Ocrelizumab interacts in the following cases:
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).
In a randomized open-label study, 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 hemocyanin neoantigen, and seasonal influenza vaccines.
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.
Due to the potential depletion of B cells in infants of mothers who have been exposed to ocrelizumab during pregnancy, it is recommended that vaccination with live or live-attenuated vaccines should be delayed until B-cell levels have recovered; therefore, measuring CD19-positive B-cell levels, in neonates and infants, prior to vaccination is recommended
It is recommended that all vaccinations other than live or live-attenuated should follow the local immunisation schedule and measurement of vaccine-induced response titers should be considered to check whether individuals have mounted a protective immune response because the efficacy of the vaccination may be decreased.
The safety and timing of vaccination should be discussed with the infant’s physician.
Ocrelizumab is a humanised monoclonal antibody of an immunoglobulin G1 subtype and immunoglobulins are known to cross the placental barrier.
There is a limited amount of data from the use of ocrelizumab in pregnant women. 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.
Animal studies (embryo-foetal toxicity) do not indicate teratogenic effects. B-cell depletion in utero was detected. 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.
It is unknown whether ocrelizumab/metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of ocrelizumab in milk. A risk to neonates and infants cannot be excluded. Women should be advised to discontinue breast-feeding during ocrelizumab therapy.
Women of child bearing potential should use contraception while receiving ocrelizumab and for 12 months after the last infusion of ocrelizumab.
Preclinical data reveal no special hazards for humans based on studies of male and female fertility in cynomologous monkeys.
Ocrelizumab has no or negligible influence on the ability to drive and use machines.
The most important and frequently reported adverse drug reactions (ADRs) were IRRs and infections.
The overall safety profile of ocrelizumab in Multiple Sclerosis is based on data from patients from pivotal clinical trials in MS (RMS and PPMS).
The list summarises the ADRs that have been reported in association with the use of ocrelizumab in 1311 patients (3054 patient years) during the controlled treatment periods of MS clinical trials.
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) and very rare (<1/10,000). Within each System Organ Class, the adverse reactions are presented in order of decreasing frequency.
ADRs reported with ocrelizumab (in RMS or PPMS):
Very Common: Upper respiratory tract infection, nasopharyngitis, influenza
Common: Sinusitis, bronchitis, oral herpes, gastroenteritis, respiratory tract infection, viral infection, herpes zoster, conjunctivitis, cellulitis
Common: Cough, catarrh
Very Common: Blood immunoglobulin M decreased
Common: Blood immunoglobulin G decreased
Common: Neutropenia
Very Common: Infusion-related reactions1
1 Symptoms reported as IRRs within 24 hours of the infusion are described below in ‘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 active-controlled (RMS) clinical trials, IRR was the most common adverse event in patients treated with ocrelizumab 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 lifethreatening IRRs.
In the placebo-controlled (PPMS) clinical trial, IRR was the most common adverse event in patients treated with ocrelizumab 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.
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. Serious infections occurred in 1.3% of patients receiving ocrelizumab vs 2.9% of patients receiving interferon beta 1a. In the placebo-controlled study in PPMS, infections occurred in 72.2% of patients receiving ocrelizumab vs 69.9% of patients receiving placebo. Serious infections occurred in 6.2% of patients receiving ocrelizumab vs 6.7% of patients receiving placebo. An increase in the rate of serious infections was observed in RMS between Years 2 and 3, but not in subsequent years. No increase was observed in PPMS.
The proportion of respiratory tract infections was higher in ocrelizumab treated patients compared to interferon beta-1a and placebo.
In the RMS clinical trials, 39.9% of ocrelizumab treated patients and 33.2% interferon beta-1a treated patients experienced an upper respiratory tract infection and 7.5% of ocrelizumab treated patients and 5.2% of interferon beta-1a treated patients experienced a lower respiratory tract infection. In the 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 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%). Infections were predominantly mild to moderate in severity and patients recovered with treatment by standard therapies.
In the placebo-controlled (PPMS) clinical trial, a higher proportion of patients with oral herpes (2.7% vs 0.8%) were observed in the ocrelizumab treatment arm.
Treatment with ocrelizumab resulted in a decrease in total immunoglobulins over the controlled period of the studies, mainly driven by reduction in IgM. Clinical trial data have shown an association between decreased levels of IgG (and less so for IgM or IgA) and serious infections.
In RMS, a decrease in lymphocyte < LLN was observed in 20.7% of ocrelizumab patients compared with 32.6% of patients treated with interferon beta-1a. In PPMS, 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 serious infections was observed during episodes of confirmed total lymphocytes counts decrease in ocrelizumab treated patients. The number of serious infections was too low to draw definitive conclusions.
In the active-controlled (RMS) treatment period, a decrease in neutrophils < LNN was observed in 14.7% of ocrelizumab patients compared with 40.9% of patients treated with interferon beta-1a. In the placebo-controlled (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 (<1500 cells/mm³) and 2 (between 1000 and 1500 cells/mm³) in severity. 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.
One patient, who received 2000 mg of ocrelizumab, died of systemic inflammatory response syndrome (SIRS) of unknown etiology, 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.
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