Duvyzat

Treatment with givinostat should be initiated by a physician experienced in the management of Duchenne muscular dystrophy. Posology Baseline platelet counts and triglycerides should be obtained and evaluated prior to initiation of givinostat.

Givinostat should not be initiated in patients with a platelet count less than 150 x 109/l. 4 and dose adjustment instructions below). 4). The recommended dose of givinostat is based on body weight and should be administered orally twice daily (see Table 1).

2 mg twice daily 6 ml twice daily (a) Based on actual body weight The decision to continue treatment in patients who become non-ambulatory should be taken at the discretion of the physician based on the overall benefit and risk assessment.

Dose adjustment for thrombocytopenia, diarrhoea or hypertriglyceridaemia A dose reduction (see Table 2) should be applied for patient with: • Platelet count < 150 x 109/l verified by two assessments one week apart, or • Moderate or severe diarrhoea (more than 4 stools per day), or • Fasting triglycerides > 300 mg/dl verified by two assessments one week apart.

Based on the severity of these adverse reactions, treatment interruption prior to dosage modification should be considered. 4 mg twice daily 4 ml twice daily (a) Based on actual body weight (b) If the adverse reaction(s) persist after the first dosage modification, proceed to the second dosage modification.

(c) If the adverse reaction(s) persist after the second dosage modification, Duvyzat should be discontinued. Patients should not take a double or extra dose if a dose is missed. Paediatric population The efficacy and safety of Duvyzat in children below 6 years of age has not been established.

No data are available. 4 Method of administration For oral use. Before its use, the suspension must be shaken for at least 30 seconds by rotating the bottle by 180° for approximately 40 times, and the homogeneity of the suspension should be visually verified.

Incorrect shaking may lead to over dosing or under dosing. e. not to be diluted in/with water or other liquids). The suspension should be administered using the provided graduated oral syringe to measure the appropriate volume of suspension corresponding to the prescribed dose for the patient.

Duvyzat should be administered with the ingestion of food to mitigate the bitter taste of givinostat.

Summary of safety profile The safety profile of Duvyzat is based on a phase 3, double-blind, placebo-controlled, 18-months study in a total of 179 ambulant DMD patients aged 6 years or older on concomitant steroid treatment, of which 118 receiving givinostat up to 62 mg twice daily and 61 receiving placebo (EPIDYS Study).

9%). Tabulated list of adverse reactions Adverse reactions are listed below according to MedDRA system organ class and frequency (see Table 3). The table contains adverse events reported in givinostat-treated patients at a frequency greater than 2% compared to placebo-treated patients in EPIDYS study.

7 Frequency groupings are defined to the following convention: Very common (≥1/10) and 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); frequency not known (cannot be estimated from the available data).

Table 3 – Adverse Drug Reactions reported in givinostat-treated patients at a frequency greater than 2% compared to placebo-treated patients in the placebo-controlled EPIDYS Study System Organ Class Very common Common Infections and infestations Gastroenteritis Blood and lymphatic system disorders Thrombocytopenia(a) Metabolism and nutrition disorders Hypertriglyceridaemia(b) Decreased appetite Psychiatric disorders Anxiety Nervous system disorders Dizziness Vascular disorders Haematoma Gastrointestinal disorders Diarrhoea(c), Vomiting, Abdominal pain(d) Constipation Skin and subcutaneous tissue disorders Erythema, Rash Musculoskeletal and connective tissue disorders Myalgia, Arthralgia, Muscular weakness General disorders and administration site conditions Pyrexia Fatigue Investigations Blood thyroid stimulating hormone increased(e) (a) Thrombocytopenia includes platelet count decreased and thrombocytopenia; (b) Hypertriglyceridaemia includes hypertriglyceridaemia and blood triglycerides increased; (c) Diarrhoea includes diarrhoea and faeces soft; (d) Abdominal pain includes abdominal pain and abdominal pain upper; (e) Blood thyroid stimulating hormone increased includes thyroid function test abnormal and blood thyroid stimulating hormone increased.

Haematological effects Givinostat is associated with dose-related thrombocytopenia and other signs of myelosuppression, including decreased haemoglobin and neutropenia. 8). A complete blood count should be obtained before starting treatment with givinostat.

e. every 2 weeks for the first 2 months of treatment, at month 3, and then every 3 months thereafter. In case of persistent thrombocytopenia, the dose of givinostat should be adjusted. 2). In patients with dose increased due to weight gain, platelet count should be closely monitored every 2 weeks for the first 2 months after the dose was increased.

Increased triglycerides Givinostat is associated with increased serum triglycerides. Triglycerides levels should be measured before starting treatment with givinostat. Triglycerides should be monitored at least on the third month, on the sixth month and then every 6 months.

2. 2). 8). Diarrhoea and vomiting usually occur within the first few weeks of initiation of treatment with givinostat. Antiemetics or antidiarrhoeal medications may be considered during treatment with givinostat. Fluid and electrolytes should be replaced as needed to prevent dehydration.

2). 2). QTc prolongation Givinostat can cause prolongation of the QTc interval at doses 5-fold higher than the recommended dose. Givinostat should be used with caution in patients who are at an increased risk for ventricular arrhythmias (including torsades de pointes), patients with congenital long QT syndrome, coronary artery disease, electrolyte disturbances, or concomitant use of other medicinal products known to cause QT prolongation.

In these patients, ECGs should be obtained when initiating treatment with Duvyzat, during concomitant use, and as clinically indicated. In patients with hypokalaemia this should be corrected prior to initiation of givinostat and monitored in case of dehydration due to diarrhoea.

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