OCREVUS 300mg 30mg / ml perfusive solution concentrate medication leaflet

Ocrevus 300 mg concentrate for solution for infusion

Each vial contains 300 mg of ocrelizumab in 10 mL at a concentration of 30 mg/mL. The finalmedicinal product concentration after dilution is approximately 1.2 mg/mL.

Ocrelizumab is a humanised monoclonal antibody produced in Chinese Hamster Ovary cells byrecombinant DNA technology.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion.

Clear to slightly opalescent, and colourless to pale brown solution.

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 multiplesclerosis (PPMS) in terms of disease duration and level of disability, and with imaging featurescharacteristic of inflammatory activity (see section 5.1).

Treatment should be initiated and supervised by specialised physicians experienced in the diagnosisand treatment of neurological conditions and who have access to appropriate medical support tomanage severe reactions such as serious infusion-related reactions (IRRs).

Premedication for infusion-related reactions

The following two premedications must be administered prior to each ocrelizumab infusion to reducethe frequency and severity of IRRs (see section 4.4 for additional steps to reduce IRRs):

* 100 mg intravenous methylprednisolone (or an equivalent) approximately 30 minutes prior toeach infusion;

* antihistamine approximately 30-60 minutes prior to each infusion;

In addition, premedication with an antipyretic (e.g., paracetamol) may also be consideredapproximately 30-60 minutes prior to each infusion.

Initial dose

The initial 600 mg dose is administered as two separate intravenous infusions; first as a 300 mginfusion, followed 2 weeks later by a second 300 mg infusion (see Table 1).

Subsequent doses of ocrelizumab thereafter are administered as a single 600 mg intravenous infusionevery 6 months (see Table 1). The first subsequent dose of 600 mg should be administered six monthsafter the first infusion of the initial dose.

A minimum interval of 5 months should be maintained between each dose of ocrelizumab.

Infusion adjustments in case of IRRs

Life-threatening IRRs

If there are signs of a life threatening or disabling IRR during an infusion, such as acutehypersensitivity or acute respiratory distress syndrome, the infusion must be stopped immediately andthe patient should receive appropriate treatment. The infusion must be permanently discontinued inthese patients (see section 4.3).

Severe IRRs

If a patient experiences a severe IRR (such as dyspnoea) or a complex of flushing, fever, and throatpain symptoms, the infusion should be interrupted immediately, and the patient should receivesymptomatic treatment. The infusion should be restarted only after all symptoms have resolved. Theinitial infusion rate at restart should be half of the infusion rate at the time of onset of the reaction. Noinfusion 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 tohalf 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. Noinfusion 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 resultin a change in the infusion rate and increase the total duration of the infusion, but not the total dose.

No dose reductions are recommended.

If an infusion is missed, it should be administered as soon as possible; do not wait until the nextplanned dose. The treatment interval of 6 months (with a minimum of 5 months) should be maintainedbetween doses (see Table 1).

Adults over 55 years old

Based on the limited data available (see sections 5.1 and 5.2), no posology adjustment is needed inpatients over 55 years of age. Patients enrolled in the ongoing clinical trials continue to be dosed with600 mg ocrelizumab every six months after they become older than 55 years old.

The safety and efficacy of ocrelizumab in patients with renal impairment has not been formallystudied. Patients with mild renal impairment were included in clinical trials. There is no experience inpatients with moderate and severe renal impairment. Ocrelizumab is a monoclonal antibody andcleared via catabolism (i.e. breakdown into peptides and amino acids), and a dose adjustment is notexpected to be required for patients with renal impairment (see section 5.2).

The safety and efficacy of ocrelizumab in patients with hepatic impairment has not been formallystudied. Patients with mild hepatic impairment were included in clinical trials. There is no experiencein patients with moderate and severe hepatic impairment. Ocrelizumab is a monoclonal antibody andcleared via catabolism (rather than hepatic metabolism), and a dose adjustment is not expected to berequired for patients with hepatic impairment (see section 5.2).

The safety and efficacy of ocrelizumab in children and adolescents aged 0 to 18 years has not yet beenestablished. No data are available.

Ocrevus 300 mg concentrate for solution for infusion is not intended for subcutaneous administrationand should be administered via an intravenous infusion only.

It is important to check the product labels to ensure that the correct formulation (intravenous orsubcutaneous) is being administered to the patient, as prescribed.

Patients may start treatment using intravenous or subcutaneous ocrelizumab.

After dilution, treatment is administered as an intravenous infusion through a dedicated line. Infusionsshould not be administered as an intravenous push or bolus.

If patients did not experience a serious infusion-related reaction (IRR) with any previous ocrelizumabinfusion, a shorter (2-hour) infusion can be administered for subsequent doses (see Table 1, Option 2).

Table 1: Dose and schedule

Amount of Infusion instructionsocrelizumab to beadministered

Initial dose Infusion 1 300 mg in 250 mL * Initiate the infusion at(600 mg) a rate of 30 mL/hourdivided into 2 infusions Infusion 2 300 mg in 250 mL for 30 minutes(2 weeks later)

* The rate can beincreased in30 mL/hour incrementsevery 30 minutes to amaximum of180 mL/hour.

* Each infusion shouldbe given overapproximately2.5 hours

Option 1 600 mg in 500 mL * Initiate the infusion ata rate of 40 mL/hour

Infusion of for 30 minutesapproximately3.5 hours duration * The rate can beincreased in40 mL/hour incrementsevery 30 minutes to amaximum of200 mL/hour

Subsequent doses * Each infusion should(600 mg) be given oversingle infusiononce every 6 months approximately3.5 hours

OR

Option 2 600 mg in 500 mL * Initiate the infusion ata rate of 100 mL/hour

Infusion of for the first 15 minutesapproximately * Increase the infusion2 hours duration rate to 200 mL/hourfor the next 15 minutes

* Increase the infusionrate to 250 mL/hourfor the next 30 minutes

Amount of Infusion instructionsocrelizumab to beadministered

* Increase theinfusion rate to300 mL/hour for theremaining 60 minutes

* Each infusionshould be given overapproximately 2 hours

Solutions for intravenous infusion are prepared by dilution of the concentrate into an infusion bagcontaining sodium chloride 9 mg/mL (0.9%) solution for infusion, to a final ocrelizumabconcentration 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 theinfusion (see section 4.4).

* 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).

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Infusion-Related Reactions (IRRs)

Ocrelizumab is associated with IRRs, which may be related to cytokine release and/or other chemicalmediators.

Symptoms of IRRs may occur during any ocrelizumab infusion, but have been more frequentlyreported during the first infusion. IRRs can occur within 24 hours of the infusion (see section 4.8).

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, tachycardia and anaphylaxis.

Before the infusion

Management of severe reactions

Appropriate resources for the management of severe reactions such as serious IRR, hypersensitivityreactions and/or anaphylactic reactions should be available.

As a symptom of IRR, hypotension may occur during infusions. Therefore, withholding ofantihypertensive treatments should be considered for 12 hours prior to and throughout each infusion.

Patients with a history of congestive heart failure (New York Heart Association III & IV) were notstudied.

Premedication

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

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 initialimprovement of clinical symptoms could be followed by deterioration.

Hypersensitivity may be clinically indistinguishable from an IRR in terms of symptoms. If ahypersensitivity reaction is suspected during infusion, the infusion must be stopped immediately andpermanently (see ‘Hypersensitivity reactions’ below).

After the infusion

Patients should be observed for at least one hour after the completion of the infusion for any symptomof IRR.

Physicians should alert patients that an IRR can occur within 24 hours of infusion.

For guidance regarding infusion adjustments in case of IRR, see section 4.2.

A hypersensitivity reaction could also occur (acute allergic reaction to medicinal product). Type 1acute hypersensitivity reactions (IgE-mediated) may be clinically indistinguishable from IRRsymptoms.

A hypersensitivity reaction may present during any administration, although typically would notpresent during the first administration. For subsequent administrations, more severe symptoms thanpreviously experienced, or new severe symptoms, should prompt consideration of a potentialhypersensitivity reaction. Patients with known Ig-E mediated hypersensitivity to ocrelizumab or any ofthe excipients must not be treated (see section 4.3).

Infection

Administration of ocrelizumab must be delayed in patients with an active infection until the infectionis resolved.

It is recommended to verify the patient’s immune status before dosing since severelyimmunocompromised patients (e.g., with lymphopenia, neutropenia, hypogammaglobulinemia) shouldnot be treated (see sections 4.3 and 4.8).

The overall proportion of patients experiencing a serious infection (SI) was similar to comparators (seesection 4.8). The frequency of grade 4 (life-threatening) and grade 5 (fatal) infections was low in alltreatment groups, but in PPMS it was higher with ocrelizumab compared with placebo for life-threatening (1.6% vs 0.4%) and fatal (0.6% vs 0%) infections. All life-threatening infections resolvedwithout discontinuing ocrelizumab.

In PPMS, patients with swallowing difficulties are at a higher risk of aspiration pneumonia. Treatmentwith ocrelizumab may further increase the risk of severe pneumonia in these patients. Physiciansshould take prompt action for patients presenting with pneumonia.

John Cunningham virus (JCV) infection resulting in PML has been observed very rarely in patientstreated with anti-CD20 antibodies, including ocrelizumab, and mostly associated with risk factors(patient population e.g., lymphopenia, advanced age, polytherapy with immunosuppressants).

Physicians should be vigilant for the early signs and symptoms of PML, which can include any newonset, or worsening of neurological signs or symptoms, as these can be similar to MS disease.

If PML is suspected, dosing with ocrelizumab 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 JCV Deoxyribonucleic acid (DNA) and repeatneurological assessments, should be considered. If PML is confirmed, treatment must be discontinuedpermanently.

Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failureand death, has been reported in patients treated with anti-CD20 antibodies.

HBV screening should be performed in all patients before initiation of treatment as per localguidelines. Patients with active HBV (i.e. an active infection confirmed by positive results for HBsAgand anti HB testing) should not be treated with ocrelizumab (see section 4.3). Patients with positiveserology (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 treatmentand should be monitored and managed following local medical standards to prevent hepatitis Breactivation.

Cases of late onset of neutropenia have been reported at least 4 weeks after the latest ocrelizumabinfusion (see section 4.8). Although some cases were Grade 3 or 4, the majority of the cases were

Grade 1 or 2. In patients with signs and symptoms of infection, measurement of blood neutrophils isrecommended.

An increased number of malignancies (including breast cancers) have been observed in the controlledperiod of the pivotal clinical trials in patients treated with ocrelizumab, compared to control groups.

The incidence was within the background rate expected for an MS population. After approximately10 years of continuous ocrelizumab treatment over the controlled period and Open-Label Extension(OLE) phase of the pivotal clinical trials, the incidence of malignancies remained within thebackground rate expected for an MS population. Patients with a known active malignancy should notbe treated with ocrelizumab (see section 4.3). Individual benefit risk should be considered in patientswith known risk factors for malignancies and in patients who are being actively monitored forrecurrence of malignancy. Patients should follow standard breast cancer screening per local guidelines.

Treatment of severely immunocompromised patients

Patients in a severely immunocompromised state must not be treated until the condition resolves (seesection 4.3).

In other auto-immune conditions, use of ocrelizumab concomitantly with immunosuppressants (e.g.,chronic corticosteroids, non-biologic and biologic disease-modifying antirheumatic drugs[DMARDS], mycophenolate mofetil, cyclophosphamide, azathioprine) resulted in an increase of SIs,including opportunistic infections. Infections included and were not limited to atypical pneumonia andpneumocystis jirovecii pneumonia, varicella pneumonia, tuberculosis, histoplasmosis. In rare cases,some of these infections were fatal. An exploratory analysis identified the following factors associatedwith risk of SIs: higher doses of ocrelizumab than recommended in MS, other comorbidities, andchronic use of immunosuppressants/corticosteroids.

It is not recommended to use other immunosuppressives concomitantly with ocrelizumab exceptcorticosteroids for symptomatic treatment of relapses. Knowledge is limited as to whether concomitantsteroid use for symptomatic treatment of relapses is associated with an increased risk of infections inclinical practice. In the ocrelizumab MS pivotal studies, the administration of corticosteroids for thetreatment of relapse was not associated with an increased risk of SI.

When initiating ocrelizumab after an immunosuppressive therapy or initiating an immunosuppressivetherapy after ocrelizumab, the potential for overlapping pharmacodynamic effects should be taken intoconsideration (see section 5.1). Caution should be exercised when prescribing ocrelizumab taking intoconsideration the pharmacodynamics of other disease modifying MS therapies.

The safety of immunisation with live or live-attenuated vaccines, following ocrelizumab therapy hasnot been studied and vaccination with live-attenuated or live vaccines is not recommended duringtreatment and not until B-cell repletion. In clinical trials, the median time for B-cell repletion was72 weeks (see section 5.1).

In a randomised open-label study, RMS patients were able to mount humoral responses, althoughdecreased, to tetanus toxoid, 23-valent pneumococcal polysaccharide with or without a boostervaccine, keyhole limpet haemocyanin neoantigen, and seasonal influenza vaccines (see section 4.5and 5.1).

It is recommended to vaccinate patients treated with ocrelizumab with seasonal influenza vaccines thatare inactivated.

Physicians should review the immunisation status of patients being considered for treatment withocrelizumab. Patients who require vaccination should complete their immunisation at least 6 weeksprior to initiation of treatment.

Exposure in utero to ocrelizumab and vaccination of neonates and infants with live or live attenuatedvaccines

Due to the potential depletion of B cells in infants of mothers who have been exposed to ocrelizumabduring pregnancy, it is recommended that vaccination with live or live-attenuated vaccines should bedelayed until B-cell levels have recovered; therefore, measuring CD19-positive B-cell levels inneonates and infants prior to vaccination is recommended.

It is recommended that all vaccinations other than live or live-attenuated should follow the localimmunisation schedule and measurement of vaccine-induced response titres should be considered tocheck whether individuals have mounted a protective immune response because the efficacy of thevaccination may be decreased.

The safety and timing of vaccination should be discussed with the infant’s physician (see section 4.6).

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially‘sodium-free’.

No interaction studies have been performed, as no interactions are expected via cytochrome

P450 enzymes, other metabolising enzymes or transporters.

The safety of immunisation with live or live-attenuated vaccines, following ocrelizumab therapy hasnot been studied.

Data are available on the effects of tetanus toxoid, 23-valent pneumococcal polysaccharide, keyholelimpet haemocyanin neoantigen, and seasonal influenza vaccines in patients receiving ocrelizumab(see section 4.4 and 5.1).

After treatment over 2 years, the proportion of patients with positive antibody titresagainst S. pneumoniae, mumps, rubella and varicella were generally similar to the proportions atbaseline.

Immunosuppressants

It is not recommended to use other immunosuppressive therapies concomitantly with ocrelizumabexcept corticosteroids for symptomatic treatment of relapses (see section 4.4).

Women of childbearing potential should use contraception while receiving ocrelizumab and for4 months after the last administered dose of ocrelizumab.

There is a limited amount of data from the use of ocrelizumab in pregnant women. Ocrelizumab is animmunoglobulin G (IgG). IgG is known to cross the placental barrier. Postponing vaccination withlive or live-attenuated vaccines should be considered for neonates and infants born to mothers whohave been exposed to ocrelizumab in utero. No B cell count data have been collected in neonates andinfants exposed to ocrelizumab and the potential duration of B-cell depletion in neonates and infants isunknown (see section 4.4).

Transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born tomothers exposed to other anti-CD20 antibodies during pregnancy. B-cell depletion in utero was alsodetected in animal studies.

Animal studies (embryo-foetal toxicity) do not indicate teratogenic effects. Reproductive toxicity wasobserved in pre- and post-natal development studies (see section 5.3).

Ocrelizumab should be avoided during pregnancy unless the potential benefit to the mother outweighsthe potential risk to the foetus.

Human IgGs are known to be excreted in breastmilk the first few days after birth (colostrum period),which decreases to low concentrations soon afterwards.

In a prospective, multicenter, open-label study MN42989 (SOPRANINO), 13 lactating womenreceived ocrelizumab at a median of 2.0 months postpartum (range 0.5-5.0 months). Lowconcentrations of ocrelizumab were detected in the breastmilk over 60 days following the mother’sfirst postpartum infusion (median relative infant dose of 0.27% [range 0.0-1.8 %]), indicating minimaltransfer of ocrelizumab to breastmilk. At 30 days after the mother’s first postpartum infusion,ocrelizumab was undetectable in all available serum samples of breastfed infants (n=9), and infant

B-cell levels were within normal range in all available blood samples (n=10). No effects ofocrelizumab on health, growth and development were observed in breastfed infants over a follow-upperiod of 44.6 weeks (range 8.6-62.7 weeks).

While no clinical data on infants potentially exposed to ocrelizumab via breastmilk receiving live orlive-attenuated vaccines are available, no risks are expected due to normal B-cell levels andundetectable serum ocrelizumab levels observed in those infants.

In a separate prospective clinical study, low ocrelizumab concentrations in breastmilk (median relativeinfant dose of 0.1% [range 0.07-0.7%]) over 90 days after the mother’s first postpartum infusion wereobserved in 29 lactating women who received ocrelizumab at a median of 4.3 months postpartum(range 0.1-36 months). Follow-up of 21 infants breastfed for at least 2 weeks showed normal growthand development up to 1 year.

Ocrelizumab can be used during breastfeeding starting a few days after birth.

Preclinical data reveal no special hazards for humans based on studies of male and female fertility incynomolgus monkeys.

Ocrevus has no or negligible influence on the ability to drive and use machines.

In the controlled period of the pivotal clinical trials, the most important and frequently reportedadverse reactions were IRRs (34.3%, 40.1% in RMS and PPMS, respectively) and infections (58.5%,72.2% in RMS and PPMS, respectively) (see section 4.4).

A total of 2,376 patients were included in the controlled period of the pivotal clinical trials; of thesepatients, 1,852 entered the OLE phase. All patients switched to ocrelizumab treatment during the OLEphase. 1,155 patients completed the OLE phase, resulting in approximately 10 years of continuousocrelizumab treatment (15,515 patient-years of exposure) across the controlled period and OLE phase.

The overall safety profile observed during the controlled period and OLE phase remains consistentwith that observed during the controlled period.

Adverse reactions reported in the controlled period of the pivotal clinical trials and derived fromspontaneous reporting are listed below in Table 2. The adverse reactions are listed by MedDRAsystem organ class and categories of frequency. 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), veryrare (< 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.

Table 2 Adverse reactions

MedDRA Very common Common Not Known

System Organ Class (SOC)

Infections and infestations Upper respiratory Sinusitis,tract infection, bronchitis,nasopharyngitis, oral herpes,influenza gastroenteritis,respiratory tractinfection,viral infection,herpes zoster,conjunctivitis,cellulitis

Blood and lymphatic system Neutropenia Late onset ofdisorders Neutropenia2

Respiratory, thoracic and Cough,mediastinal disorders catarrh

Investigations Blood Blood immunoglobulinimmunoglobulin M G decreaseddecreased

Injury, poisoning and Infusion-relatedprocedural complications reactions11 See Descriptions of selected adverse reactions.2 Observed in the postmarketing setting.

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, throatirritation, oropharyngeal pain, dyspnoea, pharyngeal or laryngeal oedema, nausea, tachycardia. Incontrolled trials there were no fatal IRRs. In addition, symptoms of IRR in the post-marketing settingincluded anaphylaxis.

In active-controlled (RMS) clinical trials, IRR was the most common adverse reaction in theocrelizumab treatment group 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 duringthe Dose 1, infusion 1 (27.5%) and decreased over time to <10% at Dose 4. The majority of IRRs inboth treatment groups were mild to moderate. 21.7% and 10.1% of ocrelizumab treated patientsexperienced mild and moderate IRRs, respectively. 2.4% experienced severe IRRs and 0.1%experienced life-threatening IRRs.

In the placebo-controlled (PPMS) clinical trial, IRR was the most common adverse reaction in theocrelizumab treatment group 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%) anddecreased with subsequent doses to <10% at Dose 4. A greater proportion of patients in each groupexperienced 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 ocrelizumab treated patientsexperienced mild and moderate IRRs respectively, 1.4% experienced severe IRRs. There were no life-threatening IRRs. See section 4.4.

Over the controlled period and OLE phase of the RMS and PPMS clinical trials, patients were givenapproximately 20 doses of ocrelizumab. Incidence of IRRs decreased to <4% by Dose 4 of the OLEphase in RMS patients and to <5% by Dose 5 of the OLE phase in PPMS patients. With subsequentdoses administered during the OLE phase, incidence of IRR remained low. The majority of IRRs weremild during the OLE phase.

Alternative shorter infusion of subsequent doses

In a study (MA30143 Shorter Infusion Substudy) designed to characterise the safety profile of shorter(2-hour) ocrelizumab infusions in patients with Relapsing-Remitting Multiple Sclerosis, the incidence,intensity, and types of symptoms of IRRs were consistent with those of infusions administered over3.5 hours (see section 5.1). The overall number of interventions needed was low in both infusiongroups, however, more interventions (slowing down or temporary interruptions) were needed tomanage 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 receivingocrelizumab vs 52.5% of patients receiving interferon beta 1a. SIs occurred in 1.3% of patientsreceiving ocrelizumab vs 2.9% of patients receiving interferon beta 1a. In the placebo-controlled studyin PPMS, infections occurred in 72.2% of patients receiving ocrelizumab vs 69.9% of patientsreceiving placebo. SIs occurred in 6.2% of patients receiving ocrelizumab vs 6.7% of patientsreceiving placebo.

All patients switched to ocrelizumab during the OLE phase in both RMS and PPMS studies. Over the

OLE phase in RMS and PPMS patients, the overall risk of SIs did not increase from that observedduring the controlled period. As observed during the controlled period, the rate of SIs in PPMSpatients remained higher than that observed in RMS patients.

In line with the previous analysis of risk factors for SIs in auto-immune conditions other than MS (seesection 4.4), a multivariate analysis of risk factors for SIs was conducted in the approximately 10 yearsof cumulative exposure data from the controlled period and OLE phase of the pivotal clinical trials.

Risk factors for SIs in RMS patients include having at least 1 comorbidity, recent clinical relapse, and

Expanded Disability Status Scale (EDSS) ≥ 6.0. Risk factors for SIs in PPMS patients include bodymass index greater than 25 kg/m2, having at least 2 comorbidities, EDSS ≥ 6.0, and IgM < lower limitof normal (LLN). Comorbidities included, but were not limited to, cardiovascular, renal and urinarytract conditions, previous infections, and depression.

Respiratory tract infections

The proportion of respiratory tract infections was higher in ocrelizumab treated patients compared tointerferon beta-1-a and placebo.

In the RMS clinical trials, 39.9% of ocrelizumab treated patients and 33.2% interferon beta-1-a treatedpatients experienced an upper respiratory tract infection and 7.5% of ocrelizumab treated patients and5.2% of interferon beta-1-a treated patients experienced a lower respiratory tract infection.

In the PPMS clinical trial, 48.8% of ocrelizumab treated patients and 42.7% of patients who receivedplacebo experienced an upper respiratory tract infection, and 9.9% of ocrelizumab treated patients and9.2% of patients who received placebo experienced a lower respiratory tract infection.

The respiratory tract infections reported in patients treated with ocrelizumab were predominately mildto moderate (80 - 90 %).

Herpes

In active-controlled (RMS) clinical trials, herpes infections were reported more frequently inocrelizumab 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%). All infections were mild to moderate in severity, except one

Grade 3 event, 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 ocrelizumab treatment arm.

Immunoglobulins

Ocrelizumab treatment resulted in a decrease in total immunoglobulins over the controlled period ofthe pivotal clinical trials, mainly driven by reduction in IgM.

Clinical trial data from the controlled period and OLE phase of the pivotal clinical trials have shownan association between decreased levels of IgG (and less so for IgM or IgA) and increased rate of SIs.2.1% of RMS patients had a SI during a period with IgG < LLN and in 2.3% of PPMS patients had a

SI during a period with IgG < LLN. The difference in rate of SIs between patients with IgG < LLNcompared to patients with IgG ≥ LLN did not increase over time. The type, severity, latency, duration,and outcome of SIs observed during episodes of immunoglobulins below LLN were consistent withthe overall SIs observed in patients treated with ocrelizumab during the controlled period and OLEphase. Throughout the 10 years of continuous ocrelizumab treatment, mean IgG levels of RMS and

PPMS patients remained above LLN.

In RMS, a decrease in lymphocyte < LLN was observed in 20.7% of patients treated with ocrelizumabcompared with 32.6% of patients treated with interferon beta-1a. In PPMS, a decrease in lymphocytes<LLN was observed in 26.3% of ocrelizumab treated patients vs 11.7% of placebo-treated patients.

The majority of these decreases reported in ocrelizumab treated patients were Grade 1 (<LLN -800 cells/mm3) and 2 (between 500 and 800 cells/mm3) in severity. Approximately 1% of the patientsin the ocrelizumab group had a Grade 3 lymphopenia (between 200 and 500 cells/mm3). None of thepatients was reported with Grade 4 lymphopenia (< 200 cells/mm3).

An increased rate of SIs was observed during episodes of confirmed total lymphocytes counts decreasein ocrelizumab treated patients. The number of SIs was too low to draw definitive conclusions.

In the active-controlled (RMS) treatment period, a decrease in neutrophils < LLN was observed in14.7% of patients treated with ocrelizumab compared with 40.9% of patients treated with interferonbeta-1a. In the placebo-controlled (PPMS) clinical trial, the proportion of ocrelizumab patientspresenting decreased neutrophils was higher (12.9 %) than placebo patients (10.0 %); among these ahigher percentage of patients (4.3%) in the ocrelizumabgroup had Grade 2 or above neutropenia vs1.3% in the placebo group; approximately 1% of the patients in the ocrelizumab group had Grade 4neutropenia vs 0% in the placebo group.

The majority of the neutrophil decreases were transient (only observed once for a given patient treatedwith ocrelizumab) and were Grade 1 (between<LLN and 1500 cells/mm3) and 2 (between 1000 and1500 cells/mm3) in severity. Overall, approximately 1% of the patients in the ocrelizumab group had

Grade 3 or 4 neutropenia. One patient with Grade 3 (between 500 and 1000 cells/mm3) and one patientwith Grade 4 (< 500 cells/mm3) neutropenia required specific treatment with granulocyte-colonystimulating factor, and remained on ocrelizumab after the episode. Neutropenia can occur severalmonths after the administration of ocrelizumab (see section 4.4).

One patient, who received 2000 mg of ocrelizumab, died of systemic inflammatory responsesyndrome (SIRS) of unknown aetiology, following a magnetic resonance imaging (MRI) examination12 weeks after the last infusion; an anaphylactoid reaction to the MRI gadolinium-contrast agent couldhave contributed to the SIRS.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is limited clinical trial experience with doses higher than the approved dose of ocrelizumab. Thehighest dose tested to date in MS patients is 2000 mg, administered as two 1000 mg intravenousinfusions separated by 2 weeks (Phase II dose finding study in RRMS) and 1200 mg, administered as asubcutaneous injection (Phase Ib dose finding study). The adverse reactions were consistent with thesafety profile in the pivotal clinical studies.

There is no specific antidote in the event of an overdose; interrupt the infusion immediately andobserve the patient for IRRs (see section 4.4).

Pharmacotherapeutic group: Immunosuppressants, monoclonal antibodies, ATC code: L04AG08.

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 onlymphoid stem cells and plasma cells.

The precise mechanisms through which ocrelizumab exerts its therapeutic clinical effects in MS is notfully elucidated but is presumed to involve immunomodulation through the reduction in the numberand function of CD20-expressing B cells. Following cell surface binding, ocrelizumab selectivelydepletes CD20-expressing B cells through antibody-dependent cellular phagocytosis (ADCP),antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), andapoptosis. The capacity of B-cell reconstitution and pre-existing humoral immunity are preserved. Inaddition, innate immunity and total T-cell numbers are not affected.

Treatment with ocrelizumab leads to rapid depletion of CD19+ B cells in blood by 14 days posttreatment (first time-point of assessment) as an expected pharmacologic effect. This was sustainedthroughout the treatment period. For the B-cell counts, CD19 is used, as the presence of ocrelizumabinterferes with the recognition of CD20 by the assay.

In the Phase III studies, between each dose of ocrelizumab, up to 5% of patients showed B-cellrepletion (>LLN or baseline) at least at one time point. The extent and duration of B-cell depletion wasconsistent in the PPMS and RMS trials.

The longest follow up time after the last infusion (Phase II study WA21493, N=51) indicates that themedian time to B-cell repletion (return to baseline/LLN whichever occurred first) was 72 weeks (range27 - 175 weeks). 90% of all patients had their B-cells repleted to LLN or baseline by approximatelytwo and a half years after the last infusion.

Relapsing forms of multiple sclerosis (RMS)

Efficacy and safety of ocrelizumab were evaluated in two randomised, double-blind, double-dummy,active comparator-controlled clinical trials (WA21092 and WA21093), with identical design, inpatients with relapsing forms of MS (in accordance with McDonald criteria 2010) and evidence ofdisease activity (as defined by clinical or imaging features) within the previous two years. Studydesign 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 ocrelizumab (Group A) were given 600 mg every 6 months (Dose 1 as 2 x 300 mgintravenous infusions, administered 2 weeks apart, and subsequent doses were administered as a single600 mg intravenous infusion). Patients in Group B were administered Interferon beta-1a 44 mcg viasubcutaneous injection 3 times per week.

Table 3 Study design, demographic and baseline characteristics

Study 1 Study 2

Study name WA21092 (OPERA I) WA21093 (OPERA II)(n=821) (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 relapsewithin the prior year; EDSS* between 0 and 5.5, inclusive

Study duration 2 years

Treatment groups Group A: Ocrelizumab 600 mg

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

Baseline characteristics Ocrelizumab IFN Ocrelizumab IFN600 mg 44 mcg 600 mg 44 mcg(n=410) (n=411) (n=417) (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/% 34.1/65.9 33.8/66.2 35.0/65.0 33.0/67.0female)

Mean/Median disease duration 3.82/1.53 3.71/1.57 4.15/2.10 4.13/1.84since diagnosis (years)

Patients naive to previous DMT 73.4 71.0 72.7 74.9(%)**

Mean number of relapses in the 1.31 1.33 1.32 1.34last year

Proportion of patients with Gd 42.5 38.1 39.0 41.4enhancing T1 lesions

Mean EDSS* 2.82 2.71 2.73 2.79

* Expanded Disability Status Scale

** Patients who had not been treated with a disease-modifying therapy (DMT) in the 2 years prior torandomisation.

Key clinical and MRI efficacy results are presented in Table 4 and Figure 1.

The results of these studies show that ocrelizumab significantly suppressed relapses, sub-clinicaldisease activity measured by MRI, and disease progression compared with interferon beta-1a 44 mcgsubcutaneous.

Table 4 Key clinical and MRI endpoints from Studies WA21092 and WA21093 (RMS)

Study 1: WA21092 Study 2: WA21093(OPERA I) (OPERA II)

Endpoints Ocrelizumab IFN Ocrelizumab IFN600 mg 44 mcg 600 mg 44 mcg(n=410) (n=411) (n=417) (n=418)

Clinical Endpoints

Annualised Relapse Rate (ARR) (primary endpoint)8 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 9.8% Ocrelizumab vs 15.2% IFN

Progression3

Risk Reduction (Pooled Analysis1 40% (p=0.0006))2 43 % (p=0.0139)7 7

Risk Reduction (Individual Studies ) 37 % (p=0.0169)

Proportion of patients with 24 week Confirmed Disability 7.6% Ocrelizumab vs 12.0% IFN

Progression (CDP)3

Risk Reduction (Pooled Analysis1) 40% (p=0.0025)

Risk Reduction (Individual Studies2) 43 % (p=0.0278)7 37 % (p=0.0370)7

Proportion of patients with at least 12 weeks Confirmed Disability 20.7% Ocrelizumab vs 15.6% IFN

Improvement4

Relative Increase (Pooled Analysis1) 33% (p=0.0194)

Relative Increase (Individual Studies2) 61% (p=0.0106) 14% (p=0.4019)80.4% 66.7% 78.9% 64.3%

Proportion of patients Relapse free at 96 weeks2(p<0.0001) (p<0.0001)

P roportion of patients with No Evidence of Disease Activity 48% 29% 48% 25%(NEDA)

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 0.323 1.413 0.325 1.904

MRI scan

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 22 Non-confirmatory p-value analysis; not part of the pre-specified testing hierarchy3 CDP defined as an increase of ≥ 1.0 point from the baseline Expanded Disability Status Scale (EDSS) score forpatients with baseline score of 5.5 or less, or ≥ 0.5 when the baseline score is > 5.5, Kaplan-Meier estimates at

Week 964 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 CDP, and any MRI activity (either Gd-enhancing T1 lesions, or new or enlarging T2 lesions) during the whole 96-week treatment. Exploratory resultbased on complete ITT population.6 Non-confirmatory p-value; hierarchical testing procedure terminated before reaching endpoint.7 Log-rank test8 Confirmed relapses (accompanied by a clinically relevant change in EDSS).

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 Occurringduring the Double-blind Treatment Period (Pooled WA21092 and WA21093 ITT Population)*40% reduction in risk of CDP

HR (95% CI): 0.60 (0.45, 0.81)(p =0.0006)

*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% riskreduction for ocrelizumab compared to interferon beta-1a (p=0.0006) were highly consistent with theresults sustained for at least 24 weeks (40% risk reduction for ocrelizumab compared to interferonbeta-1a, p=0.0025).

The studies enrolled patients with active disease. These included both active treatment naive andpreviously treated inadequate responders, as defined by clinical or imaging features. Analysis ofpatient populations with differing baseline levels of disease activity, including active and highly activedisease, showed that the efficacy of ocrelizumab on ARR and 12 week CDP was consistent with theoverall population.

Primary progressive multiple sclerosis (PPMS)

Efficacy and safety of ocrelizumab were also evaluated in a randomised, double-blind, placebo-controlled clinical trial in patients with primary progressive MS (Study WA25046) who were early intheir disease course according to the main inclusion criteria, i.e.: ages 18-55 years, inclusive; EDSS atscreening from 3.0 to 6.5 points; disease duration from the onset of MS symptoms less than 10 yearsin 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 inprogressive MS, can be imaging-related, (i.e. T1 Gd-enhancing lesions and/or active [new orenlarging] 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 studypopulation 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 enhancinglesions or T2 lesions.

During the Phase III PPMS study, patients received 600 mg ocrelizumab every 6 months as two300 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 perinfusion were also similar, independent of whether the 600 mg dose was administered as a single600 mg infusion or as two 300 mg infusions separated by two weeks (see sections 4.8 and 5.2), butdue 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 ocrelizumab in a 600 mg single infusion (seesection 4.2) to reduce the total number of infusions (with concurrent exposure to prophylacticmethylprednisolone and an antihistamine) and the related infusion reactions.

Table 5 Study design, demographics 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 confirmeddisability progression events)(Median follow-up time: Ocrelizumab 3.0 years, Placebo2.8 years

Disease history at screening Age 18-55 years, EDSS of 3.0 to 6.5

Treatment groups Group A: Ocrelizumab 600 mg

Group B: Placebo, in 2:1 randomisation

Baseline characteristics Ocrelizumab 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 (% 51.4/48.6 49.2/50.8male/% female)

Mean/Median disease duration 2.9/1.6 2.8/1.3since PPMS diagnosis (years)

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 ocrelizumab significantly delays disease progression and reducesdeterioration in walking speed compared with placebo.

Table 6 Key clinical and MRI endpoints from Study WA25046 (PPMS)

Study 3

WA25046 (Oratorio)

Endpoints Ocrelizumab Placebo600 mg (n=244)(n=488)

Clinical Endpoints

Primary efficacy endpoint 30.2% 34.0%

Proportion of patients with 12 weeks - Confirmed

Disability Progression1 (primary endpoint)

Risk reduction 24%(p=0.0321)

Proportion of patients with 24 weeks - Confirmed 28.3% 32.7%

Disability Progression1

Risk reduction 25%(p=0.0365)

Percentage change in Timed 25-Foot Walk from 38.9 55.1baseline to Week 120

Relative reduction in progression rate of walking 29.4%time (p=0.0404)

MRI Endpoints

Percentage change in T2 hyperintense lesion volume, -3.4 7.4from baseline to Week 120(p<0.0001)

Percentage change in brain volume from Week 24 to -0.902 -1.093

Week 120

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 scoreof 5.5 or less, or ≥ 0.5 when the baseline score is > 5.5, Kaplan-Meier estimates at Week 120.

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 Occurringduring the Double-blind Treatment Period (WA25046 ITT Population)*24% reduction in risk of CDP

HR (95% CI): 0.76 (0.59, 0.98);p=0.0321

* All patients in this analysis had a minimum of 120 weeks of follow-up. The primary analysis isbased on all events accrued.

Pre-specified non-powered subgroup analysis of the primary endpoint suggests that patients who areyounger or those with T1 Gd-enhancing lesions at baseline receive a greater treatment benefit thanpatients 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 baselinehave 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]).

Post-hoc analyses were performed in the Extended Controlled Period (ECP), which includes double-blinded treatment and approximately 9 additional months of controlled follow-up before continuinginto the Open-Label Extension (OLE) or until withdrawal from study treatment. The proportion ofpatients with 24 week Confirmed Disability Progression of EDSS≥7.0 (24W-CDP of EDSS≥7.0, timeto wheelchair) was 9.1% in the placebo group compared to 4.8% in the ocrelizumab group at

Week 144, resulting in a 47% risk reduction of the time to wheelchair (HR 0.53, [0.31, 0.92]) duringthe ECP. As these results were exploratory in nature and included data after unblinding, the resultsshould be interpreted with caution.

Shorter infusion substudy

The safety of the shorter (2-hour) ocrelizumab infusion was evaluated in a prospective, multicenter,randomised, double-blind, controlled, parallel arm substudy to Study MA30143 (Ensemble) in patientswith Relapsing-Remitting Multiple Sclerosis that were naïve to other disease modifying treatments.

The first dose was administered as two 300 mg infusions (600 mg total) separated by 14 days. Patientswere randomised from their second dose onwards (Dose 2 to 6) in a 1:1 ratio to either the conventionalinfusion group with ocrelizumab infused over approximately 3.5 hours every 24 weeks, or the shorterinfusion group with ocrelizumab infused over approximately 2 hours every 24 weeks. Therandomisation 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 hoursfollowing the first randomised infusion. The primary analysis was performed when 580 patients wererandomised. The proportion of patients with IRRs occurring during or within 24 hours following thefirst randomised infusion was 24.6% in the shorter infusion compared to 23.1% in the conventionalinfusion group. The stratified group difference was similar. Overall, in all randomised doses, themajority of the IRRs were mild or moderate and only two IRRs were severe in intensity, with onesevere IRR in each group. There were no life-threatening, fatal, or serious IRRs.

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 ocrelizumab, 12 (~1%) tested positive for treatment-emergent ADAs, of which 2 patients tested positive for neutralising antibodies. The impact oftreatment-emergent ADAs on safety and efficacy cannot be assessed given the low incidence of ADAassociated with ocrelizumab.

In a randomised open-label study in RMS patients (N=102), the percentage of patients with a positiveresponse to tetanus vaccine at 8 weeks after vaccination was 23.9% in the ocrelizumab groupcompared to 54.5% in the control group (no disease-modifying therapy except interferon-beta).

Geometric mean anti-tetanus toxoid specific antibody titres 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% inthe ocrelizumab group and 100% in the control group. In patients treated with ocrelizumab a boostervaccine (13-PCV) given 4 weeks after 23-PPV did not markedly enhance the response to 12 serotypesin common with 23-PPV. The percentage of patients with seroprotective titres against five influenzastrains ranged from 20.0−60.0% and 16.7−43.8% pre-vaccination and at 4 weeks post vaccinationfrom 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.

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. Seesection 4.2 for information on paediatric use.

The pharmacokinetics of ocrelizumab in the MS studies were described by a two compartment modelwith 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. Areaunder the curve (AUCτ) after the 4th dose of 600 mg ocrelizumab was 3510 µg/mL*day, and meanmaximum concentration (Cmax) was 212 µg/mL in RMS (600 mg infusion) and 141 µg/mL in PPMS(300 mg infusions).

Ocrelizumab is administered as an intravenous infusion.

The population pharmacokinetics estimate of the central volume of distribution was 2.78 L. Peripheralvolume and inter-compartment clearance were estimated at 2.68 L and 0.294 L/day.

The metabolism of ocrelizumab has not been directly studied, as antibodies are cleared principally bycatabolism (i.e. breakdown into peptides and amino acids).

Constant clearance was estimated at 0.17 L/day, and initial time-dependent clearance at0.0489 L/day which declined with a half-life of 33 weeks. The terminal elimination half-life ofocrelizumab was 26 days.

No studies have been conducted to investigate the pharmacokinetics of ocrelizumab in children andadolescents less than 18 years of age.

There are no dedicated PK studies of ocrelizumab in patients ≥55 years due to limited clinicalexperience (see section 4.2).

No formal pharmacokinetic study has been conducted. Patients with mild renal impairment wereincluded in clinical trials and no change in the pharmacokinetics of ocrelizumab was observed in thosepatients. There is no PK information available in patients with moderate or severe renal impairment.

No formal pharmacokinetic study has been conducted. Patients with mild hepatic impairment wereincluded 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.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, and embryo-foetal development. Neither carcinogenicity normutagenicity studies have been conducted with ocrelizumab.

In two pre- and post-natal development studies in cynomolgus monkeys, administrationof ocrelizumab from gestation day 20 to at least parturition was associated with glomerulopathy,lymphoid follicle formation in bone marrow, lymphoplasmacytic renal inflammation, and decreasedtesticular weight in offspring. The maternal doses administered in these studies resulted in maximummean serum concentrations (Cmax) that were 4.5- to 21-fold above those anticipated in the clinicalsetting.

There were five cases of neonatal moribundities, one attributed to weakness due to premature birthaccompanied by opportunistic bacterial infection, one due to an infective meningoencephalitisinvolving 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 aetiology suspected,possibly a polyomavirus. The course of these five confirmed or suspected infections could havepotentially been impacted by B-cell depletion. Newborn offspring of maternal animals exposed toocrelizumab were noted to have depleted B cell populations during the post-natal phase.

Sodium acetate trihydrate (E 262)

Glacial acetic acid

Trehalose dihydrate

Polysorbate 20 (E 432)

Water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

Unopened vial2 years

Diluted solution for intravenous infusion

Chemical and physical in-use stability has been demonstrated for 24 hours at 2-8 °C and subsequentlyfor 8 hours at room temperature.

From a microbiological point of view, the prepared infusion should be used immediately. If not usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user andwould normally not be longer than 24 hours at 2-8 °C and subsequently for 8 hours at roomtemperature, 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 shouldbe discarded.

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.

10 mL concentrate in a vial (colourless Type I glass).

Pack size of 1 or 2 vials. Not all pack sizes may be marketed.

The product should be prepared by a healthcare professional using aseptic technique. Do not shake thevial. A sterile needle and syringe should be used to prepare the diluted infusion solution.

The product is intended for single use only.

Do not use the concentrate if discoloured or if the concentrate contains foreign particulate matter (seesection 3).

Medicinal product must be diluted before administration. Solutions for intravenous administration areprepared by dilution of the concentrate into an infusion bag containing isotonic sodium chloride9 mg/mL (0.9%) solution for infusion (300 mg/250 mL or 600 mg/500 mL), to a final ocrelizumabconcentration of approximately 1.2 mg/mL.

No incompatibilities between this medicinal product and polyvinyl chloride (PVC) or polyolefin (PO)bags and intravenous administration sets have been observed.

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

Prior to the start of the intravenous infusion, the content of the infusion bag should be at roomtemperature.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Roche Registration GmbH

Emil-Barell-Strasse 179639 Grenzach-Wyhlen

Germany

EU/1/17/1231/001

EU/1/17/1231/002

Date of first authorisation: 8 January 2018

Date of latest renewal: 21 September 2022

Detailed information on this medicinal product is available on the website of the European Medicines

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