and 1 x 600 mg in RMS studies, as expected given an identical dose was administered.  Area 
under the curve (AUCτ) after the 4th dose of 600 mg ocrelizumab was 3510 µg/mL•day, and mean 
maximum concentration (Cmax) was 212 µg/mL in RMS (600 mg infusion) and 141 µg/mL in PPMS 
(300 mg infusions).  
 
Absorption  
 
Ocrevus is administered as an intravenous infusion. There have been no studies performed with other 
routes of administration.  
 
Distribution  
 
The population pharmacokinetics estimate of the central volume of distribution was 2.78 L.  Peripheral 
volume and inter-compartment clearance were estimated at 2.68 L and 0.294 L/day.   
 
Biotransformation  
 
The metabolism of Ocrevus has not been directly studied, as antibodies are cleared principally by 
catabolism (i.e. breakdown into peptides and amino acids). 
 



23 

Elimination  
 
Constant clearance was estimated at 0.17 L/day, and initial time-dependent clearance at  
0.0489 L/day which declined with a half-life of 33 weeks.  The terminal elimination half-life of 
ocrelizumab was 26 days.  
 
Pharmacokinetics in Special Populations  
 
Paediatrics 
 
No studies have been conducted to investigate the pharmacokinetics of ocrelizumab  in children and 
adolescents <18 years of age. 
 
Elderly 
 
There are no dedicated PK studies of ocrelizumab in patients ≥55 years due to limited clinical 
experience (see section 4.2). 
 
Renal impairment 
 
No formal pharmacokinetic study has been conducted.  Patients with mild renal impairment were 
included in clinical trials and no change in the pharmacokinetics of Ocrevus was observed in those 
patients.  There is no PK information available in patients with moderate or severe renal impairment. 
 
Hepatic impairment 
 
No formal pharmacokinetic study has been conducted.  Patients with mild hepatic impairment were 
included in clinical trials, and no change in the pharmacokinetics was observed in those patients. 
There is no PK information available in patients with moderate or severe hepatic impairment. 
 
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 embryo-foetal development. Neither carcinogenicity nor 
mutagenicity studies have been conducted with ocrelizumab.   
 
In two pre- and post-natal development studies in cynomolgus monkeys, administration 
of ocrelizumab from gestation day 20 to at least parturition was associated with glomerulopathy, 
lymphoid follicle formation in bone marrow, lymphoplasmacytic renal inflammation, and decreased 
testicular weight in offspring. The maternal doses administered in these studies resulted in maximum 
mean serum concentrations (Cmax) that were 4.5- to 21-fold above those anticipated in the clinical 
setting. 
 
There were five cases of neonatal moribundities, one attributed to weakness due to premature birth 
accompanied by opportunistic bacterial infection, one due to an infective meningoencephalitis 
involving the cerebellum of the neonate from a maternal dam with an active bacterial infection 
(mastitis) and three with evidence of jaundice and hepatic damage, with a viral etiology suspected, 
possibly a polyomavirus. The course of these five confirmed or suspected infections could have 
potentially been impacted by B-cell depletion.  Newborn offspring of maternal animals exposed to 
ocrelizumab were noted to have depleted B cell populations during the post natal phase.  Measurable 
levels of ocrelizumab were detected in milk (approximated 0.2% of steady state trough serum levels) 
during the lactation period. 
 
 



24 

6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium Acetate Trihydrate  
Glacial Acetic Acid 
Trehalose Dihydrate 
Polysorbate 20 
Water for Injection 
 
6.2 Incompatibilities 
 
No incompatibilities between Ocrevus and polyvinyl chloride (PVC) or polyolefin (PO) bags and 
intravenous  administration sets have been observed. 
 
Do not use diluents other than the one detailed in section 6.6 to dilute Ocrevus since its use has not 
been tested. 
 
This medicinal product must not be mixed with other medicinal products except those mentioned in 
section 6.6. 
 
6.3 Shelf life 
 
Unopened vial 
 
24 months 
 
Diluted solution for intravenous infusion  
 
Chemical and physical in-use stability has been demonstrated for 24 hours at 2-8°C and subsequently 
for 8 hours at room temperature. 
 
From a microbiological point of view, the prepared infusion should be used immediately. If not used 
immediately, in-use storage times and conditions prior to use are the responsibility of the user and 
would normally not be longer than 24 hours at 2-8°C and subsequently for 8 hours at room 
temperature, unless dilution is undertaken in controlled and validated aseptic conditions. 
 
In the event an intravenous infusion cannot be completed the same day, the remaining solution should 
be discarded. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C – 8°C). 
 
Do not freeze.   
 
Keep the vials 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  
 
10 mL concentrate in a glass vial.  Pack size of 1 or 2 vials.  Not all pack sizes may be marketed.   
 



25 

6.6 Special precautions for disposal and other handling 
 
Instructions for dilution  
 
Ocrevus should be prepared by a healthcare professional using aseptic technique.  Do not shake the 
vial.   
 
The product is intended for single use only.   
 
Do not use the solution if discoloured or if the solution contains foreign particulate matter (see section 
3 for a description of the solution). 
 
Ocrevus medicinal product must be diluted before administration. Solutions of Ocrevus for 
intravenous administration are prepared by dilution of the drug product into an infusion bag containing 
isotonic 0.9% sodium chloride (300 mg / 250 mL or 600 mg / 500 mL), to a final drug concentration 
of approximately 1.2 mg/mL.    
 
The diluted infusion solution must be administered using an infusion set with a 0.2 or 0.22 micron 
in-line filter.   
 
Prior to the start of the intravenous infusion, the content of the infusion bag should be at room 
temperature. 
 
Disposal  
 
Disposal of unused/expired medicines 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/17/1231/001  
EU/1/17/1231/002  
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 8 January 2018 
 
 
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. 
 

  

http://www.ema.europa.eu/


26 

    
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 

ANNEX II 
 
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 

MANUFACTURER RESPONSIBLE FOR BATCH RELEASE  
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
  



27 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturer of the biological active substance 

 
Genentech Inc. 
1000 New Horizons Way 
Vacaville 
CA 95688 
United States 
 
Name and address of the manufacturer responsible for batch release 
 
Roche Pharma AG 
Emil-Barell-Strasse 1 
79639 Grenzach-Whylen 
Germany 
 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION  

 
• Periodic safety update reports  

 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
The marketing authorisation holder shall submit the first periodic safety update report for this 
product within 6 months following authorisation.  
 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 
• Risk Management Plan (RMP) 

 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted: 
 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached.   



28 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



29 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



30 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Ocrevus 300 mg concentrate for solution for infusion 
ocrelizumab 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One vial contains 300 mg ocrelizumab in 10 ml (30 mg/ml).   
 
 
3. LIST OF EXCIPIENTS 
 
Sodium Acetate Trihydrate 
Glacial Acetic Acid 
Trehalose Dihydrate 
Polysorbate 20 
Water for injection 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Concentrate for solution for infusion 
300 mg/10 ml 
1 vial  
2 vials  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use 
For intravenous use after dilution 
Do not shake the vial 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



31 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator 
Do not freeze 
Keep the vial in the outer carton in order to protect from light 
Keep the vials in the outer carton in order to protect from light 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/17/1231/001 1-vial pack 
EU/1/17/1231/002 2-vials pack 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted.   
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:   
SN:  
NN:   
  



32 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL  
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Ocrevus 300 mg concentrate for solution for infusion 
ocrelizumab 
IV after dilution  
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot  
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
300 mg/10 ml 
 
 
6. OTHER 
 

  



33 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
  



34 

Package leaflet: Information for the patient 
 

Ocrevus 300 mg concentrate for solution for infusion 
Ocrelizumab 

 
This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 
 
Read all of this leaflet carefully before you are given this medicine because it contains important 
information for you. 
 
• Keep this leaflet.You may need to read it again.  
• If you have any further questions, ask your doctor. 
• If you get any side effects, talk to your doctor or nurse. This includes any possible side effects 

not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Ocrevus is and what it is used for  
2. What you need to know before you are given Ocrevus 
3. How Ocrevus is given  
4. Possible side effects  
5. How to store Ocrevus 
6. Contents of the pack and other information 
 
 
1. What Ocrevus is and what it is used for 
 
What Ocrevus is 
 
Ocrevus contains the active substance ‘ocrelizumab’. It is a type of protein called a ‘monoclonal 
antibody’. Antibodies work by attaching to specific targets in your body. 
 
What Ocrevus is used for 
 
Ocrevus is used to treat adults with: 
• Relapsing forms of multiple sclerosis (RMS)  
• Early primary progressive multiple sclerosis (PPMS) 
 
What is Multiple Sclerosis 
 
Multiple Sclerosis (MS) affects the central nervous system, especially the nerves in the brain and 
spinal cord. In MS, the immune system (the body’s defence system) works incorrectly and attacks a 
protective layer (called myelin sheath) around nerve cells and causes inflammation. Breakdown of the 
myelin sheath stops the nerves working properly. 
 
Symptoms of MS depend on which part of the central nervous system is affected and can include  
problems with walking and balance, weakness, numbness, double vision and blurring, poor 
coordination and bladder problems.  
 
• In relapsing forms of MS, the patient has repeated attacks of symptoms (relapses). The 

symptoms can appear suddenly within a few hours, or slowly over several days. The symptoms 
disappear or improve between relapses but damage may build up and lead to permanent 
disability.  

 



35 

• In primary progressive MS, the symptoms generally continue to worsen from the start of the 
disease.  

 
How does Ocrevus work? 
 
Ocrevus attaches to specific B cells, which are a type of white blood cells that are part of the immune 
system and play a role in MS. Ocrevus targets and removes those specific B cells. This reduces 
inflammation and attacks on the myelin sheath, reduces the chance of having a relapse and slows the 
progression of your disease. 
 
• In Relapsing forms of MS (RMS), Ocrevus helps to significantly reduce the number of attacks 

(relapses) and significantly slow down the progression of the disease. Ocrevus also significantly 
increases the chance of a patient having no evidence of disease activity (brain lesions, relapses 
and worsening of disability). 

 
• In Primary Progressive MS (PPMS), Ocrevus helps to slow down the progression of the 

disease and reduce deterioration in walking speed.  
 
 
2. What you need to know before you are given Ocrevus 
 
You must not be given Ocrevus: 
 
• if you are allergic to ocrelizumab or any of the other ingredients of this medicine (listed in 

section 6) 
• if you currently have an infection  
• if you have been told that you have severe problems with your immune system 
• if you have cancer 
 
If you are not sure, talk to your doctor before you are given Ocrevus. 
 
Warnings and precautions  
 
Talk to your doctor before you are given Ocrevus if any of the following apply to you. Your doctor 
may decide to delay your treatment with Ocrevus, or may decide you cannot receive Ocrevus if: 
• you have an infection. Your doctor will wait until the infection is resolved before giving you 

Ocrevus. 
• you have ever had hepatitis B or are a carrier of the hepatitis B virus. This is because medicines 

like Ocrevus can cause the hepatitis B virus to become active again. Before your Ocrevus 
treatment, your doctor will check if you are at risk of hepatitis B infection. Patients who have 
had hepatitis B or are carriers of the hepatitis B virus will have a blood test and will be 
monitored by a doctor for signs of hepatitis B infection.  

• you have cancer or if you have had cancer in the past. Your doctor may decide to delay your 
treatment with Ocrevus. 

 
Effect on the immune system: 
 
• Diseases that affect your immune system: if you have another disease which affects the 

immune system. You may not be able to receive Ocrevus. 
• Medicines that affect your immune system: if you have ever taken, are taking or are planning 

to take medicines that affect the immune system – such as chemotherapy, immunosuppressants 
or other medicines used to treat MS. Your doctor may decide to delay your treatment with 
Ocrevus or may ask you to stop such medicines before starting treatment with Ocrevus. See 
under ‘Other medicines and Ocrevus’, below for more information. 

 



36 

Infusion-related reactions   
 
• Infusion-related reactions are the most common side effect of Ocrevus treatment. 
• Tell your doctor or nurse straight away if you have any infusion-related reaction (see 

section 4 for a list of infusion-related reactions). Infusion-related reactions can happen during 
the infusion or up to 24 hours after the infusion.  

• To reduce the risk of infusion-related reaction, your doctor will give you other medicines before 
each infusion of Ocrevus (see section 3) and you will be closely monitored during the infusion 
and for at least one hour after the infusion has been given. 
 

Infections 
 
• Talk to your doctor before you are given Ocrevus if you think you have an infection. Your 

doctor will wait until the infection is resolved before giving you Ocrevus. 
• You might get infections more easily with Ocrevus. This is because the immune cells that 

Ocrevus targets also help to fight infection.  
• Before you start treatment with Ocrevus and before subsequent infusions, your doctor may ask 

you to have a blood test to verify your immune system because infections may occur more 
frequently in case of severe problems with your immune system. 

• If you are treated with Ocrevus for primary progressive multiple sclerosis, and you have 
swallowing difficulties, Ocrevus may increase the risk of severe pneumonia. 

• Tell your doctor or nurse straight away if you have any of these signs of infection during 
or after Ocrevus treatment:  
- fever or chills 
- cough that does not go away 
- herpes (such as cold sore, shingles or genital sores).  

• Tell your doctor or nurse straight away if you think your MS is getting worse or if you 
notice any new symptoms. This is because of a very rare and life-threatening brain infection, 
called ‘progressive multifocal leukoencephalopathy’ (PML), which can cause symptoms similar 
to those of MS. PML can occur in patients taking medicines like Ocrevus, and other medicines 
used for treating MS. 

 Tell your partner or carer about your Ocrevus treatment. They might notice symptoms of 
PML that you do not, such as memory lapses, trouble thinking, difficulty walking, sight loss, 
changes in the way you talk, which your doctor may need to investigate. 
 

Vaccinations 
 
• Tell your doctor if you have recently been given any vaccine or might be given a vaccine in the 

near future.  
• While you are being treated with Ocrevus, you should  not be given live or live attenuated 

vaccines (for example BCG for tuberculosis or vaccines against yellow fever).  
• Your doctor may recommend that you are given a seasonal influenza vaccine. 
• Your doctor will check if you need any vaccinations before you start treatment with Ocrevus. 

Any vaccinations should be given at least 6 weeks before you start treatment with Ocrevus. 
 
Children and adolescents 
 
Ocrevus is not intended to be used in children and adolescents under 18 years old. This is because it 
has not yet been studied in this age group. 
 



37 

Other medicines and Ocrevus 
 
Tell your doctor if you are taking, have recently taken or might take any other medicines.  
In particular tell your doctor if: 
• you have ever taken, are taking or are planning to take medicines that affect the immune 

system – such as chemotherapy, immunosuppressants or other medicines used to treat MS. The 
effect on the immune system of these medicines with Ocrevus could be too strong.  Your doctor 
may decide to delay your treatment with Ocrevus or may ask you to stop such medicines before 
starting treatment with Ocrevus. 

• you are taking medicines for high blood pressure. This is because Ocrevus may lower blood 
pressure. Your doctor may ask you to stop taking your blood pressure medicines for 12 hours 
before each Ocrevus infusion.  

 
If any of the above apply to you (or you are not sure), talk to your doctor before you are given 
Ocrevus. 
 
Pregnancy 
 
• Tell your doctor before being given Ocrevus if you are pregnant, think that you might be 

pregnant or are planning to have a baby. This is because Ocrevus may cross the placenta and 
affect your baby. 

• Do not use Ocrevus if you are pregnant unless you have discussed this with your doctor. Your 
doctor will consider the benefit of you taking Ocrevus against the risk to your baby.  

• Talk to your doctor before vaccinating your baby.   
 
Contraception for women 
 
If you are able to become pregnant (conceive), you must use contraception: 
• during treatment with Ocrevus and 
• for 12 months after your last infusion of Ocrevus. 
 
Breast-feeding 
 
Do not breast-feed while you are being treated with Ocrevus. This is because Ocrevus may pass into 
breast milk. 
 
Driving and using machines 
 
It is not known whether Ocrevus can affect your being able to drive or use tools or machines.  
Your doctor will tell you whether your MS may affect your ability to drive or use tools and machines 
safely.  
 
Ocrevus contains sodium 
 
This medicine contains less than 1 mmol sodium (23 mg) per dose, i.e., it is essentially sodium-free. 
 
 
3. How Ocrevus is given  
 
Ocrevus will be given to you by a doctor or nurse who is experienced in the use of this treatment. 
They will watch you closely while you are being given this medicine. This is in case you get any side 
effects. You will always be given Ocrevus as a drip (intravenous infusion). 
 



38 

Medicines you will have before you are given Ocrevus 
 
Before you are given Ocrevus, you will receive other medicines to prevent or reduce possible side 
effects such as infusion-related reactions (see sections 2 and 4 for information about infusion-related 
reactions). 
You will receive a corticosteroid and an anti-histamine before each infusion and you may also receive 
medicines to reduce fever. 
 
How Ocrevus is given  
 
• Ocrevus will be given to you by a doctor or a nurse. It will be given as an infusion into a vein 

(intravenous infusion or IV infusion). 
• You will be closely monitored while you are being given Ocrevus and for at least 1 hour after 

the infusion has been given. This is in case you have any side effects such as infusion-related 
reactions. The infusion may be slowed, temporarily stopped or permanently stopped if you have 
an infusion-related reaction, depending on how serious it is (see sections 2 and 4 for information 
about infusion-related reactions). 

 
How much and how often you will be given Ocrevus 
 
You will be given a total dose of 600 mg of Ocrevus every 6 months. 
• The first 600 mg dose of Ocrevus will be given as 2 separate infusions (300 mg each), given 

2 weeks apart. Each infusion will last about 2 hours 30 minutes. 
• The next 600 mg doses of Ocrevus will be given as a single infusion. Depending on the rate of 

the subsequent infusion, each infusion will either last about 3 hours 30 minutes or 2 hours. 
 
If you miss an infusion of Ocrevus 
 
• If you miss an infusion of Ocrevus, talk to your doctor to arrange to have it as soon as possible. 

Do not wait until your next planned infusion. 
• To get the full benefit of Ocrevus, it is important that you receive each infusion when it is due. 
 
If you stop Ocrevus treatment 
 
• It is important to continue your treatment for as long as you and your doctor decide that it is 

helping you.  
• Some side effects can be related to having low B cells.  After you stop Ocrevus treatment, you 

may still experience side effects until your B-cells return to normal. Your blood B-cells will 
gradually increase to normal levels. This can take from six months to two and a half years, or up 
to several years in rare cases.  

• Before you start any other medicines, tell your doctor when you had your last Ocrevus infusion.  
 
If you have any further questions on the use of this medicine, ask your doctor. 
 
 
4. Possible side effects  
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
The following side effects have been reported with Ocrevus: 
 
Infusion-related reactions  
 
• Infusion-related reactions are the most common side effect of Ocrevus treatment (very common: 

may affect more than 1 in 10 people). In most cases these are mild reactions but some serious 
reactions can happen. 



39 

• Tell your doctor or nurse straight away if you experience any signs or symptoms of an 
infusion-related reaction during the infusion or up to 24 hours after the infusion. 
Symptoms can include, but are not limited to: 
- itchy skin 
- rash 
- hives 
- redness of the skin 
- throat irritation or pain 
- shortness of breath 
- swelling of the throat 
- flushing 
- low blood pressure 
- fever 
- feeling tired  
- headache 
- feeling dizzy 
- feeling sick (nausea) 
- fast heart beat. 

• If you have an infusion-related reaction, you will be given medicines to treat it and the infusion 
may need to be slowed down or stopped. When the reaction has stopped, the infusion may be 
continued. If the infusion-related reaction is life-threatening, your doctor will permanently stop 
your treatment with Ocrevus.  

 
Infections 
 
• You might get infections more easily with Ocrevus. The following infections have been seen in 

patients treated with Ocrevus in MS:  
- Very common: may affect more than 1 in 10 people 

- upper respiratory tract infection 
- flu. 

- Common: may affect up to 1 in 10 people 
- sinus infection 
- bronchitis (bronchial tube inflammation) 
- herpes infection (cold sore or shingles) 
- infection of the stomach and bowel (gastroenteritis) 
- respiratory tract infection 
- viral infection    
- skin infection (cellulitis) 

 
Some of them might be serious. 

 
• Tell your doctor or nurse straight away if you notice any of these signs of infection: 
 

- fever or chills 
- cough which does not go away 
- herpes (such as cold sore, shingles and genital sores). 

 
Other side effects  
 
Very common: may affect more than 1 in 10 people 
• decrease in specific proteins in the blood (immunoglobulins) which help protect against 

infection 
Common: may affect up to 1 in 10 people 
• cough 
• a build-up of thick mucus in the nose, throat or chest 
• low levels of a type of white blood cell (neutropenia) 



40 

Not known: it is not known how often these side effects happen 
• a reduction in white blood cells which can be delayed 
 
Reporting of side effects 
 
If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not 
listed in this leaflet. You can also report side effects directly via the national reporting system listed in 
Appendix V. By reporting side effects you can help provide more information on the safety of this 
medicine. 
 
 
5. How to store Ocrevus 
 
Ocrevus will be stored by the healthcare professionals at the hospital or clinic under the following 
conditions: 
• This medicine is to be kept out of the sight and reach of children. 
• This medicine is not to be used after the expiry date which is stated on the outer carton and the 

vial label after ‘EXP’. The expiry date refers to the last day of that month. 
• This medicine is to be stored in a refrigerator (2oC - 8oC). It is not to be frozen.The vials are to 

be kept in the outer carton to protect them from light.   
 
Ocrevus must be diluted before it is given to you. Dilution will be done by a healthcare professional. It 
is recommended that the product is used immediately after dilution. If not used immediately, in-use 
storage times and conditions prior to use are the responsibility of the healthcare professional and 
would normally not be longer than 24 hours at 2°C - 8°C and subsequently 8 hours at room 
temperature.  
 
Do not throw away any medicines via wastewater. These measures will help to protect the 
environment. 
 
 
6. Contents of the pack and other information 
 
What Ocrevus contains 
 
• The active substance is ocrelizumab. Each vial contains 300 mg of ocrelizumab in 10 mL at a 

concentration of 30mg/mL. 
• The other ingredients are sodium acetate trihydrate, glacial acetic acid, trehalose dihydrate, 

polysorbate 20 and water for injection. 
 
What Ocrevus looks like and contents of the pack 
 
• Ocrevus is a clear to slightly opalescent, and colourless to pale brown solution.  
• It is supplied as a concentrate for solution for infusion. 
• This medicine is available in packs containing 1 or 2 vials (vials of 10 mL concentrate). Not all 

pack sizes may be marketed. 
 
Marketing Authorisation Holder  
 
Roche Registration GmbH  
Emil-Barell-Strasse 1 
79639 Grenzach-Wyhlen 
Germany 
 

https://www.ema.europa.eu/documents/template-form/appendix-v-adverse-drug-reaction-reporting-details_en.doc


41 

Manufacturer  
 
Roche Pharma AG 
Emil-Barell-Strasse 1 
D-79639 Grenzach-Wyhlen 
Germany 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien  
N.V. Roche S.A.  
Tél/Tel: +32 (0) 2 525 82 11  

Lietuva  
UAB “Roche Lietuva”  
Tel: +370 5 2546799  

 
България  
Рош България ЕООД  
Тел: +359 2 818 44 44  

 
Luxembourg/Luxemburg  
(Voir/siehe Belgique/Belgien)  

 
Česká republika  
Roche s. r. o.  
Tel: +420 - 2 20382111  

 
Magyarország  
Roche (Magyarország) Kft.  
Tel: +36 - 23 446 800  

 
Danmark  
Roche a/s  
Tlf: +45 - 36 39 99 99  

 
Malta  
(see Ireland)  

 
Deutschland  
Roche Pharma AG  
Tel: +49 (0) 7624 140  

 
Nederland  
Roche Nederland B.V.  
Tel: +31 (0) 348 438050  

 
Eesti  
Roche Eesti OÜ  
Tel: + 372 - 6 177 380  

 
Norge  
Roche Norge AS  
Tlf: +47 - 22 78 90 00  

 
Ελλάδα  
Roche (Hellas) A.E.  
Τηλ: +30 210 61 66 100  

 
Österreich  
Roche Austria GmbH  
Tel: +43 (0) 1 27739  

 
España  
Roche Farma S.A.  
Tel: +34 - 91 324 81 00  

 
Polska  
Roche Polska Sp.z o.o.  
Tel: +48 - 22 345 18 88  

 
France  
Roche  
Tél: +33 (0) 1 47 61 40 00  

 
Portugal  
Roche Farmacêutica Química, Lda  
Tel: +351 - 21 425 70 00  

 
Hrvatska  
Roche d.o.o.  
Tel: +385 1 4722 333  

 
România  
Roche România S.R.L.  
Tel: +40 21 206 47 01  

 
Ireland  
Roche Products (Ireland) Ltd.  
Tel: +353 (0) 1 469 0700  

 
Slovenija  
Roche farmacevtska družba d.o.o.  
Tel: +386 - 1 360 26 00  



42 

 
Ísland  
Roche a/s  
c/o Icepharma hf  
Sími: +354 540 8000  
 

 
Slovenská republika  
Roche Slovensko, s.r.o.  
Tel: +421 - 2 52638201  

Italia  
Roche S.p.A.  
Tel: +39 - 039 2471  

Suomi/Finland  
Roche Oy  
Puh/Tel: +358 (0) 10 554 500  

 
Kύπρος  
Γ.Α.Σταμάτης & Σια Λτδ.  
Τηλ: +357 - 22 76 62 76  

 
Sverige  
Roche AB  
Tel: +46 (0) 8 726 1200  

 
Latvija  
Roche Latvija SIA  
Tel: +371 - 6 7039831  

 
United Kingdom  
Roche Products Ltd.  
Tel: +44 (0) 1707 366000  

  
 
This leaflet was last revised in <{MM/YYYY}>  
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.  
  

http://www.ema.europa.eu/


43 

The following information is intended for healthcare professionals only: 
 
Read the SmPC for additional information.  
 
Posology  
 
• Initial Dose 
 
The initial 600 mg dose is administered as two separate intravenous infusions; first as a 300 mg 
infusion, followed 2 weeks later by a second 300 mg infusion. 
 
• Subsequent Doses 
 
Subsequent doses of Ocrevus thereafter are administered as a single 600 mg intravenous infusion 
every 6 months (Table 1). The first subsequent dose of 600 mg should be administered six months 
after the first infusion of the initial dose. A minimum interval of 5 months should be maintained 
between each dose of Ocrevus.   
 
Figure 1: Dose and Schedule of Ocrevus 
 

 
 
Management of IRRs before the infusion 
 
• Ocrevus treatment should be initiated and supervised by an experienced healthcare professional 

with access to appropriate medical support to manage severe reactions such as serious infusion-
related reactions (IRRs), hypersensitivity reactions and/or anaphylactic reactions.  

 
• Premedication for IRRs 
 

The two following premedications must be administered prior to each Ocrevus infusion to 
reduce the frequency and severity of IRRs: 
-100 mg intravenous methylprednisolone (or an equivalent) approximately 30 minutes prior to 
each Ocrevus infusion; 
-antihistamine approximately 30-60 minutes prior to each Ocrevus infusion; 
In addition, premedication with an antipyretic (e.g. paracetamol) may also be considered 
approximately 30-60 minutes prior to each Ocrevus infusion. 

 
• Hypotension, as a symptom of IRR, may occur during Ocrevus infusions. Therefore, 

withholding of antihypertensive treatments should be considered for 12 hours prior to and 
throughout each Ocrevus infusion.  Patients with a history of congestive heart failure (New 
York Heart Association III & IV) were not studied.   

 



44 

Instructions for dilution 
 
• Ocrevus should be prepared by a healthcare professional using aseptic technique. Do not shake 

the vial. 
• The product is intended for single use only. 
• Ocrevus may contain fine translucent and/or reflective particles associated with enhanced 

opalescence.  Do not use the solution if discoloured or if the solution contains foreign 
particulate matter. 

• Ocrevus medicinal product must be diluted before administration. Solutions of Ocrevus for 
intravenous administration are prepared by dilution of the drug product into an infusion bag 
containing isotonic 0.9% sodium chloride (300mg/250mL or 600mg/500mL), to a final drug 
concentration of approximately 1.2 mg/mL.  

• The diluted infusion solution must be administered using an infusion set with a 0.2 or 
0.22 micron in-line filter.  

• Prior to the start of the intravenous  infusion, the content of the infusion bag should be at room 
temperature to avoid an infusion reaction due to the administration of the solution at low 
temperatures. 

 
Method of administration 
 
• After dilution, Ocrevus is administered as an intravenous infusion through a dedicated line. 
• Ocrevus infusions should not be administered as an intravenous push or bolus. 
 



45 

Table 1: Dose and Schedule of Ocrevus 
 

 Amount of Ocrevus to 
be  

administered  

Infusion instruction 

Initial Dose 
(600 mg) 

divided into 2 
infusions 

Infusion 1 300 mg in 250 mL • Initiate the infusion at a rate of 
30 mL/hour for 30 minutes 

• The rate can be increased in 
30 mL/hour increments every 
30 minutes to a maximum of 
180 mL/hour. 

• Each infusion should be given 
over approximately 2.5 hours. 

Infusion 2 
(2 weeks later) 

300 mg in 250 mL 

Subsequent 
Doses 

(600 mg) 
single infusion 
once every 6 

months 
 

Option 1 
 

Infusion of 
approx. 3.5 

hours duration 

600 mg in 500 mL • Initiate the infusion at a rate of 
40 mL/hour for 30 minutes 

• The rate can be increased in 
40 mL/hour increments every 
30 minutes to a maximum of 
200 mL/hour 

• Each infusion should be given 
over approximately 3.5 hours. 

OR 
Option 2 

 
Infusion of 
approx. 2 

hours duration 

600 mg in 500 mL • Initiate the infusion at a rate of 
100 mL/hour for the first 15 
minutes 

• Increase the infusion rate to 
200 mL/hour for the next 15 
minutes 

• Increase the infusion rate to 
250 mL/hour for the next 30 
minutes  

• Increase the infusion rate to 
300 mL/hour for the remaining 
60 minutes 

• Each infusion should be given 
over approximately 2 hours. 

 
Management of IRRs during and after the infusion 
 
Patients should be monitored during the infusion and for at least one hour after the completion of the 
infusion. 
During the infusion 
 
• Infusion Adjustments in case of IRRs  
 

In case of IRRs during any infusion, see the following adjustments.   
 
Life-threatening IRRs   

 
If there are signs of a life threatening or disabling IRR during an infusion, such as acute 
hypersensitivity or acute respiratory distress syndrome the infusion must be stopped 



46 

immediately and the patient should receive appropriate treatment. Ocrevus must be permanently 
discontinued in these patients (see section 4.3). 
 

Severe IRRs 
 

If a patient experiences a severe IRR (such as dyspnea) 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 restarted 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. No infusion adjustment is necessary for subsequent new infusions, unless 
the patient experiences an IRR. 

 
Mild to Moderate IRRs 

 
If a patient experiences a mild to moderate IRR (e.g., headache), the infusion rate should be 
reduced to half the rate at the onset 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 rate. No infusion adjustment is necessary for subsequent new infusions, unless 
the patient experiences an IRR. 

 
• Patients who experience severe pulmonary symptoms, such as bronchospasm or asthma 

exacerbation, must have their infusion interrupted immediately and permanently. After 
administering symptomatic treatment, monitor the patient until the pulmonary symptoms have 
resolved because initial improvement of clinical symptoms could be followed by deterioration. 

 
• Hypersensitivity may be difficult to distinguish from an IRR in terms of symptoms. If a 

hypersensitivity reaction is suspected during infusion, the infusion must be stopped immediately 
and permanently.    

 
After the infusion 
 
• Patients treated with Ocrevus should be observed for at least one hour after the completion of 

the infusion for any symptom of an IRR. 
• Physicians should alert patients that an IRR can occur within 24 hours of infusion. 
 
Shelf life  
 
Unopened vial 
 
24 months 
 
Diluted solution for intravenous infusion 
 
• Chemical and physical in-use stability has been demonstrated for 24 hours at 2-8°C and 

subsequently 8 hours at room temperature. 
• From a microbiological point of view, the prepared infusion should be used immediately. If not 

used immediately, in-use storage times and conditions prior to use are the responsibility of the 
user and would normally not be longer than 24 hours at 2-8°C and subsequently 8 hours at room 
temperature, unless dilution undertaken in controlled and validated aseptic conditions. 

• In the event an intravenous infusion cannot be completed the same day, the remaining solution 
should be discarded. 

  



47 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX IV 
 

SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS 
OF THE MARKETING AUTHORISATION(S) 

 
 
 
 
 
 
 
 
 
 
 
  



48 

Scientific conclusions 
 
Taking into account the PRAC Assessment Report on the PSUR(s) for orelizumab, the scientific 
conclusions of the CHMP are as follows: 
  
In view of available data on the risk of late onset of neutropenia from the literature and spontaneous 
reports, and in view of a plausible class effect in therapeutic CD20 antibodies, the PRAC considers a 
causal relationship between ocrelizumab and late onset of neutropenia is at least a reasonable 
possibility. The PRAC concluded that the product information of products containing ocrelizumab 
should be amended accordingly.  
 
The CHMP agrees with the scientific conclusions made by the PRAC. 
 
Grounds for the variation to the terms of the Marketing Authorisation(s)  
 
On the basis of the scientific conclusions for ocrelizumab the CHMP is of the opinion that the benefit-
risk balance of the medicinal product(s) containing ocrelizumab is unchanged subject to the proposed 
changes to the product information. 
 
The CHMP recommends that the terms of the Marketing Authorisation(s) should be varied. 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION 
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
	SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS OF THE MARKETING AUTHORISATION(S)