Ocrevus · 4.6 Fertility, pregnancy and lactation · 2

HOS-097541 · has-adverse-reaction-information · PDF-Seite 40

Summary of the safety profile 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) (see section 4.4). 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). The safety profile of Ocrevus solution for injection was consistent with the known safety profile of intravenous ocrelizumab below in Table 1 except for the very common adverse reaction of IRs. Tabulated list of adverse reactions Adverse reactions reported in clinical trials with intravenous ocrelizumab and derived from spontaneous reporting are listed below in Table 1. 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. 40 Table 1 Adverse reactions MedDRA Very common Common Not Known System Organ Class (SOC) Infections and infestations Upper respiratory Sinusitis, tract infection, bronchitis, COVID-19, oral herpes, nasopharyngitis, gastroenteritis, influenza respiratory tract infection, COVID-19 pneumonia, viral infection, herpes zoster, conjunctivitis, cellulitis Blood and lymphatic Neutropenia Late onset of system disorders

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HOS-097535 · has-adverse-reaction-information · PDF-Seite 13

Summary of the safety profile 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) (see section 4.4). 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). Tabulated list of adverse reactions Adverse reactions reported in clinical trials and derived from spontaneous reporting are listed below in Table 4. 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. 13 Table 4 Adverse reactions MedDRA Very common Common Not Known System Organ Class (SOC) Infections and infestations Upper respiratory Sinusitis, tract infection, bronchitis, COVID-19, oral herpes, nasopharyngitis, gastroenteritis, influenza respiratory tract infection, COVID-19 pneumonia, viral infection, herpes zoster, conjunctivitis, cellulitis Blood and lymphatic system Neutropenia Late onset of disorders Neutropenia2 Respiratory, thoracic and Cough, mediastinal disorders catarrh Hepatobiliary

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HOS-097531 · has-contraindication-information · PDF-Seite 7

 Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.  Current active infection (see section 4.4).  Patients in a severely immunocompromised state (see section 4.4).  Known active malignancies (see section 4.4).

HOS-097537 · has-contraindication-information · PDF-Seite 35

 Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.  Current active infection (see section 4.4).  Patients in a severely immunocompromised state (see section 4.4).  Known active malignancies (see section 4.4).

HOS-097536 · has-indication-information · PDF-Seite 33

Ocrevus is indicated for the treatment of adult patients with relapsing forms of multiple sclerosis (RMS) with active disease defined by clinical or imaging features (see section 5.1). Ocrevus is indicated for the treatment of adult patients with early primary progressive multiple sclerosis (PPMS) in terms of disease duration and level of disability, and with imaging features characteristic of inflammatory activity (see section 5.1).

HOS-097530 · has-indication-information · PDF-Seite 2

Ocrevus is indicated for the treatment of adult patients and paediatric patients aged 10 years and older with relapsing forms of multiple sclerosis (RMS) with active disease defined by clinical or imaging features (see section 5.1). Ocrevus is indicated for the treatment of adult patients with early primary progressive multiple sclerosis (PPMS) in terms of disease duration and level of disability, and with imaging features characteristic of inflammatory activity (see section 5.1).

HOS-097533 · has-interaction-information · PDF-Seite 11

No interaction studies have been performed, as no interactions are expected via cytochrome P450 enzymes, other metabolising enzymes or transporters. Vaccinations 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 (see sections 4.4 and 5.1). 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. Immunosuppressants It is not recommended to use other immunosuppressive therapies concomitantly with ocrelizumab except corticosteroids for symptomatic treatment of relapses (see section 4.4).

HOS-097539 · has-interaction-information · PDF-Seite 39

No interaction studies have been performed, as no interactions are expected via cytochrome P450 enzymes, other metabolising enzymes or transporters. Vaccinations 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 intravenous ocrelizumab (see sections 4.4 and 5.1). After treatment over 2 years with intravenous ocrelizumab, the proportion of patients with positive antibody titres against S. pneumoniae, mumps, rubella and varicella were generally similar to the proportions at baseline. Immunosuppressants It is not recommended to use other immunosuppressive therapies concomitantly with ocrelizumab except corticosteroids for symptomatic treatment of relapses (see section 4.4).

HOS-097540 · has-pregnancy-information · PDF-Seite 39

Women of childbearing potential Women of childbearing potential should use contraception while receiving ocrelizumab and for 4 months after the last administered dose of ocrelizumab. Pregnancy 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 (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. 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 (see section 5.3). Ocrelizumab should be avoided during pregnancy unless the potential benefit to the mother outweighs the potential risk to the foetus. Breast-feeding Human IgGs are known to be excreted in breastmilk the first few days after birth (colostrum period), which decreases to low concentrations soon afterwards. 39 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 s

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HOS-097534 · has-pregnancy-information · PDF-Seite 11

Females of childbearing potential Females of childbearing potential should use contraception while receiving ocrelizumab and for 4 months after the last administered dose of ocrelizumab. 11 Pregnancy 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 (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. 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 (see section 5.3). Ocrelizumab should be avoided during pregnancy unless the potential benefit to the mother outweighs the potential risk to the foetus. Breast-feeding 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 undetectab

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HOS-097538 · has-warning-information · PDF-Seite 35

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. Injection reactions (IRs) Treatment with subcutaneous ocrelizumab is associated with IRs, which may be related to cytokine release and/or other chemical mediators. Physicians should alert patients that IRs can occur during or within 24 hours of administration. Symptoms of IRs have been more frequently reported with the first injection. IRs can be local IRs or systemic IRs. Common symptoms of local IRs at the injection site include erythema, pain, swelling and pruritus. Common symptoms of systemic IRs include headache and nausea (see section 4.8). Shortly before injection, patients should receive premedication to reduce the risk of IRs (see section 4.2). Patients should be observed for at least one hour after the initial dose of the medicinal product for any symptom of severe IR. Appropriate resources for the management of severe IRs, hypersensitivity reactions and/or anaphylactic reactions should be available for the initial dose of the medicinal product. For subsequent doses, the need for post-injection monitoring is at the treating physician’s discretion. IRs can be managed with symptomatic treatment, should they occur. If there are signs of a life-threatening IR, the injection should be stopped immediately, and the patient should receive appropriate treatment. Ocrelizumab treatment must be permanently discontinued in these patients. If a patient experiences a severe IR, the injection should be interrupted immediately, and the patient should receive symptomatic treatment. The injection should be completed only after all symptoms have resolved. 35 Intravenous ocrelizumab is associated with infusion-related reactions (IRRs), which may also be related to cytokine release and/or other chemical mediators. IRRs 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. Serious IRRs, some requiring hospitalisation, have been reported with the use of intravenous ocrelizumab. Hypersensitivity may be clinically indistinguishable from an IR or an IRR in terms of symptoms. If a hypersensitivity reaction is suspected, the injection must be stopped immediately and permanen

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HOS-097532 · has-warning-information · PDF-Seite 7

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 section 4.8). 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. 7 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 section 4.2). 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 clinically indistinguishable 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’ below). 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 section 4.2. Hypersensitivity reactions A hypersensitivity re

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