Amvuttra · 4.3 Contraindications · 1

HOS-288659 · has-adverse-reaction-information · PDF-Seite 5

Tabulated list of adverse reactions The safety profile of Amvuttra was characterised based on the data from randomised-controlled phase 3 clinical studies. Adverse reactions reported in the pooled dataset of HELIOS-A and HELIOS-B studies are presented in Table 1. The adverse reactions are presented as MedDRA preferred terms and under the MedDRA System Organ Class (SOC). The frequency of the adverse reactions is expressed according to the following category: Common (≥1/100 to <1/10). Table 1: Adverse reactions reported for Amvuttra System Organ Class Adverse Reaction Frequency General disorders and administration Injection site reactiona Common site conditions Investigations Alanine transaminase increased Common Blood alkaline phosphatase Common increased a Reported symptoms included bruising, erythema, pain, pruritus, and warmth. Injection site reactions were mild, transient, and did not lead to treatment discontinuation 5 Description of selected adverse reactions Liver function tests In the HELIOS-B study, 97 (30%) of patients treated with Amvuttra and 78 (24%) patients treated with placebo had a mild increased alanine aminotransferase (ALT) greater than the ULN and less than or equal to 3×ULN. All patients treated with Amvuttra with mild ALT elevations were asymptomatic and the majority had normalization of ALT levels with continued dosing. Immunogenicity In the HELIOS-A and HELIOS-B studies, 4 (3.3%) and 1 (0.3%) Amvuttra-treated patients, respectively, developed anti-drug antibodies (ADA). In both studies, ADA titres were low and transient with no evidence of an effect on clinical efficacy, safety, or pharmacokinetic or pharmacodynamic profiles of vutrisiran. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

HOS-288655 · has-contraindication-information · PDF-Seite 3

Severe hypersensitivity (e.g., anaphylaxis) to the active substance or to any of the excipients listed in section 6.1. 3

HOS-288654 · has-indication-information · PDF-Seite 2

Amvuttra is indicated for the treatment of hereditary transthyretin amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy (hATTR-PN). Amvuttra is indicated for the treatment of wild-type or hereditary transthyretin amyloidosis in adult patients with cardiomyopathy (ATTR-CM).

HOS-288657 · has-interaction-information · PDF-Seite 4

No clinical interaction studies have been performed. Vutrisiran is not expected to cause interactions or to be affected by inhibitors or inducers of cytochrome P450 enzymes, or to modulate the activity of transporters. Therefore, vutrisiran is not expected to have clinically significant interactions with other medicinal products.

HOS-288658 · has-pregnancy-information · PDF-Seite 4

Women of childbearing potential Treatment with Amvuttra 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 4 contraception. If a woman intends to become pregnant, Amvuttra and vitamin A supplementation should be discontinued and serum vitamin A levels should be monitored and have returned to normal before conception is attempted (see section 4.4.). Serum vitamin A levels may remain reduced for more than 12 months after the last dose of treatment. Pregnancy There are no data on the use of Amvuttra 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, Amvuttra should not be used during pregnancy. As a precautionary measure, vitamin A (see section 4.4) and thyroid stimulating hormone levels should be obtained early in pregnancy. Close monitoring of the foetus should be carried out, especially during the first trimester. Breast-feeding It is unknown whether vutrisiran is excreted in human milk. There is insufficient information on the excretion of vutrisiran in animal milk (see section 5.3). A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Amvuttra, 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 Amvuttra on human fertility. No impact on male or female fertility was detected in animal studies (see section 5.3).

HOS-288656 · has-warning-information · PDF-Seite 4

Vitamin A deficiency By reducing serum transthyretin (TTR) protein, Amvuttra 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 with Amvuttra. Patients receiving Amvuttra should take oral supplementation of approximately, but not exceeding, 2 500 IU to 3 000 IU vitamin A per day to reduce the potential risk of ocular symptoms due to vitamin A deficiency. 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. 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 Amvuttra and women of childbearing potential should practise effective contraception (see section 4.6). If a woman intends to become pregnant, Amvuttra and vitamin A supplementation should be discontinued and serum vitamin A levels should be monitored and have returned to normal before conception is attempted. Serum vitamin A levels may remain reduced for more than 12 months after the last dose of Amvuttra. In the event of an unplanned pregnancy, Amvuttra should be discontinued (see section 4.6). No recommendation can be given whether to continue or discontinue vitamin A supplementation during the first trimester of an unplanned pregnancy. If vitamin A supplementation is continued, the daily dose should not exceed 3 000 IU per day, due to the lack of data supporting higher doses. Thereafter, vitamin A supplementation of 2 500 IU to 3 000 IU per day should be resumed in the second and third trimesters if serum vitamin A levels have not yet returned to normal, because of the increased risk of vitamin A deficiency in the third trimester. It is not known whether vitamin A supplementation in pregnancy will be sufficient to prevent vitamin A deficiency if the pregnant female continues to receive Amvuttra. However, increasing vitamin A supplementation to above 3 000 IU per day during pregnancy is unlikely to correct plasma retinol levels due to the mechanism of action of Amvuttra and may be harmful to the mothe

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