Onpattro · 4.8 Undesirable effects · 1

HOS-098577 · has-adverse-reaction-information · PDF-Seite 6

Summary of the safety profile The most frequently occurring adverse reactions reported in Onpattro-treated patients were peripheral oedema (29.7%) and infusion-related reactions (18.9%). One patient (0.7%) discontinued treatment during clinical studies due to an infusion-related reaction. Tabulated list of adverse reactions The adverse reactions are presented as MedDRA preferred terms under the MedDRA System Organ Class (SOC) by frequency. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The frequency of the adverse reactions is expressed according to the following categories: • Very common (≥ 1/10) • Common (≥ 1/100 to < 1/10) • Uncommon (³ 1/1 000 to < 1/100) 6 Table 1: Adverse reactions reported for Onpattro 300 micrograms per kg System Organ Class Adverse Reaction Frequency Infections and infestations Bronchitis Common Sinusitis Common Rhinitis Common Immune system disorders Infusion-related reaction Very common Ear and labyrinth disorders Vertigo Common Respiratory, thoracic and mediastinal Dyspnoea Common disorders Gastrointestinal disorders Dyspepsia Common Skin and subcutaneous tissue disorders Erythema Common Musculoskeletal and connective tissue Arthralgia Common disorders Muscle spasms Common General disorders and administration site Peripheral oedema Very common conditions Extravasation Uncommon Description of selected adverse reactions Infusion-related reactions Symptoms of IRRs include, but are not limited to: arthralgia or pain (including back, neck, or musculoskeletal pain), flushing (including erythema of face or skin warm), nausea, abdominal pain, dyspnoea or cough, dysphonia, chest discomfort or chest pain, headache, rash, pruritus, chills, dizziness, fatig

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HOS-098573 · has-contraindication-information · PDF-Seite 4

Severe hypersensitivity (e.g., anaphylaxis) to the active substance or any of the excipients listed in section 6.1.

HOS-098572 · has-indication-information · PDF-Seite 2

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

HOS-098575 · has-interaction-information · PDF-Seite 5

No formal clinical drug interaction studies have been performed. At doses higher than the clinically relevant dose, induction and time-dependent inhibition of CYP2B6 was observed in vitro. The net effect on CYP2B6 substrates (e.g., bupropion and efavirenz) in vivo is unknown. Onpattro is not expected to cause interactions or be affected by inhibitors or inducers of cytochrome P450 enzymes. Vitamin A testing Serum TTR is a carrier of retinol binding protein, which facilitates transport of vitamin A in the blood. Treatment with Onpattro reduces serum TTR levels, which results in reduced levels of retinol binding protein and vitamin A in the serum. However, transport and tissue uptake of vitamin A can occur through alternative mechanisms in the absence of retinol binding protein. As a result, during treatment with Onpattro, laboratory tests for serum vitamin A do not reflect the total amount of vitamin A in the body and should not be used to guide vitamin A supplementation (see sections 4.4 and 5.1).

HOS-098576 · has-pregnancy-information · PDF-Seite 5

Women of childbearing potential Treatment with Onpattro reduces serum levels of vitamin A. Both too high or too low vitamin A levels may be associated with an increased risk of foetal malformation. Therefore, pregnancy should be excluded before initiation of treatment and women of childbearing potential should use effective contraception. If a woman intends to become pregnant, Onpattro and vitamin A supplementation should be discontinued and serum vitamin A levels should be monitored and have returned to normal before conception is attempted. Pregnancy There are no data on the use of Onpattro 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, Onpattro should not be used during pregnancy, unless the clinical condition of the woman requires treatment. As a precautionary measure, vitamin A and thyroid 5 stimulating hormone (TSH) levels should be obtained early in pregnancy (see section 5.3). Close monitoring of the foetus should be carried out in the event of an unplanned pregnancy, especially during the first trimester (see section 4.4). Women of childbearing potential have to use effective contraception during treatment with Onpattro. Breast-feeding It is unknown whether Onpattro is excreted in human milk. A risk to the breastfed newborn/infant cannot be excluded. Available toxicological data in animals have shown excretion of small amounts of the lipid components DLin-MC3-DMA and PEG2000-C-DMG in milk (see section 5.3). A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Onpattro, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility There are no data on the effects of Onpattro on human fertility. No impact on male or female fertility was detected in animal studies (see section 5.3).

HOS-098574 · has-warning-information · PDF-Seite 4

Infusion-related reactions IRRs have been observed in patients treated with Onpattro. In patients experiencing an IRR, the majority experienced the first IRR within the first 2 infusions (see section 4.8). Across clinical studies, the most common symptoms (reported in ≥ 2% of patients) of IRRs were flushing, back pain, nausea, abdominal pain, dyspnoea, and headache. IRRs may also include hypotension and syncope. To reduce the risk of IRRs, patients should receive premedications on the day of Onpattro infusion, at least 60 minutes prior to the start of infusion (see section 4.2). If an IRR occurs, slowing or interrupting the infusion and institution of medical management (e.g., corticosteroids or other symptomatic treatment) should be considered, as clinically indicated. If the infusion is interrupted, resumption of the infusion at a slower infusion rate may be considered after symptoms have resolved. The infusion should be discontinued in the case of a serious or life-threatening IRR. Some patients who experience IRRs may benefit from a slower infusion rate or additional or higher doses of one or more of the premedications with subsequent infusions to reduce the risk of IRRs. Vitamin A deficiency By reducing serum TTR protein, Onpattro treatment leads to a decrease in serum vitamin A (retinol) levels (see section 5.1). Serum vitamin A levels below the lower limit of normal should be corrected and any ocular symptoms or signs due to vitamin A deficiency should be evaluated prior to initiation of treatment. Patients receiving Onpattro should take oral supplementation of approximately 2 500 IU vitamin A per day to reduce the potential risk of ocular toxicity due to vitamin A deficiency. Referral for ophthalmological assessment is recommended if patients develop ocular symptoms suggestive of vitamin A deficiency, including reduced night vision or night blindness, persistent dry eyes, eye inflammation, corneal inflammation or ulceration, corneal thickening or corneal perforation. 4 Serum vitamin A levels should not be used to guide vitamin A supplementation during treatment with Onpattro (see section 4.5). During the first 60 days of pregnancy, both too high or too low vitamin A levels may be associated with an increased risk of foetal malformation. Therefore, pregnancy should be excluded before initiating Onpattro and women of childbearing potential should practise effective contraception. If a woman

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