OCREVUS 920mg 40mg / ml solution for injection medication leaflet

Ocrevus 920 mg solution for injection

Each vial contains 920 mg of ocrelizumab in 23 mL (40 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.

Solution for injection.

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. The first administration should be under clinical observationwith appropriate medical support to manage severe reactions such as severe injection reactions,hypersensitivity reactions and/or anaphylactic reactions (see section 4.4).

Premedication for injection reactions

The following two premedications are to be administered shortly before each ocrelizumab injection toreduce the risk of local and systemic injection reactions (IRs):

* 20 mg oral dexamethasone (or equivalent)

* Oral antihistamine (e.g., desloratadine or equivalent)

In addition, premedication with an antipyretic (e.g., paracetamol) may also be considered shortlybefore each administration.

The recommended dose is 920 mg administered every 6 months.

No division of the initial dose or subsequent doses into separate administrations is required.

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

Injection or treatment discontinuation in case of IRs

Life-threatening IRs

If there are signs of a life-threatening IR, the injection should be stopped immediately, and the patientshould receive appropriate treatment. Treatment must be permanently discontinued in these patients(see section 4.3).

Severe IRs

If a patient experiences a severe IR, the injection should be interrupted immediately, and the patientshould receive symptomatic treatment. The injection should be completed only after all symptomshave resolved (see section 4.4).

If an injection 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.

Adults over 55 years old

Based on the limited data available for intravenous ocrelizumab (see sections 5.1 and 5.2), noposology adjustment is needed in patients over 55 years of age. Patients enrolled in the ongoingclinical trials continue to be dosed with 600 mg intravenous ocrelizumab every six months after theybecome older than 55 years old. The use of subcutaneous ocrelizumab was not studied in patients over65 years of age.

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 920 mg solution for injection is not intended for intravenous administration and shouldalways be administered as a subcutaneous injection by a healthcare professional.

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

Patients may start treatment using intravenous or subcutaneous ocrelizumab and patients currentlyreceiving intravenous ocrelizumab may continue treatment with intravenous ocrelizumab or transitionto Ocrevus 920 mg solution for injection.

The 920 mg dose should be administered as a subcutaneous injection in the abdomen in approximately10 minutes. Use of a subcutaneous infusion set (e.g., winged/butterfly) is recommended. Any residualhold-up volume remaining in the subcutaneous infusion set should not be administered to the patient.

The injection site should be the abdomen, except for 5 cm around the navel. Injections should never begiven into areas where the skin is red, bruised, tender or hard, or areas where there are moles or scars.

Ocrevus solution for injection should always be administered by a healthcare professional. For theinitial dose, post-injection monitoring with access to appropriate medical support to manage severereactions such as IRs, for at least one hour after injection is recommended. For subsequent doses, theneed for post-injection monitoring is at the treating physician’s discretion (see section 4.4).

For instructions on use and handling of the medicinal product prior to administration, see section 6.6.

* 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.

Injection reactions (IRs)

Treatment with subcutaneous ocrelizumab is associated with IRs, which may be related to cytokinerelease and/or other chemical mediators. Physicians should alert patients that IRs can occur during orwithin 24 hours of administration. Symptoms of IRs have been more frequently reported with the firstinjection. IRs can be local IRs or systemic IRs. Common symptoms of local IRs at the injection siteinclude erythema, pain, swelling and pruritus. Common symptoms of systemic IRs include headacheand nausea (see section 4.8).

Shortly before injection, patients should receive premedication to reduce the risk of IRs (seesection 4.2). Patients should be observed for at least one hour after the initial dose of the medicinalproduct for any symptom of severe IR. Appropriate resources for the management of severe IRs,hypersensitivity reactions and/or anaphylactic reactions should be available for the initial dose of themedicinal product. For subsequent doses, the need for post-injection monitoring is at the treatingphysician’s discretion. IRs can be managed with symptomatic treatment, should they occur.

If there are signs of a life-threatening IR, the injection should be stopped immediately, and the patientshould receive appropriate treatment. Ocrelizumab treatment must be permanently discontinued inthese patients. If a patient experiences a severe IR, the injection should be interrupted immediately,and the patient should receive symptomatic treatment. The injection should be completed only after allsymptoms have resolved.

Intravenous ocrelizumab is associated with infusion-related reactions (IRRs), which may also berelated to cytokine release and/or other chemical mediators. IRRs 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.

Serious IRRs, some requiring hospitalisation, have been reported with the use of intravenousocrelizumab.

Hypersensitivity may be clinically indistinguishable from an IR or an IRR in terms of symptoms. If ahypersensitivity reaction is suspected, the injection must be stopped immediately and permanently (see‘Hypersensitivity reactions’ below).

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

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 IgE-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) in studies with intravenous ocrelizumab. The frequency of grade 4 (life-threatening) andgrade 5 (fatal) infections was low in all treatment groups, but in PPMS it was higher with intravenousocrelizumab 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. 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 intravenousocrelizumab infusion (see section 4.8). Although some cases were Grade 3 or 4, the majority of thecases were Grade 1 or 2. In patients with signs and symptoms of infection, measurement of bloodneutrophils is recommended.

An increased number of malignancies (including breast cancers) have been observed in the controlledperiod of the pivotal clinical trials in patients treated with intravenous ocrelizumab, compared tocontrol groups. The incidence was within the background rate expected for an MS population. Afterapproximately 10 years of continuous ocrelizumab treatment over the controlled period and Open-

Label Extension (OLE) phase of the pivotal clinical trials, the incidence of malignancies remainedwithin the background rate expected for an MS population. Patients with a known active malignancyshould not be treated with ocrelizumab (see section 4.3). Individual benefit risk should be consideredin patients with known risk factors for malignancies and in patients who are being actively monitoredfor recurrence of malignancy. Patients should follow standard breast cancer screening per localguidelines.

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 intravenous ocrelizumab MS pivotal studies, the administration ofcorticosteroids for the treatment 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 treated with intravenous ocrelizumab were able tomount humoral responses, although decreased, to tetanus toxoid, 23-valent pneumococcalpolysaccharide with or without a booster vaccine, keyhole limpet haemocyanin neoantigen, andseasonal influenza vaccines (see section 4.5 and 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 ocrelizumab 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 P450enzymes, 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 intravenousocrelizumab (see section 4.4 and 5.1).

After treatment over 2 years with intravenous ocrelizumab, the proportion of patients with positiveantibody titres against S. pneumoniae, mumps, rubella and varicella were generally similar to theproportions at baseline.

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 exposed to ocrelizumab.

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.

The safety profile of Ocrevus solution for injection was consistent with the known safety profile ofintravenous ocrelizumab below in Table 1 except for the very common adverse reaction of IRs.

Adverse reactions reported in the controlled period of the pivotal clinical trials with intravenousocrelizumab and derived from spontaneous reporting are listed below in Table 1. The adversereactions are listed by MedDRA system organ class and categories of frequency. Frequencies aredefined 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 theavailable data). Within each System Organ Class, the adverse reactions are presented in order ofdecreasing frequency.

Table 1 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 Neutropenia Late onset ofsystem disorders Neutropenia3

Respiratory, thoracic and Cough,mediastinal disorders catarrh

Investigations Blood Blood immunoglobulinimmunoglobulin M G decreaseddecreased

Injury, poisoning and Infusion-relatedprocedural complications reactions1, injectionreaction2,31 Observed only in the pooled intravenous ocrelizumab dataset2 Observed in a study outside of the pooled intravenous ocrelizumab dataset (associated withsubcutaneous administration).3 Observed in the postmarketing setting .

Injection reactions

Based on the observed symptoms, IRs are categorised into systemic IRs and local IRs.

In OCARINA II, 118 patients (ocrelizumab-naïve) received the first injection of the product. The mostcommon symptoms reported with systemic IRs and local IRs included: headache (2.5%), nausea(1.7%), injection site erythema (29.7%), injection site pain (14.4%), injection site swelling (8.5%), andinjection site pruritus (6.8%). IRs occurred in 48.3% of these patients after the first injection. Of the118 patients, 11.0% and 45.8% of patients experienced at least one event of systemic IR and local IR,respectively. Among the patients with IR, the majority of patients (82.5%) had IRs occur within24 hours after the end of injection as opposed to during the injection. All IRs were non serious and ofmild (71.9%) or moderate (28.1%) severity. The median duration of IR was 3 days for systemic IRsand 4 days for local IRs. All patients recovered from IRs, of which 26.3% required symptomatictreatment.

In OCARINA I, 125 patients received one or more subcutaneous injections of ocrelizumab 1200 mg.

Of the 125 patients who received the first injection, 16.0% of patients experienced at least one event ofsystemic IR and 64.0% of patients experienced at least one event of local IR. Of the 104 patients whoreceived the second injection, the incidence of systemic IR and local IR decreased to 7.7% and 37.5%,respectively. All IRs were non serious and all except one IR were of mild or moderate severity for thefirst injection. All IRs were non serious and of mild or moderate severity for the second injection.21.2% and 17.9% of patients experiencing IR required symptomatic treatment after the first andsecond injection, respectively.

Intravenous ocrelizumab is associated with infusion-related reactions (IRRs), which may also berelated to cytokine release and/or other chemical mediators. IRRs 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.

Serious IRRs, some requiring hospitalisation, have been reported with the use of intravenousocrelizumab.

Infection

In the active-controlled studies in RMS, infections occurred in 58.5% of patients receiving intravenousocrelizumab vs 52.5% of patients receiving interferon beta 1a. SIs occurred in 1.3% of patientsreceiving intravenous ocrelizumab vs 2.9% of patients receiving interferon beta 1a. In the placebo-controlled study in PPMS, infections occurred in 72.2% of patients receiving intravenous ocrelizumabvs 69.9% of patients receiving placebo. SIs occurred in 6.2% of patients receiving intravenousocrelizumab vs 6.7% of patients receiving placebo.

All patients switched to intravenous ocrelizumab during the OLE phase in both RMS and PPMSpivotal intravenous ocrelizumab studies. Over the OLE phase in RMS and PPMS patients, the overallrisk of SIs did not increase from that observed during the controlled period. As observed during thecontrolled period, the rate of SIs in PPMS patients remained higher than that observed in RMSpatients.

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 intravenous ocrelizumab treated patientscompared to interferon beta-1-a and placebo.

In the RMS clinical trials, 39.9% of intravenous ocrelizumab treated patients and 33.2% interferonbeta-1-a treated patients experienced an upper respiratory tract infection and 7.5% of intravenousocrelizumab treated patients and 5.2% of interferon beta-1-a treated patients experienced a lowerrespiratory tract infection.

In the PPMS clinical trial, 48.8% of intravenous ocrelizumab treated patients and 42.7% of patientswho received placebo experienced an upper respiratory tract infection, and 9.9% of intravenousocrelizumab treated patients and 9.2% of patients who received placebo experienced a lowerrespiratory tract infection.

The respiratory tract infections reported in patients treated with intravenous ocrelizumab werepredominately mild to moderate (80 - 90 %).

Herpes

In active-controlled (RMS) clinical trials, herpes infections were reported more frequently inintravenous ocrelizumab treated patients than in interferon-beta-1a treated patients including herpeszoster (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 inseverity, 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 intravenous ocrelizumab treatment arm.

Immunoglobulins

Ocrelizumab treatment resulted in a decrease in total immunoglobulins over the controlled period ofthe pivotal clinical intravenous ocrelizumab 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 intravenousocrelizumab compared with 32.6% of patients treated with interferon beta-1a. In PPMS, a decrease inlymphocytes <LLN was observed in 26.3% of intravenous ocrelizumab treated patients vs 11.7% ofplacebo-treated patients.

The majority of these decreases reported in intravenous ocrelizumab treated patients were Grade 1(<LLN - 800 cells/mm3) and 2 (between 500 and 800 cells/mm3) in severity. Approximately 1% of thepatients in the intravenous ocrelizumab group had a Grade 3 lymphopenia (between 200 and500 cells/mm3). None of the patients was reported with Grade 4 lymphopenia (< 200 cells/mm3).

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

In the active-controlled (RMS) treatment period, a decrease in neutrophils < LLN was observed in14.7% of patients treated with intravenous ocrelizumab compared with 40.9% of patients treated withinterferon beta-1a. In the placebo-controlled (PPMS) clinical trial, the proportion of intravenousocrelizumab patients presenting decreased neutrophils was higher (12.9 %) than placebo patients(10.0 %); among these a higher percentage of patients (4.3%) in the intravenous ocrelizumab grouphad Grade 2 or above neutropenia vs 1.3% in the placebo group; approximately 1% of the patients inthe intravenous ocrelizumab 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 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 intravenous ocrelizumabgroup had Grade 3 or 4 neutropenia. One patient with Grade 3 (between 500 and 1000 cells/mm3) andone 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 occurseveral months after the administration of ocrelizumab (see section 4.4).

One patient, who received 2000 mg of intravenous ocrelizumab, died of systemic inflammatoryresponse syndrome (SIRS) of unknown aetiology, 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 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 injection immediately andobserve the patient for IRs (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.

Subcutaneous ocrelizumab contains recombinant human hyaluronidase (rHuPH20), an enzyme used toincrease the dispersion and absorption of co-formulated active substances when administeredsubcutaneously.

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 with intravenous ocrelizumab. For the B-cell counts, CD19 is used, asthe presence of ocrelizumab interferes with the recognition of CD20 by the assay.

In the Phase III studies, between each dose of intravenous ocrelizumab, up to 5% of patients showed

B-cell repletion (> LLN or baseline) at least at one time point. The extent and duration of B-celldepletion was consistent in the PPMS and RMS trials.

The longest follow up time after the last intravenous 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 baselineby approximately two and a half years after the last infusion.

Subcutaneous formulation

OCARINA II

Study CN42097 (OCARINA II) was a multi-center, randomised, open-label, parallel arm trialconducted to evaluate the pharmacokinetics, pharmacodynamics, safety, immunogenicity, radiologicaland clinical effects of subcutaneous ocrelizumab compared with intravenous ocrelizumab in patientswith either RMS or PPMS. OCARINA II was designed to demonstrate non-inferiority of treatmentwith subcutaneous ocrelizumab versus intravenous ocrelizumab based on the primary PK endpoint ofarea under the concentration time curve (AUC) up to week 12 post-injection/infusion (AUCw1-12).

A total of 236 patients with RMS or PPMS (213 patients with RMS, 23 patients with PPMS) wererandomised in a 1:1 ratio to the subcutaneous arm or intravenous arm. During the controlled period(Day 0 to Week 24), patients received either a single 920 mg subcutaneous injection at study Day 1 ortwo 300 mg intravenous infusions at study Day 1 and 14. After the controlled period, all patients hadthe opportunity to receive further subcutaneous injections of 920 mg ocrelizumab at Weeks 24 and 48(Dose 2 and 3, respectively). Patients were excluded if they had previous treatment with anti-CD20antibodies within the last 24 months, including ocrelizumab.

Patients were aged 18-65 years with an EDSS between 0 to 6.5 at screening. The demographics weresimilar and baseline characteristics were well balanced across the two treatment groups. The mean agewas 39.9 years in the subcutaneous arm and 40.0 years in the intravenous arm. 34.7% of patients weremale in the subcutaneous arm and 40.7% of patients were male in the intravenous arm. Themean/median duration since MS diagnosis was 5.70/3.10 years in the subcutaneous arm and4.78/2.35 years in the intravenous arm.

Non-inferiority of the ocrelizumab exposure after administration of 920 mg subcutaneous ocrelizumabcompared to 600 mg intravenous ocrelizumab was demonstrated based on the PK primary endpoint,

AUC up to week 12 (AUCw1-12) post-injection (see section 5.2).

Intravenous formulation

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 2.

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 2 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 3 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 3 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

Progression340% (p=0.0006)7

Risk Reduction (Pooled Analysis1) 43 % (p=0.0139)7 37 % (p=0.0169)7

Risk Reduction (Individual Studies2)

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

Progression (CDP)340% (p=0.0025)7

Risk Reduction (Pooled Analysis1) 43 % (p=0.0278)7 37 % (p=0.0370)7

Risk Reduction (Individual Studies2)

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)

Proportion of patients with No Evidence of Disease Activity 48% 29% 48% 25%( NEDA)5

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 forat Least 12 Weeks with the Initial Event of Neurological Worsening Occurring during 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 4.

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 4 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 5 and Figure 2.

The results of this study show that ocrelizumab significantly delays disease progression and reducesdeterioration in walking speed compared with placebo.

Table 5 Key clinical and MRI endpoints from Study WA25046 (PPMS)

Study 3

WA25046 (Oratorio)

Ocrelizumab Placebo

Endpoints 600 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 forat Least 12 Weeks with the Initial Event of Neurological Worsening Occurring during 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.

Subcutaneous formulation

Across OCARINA I and OCARINA II, no patients had treatment-emergent anti-drug antibodies(ADAs) to ocrelizumab. Patients in OCARINA II were tested at baseline and every 6 months posttreatment for the duration of the trial for ADAs. Transient ADAs may therefore not be detectedbetween the assessed time points.

The incidence of treatment-emergent anti-rHuPH20 (hyaluronidase) antibodies in patients treated withsubcutaneous ocrelizumab in OCARINA I was 2.3% (3/132). No patients from OCARINA II hadtreatment-emergent anti-rHuPH20 antibodies.

Intravenous formulation

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 ADAs. Out of1311 patients treated with ocrelizumab, 12 (~1%) tested positive for treatment-emergent ADAs, ofwhich 2 patients tested positive for neutralising antibodies. The impact of treatment-emergent ADAson safety and efficacy cannot be assessed given the low incidence of ADA associated withocrelizumab.

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 intravenous ocrelizumabgroup compared 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 intravenous ocrelizumab group and 100% in the control group. In patients treated with intravenousocrelizumab a booster vaccine (13-PCV) given 4 weeks after 23-PPV did not markedly enhance theresponse to 12 serotypes in common with 23-PPV. The percentage of patients with seroprotectivetitres against five influenza strains ranged from 20.0−60.0% and 16.7−43.8% pre-vaccination and at4 weeks post vaccination from 55.6−80.0% in patients treated with intravenous ocrelizumab and75.0−97.0% 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.

After administration of 920 mg subcutaneous ocrelizumab, the predicted mean exposure (AUC over the24 week dosing interval) was 3730 µg/mL*day. The primary PK endpoint in OCARINA II, AUCw1-12,after 920 mg subcutaneous ocrelizumab was shown to be non-inferior to 600 mg intravenousocrelizumab. The geometric mean ratio for AUCw1-12 was 1.29 (90% CI: 1.23-1.35).

The estimated bioavailability after subcutaneous administration of 920 mg ocrelizumab was 81%. Themean Cmax was 132 µg/mL and tmax was reached after approximately 4 days (range 2-13 days).

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, administration of intravenousocrelizumab 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.

Hyaluronidase

Non-clinical data for recombinant human hyaluronidase reveal no special hazard based onconventional studies of repeated dose toxicity including safety pharmacology endpoints.

Hyaluronidase (rHuPH20) is found in most tissues of the human body. Subcutaneous administration ofocrelizumab with hyaluronidase was well tolerated in rats and minipigs in local tolerance studies.

Reproductive toxicology studies with rHuPH20 revealed embryofetal toxicity in mice, with no effectlevel >1,100-fold higher than the suggested clinical dose, however, without evidence of teratogenicity.

Recombinant human hyaluronidase (rHuPH20)

Sodium acetate trihydrate (E 262)

Glacial acetic acidα,α-trehalose dihydrate

Polysorbate 20 (E 432)

L-methionine

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

Unopened vial2 years

Prepared syringe

* Chemical and physical in-use stability has been demonstrated for 30 days at 2 °C to 8 °C andadditionally for 8 hours unprotected from light at ≤30 °C.

* From a microbiological point of view, the product should be used immediately once transferredfrom the vial to the syringe. If not used immediately, in-use storage times and conditions priorto use are the responsibility of the user and normally not longer than 24 hours at 2 °C to 8 °C,unless the preparation has taken place in controlled and validated aseptic conditions.

Store in a refrigerator (2 °C - 8 °C).

Do not freeze. Do not shake.

Keep the vials in the outer carton in order to protect from light.

If necessary, the unopened vial may be stored outside the refrigerator at temperatures ≤25 °C for up to12 hours.

The vials can be removed and placed back into the refrigerator so that the total combined time out ofthe refrigerator of the unopened vial may not exceed 12 hours at ≤25 °C.

For storage conditions after preparation of the syringe, see section 6.3.

23 mL of solution for injection in a vial (colourless Type I glass).

Pack size of 1 vial.

The medicinal product should be inspected visually to ensure there is no particulate matter ordiscolouration prior to administration.

The medicinal product is for single use only and should be prepared by a healthcare professional usingaseptic technique.

No incompatibilities between this medicinal product and polypropylene (PP), polycarbonate (PC),polyethylene (PE), polyvinyl chloride (PVC), polyurethane (PUR) and stainless steel have beenobserved.

Preparation of the syringe

* Prior to use, the vial should be removed from the refrigerator to allow the solution to come toroom temperature.

* Withdraw the entire contents of Ocrevus solution for injection from the vial with a syringe andtransfer needle (21G recommended).

* Remove the transfer needle and attach a subcutaneous infusion set (e.g., winged/butterfly)containing a 24 - 26G needle for injection. Use a subcutaneous infusion set with residual hold-up volume NOT exceeding 0.8 mL for administration.

* Prime the subcutaneous infusion line with the solution for injection to eliminate the air in theinfusion line and stop before the fluid reaches the needle.

* Ensure the syringe contains exactly 23 mL of the solution after priming and expelling anyexcess volume from the syringe.

* Administer immediately to avoid needle clogging. Do not store the prepared syringe that hasbeen attached to the already-primed subcutaneous infusion set.

If the dose is not administered immediately, refer to “Storage of the syringe” below.

Storage of the syringe

* If the dose is not to be administered immediately, use aseptic technique to withdraw the entirecontents of Ocrevus solution for injection from the vial into the syringe to account for the dosevolume (23 mL) and priming volume for the subcutaneous infusion set. Replace the transferneedle with a syringe closing cap. Do not attach a subcutaneous infusion set for storage.

* If the syringe was stored in a refrigerator, allow the syringe to reach room temperature prior toadminsitration.

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/1/17/1231/003

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.