4.1. Therapeutic indications

Treatment of adult patients with:

• relapsing forms of multiple sclerosis (RMS) with active disease defined by clinical or imaging features (see section 5.1).

• early primary progressive multiple sclerosis (PPMS) in terms of disease duration and level of disability, and with imaging features characteristic of inflammatory activity (see section 5.1).

4.2. Posology and method of administration

Treatment should be initiated and supervised by specialised physicians experienced in the diagnosis and treatment of neurological conditions.

Ocrevus subcutaneous (SC) formulation is not intended for intravenous administration. It is important to check the product labels to ensure that the correct formulation (intravenous or subcutaneous) is being administered to the patient by the correct route, as prescribed.

Patients may start treatment using Ocrevus SC or intravenous ocrelizumab and patients currently receiving intravenous ocrelizumab may continue treatment with intravenous ocrelizumab or transition to Ocrevus SC.

Premedication for injection reactions

The following two premedications are to be administered approximately 30 minutes before each ocrelizumab injection to reduce 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 shortly before each administration.

Posology

The recommended dose of Ocrevus SC is 920 mg administered every 6 months in a single subcutaneous injection. A minimum interval of 5 months should be maintained between each dose of ocrelizumab.

Delayed or Missed Doses

If an injection is missed, it should be administered as soon as possible. The treatment interval of 6 months (with a minimum of 5 months) should be maintained between doses.

Special Populations

Adults over 55 years old and elderly population

Based on the limited data available for subcutaneous ocrelizumab (see sections 5.1 and 5.2), no posology adjustment is needed in patients over 55 years of age. There are no data available in patients over 65 years of age.

Renal Impairment

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

Hepatic Impairment

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

Paediatric Population

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

Method of administration

The 920 mg dose (23 mL) should be administered as a subcutaneous injection in the abdomen in approximately 10 minutes. Use of a SC infusion set (e.g., winged/butterfly) is recommended.

The injection site should be the abdomen, except for 2 inches (5 cm) around the navel. Injections should never be given into areas where the skin is red, bruised, tender or hard, or areas where there are moles or scars.

Ocrevus SC should always be administered under the supervision of a healthcare professional. For the initial dose, post-injection monitoring with access to appropriate medical support to manage severe reactions such as injection reactions, for at least one hour after injection is recommended. For subsequent doses the need 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.

4.3. Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

• Current active infection (see section 4.4).

• Patients in a severely immunocompromised state (see section 4.4).

• Known active malignancies (see section 4.4).

4.4. Special warnings and precautions for use

Traceability

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

Injection Reactions (IRs)

Treatment with subcutaneous ocrelizumab is associated with IRs, which may be related to cytokine release and/or other chemical mediators. Serious infusion-related reactions (IRRs), some requiring hospitalisation, have been reported with the use of intravenous ocrelizumab (for further information, see the product information of Ocrevus 300 mg concentrate for solution for infusion).

Physicians should alert patients that IRs can occur during or within 24 hours of administration. Symptoms of IRs have been more frequently reported with the first injection. IRs can be local IRs or systemic IRs. Common symptoms of local IRs at the injection site include erythema, pain, swelling and pruritus. Common symptoms of systemic IRs include headache and nausea (see section 4.8).

Shortly before injection, patients should receive premedication to reduce the risk of IRs (see section 4.2). Patients should be observed for at least one hour after the initial dose of the medicinal product for any symptom of severe IR. For subsequent doses, the need for post-injection monitoring is at the treating physician's discretion. Appropriate resources for the management of severe IRs, hypersensitivity reactions and/or anaphylactic reactions should be available for the initial dose of the medicinal product. 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 patient should receive appropriate treatment. Ocrelizumab treatment must be permanently discontinued in these 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 all symptoms have resolved.

Hypersensitivity reactions

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

Hypersensitivity may be difficult to distinguish from an IR in terms of symptoms. If a hypersensitivity reaction is suspected, the injection must be stopped immediately and permanently.

Infection

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

It is recommended to verify the patient's immune status before dosing since severely immunocompromised patients (e.g., with lymphopenia, neutropenia, hypogammaglobulinemia) should not be treated (see sections 4.3 and 4.8).

The overall proportion of patients experiencing a serious infection (SI) was similar to comparators (see section 4.8) in studies with intravenous ocrelizumab. The frequency of grade 4 (life-threatening) and grade 5 (fatal) infections was low in all treatment groups, but in PPMS it was higher with intravenous ocrelizumab 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. Treatment with ocrelizumab may further increase the risk of severe pneumonia in these patients. Physicians should take prompt action for patients presenting with pneumonia.

Progressive multifocal leukoencephalopathy (PML)

JC virus (JCV) infection resulting in PML has been observed very rarely in patients treated with anti-CD20 antibodies, including ocrelizumab, and mostly associated with risk factors (e.g., lymphopenia, advanced age, polytherapy with immunosuppressants or concomitant immunosuppressive conditions).

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

If PML is suspected, dosing with 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 repeat neurological assessments, should be considered. If PML is confirmed, treatment must be discontinued permanently.

Hepatitis B reactivation

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

HBV screening should be performed in all patients before initiation of treatment with ocrelizumab as per local guidelines. Patients with active HBV (i.e. an active infection confirmed by positive results for HBsAg and anti HB testing) should not be treated with ocrelizumab (see section 4.3). Patients with positive serology (i.e. negative for HBsAg and positive for HB core antibody (HBcAb +); carriers of HBV (positive for surface antigen, HBsAg+) should consult liver disease experts before start of treatment and should be monitored and managed following local medical standards to prevent hepatitis B reactivation.

Late neutropenia

Cases of late onset of neutropenia have been reported at least 4 weeks after the latest intravenous ocrelizumab infusion (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 is recommended.

Malignancies

An increased number of malignancies (including breast cancers) have been observed in the controlled period of the pivotal clinical trials in patients treated with intravenous ocrelizumab, compared to control groups. The incidence was within the background rate expected for an MS population. After approximately 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 remained within the background rate expected for an MS population. Patients with a known active malignancy should not be treated with ocrelizumab (see section 4.3). Individual benefit risk should be considered in patients with known risk factors for malignancies and in patients who are being actively monitored for recurrence of malignancy. Patients 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 (see section 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 and pneumocystis jirovecii pneumonia, varicella pneumonia, tuberculosis, histoplasmosis. In rare cases, some of these infections were fatal. An exploratory analysis identified the following factors associated with risk of SIs: higher doses of ocrelizumab than recommended in MS, other comorbidities, and chronic use of immunosuppressants/corticosteroids.

It is not recommended to use other immunosuppressives concomitantly with ocrelizumab except corticosteroids for symptomatic treatment of relapses. Knowledge is limited as to whether concomitant steroid use for symptomatic treatment of relapses is associated with an increased risk of infections in clinical practice. In the intravenous ocrelizumab MS pivotal studies, the administration of corticosteroids for the treatment of relapse was not associated with an increased risk of SI.

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

Vaccinations

The safety of immunisation with live or live-attenuated vaccines, following ocrelizumab therapy has not been studied and vaccination with live-attenuated or live vaccines is not recommended during treatment and not until B-cell repletion. In clinical trials, the median time for B-cell repletion was 72 weeks (see section 5.1).

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

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

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

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

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

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

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

Sodium

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

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed, as no interactions are expected via cytochrome P450 enzymes, other metabolising enzymes or transporters.

Vaccinations

The safety of immunisation with live or live-attenuated vaccines, following ocrelizumab therapy has not been studied.

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

After treatment over 2 years with intravenous ocrelizumab, the proportion of patients with positive antibody titers against S. pneumoniae, mumps, rubella and varicella were generally similar to the proportions at baseline.

Immunosuppressants

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

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential should use contraception while receiving ocrelizumab and for 4 months after the last administered dose of ocrelizumab.

Pregnancy

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

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

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

Ocrelizumab should be avoided during pregnancy unless the potential benefit to the mother outweighs the potential risk to the fetus.

Breast-Feeding

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, multicentre, open label study MN42989 (SOPRANINO), 13 lactating women received ocrelizumab at a median of 2.0 months postpartum (range 0.5-5.0 months). Low concentrations of ocrelizumab were detected in the breastmilk over 60 days following the mother's first postpartum infusion (median relative infant dose of 0.27% [range 0.0-1.8 %]), indicating minimal transfer 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 of ocrelizumab on health, growth and development were observed in breastfed infants over a follow-up period of 44.6 weeks (range 8.6-62.7 weeks).

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

In a separate prospective clinical study, low ocrelizumab concentrations in breastmilk (median relative infant dose of 0.1% [range 0.07-0.7%]) over 90 days after the mother's first postpartum infusion were observed 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 growth and development up to 1 year.

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

Fertility

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

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

The safety profile of ocrelizumab is based on data in patients with RMS and PPMS who were administered ocrelizumab intravenously or subcutaneously.

In the controlled period of pivotal clinical trials with intravenous ocrelizumab, the most important and frequently reported adverse 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 these patients, 1,852 entered the OLE phase. All patients switched to ocrelizumab treatment during the OLE phase. 1,155 patients completed the OLE phase, resulting in approximately 10 years of continuous ocrelizumab 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 consistent with that observed during the controlled period.

The safety of Ocrevus SC has been evaluated in 312 patients from MS clinical studies, 181 patients from OCARINA II and 118 patients from OCARINA I, who were given at least one dose of Ocrevus SC 920 mg.

The safety observed for Ocrevus SC was consistent with the known safety profile of intravenous ocrelizumab, except for the very common adverse reaction of IRs, which are related to the subcutaneous route of administration.

Tabulated list of adverse drug reactions

Adverse reactions reported in the controlled period of the pivotal clinical trials with ocrelizumab and derived from spontaneous reporting are listed below in Table 2. The adverse reactions are listed by MedDRA system 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), very rare (< 1/10,000) and not known (cannot be estimated from the available data). Within each System Organ Class, the adverse reactions are presented in order of decreasing frequency.

Table 2 Adverse reactions

MedDRA

System Organ Class (SOC)

Very common

Common

Not Known

Infections and infestations

Upper respiratory tract infection, nasopharyngitis, influenza

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

Blood and lymphatic system disorders

Neutropenia

Late onset of neutropenia3

Respiratory, thoracic and mediastinal disorders

Cough, catarrh

Investigations

Blood immunoglobulin M decreased

Blood immunoglobulin G decreased

Injury, poisoning and procedural complications

Infusion-related reactions1, injection reaction2

1 Observed only in the pooled intravenous ocrelizumab dataset

2 Observed in a study outside of the pooled intravenous ocrelizumab dataset (associated with subcutaneous administration). Frequency is based on exposure to Ocrevus SC in OCARINA II

3 Observed in the postmarketing setting - frequency cannot be estimated from the available data.

Description of selected adverse drug reactions

The data below reflect information for selected adverse reactions from intravenous and subcutaneous ocrelizumab clinical trials. Active-controlled and placebo-controlled data are from RMS and PPMS clinical trials with intravenous ocrelizumab.

Injection Reactions

Based on the observed symptoms, IRs are categorised into local IRs and systemic IRs. The most common symptoms reported with local injection reactions included erythema, pain, swelling and pruritis. The most common symptoms reported with systemic injection reactions included headache and nausea.

In OCARINA II, all injection reactions were non-serious and of mild (85%) or moderate (15%) severity. IRs occurred in 48.3% (57/118) of ocrelizumab naïve patients (SC arm) after the first injection, of which 45.8% (54/118 patients) were LIR and 11% (13/118 patients) were SIR. The proportions of IRs with the second Ocrevus dose was similar between the patients whose first dose was administered as IV (33.9%) and SC (33.1%). Overall, the rate and intensity of IRs decreased over time.

Infection

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

All patients switched to intravenous ocrelizumab during the OLE phase in both RMS and PPMS pivotal intravenous ocrelizumab studies. Over the OLE phase in RMS and PPMS patients, the overall risk of SIs did not increase from that observed during the controlled period. As observed during the controlled period, the rate of SIs in PPMS patients 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 (see section 4.4), a multivariate analysis of risk factors for SIs was conducted in the approximately 10 years of 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 EDSS ≥ 6.0. Risk factors for SIs in PPMS patients include body mass index greater than 25 kg/m2, having at least 2 comorbidities, Expanded Disability Status Scale (EDSS) ≥ 6.0, and IgM < lower limit of normal (LLN). Comorbidities included, but were not limited to, cardiovascular, renal and urinary tract conditions, previous infections, and depression.

Respiratory tract infections

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

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

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

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

Herpes

In active-controlled (RMS) clinical trials, herpes infections were reported more frequently in intravenous ocrelizumab 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 intravenous ocrelizumab treatment arm.

Laboratory Abnormalities

Immunoglobulins

Ocrelizumab treatment resulted in a decrease in total immunoglobulins over the controlled period of the 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 shown an 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 < LLN compared 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 with the overall SIs observed in patients treated with ocrelizumab during the controlled period and OLE phase. Throughout the 10 years of continuous ocrelizumab treatment, mean IgG levels of RMS and PPMS patients remained above LLN.

Lymphocytes

In RMS, a decrease in lymphocyte < LLN was observed in 20.7% of patients treated with intravenous ocrelizumab compared with 32.6% of patients treated with interferon beta-1a. In PPMS, a decrease in lymphocytes <LLN was observed in 26.3% of intravenous ocrelizumab treated patients vs 11.7% of placebo-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 the patients in the intravenous ocrelizumab group had a Grade 3 lymphopenia (between 200 and 500 cells/mm3). None of the patients was reported with Grade 4 lymphopenia (< 200 cells/mm3).

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

Neutrophils

In the active-controlled (RMS) treatment period, a decrease in neutrophils < LLN was observed in 14.7% of patients treated with intravenous ocrelizumab compared with 40.9% of patients treated with interferon beta-1a. In the placebo-controlled (PPMS) clinical trial, the proportion of intravenous ocrelizumab 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 group had Grade 2 or above neutropenia vs 1.3% in the placebo group; approximately 1% of the patients in the 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 treated with ocrelizumab) and were Grade 1 (between<LLN and 1,500 cells/mm3) and 2 (between 1,000 and 1,500 cells/mm3) in severity. Overall, approximately 1% of the patients in the intravenous ocrelizumab group had Grade 3 or 4 neutropenia. One patient with Grade 3 (between 500 and 1,000 cells/mm3) and one patient with Grade 4 (< 500 cells/mm3) neutropenia required specific treatment with granulocyte-colony stimulating factor, and remained on ocrelizumab after the episode. Neutropenia can occur several months after the administration of ocrelizumab (see section 4.4).

Other

One patient, who received 2,000 mg of intravenous ocrelizumab, died of systemic inflammatory response 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 of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is limited clinical trial experience with doses higher than the approved dose of ocrelizumab. The highest dose tested to date in MS patients is 2,000 mg, administered as two 1,000 mg intravenous infusions separated by 2 weeks (Phase II dose finding study in RRMS) and 1,200 mg, administered as a subcutaneous injection (Phase Ib dose finding study). The adverse reactions were consistent with the safety profile in the pivotal clinical studies.

There is no specific antidote in the event of an overdose; interrupt the injection immediately and observe the patient for IRs (see section 4.4).