4.1. Therapeutic indications

Duvyzat is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients 6 years of age and older.

4.2. Posology and method of administration

Obtain and evaluate baseline platelet counts and triglycerides prior to initiation of Duvyzat.

Do not initiate Duvyzat in patients with a platelet count less than 150 x 109/L.

Monitor platelet counts and triglycerides as recommended during treatment to determine if dosage modifications are needed.

In addition, in patients with underlying cardiac disease or taking concomitant medications that cause QT prolongation, obtain ECGs when initiating treatment with Duvyzat, during concomitant use, and as clinically indicated.

Posology

The recommended dosage of Duvyzat is based on body weight and administered orally twice daily with food (see Table 1).

Table 1 – Recommended Dosage in Patients 6 Years of Age and Older for the Treatment of DMD

Weight±

Dosage

Oral Suspension Volume

10 kg to less than 20 kg

22.2 mg twice daily

2.5 mL twice daily

20 kg to less than 40 kg

31 mg twice daily

3.5 mL twice daily

40 kg to less than 60 kg

44.3 mg twice daily

5 mL twice daily

60 kg or more

53.2 mg twice daily

6 mL twice daily

± Based on actual body weight

If a dose is missed, patients should not take double or extra doses.

Dose modification for Decrease in Platelets, Diarrhoea, Increase in Triglycerides

Duvyzat may cause adverse reactions, which may necessitate a dosage modification (see Table 2) if the following occur:

• Platelet count <150 x 109/L verified in two assessments one week apart,

or

• Moderate or severe diarrhoea,

or

• Fasting triglycerides >3.42 mmol/L verified by two assessments one week apart.

Based on the severity of these adverse reactions, treatment interruption prior to dosage modification should be considered.

Table 2 – Dosage Modifications for Adverse Reactions in Patients 6 Years of Age and Older for the Treatment of DMD

First Dosage Modification*

Second Dosage Modification**

Weight±

Dosage

Oral Suspension Volume

Dosage

Oral Suspension Volume

10 kg to less than 20 kg

17.7 mg twice daily

2 mL twice daily

13.3 mg twice daily

1.5 mL twice daily

20 kg to less than 40 kg

22.2 mg twice daily

2.5 mL twice daily

17.7 mg twice daily

2 mL twice daily

40 kg to less than 60 kg

31 mg twice daily

3.5 mL twice daily

26.6 mg twice daily

3 mL twice daily

60 kg or more

39.9 mg twice daily

4.5 mL twice daily

35.4 mg twice daily

4 mL twice daily

± Based on actual body weight

* If the adverse reaction(s) persist after the first dosage modification, proceed to the second dosage modification.

** If the adverse reaction(s) persist after the second dosage modification, Duvyzat should be discontinued.

Dose modification for QTc Interval Prolongation

Withhold Duvyzat if the QTc interval is > 500 ms or the change from baseline is > 60 ms.

Paediatric population

The safety and effectiveness of Duvyzat in children aged 6 years and older have been established. Safety and effectiveness in pediatric patients below the age of 6 years have not been established.

Method of Administration

For oral use.

Before use, shake the Duvyzat suspension for at least 30 seconds by inverting the bottle by 180º.

• Visually verify the homogeneity of the suspension.

• Using a graduated oral syringe, measure the appropriate volume of suspension corresponding to the prescribed dose of Duvyzat.

• Administer orally with the provided graduated oral syringe.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Haematological changes

Duvyzat can cause dose-related thrombocytopenia and other signs of myelosuppression, including decreased hemoglobin and neutropenia.

In Study EPIDYS, thrombocytopenia occurred in 33% of patients treated with Duvyzat compared to no patients on placebo. The maximum decrease in platelets occurred within the first 2 months of therapy and remained low throughout the course of therapy. In a few patients, thrombocytopenia was associated with bleeding events including epistaxis, hematoma or contusions. Low platelet counts resulted in Duvyzat dose reduction in 28% of patients. Patients with baseline platelet counts below the lower limit of normal were excluded from the study.

Decreased hemoglobin and decreased neutrophils were also observed in patients treated with Duvyzat compared to placebo.

Blood counts should be monitored every 2 weeks for the first 2 months of treatment, at month 3, and then every 3 months thereafter. The dose of Duvyzat should be modified in case of confirmed thrombocytopenia. Treatment should be permanently discontinued if the abnormalities worsen despite dose modification. If a patient develops signs or symptoms of thrombocytopenia, a platelet count should be obtained as soon as possible, and dosing should be held until platelet count is confirmed.

Increased Triglycerides

Duvyzat can cause elevations in triglycerides.

In Study EPIDYS, hypertriglyceridemia occurred in 23% of patients treated with Duvyzat (one of whom had familial hypertriglyceridemia) compared to 7% of patients on placebo.

High triglycerides (i.e., levels greater than 3.42 mmol/L) resulted in discontinuation and led to dosage modification in 2% and 8%, respectively, of patients treated with Duvyzat.

Triglycerides level should be monitored at 1 month, 3 months, 6 months, and then every 6 months thereafter. The dosage should be modified if fasting triglycerides are verified >3.42 mmol/L. Treatment with Duvyzat should be discontinued if triglycerides remain elevated despite adequate dietary intervention and dosage adjustment.

Gastrointestinal disturbances

Gastrointestinal disturbances, including diarrhoea, nausea/vomiting, and abdominal pain were common adverse reactions in Duvyzat clinical trials in DMD.

In Study EPIDYS, diarrhoea was reported in 37% of patients treated with Duvyzat (with 1 severe case reported) compared to 20% of patients on placebo. Diarrhoea usually occurred within the first few weeks of initiation of treatment with Duvyzat.

Vomiting and nausea, sometimes severe and usually occurring within the first 2 months of treatment, occurred in 32% of patients treated with Duvyzat compared to 18% of patients on placebo.

Abdominal pain occurred in 34% of patients treated with Duvyzat compared to 25% of patients on placebo. One case of abdominal pain was serious.

Antiemetics or antidiarrheal medications may be considered during treatment with Duvyzat. Fluid and electrolytes should be replaced as needed to prevent dehydration. The dosage of Duvyzat in patients with moderate or severe diarrhoea should be modified, and treatment should be discontinued if significant symptoms persist.

QTc prolongation

Duvyzat can cause prolongation of QTc. Avoid use of Duvyzat in patients who are at an increased risk for ventricular arrhythmias (including torsades de pointes), such as those with congenital long QT syndrome, coronary artery disease, electrolyte disturbance, concomitant use of other medicinal products known to cause QT prolongation. In patients with underlying cardiac disease or in patients who are taking concomitant medications that cause QT prolongation, obtain ECGs prior to initiating treatment with Duvyzat, during concomitant use and as clinically indicated.

Excipients with known effects

Patients with hereditary fructose intolerance (HFI) should not take this medicinal product.

This medicinal product contains 400 mg sorbitol in each mL which is equivalent to 40 mg/kg.

The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account.

The content of sorbitol in medicinal products for oral use may affect the bioavailability of other medicinal products for oral use administered concomitantly.

This medicinal product contains 4.4 mg sodium benzoate in each mL which is equivalent to 0.44 mg/kg.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose and therefore, is essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Effect of other medicinal products on givinostat pharmacokinetics

Avoid concomitant use of Duvyzat with other product(s) with a known potential to prolong the QTc interval. If concomitant use cannot be avoided, obtain ECGs when initiating, during concomitant use, and as clinically indicated (see section 4.4). Withhold Duvyzat if the QTc interval is > 500 ms or the change from baseline is > 60 ms.

Duvyzat can cause QTc interval prolongation. Caution is advised when prescribing Duvyzat with medicinal products known to prolong the QTc interval with known or possible risk for torsades de pointes, e.g. anaesthetics (e.g. sevoflurane, propofol), class III antiarrhythmics (e.g. amiodarone, sotalol), antiemetics (ondansetron), antibiotics (fluconazole, azithromycin, clarithromycin, ciprofloxacin), antipsychotics (aripiprazole, risperidone), and antihistamines (e.g. famotidine). This list is indicative and not exhaustive.

Effect of givinostat on pharmacokinetics of other medicinal products

Givinostat is a weak intestinal CYP3A4 inhibitor.

Closely monitor when Duvyzat is used in combination with orally administered CYP3A4 sensitive substrates (e.g., alfentanil, tacrolimus, sirolimus, lovastatin, simvastatin, indinavir, sildenafil, eletriptan, midazolam) for which a small change in substrate plasma concentration may lead to serious toxicities.

Givinostat is a weak inhibitor of the renal uptake transporter OCT2.

Closely monitor when Duvyzat is used in combination with drugs known as a sensitive substrate of the OCT2 transporter (e.g.: metformin, dofetilide) for which a small change in substrate plasma concentration may lead to serious toxicities.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of givinostat in pregnant women. Reproductive toxicity studies in animal species have shown changes in reproduction at doses causing maternal toxicity (see section 5.3).

Givinostat should not be used during pregnancy.

Breast-feeding

It is unknown whether givinostat or its metabolites are excreted in human milk. A risk to the suckling child cannot be excluded. Givinostat should not be used during breast-feeding.

Fertility

There are no human data on the effect of givinostat on fertility. Givinostat had no obvious adverse effects on fertility in male and female rats (see section 5.3).

4.7. Effects on ability to drive and use machines

The effect of givinostat on driving or using machines has not been tested.

4.8. Undesirable effects

Summary of safety profile

The safety profile of Duvyzat is based on a double-blind, placebo-controlled, 18-month study in a total of 179 ambulant DMD patients aged 6 years or older on concomitant steroid treatment (EPIDYS STUDY).

The dosage in EPIDYS Study was weight-based. Patients were excluded from the study if they had the following abnormalities at the screening visit: platelets, white blood cell count, or hemoglobin less than the lower limit of normal, triglycerides >3.42 mmol/L in fasting condition, or had a baseline-corrected QT interval, Fridericia's correction (QTcF) of > 450 msec (mean of 3 consecutive readings 5 minutes apart) or a history of additional risk factors for torsades de pointes (e.g., heart failure, hypokalemia, or family history of long QT syndrome). Overall, 2% of the patients discontinued the study because of adverse reactions.

Tabulated list of adverse reactions

Adverse reactions are listed below according to MedDRA system organ class and frequency (see Table 3). Adverse reactions reported in >5% of Duvyzat-treated patients in EPIDYS study at a frequency at least 5% greater than that of the placebo group are presented in Table 3 below.

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 Reactions Reported in >5% of Duvyzat-Treated Patients and at Least 5% Greater than Placebo in EPIDYS Study

System Organ Class

Very common

Common

Blood and lymphatic system disorders

Thrombocytopenia(a)

Gastrointestinal disorders

Diarrhoea(b), Nausea/Vomiting, Abdominal pain(c)

Constipation

General disorders and administration site conditions

Pyrexia

Fatigue

Metabolism and nutrition disorders

Hypertriglyceridaemia(d)

Decreased appetite

Musculoskeletal and connective tissue disorders

Myalgia, Arthralgia,

Skin and subcutaneous tissue disorders

Rash

(a) Thrombocytopenia includes platelet count decreased and thrombocytopenia;

(b) Diarrhoea includes diarrhoea and faeces soft;

(c) Abdominal pain includes abdominal pain and abdominal pain upper;

(d) Hypertriglyceridaemia includes hypertriglyceridaemia and blood triglycerides increased.

Less common adverse events

Adverse reactions of hypothyroidism and/or thyroid stimulating hormone (TSH) increased occurred in 5% of patients treated with Duvyzat compared to 2% of patients who received placebo.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play and Apple App store.

4.9. Overdose

In the event of a suspected overdose, supportive medical care, including cardiac monitoring should be provided.