Ocrevus 920 mg solution for injection

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).

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.

• 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).

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 IgE 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 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 clinical trials in patients treated with intravenous ocrelizumab, compared to control groups. The incidence was 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.

In the controlled period of the intravenous ocrelizumab clinical trials, the incidence of non-melanoma skin cancers was low and there was no imbalance between treatment groups. An increase in incidence was observed between years 3 and 4 of treatment due to basal cell carcinoma, which was not observed in subsequent years. The incidence was within the background rate expected for an MS population.

Treatment of severely immunocompromised patients

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

In other auto-immune conditions, use of 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 serious infections, including opportunistic infections. Infections included and were not limited to atypical pneumonia and pneumocystis jirovecii pneumonia, varicella pneumonia, tuberculosis, histoplasmosis. In rare cases, some of these infections were fatal. An exploratory analysis identified the following factors associated with risk of serious infections: higher doses of 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 serious infection.

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 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 hemocyanin 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 titers should be considered to check whether individuals have mounted a protective immune response because the efficacy of the vaccination may be decreased.

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

Sodium

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

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

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).

Women of childbearing potential

Women of childbearing potential should use contraception while receiving ocrelizumab and for 12 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

It is unknown whether ocrelizumab/metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of ocrelizumab in milk (see section 5.3). A risk to neonates and infants cannot be excluded. Women should be advised to discontinue breast-feeding during therapy.

Fertility

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

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

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).

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 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

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 naï ve 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. Serious infections 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. Serious infections occurred in 6.2% of patients receiving intravenous ocrelizumab vs 6.7% of patients receiving placebo. All patients switched to intravenous ocrelizumab during the open-label phase in both RMS and PPMS pivotal intravenous ocrelizumab studies. An increase in the rate of serious infections was observed in RMS between Years 2 and 3, but not in subsequent years. No increase was observed in PPMS.

Respiratory tract infections

The proportion of respiratory tract infections was higher in 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 intravenous ocrelizumab studies, mainly driven by reduction in IgM. Clinical trial data have shown an association between decreased levels of IgG (and less so for IgM or IgA) and serious infections.

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

Neutrophils

In the active-controlled (RMS) treatment period, a decrease in neutrophils < LNN was observed in 14.7% of 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.

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).

Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants,

ATC Code: L04AA36

Mechanism of action

Ocrevus SC formulation contains the active substance ocrelizumab which provides the therapeutic effect of the medicinal product and recombinant human hyaluronidase (rHuPH20), an enzyme used to increase the dispersion and absorption of co-formulated drugs when administered subcutaneously.

Ocrelizumab is a recombinant humanised monoclonal antibody that selectively targets CD20-expressing B cells.

CD20 is a cell surface antigen found on pre-B cells, mature and memory B cells but not expressed on lymphoid stem cells and plasma cells.

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

Pharmacodynamic effects

Treatment with ocrelizumab leads to rapid depletion of CD19+ B cells in blood by 14 days post treatment (first time-point of assessment) as an expected pharmacologic effect. This was sustained throughout the treatment period with intravenous ocrelizumab. For the B-cell counts, CD19 is used, as the 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 (> lower limit of normal (LLN) or baseline) at least at one time point. The extent and duration of B-cell depletion was consistent in the PPMS and RMS trials.

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

Clinical efficacy and safety

Subcutaneous formulation

Study CN42097 (OCARINA II) was a multi-centre, randomised, open-label, parallel arm trial conducted to evaluate the pharmacokinetics, pharmacodynamics, safety, immunogenicity, radiological and clinical effects of Ocrevus SC compared with intravenous ocrelizumab in patients with either RMS or PPMS. OCARINA II was designed to demonstrate non-inferiority of treatment with Ocrevus SC versus intravenous ocrelizumab based on the primary PK endpoint of area 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) were randomised in a 1:1 ratio to the SC arm or IV arm. During the controlled period (Day 0 to Week 24), patients received either a single 920 mg Ocrevus SC injection at Study Day 1 or two 300 mg intravenous infusions at Study Day 1 and 14. After the controlled period, all patients had the opportunity to receive further injections of 920 mg Ocrevus SC at Weeks 24 and 48 (Dose 2 and 3, respectively). Patients were excluded if they had previous treatment with anti-CD20 antibodies 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 were similar and baseline characteristics were well balanced across the two treatment groups. The mean age was 39.9 years in the SC arm and 40.0 years in the IV arm. There were 14 (12%) patients older than 55 years in the SC arm and 10 (8%) in the IV arm. 34.7% of patients were male in the SC arm and 40.7% in the IV arm. The mean/median duration since MS diagnosis was 5.70/3.10 years in the SC arm and 4.78/2.35 years in the IV arm.

Non-inferiority of the ocrelizumab exposure after administration of 920 mg Ocrevus SC compared to 600 mg intravenous ocrelizumab was demonstrated based on the PK primary endpoint, (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, in patients with relapsing forms of MS (in accordance with McDonald criteria 2010) and evidence of disease activity (as defined by clinical or imaging features) within the previous two years. Study design and baseline characteristics of the study population are summarised in Table 3.

Demographic and baseline characteristics were well balanced across the two treatment groups. Patients receiving ocrelizumab (Group A) were given 600 mg every 6 months (Dose 1 as 2 x 300 mg intravenous infusions, administered 2 weeks apart, and subsequent doses were administered as a single 600 mg intravenous infusion). Patients in Group B were administered Interferon beta-1a 44 mcg via subcutaneous injection 3 times per week.

Table 3 Study Design, Demographic and Baseline Characteristics

* Expanded Disability Status Scale

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

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

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

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

¹ Data prospectively pooled from Study 1 and 2

² Non-confirmatory p-value analysis; not part of the pre-specified testing hierarchy

³ CDP defined as an increase of ≥ 1.0 point from the baseline Expanded Disability Status Scale (EDSS) score for patients with baseline score of 5.5 or less, or ≥ 0.5 when the baseline score is > 5.5, Kaplan-Meier estimates at Week 96

⁴ Defined as decrease of ≥ 1.0 point from the baseline EDSS score for patients with baseline EDSS score ≥ 2 and ≤ 5.5, or ≥ 0.5 when the baseline score is > 5.5. Patients with baseline score < 2 were not included in analysis.

⁵ NEDA defined as absence of protocol defined relapses, 12-week CDP, and any MRI activity (either Gd-enhancing T1 lesions, or new or enlarging T2 lesions) during the whole 96-week treatment. Exploratory result based on complete ITT population.

⁶ Non-confirmatory p-value; hierarchical testing procedure terminated before reaching endpoint.

⁷ Log-rank test

⁸ Confirmed relapses (accompanied by a clinically relevant change in EDSS).

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

^*Pre-specified pooled analysis of WA21092 and WA21093.

Results of the pre-specified pooled analyses of time to CDP sustained for at least 12 weeks (40% risk reduction for ocrelizumab compared to interferon beta-1a (p=0.0006) were highly consistent with the results sustained for at least 24 weeks (40% risk reduction for ocrelizumab compared to interferon beta-1a, p=0.0025).

The studies enrolled patients with active disease. These included both active treatment naive and previously treated inadequate responders, as defined by clinical or imaging features. Analysis of patient populations with differing baseline levels of disease activity, including active and highly active disease, showed that the efficacy of ocrelizumab on ARR and 12 week CDP was consistent with the overall 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 in their disease course according to the main inclusion criteria, i.e.: ages 18-55 years, inclusive; EDSS at screening from 3.0 to 6.5 points; disease duration from the onset of MS symptoms less than 10 years in patients with an EDSS at screening ≤ 5.0 or less than 15 years in patients with an EDSS at screening >5.0. With regard to disease activity, features characteristic of inflammatory activity, even in progressive MS, can be imaging-related, (i.e. T1 Gd-enhancing lesions and/or active [new or enlarging] T2 lesions). MRI evidence should be used to confirm inflammatory activity in all patients. Patients over 55 years of age were not studied. Study design and baseline characteristics of the study population are presented in Table 5.

Demographic and baseline characteristics were well balanced across the two treatment groups. Cranial MRI showed imaging features characteristic of inflammatory activity either by T1 Gd enhancing lesions or T2 lesions.

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

Table 5 Study design, demographics and baseline characteristics for Study WA25046

Key clinical and MRI efficacy results are presented in Table 6 and Figure 2.

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

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

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

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

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

Pre-specified non-powered subgroup analysis of the primary endpoint suggests that patients who are younger or those with T1 Gd-enhancing lesions at baseline receive a greater treatment benefit than patients who are older or without T1 Gd-enhancing lesions (≤ 45 years: HR 0.64 [0.45, 0.92], >45 years: HR 0.88 [0.62, 1.26]; with T1 Gd-enhancing lesions at baseline: HR 0.65 [0.40-1.06], without T1 Gd-enhancing lesions at baseline: HR 0.84 [0.62-1.13]).

Moreover, post-hoc analyses suggested that younger patients with T1 Gd-enhancing lesions at baseline have the better treatment effect (≤ 45 years: HR 0.52 [0.27-1.00]; ≤ 46 years [median age of the WA25046 study]; HR 0.48 [0.25-0.92]; <51 years: HR 0.53 [0.31-0.89]).

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 continuing into the Open-Label Extension (OLE) or until withdrawal from study treatment. The proportion of patients with 24 week Confirmed Disability Progression of EDSS≥ 7.0 (24W-CDP of EDSS≥ 7.0, time to 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]) during the ECP. As these results were exploratory in nature and included data after unblinding, the results should be interpreted with caution.

Immunogenicity

Subcutaneous formulation

Across OCARINA I (Phase Ib dose finding study) and OCARINA II, out of 194 patients, none had treatment emergent anti-drug antibodies (ADAs) to ocrelizumab.

The incidence of treatment-emergent anti-rHuPH20 (hyaluronidase) antibodies in OCARINA I was 2.3% (3/131). No patients from OCARINA II had treatment-emergent anti-rHuPH20 antibodies.

Intravenous formulation

Out of 1,311 patients treated with ocrelizumab, 12 (~1%) tested positive for treatment-emergent ADAs, of which 2 patients tested positive for neutralising antibodies. The impact of treatment-emergent ADAs on safety and efficacy cannot be assessed given the low incidence of ADA associated with ocrelizumab.

Immunisations

In a randomised open-label study in RMS patients (N=102), the percentage of patients with a positive response to tetanus vaccine at 8 weeks after vaccination was 23.9% in the intravenous ocrelizumab group 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% in the intravenous ocrelizumab group and 100% in the control group. In patients treated with intravenous ocrelizumab a booster vaccine (13-PCV) given 4 weeks after 23-PPV did not markedly enhance the response to 12 serotypes in common with 23-PPV. The percentage of patients with seroprotective titres against five influenza strains ranged from 20.0-60.0% and 16.7-43.8% pre-vaccination and at 4 weeks post vaccination from 55.6-80.0% in patients treated with intravenous ocrelizumab and 75.0-97.0% in the control group, respectively. See sections 4.4 and 4.5.

Paediatric population

The licensing authority has deferred the obligation to submit the results of studies with Ocrevus in one or more subsets of the paediatric population in the treatment of multiple sclerosis. See section 4.2 for information on paediatric use.

The pharmacokinetics of ocrelizumab in the MS studies were described by a two compartment model with time-dependent clearance, and with PK parameters typical for an IgG1 monoclonal antibody.

After administration of 920 mg Ocrevus SC, the estimated mean exposure (AUC over the 24 week dosing interval) was 3730 µ g/mL• day. The primary PK endpoint in OCARINA II, AUCw1-12, after 920 mg Ocrevus SC was shown to be non-inferior to 600 mg intravenous ocrelizumab. The geometric mean ratio for AUCw1-12 was 1.29 (90% CI: 1.23– 1.35).

Absorption

The estimated bioavailability after SC administration of 920 mg ocrelizumab was 81%. The mean C_max was 132 µ g/mL and t_max was reached after approximately 4 days (range 2-13 days).

Distribution

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

Biotransformation

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

Elimination

Constant clearance was estimated at 0.17 L/day, and initial time-dependent clearance at 0.0489 L/day which declined with a half-life of 33 weeks. The terminal elimination half-life of ocrelizumab was 26 days.

Special populations

Paediatric Population

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

Elderly

There are no dedicated PK studies of ocrelizumab in patients ≥ 55 years due to limited clinical experience (see section 5.1).

Renal Impairment

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

Hepatic Impairment

No formal pharmacokinetic study has been conducted. Patients with mild hepatic impairment were included in clinical trials, and no change in the pharmacokinetics was observed in those patients. There is no PK information available in patients with moderate or severe hepatic impairment.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, and embryo-fetal development. Neither carcinogenicity nor mutagenicity studies have been conducted with ocrelizumab.

In two pre- and post-natal development studies in cynomolgus monkeys, administration of intravenous ocrelizumab from gestation day 20 to at least parturition was associated with glomerulopathy, lymphoid follicle formation in bone marrow, lymphoplasmacytic renal inflammation, and decreased testicular weight in offspring. The maternal doses administered in these studies resulted in maximum mean serum concentrations (C_max) that were 4.5- to 21-fold above those anticipated in the clinical setting.

There were five cases of neonatal moribundities, one attributed to weakness due to premature birth accompanied by opportunistic bacterial infection, one due to an infective meningoencephalitis involving the cerebellum of the neonate from a maternal dam with an active bacterial infection (mastitis) and three with evidence of jaundice and hepatic damage, with a viral aetiology suspected, possibly a polyomavirus. The course of these five confirmed or suspected infections could have potentially been impacted by B-cell depletion. Newborn offspring of maternal animals exposed to ocrelizumab were noted to have depleted B cell populations during the post-natal phase. Measurable levels of ocrelizumab were detected in milk (approximated 0.2% of steady state trough serum levels) during the lactation period.

Subcutaneous Formulation

Hyaluronidase is found in most tissues of the human body. SC administration of ocrelizumab with hyaluronidase was well tolerated in rats and minipigs in local tolerance studies.

Non-clinical data for recombinant human hyaluronidase reveal no special hazard based on conventional studies of repeated dose toxicity including safety pharmacology endpoints. Reproductive toxicology studies with rHuPH20 revealed embryofetal toxicity in mice, with no effect level >1,100-fold higher than the suggested clinical dose and there was no evidence of teratogenicity.

Recombinant human hyaluronidase (rHuPH20), sodium acetate trihydrate (E 262), glacial acetic acid, α ,α -trehalose dihydrate, polysorbate 20 (E 432), L-methionine, water for injections

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

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

Unopened vial

2 years

Prepared syringe

• From a microbiological point of view, the product should be used immediately once transferred from the vial to the syringe since the medicine does not contain any antimicrobial-preservative. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and normally not longer than 24 hours at 2 ° C to 8 ° C.

• If preparation has taken place under controlled and validated aseptic conditions, the closed syringe can be stored for up to 30 days in the refrigerator at 2° C to 8 ° C followed by 8 hours in diffuse daylight at temperatures ≤ 30° C.

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 to 12 hours.

The vials can be removed and placed back into the refrigerator so that the total combined time out of the 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 or discolouration prior to administration.

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

Ocrevus SC is a ready-to-use solution for subcutaneous injection only and should not be diluted or mixed with other medicinal products.

Preparation of the syringe

The medicinal product does not contain any antimicrobial preservative. If the dose is not administered immediately, refer to “ Storage of the syringe” below.

• Prior to use, remove the vial from the refrigerated storage and allow the solution to come to room temperature.

• Withdraw the entire contents of Ocrevus SC solution from the vial with a syringe and transfer needle (21G recommended).

• Remove the transfer needle and attach a SC infusion set (e.g., winged/butterfly) containing a 24 – 26G needle for injection. Use a SC infusion set with residual hold-up volume NOT exceeding 0.8 mL for administration. DO NOT administer any residual hold-up volume remaining in the SC infusion set to the patient.

• Prime the SC infusion line with the drug product solution to eliminate the air in the infusion line and stop before the fluid reaches the needle.

• Ensure the syringe contains exactly 23 mL of medicinal product solution after priming and expelling any excess volume from the syringe.

• Administer immediately to avoid needle clogging. DO NOT store the prepared syringe that has been attached to the already-primed SC infusion set.

Storage of the syringe

• If the dose is not to be administered immediately, use aseptic technique to withdraw the entire contents of Ocrevus SC solution for injection from the vial into the syringe to account for the dose volume (23 mL) and priming volume for the SC infusion set. Replace the transfer needle with a syringe closing cap. DO NOT attach an SC infusion set for storage.

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

Disposal

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