Waylivra

Posology Treatment should be initiated by and remain under the supervision of a physician experienced in the treatment of patients with FCS. g. uncontrolled diabetes, hypothyroidism) should be excluded or appropriately addressed. 5 ml injected subcutaneously once weekly for 3 months.

Following 3 months, dose frequency should be reduced to 285 mg every 2 weeks. 6 mmol/L after 3 months on volanesorsen 285 mg weekly. After 6 months of treatment with volanesorsen, increase of dose frequency to 285 mg weekly should be considered if response has been inadequate in terms of serum triglyceride reduction as evaluated by the supervising experienced specialist and in the condition that platelet counts are in the normal range.

Patients should be re-downtitrated to 285 mg every 2 weeks if the higher 285 mg once weekly dose does not provide significant additional triglyceride reduction after 9 months. Patients should be instructed to give the injection on the same day of the week, according to medically determined frequency of administration.

3 If a dose is missed and noticed within 48 hours, the patient should be directed to give the missed dose as soon as possible. If not noticed within 48 hours, then the missed dose should be skipped and the next planned injection given.

Platelet monitoring and dose adjustments Before initiation of treatment, platelet count should be measured. If the platelet count is below 140 x 109/L another measurement should be taken approximately a week later to reassess. 3). After commencing treatment, patients should have platelet levels monitored at least every two weeks, depending on the platelet levels.

Treatment and monitoring should be adjusted according to laboratory values in line with Table 1. For any patient dose paused or discontinued due to severe thrombocytopenia, the benefits and risks of returning to treatment once platelet count ≥100 x 109/L should be carefully considered.

For discontinued patients, a haematologist should be consulted prior to resuming treatment. Table 1. 4 for recommendations regarding use of antiplatelet agents/non-steroidal anti- inflammatory drugs (NSAIDs)/anticoagulants b Consultation of a haematologist is needed to reconsider the benefit/risk for possible further treatment with volanesorsen.

Special populations Elderly population No starting dose adjustment is necessary for elderly patients. 2). Renal impairment No starting dose adjustment is necessary in patients with mild to moderate renal impairment. The safety and efficacy in patients with severe renal impairment has not been established and these patients should be closely observed.

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.

7 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) System organ class Very common Common Blood and lymphatic system disorders Thrombocytopenia Leukopenia Lymphopenia Eosinophilia Immune thrombocytopenic purpura Spontaneous haematoma Immune system disorders Immunisation reaction Hypersensitivity Serum sickness- like reaction Metabolism and nutrition disorders Diabetes mellitus Psychiatric disorders Insomnia Nervous system disorders Headache Syncope Hypoaesthesia Presyncope Retinal migraine Dizziness Tremor Eye disorders Conjunctival haemorrhage Vision blurred Vascular disorders Hypertension Haemorrhage Haematoma Hot flush Respiratory, thoracic and mediastinal disorders Dyspnoea Pharyngeal oedema Wheezing Epistaxis Cough Nasal congestion Gastrointestinal disorders Nausea Diarrhoea Vomiting Abdominal distension Abdominal pain Dry mouth Gingival bleeding Mouth haemorrhage 8 System organ class Very common Common Parotid gland enlargement Dyspepsia Gingival swelling Skin and subcutaneous tissue disorders Erythema Pruritus Rash Urticaria Hyperhidrosis Petechiae Ecchymosis Night sweats Papule Skin hypertrophy Swelling face Musculoskeletal and connective tissue disorders Myalgia Arthralgia Pain in extremity Arthritis Musculoskeletal pain Back pain Neck pain Pain in jaw Muscle spasms Joint stiffness Myositis Peripheral arthritis Renal and urinary disorders Haematuria Proteinuria General disorders and administration site conditions Injection site erythema Injection site pain Injection site swelling Injection site discolouration Injection site induration Injection site pruritus Injection site bruising Chills Injection site oedema Injection site haematoma Asthenia Fatigue Injection site reaction Pyrexia Injection site hypoaesthesia Injection site haemorrhage Injection site warmth Injection site dryness Injection site pallor Injection site urticaria Injection site vesicles Malaise Feeling hot Influenza-like illness Injection site discomfort 9 System organ class Very common Common Injection site inflammation Injection site mass Oedema Pain Injection site paraesthesia Injection site scab Injection site papule Injection site rash Non-cardiac chest pain Vessel puncture site haemorrhage Investigations Platelet count decreased Haemoglobin decreased White blood cell count decreased Blood creatinine increased Blood urea increased Creatinine renal clearance decreased Hepatic enzyme increased International normalised ratio increased Transaminases increased Injury, poisoning and procedural complications Contusion 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 x 109/L) were observed in 75% of FCS patients treated with volanesorsen and 24% of placebo patients; confirmed reductions to below 100 x 109/L were observed in 47% of patients treated with volanesorsen compared with no placebo patients.

8). Patients with lower body weight (less than 70 kg) may be more prone to thrombocytopenia during treatment with this medicinal product. 2). 2). 5 Discontinuation of antiplatelet medicinal products/NSAIDs/anticoagulants should be considered for platelet levels < 75 x 109/L.

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.

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. 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.

1. Chronic or unexplained thrombocytopenia. Treatment should not be initiated in patients with thrombocytopenia (platelet count <140 x 109/L).