DUVYZAT Oral suspension Ref.[115472] Active ingredients: Givinostat

Haematological effects

Givinostat is associated with dose-related thrombocytopenia and other signs of myelosuppression, including decreased haemoglobin and neutropenia.

The effect is most prominent in platelet counts (see section 4.8).

A complete blood count should be obtained before starting treatment with givinostat. Platelet counts should be closely monitored during treatment with givinostat, i.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. Treatment should be discontinued if the abnormalities are still persistent (see section 4.2).

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.

In DMD patients with persistent increase in triglycerides levels in fasting condition (>300 mg/dl), the dose of givinostat should be adjusted as indicated in section 4.2.

Treatment with givinostat should be discontinued if triglycerides remain elevated despite adequate dietary intervention and dosage adjustment (see section 4.2).

Gastrointestinal disturbances

Diarrhoea and vomiting were very common adverse drug reactions in givinostat clinical trials in DMD (see section 4.8).

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.

The dose of givinostat should be adjusted in case of moderate or severe diarrhoea (more than 4 stools per day) (see section 4.2).

Treatment should be discontinued if the abnormalities are still persistent (see section 4.2).

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.

Duvyzat should be withheld if the QTc interval is >500 ms or the change from baseline is >60 ms.

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'.

Caution is advised when prescribing Duvyzat with medicinal products known to prolong the QT 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 (azithromycin, clarithromycin, ciprofloxacin), antimycotics (fluconazole), antipsychotics (aripiprazole, risperidone), and antihistamines (e.g. famotidine). This list is indicative and not exhaustive.

The effect of concomitant use of Duvyzat with antithrombotic medications on platelets count is unknown.

Duvyzat should be used with caution in patients taking concomitant medication known to increase triglyceride values as it might increase the risk for hypertriglyceridaemia.

Effect of givinostat on pharmacokinetics of other medicinal products

A weak CYP3A4 inhibition, mainly in the intestine was shown in a Drug-Drug Interaction (DDI) study in humans. Caution should be exercised when givinostat is co-administered with medicinal products that are substrates of CYP3A4 and have a narrow therapeutic margin.

The potential to inhibit the intestinal transporter protein P-gp cannot be excluded. Medicinal products known to be a substrate of the P-gp transporter and have a narrow therapeutic margin should be used with caution with givinostat.

A weak inhibition of the renal uptake transporter OCT2 was seen in vitro and in clinical trials with givinostat by creatinine measurements. Medicinal products known to be a substrate of the OCT2 transporter and have a narrow therapeutic margin should be used with caution with givinostat.

Pregnancy

There are no data from the use of givinostat in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of givinostat 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 showed adverse effects on accessory glands in male rats, however, fertility of animals was not affected (see section 5.3). The relevance for humans is not known.

Givinostat may have a minor influence on the ability to drive and use machines. Dizziness and fatigue may occur following administration of givinostat (see section 4.8).

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).

The most common events occurring in the placebo-controlled study (based on aggregated terms where applicable) were diarrhoea (38.1%), abdominal pain (33.9%), thrombocytopenia (32.2%), vomiting (28.8%) and hypertriglyceridaemia (22.9%).

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.

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:

^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.

Description of selected adverse reactions

Haematological changes

Givinostat has been shown to reduce platelet count with the greatest reduction observed after approximately 88 days and platelet counts remained low throughout treatment. There were no serious bleeding events related to thrombocytopenia. After givinostat dose reduction, platelets return to normal values in approximately 3-4 weeks.

Thrombocytopenia occurred in 32.2% of patients treated with Duvyzat and in no patient on placebo. Of these reactions, 86.8% were reported as mild and 13.2% as moderate.

Low platelet counts resulted in Givinostat dose reduction in 28% of patients. Patients with baseline platelet counts below the lower limit of normal were excluded from the studies.

Decreased haemoglobin and decreased neutrophils were also observed in patients treated with givinostat compared to placebo.

Triglyceride changes

Givinostat has been shown to increase triglyceride levels, with the greatest increase observed after approximately 221 days. After givinostat dose interruption, triglyceride levels return to baseline values in approximately 90 days.

High triglycerides (i.e., levels >300 mg/dl) resulted in discontinuation and led to dosage modification in 2% and 8%, respectively, of patients treated with Duvyzat.

Hypertriglyceridaemia occurred in 22.9% of patients treated with Duvyzat. Of these events, 70.4% were reported as mild, 25.9% as moderate and in one case (3.7%) as severe.

Gastrointestinal disturbances

Gastrointestinal disturbances, including diarrhoea, vomiting and abdominal pain occurred in patients treated with givinostat.

Diarrhoea was reported in 38% of patients treated with Duvyzat (with 1 severe case reported) compared to 18% of patients on placebo. Diarrhoea usually occurred within the first few weeks of initiation of treatment with Duvyzat.

Vomiting occurred in 29% of patients treated with Duvyzat (with 2 severe cases reported) compared to 13% of patients on placebo. Vomiting usually occurred within the first 2 months of treatment.

Abdominal pain occurred in 34% of patients treated with Duvyzat compared to 23% of patients on placebo. One case of abdominal pain was serious.

Description of other laboratory abnormalities

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.

In addition, hypothyroidism (common) events were observed during long-term treatment.

Blood thyroid stimulating hormone levels were generally within 2 times the upper limit of normal with no or minor changes in thyroid hormones.

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.

Not applicable.