Uplizna · 4.6 Fertility, pregnancy, and lactation · 1

HOS-288619 · has-adverse-reaction-information · PDF-Seite 9

Summary of the safety profile The most frequently reported adverse reactions by inebilizumab-treated patients from the 3 NMOSD, IgG4-RD and gMG pivotal clinical trials were urinary tract infection (26.2%), nasopharyngitis (20.9%), upper respiratory tract infection (15.6%), arthralgia (17.3%), back pain (13.8%), lymphopenia (10.7%) and headache (10.3%) across both the randomised controlled period (RCP) and open-label period (OLP). The most frequently reported serious adverse reactions by inebilizumab-treated patients across the RCP and OLP were infections (11.1%) (including urinary tract infections (4.0%), pneumonia (1.8%)) and NMOSD (1.8%). 9 Tabulated list of adverse reactions Adverse reactions reported in clinical trials and post-marketing experience following treatment with inebilizumab are listed in table 2 according to the following frequency categories: 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), not known (cannot be estimated from the available data). Table 2. Adverse reactions reported in inebilizumab clinical trials, including patients with NMOSD, gMG and IgG4-RD as well as from post-marketing experience MedDRA system Very common Common Uncommon organ class (≥ 1/10) (≥ 1/100 to < 1/10) (≥ 1/1 000 to < 1/100) Infections and Urinary tract infection, Pneumonia, Sepsis, infestations respiratory tract cellulitis, subcutaneous abscess, infection, herpes zoster, bronchiolitis nasopharingitis, sinusitis influenza Blood and lymphatic Lymphopenia* Neutropenia, system disorders Late-on-set neutropenia Musculoskeletal and Arthralgia, Myalgia connective tissue back pain disorders General disorders Pyrexia and administration site conditions Nervous system Headache disorder Investigations Immunoglobulins decreased Injury, poisoning and Infusion-related procedural reaction complications Respiratory, thoracic

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HOS-288615 · has-contraindication-information · PDF-Seite 4

• Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1 • Severe active infection, including active chronic infection such as hepatitis B • Active or untreated latent tuberculosis • History of progressive multifocal leukoencephalopathy (PML) • Severely immunocompromised state • Active malignancies 4

HOS-288614 · has-indication-information · PDF-Seite 2

Neuromyelitis optica spectrum disorders (NMOSD) Uplizna is indicated as monotherapy for the treatment of adult patients with NMOSD who are anti-aquaporin-4 immunoglobulin G (AQP4-IgG) seropositive (see section 5.1). Immunoglobulin G4-related disease (IgG4-RD) Uplizna is indicated for the treatment of adult patients with active IgG4-RD (see section 5.1). Generalized myasthenia gravis (gMG) Uplizna is indicated as an add-on to standard therapy for the treatment of gMG in adult patients who are anti-acetylcholine receptor (AChR) or anti-muscle-specific tyrosine kinase (MuSK) antibody positive (see section 5.1). 2

HOS-288617 · has-interaction-information · PDF-Seite 8

No interaction studies have been performed. The primary elimination pathway for therapeutic antibodies is clearance by the reticuloendothelial system. Cytochrome P450 enzymes, efflux pumps, and protein-binding mechanisms are not involved in the clearance of therapeutic antibodies. Therefore, the potential risk of pharmacokinetic interactions between inebilizumab and other medicinal products is low. Vaccinations The efficacy and safety of immunisation with live or live-attenuated vaccines following inebilizumab therapy has not been studied. The response to vaccination could be impaired when B cells are depleted. It is recommended that patients complete immunisations prior to the start of inebilizumab therapy (see section 4.4). Immunosuppressants In the pivotal NMOSD study, during the RCP, a 2-week course of oral corticosteroids (plus a 1-week taper) was given to all subjects following the first administration of inebilizumab. In the pivotal IgG4-RD study, during the RCP, subjects were at a uniform dose of glucocorticoids (GCs) at the time of initiation of inebilizumab and then began a prespecified taper to discontinuation at the end of 8 weeks. In the pivotal gMG study, subjects were on oral corticosteroids or stable dose of other immunosuppressants at the time of initiation of inebilizumab treatment. Subjects began a prespecified corticosteroid taper to 5 mg/day from week 4 to week 24, but were permitted to continuing receiving other immunosuppressants while receiving inebilizumab (see section 5.1). Concomitant usage of inebilizumab with immunosuppressants, including systemic corticosteroids, may increase the risk of infection. The effects of inebilizumab on B cells and immunoglobulins may persist for 6 months or longer following its administration. When initiating inebilizumab after other immunosuppressive therapies with prolonged immune effects or initiating other immunosuppressive therapies with prolonged immune effects after inebilizumab, the duration and mode of action of these medicinal products should be taken into account because of potential additive immunosuppressive effects (see section 5.1).

HOS-288618 · has-pregnancy-information · PDF-Seite 8

Women of childbearing potential Women of childbearing potential should use effective contraception (methods that result in less than 1% pregnancy rates) while receiving Uplizna and for 6 months after the last administration of Uplizna. 8 Pregnancy There are limited amount of data from the use of inebilizumab in pregnant women. Inebilizumab is a humanised IgG1 monoclonal antibody and immunoglobulins are known to cross the placental barrier. Transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other B-cell-depleting antibodies during pregnancy. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity; however, they have shown a B-cell depletion in the foetal livers of progeny (see section 5.3). Treatment with inebilizumab should be avoided during pregnancy unless the potential benefit to the mother outweighs the potential risk to the foetus. In case of exposure during pregnancy, depletion of B cells may be expected in newborns due to the pharmacological properties of the product and findings from animal studies (see section 5.3). B-cell levels in infants following maternal exposure to inebilizumab have not been studied in clinical trials. The potential duration of B-cell depletion in infants exposed to inebilizumab in utero, and the impact of B-cell depletion on the safety and effectiveness of vaccines, are unknown (see sections 4.4 and 5.1). Consequently, newborns should be monitored for B-cell depletion and vaccinations with live virus vaccines, such as Bacillus Calmette-Guérin (BCG) vaccine, should be postponed until the infant’s B-cell count has recovered (see section 4.4). Breast-feeding The use of inebilizumab in women during lactation has not been studied. It is unknown whether inebilizumab is excreted in human milk. In humans, excretion of IgG antibodies in milk occurs during the first few days after birth, which is decreasing to low concentrations soon afterwards. Consequently, a risk to the breast-fed child cannot be excluded during this short period. Afterwards, Uplizna could be used during breast-feeding if clinically needed. However, if the patient was treated with Uplizna up to the last few months of pregnancy, breast-feeding can be started immediately after birth. Fertility There are limited data on the effect of inebilizumab on human fertility; however, studies in animals

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HOS-288616 · has-warning-information · PDF-Seite 5

Instructions for patients at the time of prescribing Patients treated with Uplizna should be given a patient card which includes information that inebilizumab treatment may increase the risk of infections, including serious infections, viral reactivation, opportunistic infections, and progressive multifocal leukoencephalopathy (PML), and how to seek early medical care in case of signs and symptoms of infection and PML. 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 and hypersensitivity Inebilizumab can cause infusion-related reactions and hypersensitivity reactions, which can include headache, nausea, somnolence, dyspnoea, fever, myalgia, rash, palpitations or other symptoms. Infusion-related reactions were most common with the first infusion but were also observed during subsequent infusions. Although rare, serious infusion reactions did occur in clinical trials of inebilizumab (see section 4.8). Before the infusion Premedication with a corticosteroid (e.g., methylprednisolone 80-125 mg intravenous or equivalent), an antihistamine (e.g., diphenhydramine 25-50 mg orally or equivalent), and an antipyretic (e.g., paracetamol 500-650 mg orally or equivalent) should be administered (see section 4.2). During the infusion The patient should be monitored for infusion-related reactions. Management recommendations for infusion reactions depend on the type and severity of the reaction. For life-threatening infusion reactions, treatment should be stopped immediately and permanently, and appropriate supportive treatment should be administered. For less severe infusion reactions, management may involve temporarily stopping the infusion, reducing the infusion rate, and/or administering symptomatic treatment. After the infusion The patient should be monitored for infusion reactions for at least one hour after the completion of the infusion. Infections Inebilizumab causes reduction in peripheral blood lymphocyte count and Ig levels consistent with the mechanism of action of B-cell depletion. Reduction of neutrophil counts were also reported. Therefore, inebilizumab may increase the susceptibility to infections (see section 4.8). A recent (i.e. within 6 months) complete blood cell count (CBC) including differentials and immunoglobulins should be obtained before initiation of inebilizumab. Assessments of CBC incl

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