ocrelizumab: prescribing information – dosing, contraindications, interactions, side effects

Ocrevus is indicated for the treatment of adult patients and paediatric patients aged 10 years and older with relapsing forms of multiple sclerosis (RMS) with active disease defined by clinical or imaging features (see section 5.1).
Ocrevus is indicated for the treatment of adult patients with early primary progressive multiple sclerosis (PPMS) in terms of disease duration and level of disability, and with imaging features characteristic of inflammatory activity (see section 5.1).

Ocrevus is indicated for the treatment of adult patients with relapsing forms of multiple sclerosis (RMS) with active disease defined by clinical or imaging features (see section 5.1).
Ocrevus is indicated for the treatment of adult patients with early primary progressive multiple sclerosis (PPMS) in terms of disease duration and level of disability, and with imaging features characteristic of inflammatory activity (see section 5.1).

Treatment should be initiated and supervised by specialised physicians experienced in the diagnosis and treatment of neurological conditions and who have access to appropriate medical support to manage severe reactions such as serious infusion-related reactions (IRRs).
Premedication for infusion-related reactions
The following two premedications must be administered prior to each ocrelizumab infusion to reduce the frequency and severity of IRRs (see section 4.4 for additional steps to reduce IRRs) (Table 1):
● intravenous methylprednisolone (or an equivalent)
● antihistamine
In addition, premedication with an antipyretic (e.g., paracetamol) may also be considered prior to each infusion.

Table 1
Premedication prior to Ocrevus intravenous infusion
Premedication
Timing
Methylprednisolone intravenous
(or an equivalent) approximately 30 minutes prior to
Ocrevus intravenous infusion
Antihistamine
(e.g. diphenhydramine) approximately 30-60 minutes prior to
Ocrevus intravenous infusion
Antipyretic (e.g. acetaminophen/paracetamol) may be considered approximately 30-60 minutes prior to Ocrevus intravenous infusion Posology Initial dose In adults, the initial 600 mg dose is administered as two separate intravenous infusions; first as a 300 mg infusion, followed 2 weeks later by a second 300 mg infusion (see Table 2).
In paediatric patients (aged 10 years and older), the initial dose is administered according to the patient’s body weight (see Table 3):
●
Paediatric patients with body weight less than 35 kg: The initial 300 mg dose is administered as two separate intravenous infusions: first as a 150 mg infusion, followed 2 weeks later by a second 150 mg infusion.
●
Paediatric patients with body weight 35 kg or more: The initial 600 mg dose is administered as two separate intravenous infusions: first as a 300 mg infusion, followed 2 weeks later by a second 300 mg infusion.
Subsequent doses
In adults, subsequent doses of ocrelizumab thereafter are administered as a single 600 mg intravenous infusion every 6 months (see Table 2).
In paediatric patients (aged 10 years and older), subsequent doses of ocrelizumab thereafter are administered as a single intravenous infusion every 6 months according to the patient’s body weight (see Table 3):
●
Paediatric patients with body weight less than 35 kg: 300 mg.
●
Paediatric patients with body weight 35 kg or more: 600 mg.
Paediatric patients who start on a 300 mg dose and subsequently reach a stable body weight of 35 kg or more should be switched to the 600 mg dose.
The first subsequent dose should be administered six months after the first infusion of the initial dose.
A minimum interval of 5 months should be maintained between each dose of ocrelizumab.
Infusion adjustments in case of IRRs
Life-threatening IRRs
If there are signs of a life threatening or disabling IRR during an infusion, such as acute hypersensitivity or acute respiratory distress syndrome, the infusion must be stopped immediately and the patient should receive appropriate treatment. The infusion must be permanently discontinued in these patients (see section 4.3).

Severe IRRs
If a patient experiences a severe IRR (such as dyspnoea) or a complex of flushing, fever, and throat pain symptoms, the infusion should be interrupted immediately, and the patient should receive symptomatic treatment. The infusion should be restarted only after all symptoms have resolved. The initial infusion rate at restart should be half of the infusion rate at the time of onset of the reaction. No infusion adjustment is necessary for subsequent new infusions, unless the patient experiences an IRR.
Mild to moderate IRRs
If a patient experiences a mild to moderate IRR (e.g., headache), the infusion rate should be reduced to half the rate at the onset of the event. This reduced rate should be maintained for at least 30 minutes.
If tolerated, the infusion rate may then be increased according to the patient’s initial infusion rate. No infusion adjustment is necessary for subsequent new infusions, unless the patient experiences an IRR.
Dose modifications during treatment
The above examples of dose interruption and slowing (for mild/moderate and severe IRRs) will result in a change in the infusion rate and increase the total duration of the infusion, but not the total dose.
No dose reductions are recommended.
Delayed or missed doses
If an infusion is missed, it should be administered as soon as possible; do not wait until the next planned dose. The treatment interval of 6 months (with a minimum of 5 months) should be maintained between doses (see Table 2).
Special populations
Adults over 55 years old
Based on the limited data available (see sections 5.1 and 5.2), no posology adjustment is needed in patients over 55 years of age. Patients enrolled in the ongoing clinical trials continue to be dosed with 600 mg ocrelizumab every six months after they become older than 55 years old.
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 paediatric patients under 10 years of age have not been established. No data are available.

Limited clinical data are available in paediatric patients weighing less than 40 kg. The recommended posology is based on pharmacokinetic modelling (see section 5.2).
Method of administration
Ocrevus 300 mg concentrate for solution for infusion is not intended for subcutaneous administration and should be administered via an intravenous infusion only.
It is important to check the product labels to ensure that the correct formulation (intravenous or subcutaneous) is being administered to the patient, as prescribed.
Adult patients may start treatment using intravenous or subcutaneous ocrelizumab. Paediatric patients (aged 10 years and older) can only be treated with intravenous ocrelizumab.
After dilution, treatment is administered as an intravenous infusion through a dedicated line. Infusions should not be administered as an intravenous push or bolus.
If adult patients did not experience a serious infusion-related reaction (IRR) with any previous ocrelizumab infusion, a shorter (2-hour) infusion can be administered for subsequent doses (see Table 2, Option 2). A shorter (2-hour) infusion has not been studied in paediatric patients.
Table 2
Dose and schedule for adult patients
Amount of ocrelizumab to be administered
Infusion instructions
Initial dose
(600 mg) divided into
2 infusions
Infusion 1
300 mg in
250 mL

Initiate the infusion at a rate of
30 mL/hour for 30 minutes

The rate can be increased in
30 mL/hour increments every
30 minutes to a maximum of
180 mL/hour.

Each infusion should be given over approximately 2.5 hours
Infusion 2
(2 weeks later)
300 mg in
250 mL
Subsequent doses
(600 mg) single infusion once every
6 months
Option 1
Infusion of approximately

Treatment should be initiated and supervised by specialised physicians experienced in the diagnosis and treatment of neurological conditions. The first administration should be under clinical observation with 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 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 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 patient should 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 patient should receive symptomatic treatment. The injection should be completed only after all symptoms have resolved (see section 4.4).
Delayed or missed doses
If an injection is missed, it should be administered as soon as possible; do not wait until the next planned dose. The treatment interval of 6 months (with a minimum of 5 months) should be maintained between doses.
Special populations
Adults over 55 years old
Based on the limited data available for intravenous ocrelizumab (see sections 5.1 and 5.2), no posology adjustment is needed in patients over 55 years of age. Patients enrolled in the ongoing clinical trials continue to be dosed with 600 mg intravenous ocrelizumab every six months after they become older than 55 years old. The use of subcutaneous ocrelizumab was not studied 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 subcutaneous ocrelizumab in children and adolescents less than 18 years of age has not yet been established. No data are available.
Method of administration
Ocrevus 920 mg solution for injection is not intended for intravenous administration and should always 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 or subcutaneous) is being administered to the patient by the correct route, as prescribed.
Patients may start treatment using intravenous or subcutaneous ocrelizumab and patients currently receiving intravenous ocrelizumab may continue treatment with intravenous ocrelizumab or transition to Ocrevus 920 mg solution for injection.
The 920 mg dose should be administered as a subcutaneous injection in the abdomen in approximately 10 minutes. Use of a subcutaneous infusion set (e.g., winged/butterfly) is recommended. Any residual hold-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 be given 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 the initial dose, post-injection monitoring with access to appropriate medical support to manage severe reactions such as IRs, 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).

Summary of the safety profile
The most important and frequently reported adverse reactions are 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).
Other frequently reported adverse reactions are COVID-19 (16.0% in PPMS) and decreased blood immunoglobulin M (16.5%, 15.5% in RMS and PPMS, respectively).
Tabulated list of adverse reactions
Adverse reactions reported in clinical trials and derived from spontaneous reporting are listed below in Table 4. The frequencies of adverse reactions are based on the controlled period of the pivotal studies in RMS and PPMS and the controlled period of Study WA40404 in PPMS. 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 4
Adverse reactions
MedDRA
System Organ Class (SOC)
Very common
Common
Not Known
Infections and infestations
Upper respiratory tract infection,
COVID-19, nasopharyngitis, influenza
Sinusitis, bronchitis, oral herpes, gastroenteritis, respiratory tract infection, COVID-19 pneumonia, viral infection, herpes zoster, conjunctivitis, cellulitis Blood and lymphatic system disorders Neutropenia Late onset of Neutropenia2 Respiratory, thoracic and mediastinal disorders Cough, catarrh Hepatobiliary disorders Drug-induced liver injury2 Investigations Blood immunoglobulin M decreased Blood immunoglobulin G decreased Injury, poisoning and procedural complications Infusion-related reactions1 1 See Descriptions of selected adverse reactions.
2 Observed in the post-marketing setting.
Description of selected adverse reactions
Adults
Infusion-related reactions
Across the RMS and PPMS trials, symptoms associated with IRRs included, but are not limited to:
pruritus, rash, urticaria, erythema, flushing, hypotension, pyrexia, fatigue, headache, dizziness, throat irritation, oropharyngeal pain, dyspnoea, pharyngeal or laryngeal oedema, nausea, tachycardia. In controlled trials there were no fatal IRRs. In addition, symptoms of IRR in the post-marketing setting included anaphylaxis.
In active-controlled (RMS) clinical trials, IRR was the most common adverse reaction in the ocrelizumab treatment group with an overall incidence of 34.3% compared with an incidence of 9.9% in the interferon beta-1a treatment group (placebo infusion). The incidence of IRRs was highest during the Dose 1, infusion 1 (27.5%) and decreased over time to <10% at Dose 4. The majority of IRRs in both treatment groups were mild to moderate. 21.7% and 10.1% of ocrelizumab treated patients experienced mild and moderate IRRs, respectively. 2.4% experienced severe IRRs and 0.1% experienced life-threatening IRRs.

In the pivotal placebo-controlled (PPMS) clinical trial, IRR was the most common adverse reaction in the ocrelizumab treatment group with an overall incidence of 40.1% compared with an incidence of 25.5% in the placebo group. The incidence of IRRs was highest during Dose 1, infusion 1 (27.4%) and decreased with subsequent doses to <10% at Dose 4. A greater proportion of patients in each group experienced IRRs with the first infusion of each dose compared with the second infusion of that dose.
The majority of IRRs were mild to moderate. 26.7% and 11.9% of ocrelizumab treated patients experienced mild and moderate IRRs respectively, 1.4% experienced severe IRRs. There were no life- threatening IRRs. See section 4.4.
Over the controlled period and OLE phase of the RMS and PPMS pivotal clinical trials, patients were given approximately 20 doses of ocrelizumab. Incidence of IRRs decreased to <4% by Dose 4 of the OLE phase in RMS patients and to <5% by Dose 5 of the OLE phase in PPMS patients. With subsequent doses administered during the OLE phase, incidence of IRR remained low. The majority of IRRs were mild during the OLE phase.
Alternative shorter infusion of subsequent doses
In a study (MA30143 Shorter Infusion Substudy) designed to characterise the safety profile of shorter (2-hour) ocrelizumab infusions in patients with Relapsing-Remitting Multiple Sclerosis, the incidence, intensity, and types of symptoms of IRRs were consistent with those of infusions administered over 3.5 hours (see section 5.1). The overall number of interventions needed was low in both infusion groups, however, more interventions (slowing down or temporary interruptions) were needed to manage IRRs in the shorter (2-hour) infusion group compared to the 3.5-hour infusion group (8.7% vs.
4.8%, respectively).
Infections
In the active-controlled studies in RMS, infections occurred in 58.5% of patients receiving ocrelizumab vs 52.5% of patients receiving interferon beta 1a. SIs occurred in 1.3% of patients receiving ocrelizumab vs 2.9% of patients receiving interferon beta 1a. In the placebo-controlled pivotal study in PPMS, infections occurred in 72.2% of patients receiving ocrelizumab vs 69.9% of patients receiving placebo. SIs occurred in 6.2% of patients receiving ocrelizumab vs 6.7% of patients receiving placebo.
All patients switched to ocrelizumab during the OLE phase in the pivotal RMS and PPMS studies.
Over the OLE phase in RMS and PPMS patients in the pivotal studies, 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 Expanded Disability Status Scale (EDSS) ≥ 6.0. Risk factors for SIs in PPMS patients include body mass index greater than 25 kg/m2, having at least 2 comorbidities, EDSS ≥ 6.0, and IgM < 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 ocrelizumab treated patients compared to interferon beta-1-a and placebo.
In the RMS clinical trials, 39.9% of ocrelizumab treated patients and 33.2% interferon beta-1-a treated patients experienced an upper respiratory tract infection and 7.5% of ocrelizumab treated patients and 5.2% of interferon beta-1-a treated patients experienced a lower respiratory tract infection.

In the pivotal PPMS clinical trial, 48.8% of ocrelizumab treated patients and 42.7% of patients who received placebo experienced an upper respiratory tract infection, and 9.9% of 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 ocrelizumab were predominately mild to moderate (80 – 90%).
COVID-19 and COVID-19 pneumonia
In a placebo-controlled phase IIIb study in patients with PPMS (Study WA40404), COVID-19 was observed more frequently in ocrelizumab treated patients compared to patients who received placebo.
COVID-19 was observed in 16.0% of ocrelizumab treated patients and 11.3% of patients who received placebo. In patients treated with ocrelizumab, COVID-19 was predominantly mild to moderate in severity (14.2%).
COVID-19 pneumonia was observed more frequently in ocrelizumab treated patients compared to patients who received placebo. COVID-19 pneumonia was observed in 3.2% of ocrelizumab treated patients and 1.8% of patients who received placebo. COVID-19 pneumonia was predominantly observed as a serious infection, which occurred in 2.6% of ocrelizumab treated patients and 1.6% of patients who received placebo. Fatalities due to COVID-19 pneumonia were uncommon, occurring in 0.8% of ocrelizumab treated patients and 0.2% of patients who received placebo, and were associated with known risk factors in both arms.
Herpes
In active-controlled (RMS) clinical trials, herpes infections were reported more frequently in 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 pivotal placebo-controlled (PPMS) clinical trial, a higher proportion of patients with oral herpes (2.7% vs 0.8%) were observed in the ocrelizumab treatment arm.
Drug-induced liver injury
Drug-induced liver injury and increased liver enzymes have been reported during the post-marketing phase (see section 4.4).
Laboratory abnormalities
Immunoglobulins
Ocrelizumab treatment resulted in a decrease in total immunoglobulins over the controlled period of the pivotal clinical trials, mainly driven by reduction in IgM.
Clinical trial data from the controlled period and OLE phase of the pivotal clinical trials have 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 ocrelizumab compared with 32.6% of patients treated with interferon beta-1a. In the pivotal PPMS clinical trial, a decrease in lymphocytes <LLN was observed in 26.3% of ocrelizumab treated patients vs 11.7% of placebo-treated patients.
The majority of these decreases reported in ocrelizumab treated patients were Grade 1 (<LLN - 800 cells/mm3) and 2 (between 500 and 800 cells/mm3) in severity. Approximately 1% of the patients in the 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 ocrelizumab treated patients in the pivotal studies. 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 ocrelizumab compared with 40.9% of patients treated with interferon beta-1a. In the placebo-controlled pivotal (PPMS) clinical trial, the proportion of 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 ocrelizumab group had Grade 2 or above neutropenia vs 1.3% in the placebo group; approximately 1% of the patients in the 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 1500 cells/mm3) and 2 (between 1000 and 1500 cells/mm3) in severity. Overall, approximately 1% of the patients in the ocrelizumab group had Grade 3 or 4 neutropenia. One patient with Grade 3 (between 500 and 1000 cells/mm3) and one 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 2000 mg of 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.
Paediatric population
In a randomised, double-blind, active comparator-controlled trial of flexible duration (at least 24 weeks; median treatment duration 76.7 weeks), paediatric patients with RRMS aged 10 to less than 18 years (n=14 aged 11 to less than 14 years and n=79 aged 14 to less than 18 years; total n=93 in the ocrelizumab arm) were treated with intravenous ocrelizumab 600 mg every 24 weeks (administered as two 300 mg intravenous infusions 2 weeks apart for Dose 1, followed by single 600 mg intravenous infusions for subsequent doses) (see section 5.1). The overall safety profile in paediatric patients was generally consistent with that observed in adult patients.
In paediatric patients, the most common symptoms associated with IRRs included headache, throat irritation, pruritus, rash, erythema, and nausea. IRRs were the most common adverse reaction reported in paediatric patients. IRRs were reported in 48.4% of ocrelizumab-treated patients and 23.9% of fingolimod-treated patients (placebo infusion). The incidence of IRRs was highest during Dose 1, infusion 1 (31.2%) and decreased to 8.6% for Dose 1, infusion 2 (on Day 15). At Dose 2, 16.3% of patients had an IRR. The incidence and intensity of IRRs decreased with subsequent infusions. The

majority of IRRs were mild to moderate. One IRR was reported as serious (with a Grade 3 intensity at Dose 1).
Infections occurred in 73.1% of ocrelizumab-treated patients (1.5 infections per patient year) and 58.7% of fingolimod-treated patients (1.2 infections per patient year). Upper respiratory tract infection, nasopharyngitis, and influenza were more frequently reported in the ocrelizumab-treated patients and were all mild to moderate. There was no increase in serious infections (SIs) associated with ocrelizumab in paediatric patients (the rate of SIs was similar to fingolimod).
Treatment with ocrelizumab resulted in a decrease in total immunoglobulins over the controlled period of the study, mainly driven by reduction in IgM. Similar to the pattern observed in the adult population, reduction in IgM occurred earlier and in a higher proportion of patients compared with IgG and IgA.
No decreased neutrophil counts were observed in ocrelizumab-treated patients, compared with 3.3% in fingolimod-treated patients.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Summary of the safety profile
The most important and frequently reported adverse reactions are 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).
Other frequently reported adverse reactions are COVID-19 (16.0% in PPMS) and decreased blood immunoglobulin M (16.5%, 15.5% in RMS and PPMS, respectively).
The safety profile of Ocrevus solution for injection was consistent with the known safety profile of intravenous ocrelizumab below in Table 1 except for the very common adverse reaction of IRs.
Tabulated list of adverse reactions
Adverse reactions reported in clinical trials with intravenous ocrelizumab and derived from spontaneous reporting are listed below in Table 1. The frequencies of adverse reactions are based on the controlled period of the pivotal studies in RMS and PPMS and the controlled period of Study WA40404 in PPMS. 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 1 Adverse reactions
MedDRA
System Organ Class (SOC)
Very common
Common
Not Known
Infections and infestations
Upper respiratory tract infection,
COVID-19, nasopharyngitis, influenza
Sinusitis, bronchitis, oral herpes, gastroenteritis, respiratory tract infection, COVID-19 pneumonia, viral infection, herpes zoster, conjunctivitis, cellulitis Blood and lymphatic system disorders Neutropenia Late onset of Neutropenia3 Respiratory, thoracic and mediastinal disorders Cough, catarrh Hepatobiliary disorders Drug-induced liver injury3 Investigations Blood immunoglobulin M decreased Blood immunoglobulin G decreased Injury, poisoning and procedural complications Infusion-related reactions1, injection reaction2,3 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).
3 Observed in the post-marketing setting.
Description of selected adverse reactions
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 most common 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%), and injection site pruritus (6.8%). IRs occurred in 48.3% of these patients after the first injection. Of the 118 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 within 24 hours after the end of injection as opposed to during the injection. All IRs were non serious and of mild (71.9%) or moderate (28.1%) severity. The median duration of IR was 3 days for systemic IRs and 4 days for local IRs. All patients recovered from IRs, of which 26.3% required symptomatic treatment.

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 of systemic IR and 64.0% of patients experienced at least one event of local IR. Of the 104 patients who received 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 the first 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 and second injection, respectively.
Intravenous ocrelizumab is associated with infusion-related reactions (IRRs), which may also be related 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 intravenous ocrelizumab.
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 pivotal 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 in the pivotal studies, 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 Expanded Disability Status Scale (EDSS) ≥ 6.0. Risk factors for SIs in PPMS patients include body mass index greater than 25 kg/m2, having at least 2 comorbidities, EDSS ≥ 6.0, and IgM < 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 pivotal 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%).

COVID-19 and COVID-19 pneumonia
In a placebo-controlled phase IIIb study in patients with PPMS (Study WA40404), COVID-19 was observed more frequently in intravenous ocrelizumab treated patients compared to patients who received placebo. COVID-19 was observed in 16.0% of intravenous ocrelizumab treated patients and 11.3% of patients who received placebo. In patients treated with intravenous ocrelizumab, COVID-19 was predominantly mild to moderate in severity (14.2%).
COVID-19 pneumonia was observed more frequently in intravenous ocrelizumab treated patients compared to patients who received placebo. COVID-19 pneumonia was observed in 3.2% of intravenous ocrelizumab treated patients and 1.8% of patients who received placebo.
COVID-19 pneumonia was predominantly observed as a serious infection, which occurred in 2.6% of intravenous ocrelizumab treated patients and 1.6% of patients who received placebo. Fatalities due to COVID-19 pneumonia were uncommon, occurring in 0.8% of intravenous ocrelizumab treated patients and 0.2% of patients who received placebo, and were associated with known risk factors in both arms.
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 pivotal 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.
Drug-induced liver injury
Drug-induced liver injury and increased liver enzymes have been reported during the post-marketing phase (see section 4.4).
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 the pivotal PPMS clinical trial, 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 in the pivotal studies. 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 pivotal (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 1500 cells/mm3) and 2 (between 1000 and 1500 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 1000 cells/mm3) and one patient with Grade 4 (< 500 cells/mm3) neutropenia required specific treatment with granulocyte- colony stimulating factor, and remained on ocrelizumab after the episode. Neutropenia can occur several months after the administration of ocrelizumab (see section 4.4).
Other
One patient, who received 2000 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 national reporting system listed in Appendix V.

Traceability
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Infusion-Related Reactions (IRRs)
Ocrelizumab is associated with IRRs, which may be related to cytokine release and/or other chemical mediators.
Symptoms of IRRs may occur during any ocrelizumab infusion, but have been more frequently reported during the first infusion. IRRs can occur within 24 hours of the infusion (see section 4.8).
These reactions may present as pruritus, rash, urticaria, erythema, throat irritation, oropharyngeal pain, dyspnoea, pharyngeal or laryngeal oedema, flushing, hypotension, pyrexia, fatigue, headache, dizziness, nausea, tachycardia and anaphylaxis.
Before the infusion

Management of severe reactions
Appropriate resources for the management of severe reactions such as serious IRR, hypersensitivity reactions and/or anaphylactic reactions should be available.
Infusion
Amount of ocrelizumab to be administered
Infusion instruction

Each infusion should be given over approximately 3.5 hours

Hypotension
As a symptom of IRR, hypotension may occur during infusions. Therefore, withholding of antihypertensive treatments should be considered for 12 hours prior to and throughout each infusion.
Patients with a history of congestive heart failure (New York Heart Association III & IV) were not studied.
Premedication
Patients must receive premedication to reduce the frequency and severity of IRRs (see section 4.2).
During the infusion
The following measures need to be taken for patients who experience severe pulmonary symptoms, such as bronchospasm or asthma exacerbation:
 their infusion must be interrupted immediately and permanently;
 symptomatic treatment must be administered;
 the patient must be monitored until the pulmonary symptoms have resolved because initial improvement of clinical symptoms could be followed by deterioration.
Hypersensitivity may be clinically indistinguishable from an IRR in terms of symptoms. If a hypersensitivity reaction is suspected during infusion, the infusion must be stopped immediately and permanently (see ‘Hypersensitivity reactions’ below).
After the infusion
Patients should be observed for at least one hour after the completion of the infusion for any symptom of IRR.
Physicians should alert patients that an IRR can occur within 24 hours of infusion.
For guidance regarding infusion adjustments in case of IRR, see section 4.2.
Hypersensitivity reactions
A hypersensitivity reaction could also occur (acute allergic reaction to medicinal product). Type 1 acute hypersensitivity reactions (IgE-mediated) may be clinically indistinguishable from IRR symptoms.
A hypersensitivity reaction may present during any 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).
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). 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 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)
John Cunningham 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 (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 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 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 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 adult patients treated with 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 ocrelizumab MS pivotal studies in adult patients, 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 in adult patients, the median time for B-cell repletion was 72 weeks (see section 5.1).
In a randomised open-label study, adult RMS patients were able to mount humoral responses, although decreased, to tetanus toxoid, 23-valent pneumococcal polysaccharide with or without a booster vaccine, keyhole limpet 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 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).

Drug-induced liver injury
Drug-induced liver injury, including severe and life-threatening cases, has been observed in the post-marketing setting in patients treated with ocrelizumab. Signs of liver injury, including markedly elevated serum hepatic enzymes with elevated total bilirubin, have occurred from days to months after administration of the first dose.
Liver function tests should be performed before initiation of treatment with ocrelizumab and prior to the second initial infusion. Patients should be monitored for signs and symptoms of any hepatic injury during treatment. Liver function tests should be performed in patients who report symptoms that may indicate liver injury, including new or worsening fatigue, anorexia, nausea, vomiting, right upper abdominal discomfort, dark urine, or jaundice.
If liver injury is confirmed, ocrelizumab should be discontinued. Treatment should not be resumed unless a plausible alternative aetiology for the signs and symptoms of liver injury can be established.
Excipients with known effect
Sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’. Medicinal product will be prepared for administration with sodium-containing solution and this should be considered in relation to the total sodium intake of the patient from all sources per day.
Polysorbate 20
This medicinal product contains 2 mg of polysorbate 20 in each vial, which is equivalent to 0.2 mg/mL. Polysorbates may cause allergic reactions.

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. 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. 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. For subsequent doses, the need for post-injection monitoring is at the treating physician’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 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.

Intravenous ocrelizumab is associated with infusion-related reactions (IRRs), which may also be related 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 intravenous ocrelizumab.
Hypersensitivity may be clinically indistinguishable from an IR or an IRR in terms of symptoms. If a hypersensitivity reaction is suspected, the injection must be stopped immediately and permanently (see ‘Hypersensitivity reactions’ below).
Hypersensitivity reactions
A hypersensitivity reaction could also occur (acute allergic reaction to medicinal product). Type 1 acute hypersensitivity reactions (IgE-mediated) may be clinically indistinguishable from IR symptoms.
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).
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)
John Cunningham 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 (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 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 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).
Drug-induced liver injury
Drug-induced liver injury, including severe and life-threatening cases, has been observed in the post-marketing setting in patients treated with ocrelizumab. Signs of liver injury, including markedly elevated serum hepatic enzymes with elevated total bilirubin, have occurred from days to months after administration of the first dose.
Liver function tests should be performed before initiation of treatment with ocrelizumab. Patients should be monitored for signs and symptoms of any hepatic injury during treatment. Liver function tests should be performed in patients who report symptoms that may indicate liver injury, including new or worsening fatigue, anorexia, nausea, vomiting, right upper abdominal discomfort, dark urine, or jaundice.
If liver injury is confirmed, ocrelizumab should be discontinued. Treatment should not be resumed unless a plausible alternative aetiology for the signs and symptoms of liver injury can be established.
Excipients with known effect
Sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

Polysorbate 20
This medicinal product contains 13.8 mg of polysorbate 20 in each vial, which is equivalent to 0.6 mg/mL. Polysorbates may cause allergic reactions.

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 haemocyanin neoantigen, and seasonal influenza vaccines in patients receiving ocrelizumab (see sections 4.4 and 5.1).
After treatment over 2 years, the proportion of adult patients with positive antibody titres 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).

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 haemocyanin neoantigen, and seasonal influenza vaccines in patients receiving intravenous ocrelizumab (see sections 4.4 and 5.1).
After treatment over 2 years with intravenous ocrelizumab, the proportion of patients with positive antibody titres 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).

Females of childbearing potential
Females 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-foetal 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 foetus.
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, multicenter, 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.

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-foetal 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 foetus.
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, multicenter, 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 exposed to ocrelizumab.

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

Table 8
Key clinical and MRI endpoints from Study WA25046 (PPMS)
Study 3
Endpoints
WA25046 (Oratorio)
Ocrelizumab
600 mg
(n=488)
Placebo
(n=244)
Clinical Endpoints
Primary efficacy endpoint
Proportion of patients with 12 weeks - Confirmed
Disability Progression1 (primary endpoint)
Risk reduction
30.2%
34.0%
24%
(p=0.0321)
Proportion of patients with 24 weeks - Confirmed
Disability Progression1
28.3%
32.7%
Risk reduction
25%
(p=0.0365)
Percentage change in Timed 25-Foot Walk from baseline to Week 120

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

Table 5
Key clinical and MRI endpoints from Study WA25046 (PPMS)
Study 3
Endpoints
WA25046 (Oratorio)
Ocrelizumab
600 mg
(n=488)
Placebo
(n=244)
Clinical Endpoints
Primary efficacy endpoint
Proportion of patients with 12 weeks - Confirmed
Disability Progression1 (primary endpoint)
Risk reduction
30.2%
34.0%
24%
(p=0.0321)
Proportion of patients with 24 weeks - Confirmed
Disability Progression1
28.3%
32.7%
Risk reduction
25%
(p=0.0365)
Percentage change in Timed 25-Foot Walk from baseline to Week 120

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 2000 mg, administered as two 1000 mg intravenous infusions separated by 2 weeks (Phase II dose finding study in RRMS) and 1200 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 infusion immediately and observe the patient for IRRs (see section 4.4).
5.
PHARMACOLOGICAL PROPERTIES

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 2000 mg, administered as two 1000 mg intravenous infusions separated by 2 weeks (Phase II dose finding study in RRMS) and 1200 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).
5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Immunosuppressants, monoclonal antibodies, ATC code: L04AG08.
Mechanism of action
Ocrelizumab is a recombinant humanised monoclonal antibody that selectively targets CD20-expressing B cells.
CD20 is a cell surface antigen found on pre-B cells, mature and memory B cells but not expressed on lymphoid stem cells and plasma cells.
The precise mechanisms through which ocrelizumab exerts its therapeutic clinical effects in MS is not fully elucidated but is presumed to involve immunomodulation through the reduction in the number and function of CD20-expressing B cells. Following cell surface binding, ocrelizumab selectively depletes CD20-expressing B cells through antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis. The capacity of B-cell reconstitution and 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. 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 adult studies, between each dose of 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-cell depletion was consistent in the PPMS and RMS trials.
The longest follow up time after the last 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 in adults
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 5.
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 × 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 5

Pharmacotherapeutic group: Immunosuppressants, monoclonal antibodies, ATC code: L04AG08.
Mechanism of action
Ocrelizumab is a recombinant humanised monoclonal antibody that selectively targets CD20- expressing B cells.
CD20 is a cell surface antigen found on pre-B cells, mature and memory B cells but not expressed on lymphoid stem cells and plasma cells.
The precise mechanisms through which ocrelizumab exerts its therapeutic clinical effects in MS is not fully elucidated but is presumed to involve immunomodulation through the reduction in the number and function of CD20-expressing B cells. Following cell surface binding, ocrelizumab selectively depletes CD20-expressing B cells through antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis. The capacity of B-cell reconstitution and pre-existing humoral immunity are preserved. In addition, innate immunity and total T-cell numbers are not affected.
Subcutaneous ocrelizumab contains recombinant human hyaluronidase (rHuPH20), an enzyme used to increase the dispersion and absorption of co-formulated active substances when administered subcutaneously.
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 (> 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
OCARINA II
Study CN42097 (OCARINA II) was a multicenter, randomised, open-label, parallel arm trial conducted to evaluate the pharmacokinetics, pharmacodynamics, safety, immunogenicity, radiological and clinical effects of subcutaneous ocrelizumab compared with intravenous ocrelizumab in patients with either RMS or PPMS. OCARINA II was designed to demonstrate non-inferiority of treatment with subcutaneous ocrelizumab 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).

The pharmacokinetics of ocrelizumab in the MS studies were described by a two compartment model with time-dependent clearance, and with PK parameters typical for an IgG1 monoclonal antibody.
The overall exposure (AUC over the 24 weeks dosing interval) was identical in the 2 × 300 mg in PPMS and 1 × 600 mg in RMS studies, as expected given an identical dose was administered. Area under the curve (AUCτ) after the 4th dose of 600 mg ocrelizumab was 3510 µg/mL•day, and mean maximum concentration (Cmax) was 212 µg/mL in RMS (600 mg infusion) and 141 µg/mL in PPMS (300 mg infusions).
Absorption
Ocrelizumab is administered as an intravenous infusion.
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
The median AUC over the first 24-week dosing interval was 3130 µg/mL•day, and Cmax was 147 µg/mL, in paediatric patients aged 10 years and older with RRMS receiving ocrelizumab 600 mg (body weight 35 kg or more) or 300 mg (body weight less than 35 kg).
The recommended posology is derived from the PK model, which was based on clinical data from 110 patients with a body weight of 40 kg or higher receiving 600 mg ocrelizumab, and 6 patients from the Phase II study weighing less than 40 kg receiving 300 mg ocrelizumab (see section 4.2).
No studies have been conducted to investigate the pharmacokinetics of ocrelizumab in paediatric patients less than 10 years of age.
Elderly

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 subcutaneous ocrelizumab, the predicted mean exposure (AUC over the 24 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 intravenous ocrelizumab. The geometric mean ratio for AUCw1-12 was 1.29 (90% CI: 1.23–1.35).
Absorption
The estimated bioavailability after subcutaneous administration of 920 mg ocrelizumab was 81%. The mean Cmax was 132 µg/mL and tmax 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 subcutaneous 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 4.2).
Renal impairment
No formal pharmacokinetic study has been conducted. Patients with mild renal impairment were included in clinical trials and no change in the pharmacokinetics of ocrelizumab was observed in those patients. There is no PK information available in patients with moderate or severe renal impairment.