Ocrevus Adverse Reactions

Summary of the safety profile: The most important and frequently reported adverse reactions were IRRs (34.3%, 40.1% in RMS and PPMS, respectively) and infections (58.5%, 72.2% in RMS and PPMS, respectively) (see Precautions).
Tabulated list of adverse reactions: Adverse reactions reported in clinical trials and derived from spontaneous reporting are listed as follows in Table 6. 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. (See Table 6.)

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Description of selected adverse reactions: 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 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 Precautions.
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 Pharmacology: Pharmacodynamics under Actions). 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).
Infection: 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. All patients switched to ocrelizumab during the open-label phase in both RMS and PPMS studies. An increase in the rate of serious infections was observed in RMS between Years 2 and 3, but not in subsequent years. No increase was observed in PPMS.
Respiratory tract infections: The proportion of respiratory tract infections was higher in 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 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%).
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 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.
Laboratory abnormalities: Immunoglobulins: Ocrelizumab treatment 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.
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 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.
Neutrophils: In the active-controlled (RMS) treatment period, a decrease in neutrophils <LNN 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 (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 Precautions).
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.
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.