Tegsedi · 4.6 Fertility, pregnancy and lactation · 1

HOS-098735 · has-adverse-reaction-information · PDF-Seite 7

Summary of the safety profile The most frequently observed adverse reactions during treatment with inotersen were events associated with injection site reactions (50.9%). Other most commonly reported adverse reactions with inotersen were nausea (31.3%), headache (23.2%), pyrexia (19.6%), peripheral oedema (18.8%), chills (17.9%), vomiting (15.2%), anaemia (13.4%), thrombocytopenia (13.4%) and platelet count decreased (10.7%). Tabulated summary of adverse reactions Table 2 presents the adverse drug reactions (ADRs) listed by MedDRA system organ class. Within each system organ class, the ADRs are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each ADR is based on the following convention: 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). Table 2. List of adverse reactions in clinical studies and post-marketing sources 7  System Organ Common Uncommon Not known Very Common Class Blood and Thrombocytopenia Eosinophilia lymphatic system Anaemia disorders Platelet count Decreased Immune system Hypersensitivity disorders Metabolism and Decreased appetite nutrition disorders Nervous system Headache disorders Vascular Orthostatic disorders hypotension Hypotension Haematoma Gastrointestinal Vomiting disorders Nausea Hepatobiliary Transaminases Drug-induced disorders increased liver injury Skin and Pruritus subcutaneous Rash disorders Renal and urinary Glomerulonephritis disorders Proteinuria Re

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HOS-098731 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Platelet count < 100 x 109/L prior to treatment. Urine protein to creatinine ratio (UPCR) ≥ 113 mg/mmol (1 g/g) prior to treatment. Estimated glomerular filtration rate (eGFR) < 45 ml/min/1.73 m2 . Severe hepatic impairment.

HOS-098730 · has-indication-information · PDF-Seite 2

Tegsedi is indicated for the treatment of stage 1 or stage 2 polyneuropathy in adult patients with hereditary transthyretin amyloidosis (hATTR).

HOS-098733 · has-interaction-information · PDF-Seite 6

Caution should be used with antithrombotic medicinal products, antiplatelet medicinal products, and medicinal products that may lower platelet count, for example acetylsalicylic acid, clopidogrel, warfarin, heparin, low-molecular weight heparins, Factor Xa inhibitors such as rivaroxaban and apixaban, and thrombin inhibitors such as dabigatran (see sections 4.2 and 4.4). Caution should be exercised with concomitant use of nephrotoxic medicinal products and other medicines that may impair renal function, such as sulfonamides, aldosterone antagonists, anilides, natural opium alkaloids and other opioids (see section 4.4). A systematic assessment of co- administration of inotersen and potentially nephrotoxic medicinal products has not been conducted.

HOS-098734 · has-pregnancy-information · PDF-Seite 6

Women of child-bearing potential Inotersen will reduce the plasma levels of vitamin A, which is crucial for normal foetal development. It is not known whether vitamin A supplementation will be sufficient to reduce the risk to the foetus (see section 4.4). For this reason, pregnancy should be excluded before initiation of inotersen therapy and women of child-bearing potential should practise effective contraception. 6 Pregnancy There are no or limited amount of data from the use of inotersen in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Due to the potential teratogenic risk arising from unbalanced vitamin A levels, inotersen should not be used during pregnancy, unless the clinical condition of the woman requires treatment with inotersen. Women of child-bearing potential have to use effective contraception during treatment with inotersen. Breast-feeding It is unknown whether inotersen/metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of inotersen metabolites in milk (see section 5.3). A risk to the breastfed newborn/infant cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Tegsedi therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility There is no information available on the effects of inotersen on human fertility. Animal studies did not indicate any impact of inotersen on male or female fertility.

HOS-098732 · has-warning-information · PDF-Seite 4

Thrombocytopenia Inotersen is associated with reductions in platelet count, which may result in thrombocytopenia at any time during treatment (see section 4.8). Platelet count should be monitored every 2 weeks during the entire course of treatment with inotersen and for 8 weeks following discontinuation of treatment. Recommendations for adjustments to monitoring frequency and inotersen dosing are specified in Table 1 (see section 4.2). Patients should be instructed to report to their physician immediately if they experience any signs of unusual or prolonged bleeding (e.g. petechia, spontaneous bruising, subconjunctival bleeding, nosebleeds, bleeding from the gums, blood in urine or stools, bleeding in the whites of eyes), neck stiffness or atypical severe headache because these symptoms may be caused by bleeding in the brain. Special caution should be used in elderly patients, in patients taking antithrombotic medicinal products, antiplatelet medicinal products, or medicinal products that may lower platelet count (see section 4.5), and in patients with prior history of major bleeding events. Glomerulonephritis/ renal function decline Glomerulonephritis has occurred in patients treated with inotersen (see section 4.8). Renal function decline has also been observed in a number of subjects without signs of glomerulonephritis (see section 4.8). 4 UPCR and eGFR should be monitored every 3 months or more frequently, as clinically indicated, based on history of chronic kidney disease and/or renal amyloidosis. UPCR and eGFR should be monitored for 8 weeks following discontinuation of treatment. Patients with UPCR more than or equal to twice the upper limit of normal, or eGFR < 60 ml/min, which is confirmed on repeat testing and in the absence of an alternative explanation, should be monitored every 4 weeks. In the case of a decrease in eGFR > 30%, in the absence of an alternative explanation, pausing of inotersen dosing should be considered pending further evaluation of the cause. In the case of UPCR ≥ 2 g/g (226 mg/mmol), which is confirmed on repeat testing, dosing of inotersen should be paused while further evaluation for acute glomerulonephritis is performed. Inotersen should permanently be discontinued if acute glomerulonephritis is confirmed. If glomerulonephritis is excluded, dosing may be resumed if clinically indicated and following improvement of renal function (see section 4.3). Early initia

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