WAYLIVRA Solution for injection Ref.[11028] Active ingredients: Volanesorsen

Thrombocytopenia

Waylivra is very commonly associated with reductions in platelet count in patients with FCS, which may result in thrombocytopenia (see section 4.8). Patients with lower body weight (less than 70 kg) may be more prone to thrombocytopenia during treatment with this medicinal product. Careful monitoring for thrombocytopenia is important during treatment with this medicinal product in patients with FCS (see section 4.2). Recommendations for adjustments to monitoring frequency and dosing are specified in Table 1 (see section 4.2).

Discontinuation of antiplatelet medicinal products/NSAIDs/anticoagulants should be considered for platelet levels <75 × 10⁹/L. Treatment with these medicinal products must be discontinued at platelet levels <50 × 10⁹/L (see section 4.5).

Patients should be instructed to report to their physician immediately if they experience any signs of bleeding, which can include petechiae, spontaneous bruising, subconjunctival bleeding, or other unusual bleeding (including nosebleeds, bleeding from gums, stools, or unusually heavy menstrual bleeding), neck stiffness, atypical severe headache, or any prolonged bleeding.

LDL-C Levels

With treatment with Waylivra, LDL-C levels may rise but will usually remain within the normal range.

Renal toxicity

Renal toxicity has been observed after administration of volanesorsen and other subcutaneously and intravenously administered antisense oligonucleotides. Monitoring for evidence of nephrotoxicity by routine urine dipstick is recommended on a quarterly basis. In the case of a positive assessment, a broader assessment of renal function, including serum creatinine and a 24-hour collection to quantify the proteinuria and assess creatinine clearance, should be performed. Treatment should be discontinued if: proteinuria of ≥500 mg/24 hour is recorded, or an increase in serum creatinine ≥0.3 mg/dL (26.5 μmol/L) that is >ULN is recorded, or creatinine clearance estimated by the CKD-EPI equation is ≤30 mL/min/1.73m². Treatment should also be discontinued for any clinical symptoms or signs of renal impairment pending the previous confirmatory assessments.

Hepatotoxicity

Elevations of liver enzymes have been observed after administration of other subcutaneously and intravenously administered antisense oligonucleotides. Monitoring for hepatotoxicity through serum liver enzymes and bilirubin should be assessed on a quarterly basis. Treatment should be discontinued if there is a single increase in ALT or AST >8 x ULN, or an increase >5 x ULN, which persists for ≥2 weeks, or lesser increases in ALT or AST that are associated with total bilirubin >2 x ULN or INR >1.5. Treatment should also be discontinued for any clinical symptoms or signs of hepatic impairment or hepatitis.

Immunogenicity and inflammation

No evidence of altered safety profile or clinical response was associated with presence of anti-drug antibodies. If formation of anti-drug antibodies with a clinically significant effect is suspected, contact the Marketing Authorisation Holder to discuss antibody testing.

Monitoring of inflammation should be assessed through quarterly assessment of erythrocyte sedimentation rate (ESR).

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per dose of 285 mg, that is to say it is essentially ‘sodium-free’.

No clinical drug interaction studies have been conducted.

Clinically relevant pharmacokinetic interactions are not expected between volanesorsen and substrates, inducers or inhibitors of cytochrome P450 (CYP) enzymes, and drug transporters. It is unknown whether triglyceride lowering by volanesorsen and the potentially ensuing decrease in inflammation leads to normalisation of CYP enzyme expression.

In clinical studies, this medicinal product has been used in combination with fibrates and fish oils with no impact on the medicinal product pharmacodynamics or pharmacokinetics. There were no adverse events related to drug-drug interactions reported during the clinical program, however this is based on limited data.

The effect of concomitant administration of this medicinal product with alcohol or medicinal products known to have potential for hepatotoxicity (e.g., paracetamol) is unknown. If signs and symptoms of hepatotoxicity develop, use of the hepatotoxic medicinal product should be discontinued.

Antithrombotic agents and medicinal products that may lower platelet count

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 (see section 4.4).

Pregnancy

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 (see section 5.3).

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

Breastfeeding

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 (see section 5.3). 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% (see section 4.4), and injection site reactions occurring in 82% of patients during the pivotal studies.

Tabulated list of adverse reactions

Table 2 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.

Table 2. 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 (see section 4.4).

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).

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.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.