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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 Adverse Reactions). 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.
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 Dosage & Administration).
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 difficult to distinguish 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 as follows).
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 Dosage & Administration.
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 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 Contraindications).
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 Contraindications and Adverse Reactions).
The overall proportion of patients experiencing a serious infection was similar to comparators (see Adverse Reactions). 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 Contraindications). 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 Adverse Reactions). 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 clinical trials in patients treated with ocrelizumab, compared to control groups. The incidence was within the background rate expected for an MS population. Patients with a known active malignancy should not be treated with ocrelizumab (see Contraindications). 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.
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 was within the background rate expected for an MS population.
Treatment of severely immunocompromised patients: Patients in a severely immunocompromised state must not be treated until the condition resolves (see Contraindications).
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 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 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, the administration of corticosteroids for the treatment of relapse was not associated with an increased risk of serious infection.
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 Pharmacology: Pharmacodynamics under Actions). 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 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 Pharmacology: Pharmacodynamics under Actions).
In a randomised 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 Interactions and Pharmacology: Pharmacodynamics under Actions).
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 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 Use in Pregnancy & Lactation).
Sodium: This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'.
Effects on ability to drive and use machines: Ocrevus has no or negligible influence on the ability to drive and use machines.
