Volanesorsen

The safety and efficacy in patients with severe renal impairment has not been established and these patients should be closely observed.

It is not known whether the risk of bleeding is increased by concomitant use of volanesorsen and antithrombotic agents or medicinal products that may lower platelet count or affect platelet function. Discontinuation of antiplatelet medicinal products/NSAIDs/anticoagulants should be considered for platelet levels <75 × 10⁹/L and treatment with these medicinal products should be stopped at platelet levels <50 × 10⁹/L.

There are no data on the use of volanesorsen in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.

As a precautionary measure, it is preferable to avoid the use of this medicinal product during pregnancy.

In non-clinical studies, levels of volanesorsen in milk were very low in lactating mice. Available pharmacodynamic/toxicological data in animals have shown excretion of very low amounts of volanesorsen in milk. Due to the poor oral bioavailability of this medicinal product, it is considered unlikely that these low milk concentrations would result in systemic exposure from nursing.

It is unknown whether volanesorsen or metabolites are excreted in human milk.

A risk to the newborn infant cannot be excluded.

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

Fertility

No clinical data on the effect of this medicinal product on human fertility are available. Volanesorsen had no effect on fertility in mice.

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

Summary of the safety profile

In clinical studies in patients with FCS, the most commonly reported adverse reactions during treatment were platelet count decreased occurring in 29%, thrombocytopenia occurring in 21%, and injection site reactions occurring in 82% of patients during the pivotal studies.

Tabulated list of adverse reactions

The table below presents the adverse reactions from the Phase 3 studies in patients with FCS in receiving volanesorsen subcutaneously.

The frequency of adverse reactions is defined using 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 available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Summary of adverse reactions in clinical studies in patients with FCS (N=87):

Description of selected adverse reactions

Thrombocytopenia

In the pivotal Phase 3 study in patients with FCS (the APPROACH study), confirmed reductions in platelet counts to below normal (140 × 10⁹/L) were observed in 75% of FCS patients treated with volanesorsen and 24% of placebo patients; confirmed reductions to below 100 × 10⁹/L were observed in 47% of patients treated with volanesorsen compared with no placebo patients. In APPROACH 5 patients who discontinued therapy due to platelet levels included 2 patients with platelet counts <25 × 10⁹/L and 3 with platelet counts between 50 × 10⁹/L and 75 × 10⁹/L. It was also reported in this study that platelet count decreased was reported in 11 (33%) patients versus 1 (3%), and thrombocytopenia was reported in 4 (12%) patients vs none for subjects treated with volanesorsen compared to placebo, respectively.

In the open-label extension (CS7), confirmed reductions in platelet counts to below normal (140 × 10⁹/L) were observed in 52 (79%) patients overall, including 37 (74%) patients in the treatment-naïve group. Confirmed reductions to below 100 × 10⁹/L were observed in 33 (50%) patients overall including 24 (48%) treatment naïve patients. In the open-label extension, 11 patients discontinued due to thrombocytopenia and platelet-related events. None of these patients had any major bleeding events and all recovered to normal platelet count following drug discontinuation and administration of glucocorticoids where medically indicated. In this open-label extension study, platelet count decreased was reported in 16 (24%) and thrombocytopenia was reported in 14 (21%) patients.

For pooled data with the APPROACH study and the CS7 study, platelet count decreased was reported in 25 (29%) patients, and thrombocytopenia was reported in 18 (21%).

Immunogenicity

In the Phase 3 clinical studies (CS16 and APPROACH), 16% and 33% of volanesorsen-treated patients tested positive for anti-drug antibodies during 6-month and 12-month treatment, respectively. No evidence of altered safety profile or clinical response was associated with presence of anti-drug antibodies; however this is based on the limited long-term data.

Injection site reactions

Injection site reactions defined as any local cutaneous reaction at the injection site persisting more than 2 days occurred in 79% of volanesorsen-treated patients in the APPROACH study and 81% of patients in its open-label extension (CS7). Injection site reactions occurred in 80% of volanesorsentreated patients across both studies. These local reactions were mostly mild and typically consisted of 1 or more of the following: erythema, pain, pruritus, or local swelling. Injection site reactions did not occur with all injections and resulted in discontinuation for 1 patient in the APPROACH study and 1 patient in the open label extension (CS7).