Patisiran

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

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

There are no data on the use of patisiran in pregnant women. Animal studies are insufficient with respect to reproductive toxicity. Due to the potential teratogenic risk arising from unbalanced vitamin A levels, patisiran should not be used during pregnancy, unless the clinical condition of the woman requires treatment. As a precautionary measure, vitamin A and thyroid stimulating hormone (TSH) levels should be obtained early in pregnancy. Close monitoring of the foetus should be carried out in the event of an unplanned pregnancy, especially during the first trimester. Women of childbearing potential have to use effective contraception during treatment with patisiran.

It is unknown whether patisiran is excreted in human milk. Available toxicological data in animals have shown excretion of small amounts of components in milk.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from patisiran, 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 patisiran 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, patisiran and vitamin A supplementation should be discontinued and serum vitamin A levels should be monitored and have returned to normal before conception is attempted.

Fertility

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

On the basis of the pharmacodynamic and pharmacokinetic profiles, patisiran is considered to have no or negligible influence on the ability to drive or use machines.

Summary of the safety profile

The most frequently occurring adverse reactions reported in patisiran-treated patients were peripheral oedema (29.7%) and infusion-related reactions (18.9%). The only adverse reaction resulting in the discontinuation of patisiran was an infusion-related reaction (0.7%).

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 (≥1/1,000 to <1/100).

Adverse reactions reported for patisiran 300 micrograms per kg:

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, chest discomfort or chest pain, headache, rash, chills, dizziness, fatigue, increased heart rate or palpitations, hypotension which may include syncope, hypertension, facial oedema.

In clinical studies, all patients received premedication with a corticosteroid, paracetamol, and H1 and H2 blockers to reduce the risk of IRRs. In the double-blind placebo-controlled study, 18.9% of patisiran-treated patients experienced IRRs, compared to 9.1% of placebo-treated patients. In patisiran-treated patients, all IRRs were either mild (95.2%) or moderate (4.8%) in severity. Among patisiran-treated patients who experienced an IRR, 78.6% experienced the first IRR within the first 2 infusions. The frequency of IRRs decreased over time. Few IRRs led to infusion interruption. IRRs resulted in permanent discontinuation of patisiran in <1% of patients in clinical studies.

Peripheral oedema

In the placebo-controlled study, peripheral oedema was reported in 29.7% of patisiran-treated patients and 22.1% of placebo-treated patients. All events were mild or moderate in severity and did not lead to treatment discontinuation. In patisiran-treated patients, the events decreased in frequency over time.

Extravasation

Extravasation was observed in <0.5% of infusions in clinical studies. Signs and symptoms included phlebitis or thrombophlebitis, infusion or injection site swelling, dermatitis (subcutaneous inflammation), cellulitis, erythema or injection site redness, burning sensation, or injection site pain.

Other special population(s)

Liver transplant recipients

In an open-label study in 23 hATTR amyloidosis patients with polyneuropathy progression post liver transplant, the safety profile of patisiran was consistent with previous clinical studies.

Immunogenicity

Anti-drug antibodies to patisiran were evaluated by measuring antibodies specific to PEG₂₀₀₀-C-DMG, a lipid component exposed on the surface of patisiran. In the placebo-controlled and open-label clinical studies, 7 of 194 (3.6%) patients with hATTR amyloidosis developed anti-drug antibodies during treatment with patisiran. One additional patient had pre-existing anti-drug antibodies. Antidrug antibody titres were low and transient with no evidence of an effect on clinical efficacy, the safety profile, or the pharmacokinetic or pharmacodynamic profiles of patisiran.