Vutrisiran

Vutrisiran has not been studied in patients with severe renal impairment or end-stage renal disease and should only be used in these patients if the anticipated clinical benefit outweighs the potential risk.

Vutrisiran has not been studied in patients with moderate or severe hepatic impairment and should only be used in these patients if the anticipated clinical benefit outweighs the potential risk.

There are no data on the use of vutrisiran in pregnant women. Animal studies are insufficient with respect to reproductive toxicity. Due to the potential teratogenic risk arising from unbalanced vitamin A levels, vutrisiran should not be used during pregnancy. As a precautionary measure, vitamin A 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.

It is unknown whether vutrisiran is excreted in human milk. There is insufficient information on the excretion of vutrisiran in animal milk.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from vutrisiran, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Women of childbearing potential

Treatment with vutrisiran 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, vutrisiran 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 treatment.

Fertility

There are no data on the effects of vutrisiran on human fertility. No impact on male or female fertility was detected in animal studies.

Vutrisiran has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

During the HELIOS-A 18-month treatment period, the most frequently occurring adverse reactions reported in vutrisiran-treated patients were pain in extremity (15%) and arthralgia (11%).

Tabulated list of adverse reactions

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 categories:

• Very common (≥1/10)
• Common (≥1/100 to <1/10)
• Uncommon (≥1/1,000 to <1/100)

Adverse reactions reported for vutrisiran:

^a Includes dyspnoea, dyspnoea exertional and dyspnoea paroxysmal nocturnal
^b Reported symptoms included bruising, erythema, pain, pruritus, and warmth. Injection site reactions were mild, transient, and did not lead to treatment discontinuation.

Description of selected adverse reactions

Immunogenicity

During the HELIOS-A 18-month treatment period, 4 (3.3%) vutrisiran-treated patients developed antidrug antibodies (ADA). ADA titres were low and transient with no evidence of an effect on clinical efficacy, safety, or pharmacokinetic or pharmacodynamic profiles of vutrisiran.