Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Roche Registration GmbH, Emil-Barell-Strasse 1, 79639, Grenzach-Wyhlen, Germany
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Ocrevus is associated with IRRs, which may be related to cytokine release and/or other chemical mediators.
Symptoms of IRRs may occur during any infusion, but have been more frequently reported during the first infusion. IRRs can occur within 24 hours of the infusion. 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 and tachycardia (see section 4.8).
Before the infusion:
During the infusion:
After the infusion:
For guidance regarding posology for patients experiencing IRR symptoms see section 4.2.
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 infusion, although typically would not present during the first infusion. For subsequent infusions, 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 must not be treated (see section 4.3).
Ocrevus administration must be delayed in patients with an active infection until the infection is resolved.
It is recommended to verify the patient’s immune status before dosing since severely immunocompromised patients (e.g. with lymphopenia, neutropenia, hypogammaglobulinemia) should not be treated (see sections 4.3 and 4.8).
The overall proportion of patients experiencing a serious infection was similar to comparators (see section 4.8). 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 Ocrevus 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. Ocrevus treatment may further increase the risk of severe pneumonia in these patients. Physicians should take prompt action for patients presenting with pneumonia.
A risk of PML cannot be ruled-out since John Cunningham (JC) virus infection resulting in PML has been observed in patients treated with anti-CD20 antibodies and other MS therapies, and associated with risk factors (e.g. patient population, 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 Ocrevus 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 John Cunningham (JC) Viral Deoxyribonucleic acid (DNA) and repeat neurological assessments, should be considered. If PML is confirmed, treatment must be discontinued permanently.
Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, has been reported in patients treated with other anti-CD20 antibodies.
HBV screening should be performed in all patients before initiation of treatment with Ocrevus 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 Ocrevus. 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.
An increased number of malignancies (including breast cancers) have been observed in clinical trials in patients treated with ocrelizumab, compared to control groups. However, the incidence was within the background rate expected for an MS population. 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 with a known active malignancy should not be treated with Ocrevus (see section 4.3). Patients should follow standard breast cancer screening per local guidelines. Please see section 4.2 for populations not studied.
In the controlled period of the clinical trials, the incidence of non-melanoma skin cancers was low and there was no imbalance between treatment groups. An increase in incidence was observed between years 3 and 4 of treatment due to basal cell carcinoma, which was not observed in subsequent years. The incidence remains within the background rate expected for an MS population.
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 Ocrevus concomitantly with immunosuppressive medications (e.g. chronic corticosteroids, non-biologic and biologic disease-modifying antirheumatic drugs [DMARDS], mycophenolate mofetil, cyclophosphamide, azathioprine) resulted in an increase of serious infections, including opportunistic infections. Infections included and were not limited to atypical pneumonia and pneumocystis jirovecii pneumonia, varicella pneumonia, tuberculosis, histoplasmosis. In rare cases, some of these infections were fatal. An exploratory analysis identified the following factors associated with risk of serious infections: higher doses of Ocrevus than recommended in MS, other comorbidities, and chronic use of immunosuppressants/corticosteroids.
It is not recommended to use other immunosuppressives concomitantly with Ocrevus 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 the administration of corticosteroids for the treatment of relapse was not associated with an increased risk of serious infection.
When initiating Ocrevus after an immunosuppressive therapy or initiating an immunosuppressive therapy after Ocrevus, the potential for overlapping pharmacodynamic effects should be taken into consideration (see section 5.1 Pharmacodynamic effects). Caution should be exercised when prescribing Ocrevus taking into consideration the pharmacodynamics of other disease modifying MS therapies.
The safety of immunisation with live or live-attenuated vaccines, following Ocrevus 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 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. See section 4.5 and 5.1.
It is recommended to vaccinate patients treated with Ocrevus with seasonal influenza vaccines that are inactivated.
Physicians should review the immunisation status of patients being considered for treatment with Ocrevus. Patients who require vaccination should complete their immunisation at least 6 weeks prior to initiation of Ocrevus.
See section 4.5 and 5.1 for further information about vaccinations.
Due to the potential depletion of B cells in infants of mothers who have been exposed to Ocrevus during pregnancy, it is recommended that vaccination with live or live-attenuated vaccines should be delayed until B-cell levels have recovered; therefore, measuring CD19-positive B-cell levels, in neonates and infants, prior to vaccination is recommended
It is recommended that all vaccinations other than live or live-attenuated should follow the local immunisation schedule and measurement of vaccine-induced response titers should be considered to check whether individuals have mounted a protective immune response because the efficacy of the vaccination may be decreased.
The safety and timing of vaccination should be discussed with the infant’s physician (see section 4.6).
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. it is essentially sodium-free.
No formal drug interaction studies have been performed, as no drug interactions are expected via cytochrome P450 enzymes, other metabolising enzymes or transporters.
The safety of immunisation with live or live-attenuated vaccines, following Ocrevus therapy has not been studied.
Data are available on the effects of tetanus toxoid, 23-valent pneumococcal polysaccharide, keyhole limpet hemocyanin neoantigen, and seasonal influenza vaccines in patients receiving Ocrevus. See section 4.4 and 5.1.
After treatment with Ocrevus over 2 years, the proportion of patients with positive antibody titers against S. pneumoniae, mumps, rubella and varicella were generally similar to the proportions at baseline.
It is not recommended to use other immunosuppressives concomitantly with Ocrevus except corticosteroids for symptomatic treatment of relapses.
See section 4.4 ‘Treatment of severely immunocompromised patients’ for information about the use of immunosuppressants before, during or after Ocrevus treatment.
Women of child bearing potential should use contraception while receiving Ocrevus and for 12 months after the last infusion of Ocrevus (see below and section 5.1 and 5.2).
Ocrevus 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 Ocrevus 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 Ocrevus 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.
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 (see section 5.3).
Ocrevus 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 (for details see section 5.3). A risk to neonates and infants cannot be excluded. Women should be advised to discontinue breast-feeding during Ocrevus therapy.
Preclinical data reveal no special hazards for humans based on studies of male and female fertility in cynomologous monkeys.
Ocrevus 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. See section 4.4 and section 4.8 (subsection ‘Description of selected adverse reactions’) for further details.
The overall safety profile of Ocrevus in Multiple Sclerosis is based on data from patients from pivotal clinical trials in MS (RMS and PPMS).
The table 2 summarises the ADRs that have been reported in association with the use of Ocrevus 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.
Table 2. ADRs reported with Ocrevus (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 Ocrevus 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 Ocrevus treated patients experienced mild and moderate IRRs respectively, 2.4% experienced severe IRRs and 0.1% experienced lifethreatening IRRs. See section 4.4.
In the placebo-controlled (PPMS) clinical trial, IRR was the most common adverse event in patients treated with Ocrevus 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 Ocrevus treated patients experienced mild and moderate IRRs respectively, 1.4% experienced severe IRRs. There were no life-threatening IRRs. See section 4.4.
In the active-controlled studies in RMS, infections occurred in 58.5% of patients receiving Ocrevus vs 52.5% of patients receiving interferon beta 1a. Serious infections occurred in 1.3% of patients receiving Ocrevus vs 2.9% of patients receiving interferon beta 1a. In the placebo-controlled study in PPMS, infections occurred in 72.2% of patients receiving Ocrevus vs 69.9% of patients receiving placebo. Serious infections occurred in 6.2% of patients receiving Ocrevus 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 Ocrevus treated patients compared to interferon beta-1a and placebo.
In the RMS clinical trials, 39.9% of Ocrevus treated patients and 33.2% interferon beta-1a treated patients experienced an upper respiratory tract infection and 7.5% of Ocrevus 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 Ocrevus treated patients and 42.7% of patients who received placebo experienced an upper respiratory tract infection, and 9.9% of Ocrevus 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 Ocrevus were predominately mild to moderate (80–90%).
In active-controlled (RMS) clinical trials, herpes infections were reported more frequently in Ocrevus-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 Ocrevus treatment arm.
Treatment with Ocrevus 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 Ocrevus 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 Ocrevus treated patients vs 11.7% of placebo-treated patients.
The majority of these decreases reported in Ocrevus 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 Ocrevus 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 Ocrevus patients compared with 40.9% of patients treated with interferon beta-1a. In the placebo-controlled (PPMS) clinical trial, the proportion of Ocrevus patients presenting decreased neutrophils was higher (12.9%) than placebo patients (10.0%); among these a higher percentage of patients (4.3%) in the Ocrevus group had Grade 2 or above neutropenia vs 1.3% in the placebo group; approximately 1% of the patients in the Ocrevus 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 Ocrevus) 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 Ocrevus, 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.
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.
No incompatibilities between Ocrevus and polyvinyl chloride (PVC) or polyolefin (PO) bags and intravenous administration sets have been observed.
Do not use diluents other than the one detailed in section 6.6 to dilute Ocrevus since its use has not been tested.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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