Ocrelizumab interacts in the following cases:
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.
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.
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.
It is not recommended to use other immunosuppressive therapies concomitantly with ocrelizumab except corticosteroids for symptomatic treatment of relapses.
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.
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.
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.
Ocrelizumab should be avoided during pregnancy unless the potential benefit to the mother outweighs the potential risk to the foetus.
Human IgGs are known to be excreted in breastmilk the first few days after birth (colostrum period), which decreases to low concentrations soon afterwards.
In a prospective, multicenter, open-label study MN42989 (SOPRANINO), 13 lactating 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.
Females of childbearing potential should use contraception while receiving ocrelizumab and for 4 months after the last administered dose of ocrelizumab.
Preclinical data reveal no special hazards for humans based on studies of male and female fertility in cynomolgus monkeys.
Ocrelizumab has no or negligible influence on the ability to drive and use machines.
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). 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).
Adverse reactions reported in clinical trials and derived from spontaneous reporting are listed below in the table below. 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.
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 injury2 | ||
| 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.
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.
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.
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. 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).
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.
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, 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.
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%).
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.
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 and increased liver enzymes have been reported during the post-marketing phase.
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.
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.
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.
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.
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). 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.
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