Duvyzat 8.86 mg/mL Oral suspension

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

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

^± 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

^± 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.

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

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'.

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.

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).

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

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

^(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.

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

Pharmacotherapeutic group: Other drugs for disorders of the musculoskeletal system, ATC code: M09AX14.

Mechanism of action

Duvyzat is a histone deacetylase inhibitor. The precise mechanism by which Duvyzat exerts its effect in patients with DMD is unknown.

Pharmacodynamic effects

Muscle Fat Fraction as Assessed by MR Spectroscopy

The percentage of fat fraction present in the vastus lateralis muscles (VLM) of the thigh was measured in Study EPIDYS using magnetic resonance spectroscopy. At 18 months, for the patients with VLM fat fraction baseline in the range of >5% to ≤30%, a mean increase (absolute difference from baseline levels) of VLM fat fraction was 7.48% in the Duvyzat-treated patients compared to a 10.89% increase in patients who received placebo.

Cardiac Electrophysiology

The largest mean increase in QTc interval of 13.6 ms (upper confidence interval of 17.1 ms) occurred 5 hours after administration of givinostat 265.8 mg to healthy subjects (approximately 5 times the 53.2 mg dose recommended for DMD patients weighing 60 kg or more).

Clinical efficacy and safety

The effectiveness of Duvyzat for the treatment of Duchenne muscular dystrophy (DMD) was evaluated in a randomized, double-blind, placebo-controlled 18-month study (Study EPIDYS). A total of 179 patients were randomized 2:1 to receive either Duvyzat (n = 118) or placebo (n = 61). A weight-based dose regimen was applied. The study included male patients 6 years of age and older with a confirmed diagnosis of DMD who were ambulatory and on a stable dosage of corticosteroids. At baseline, patients had a mean age of 9.8 years, 90% were White, 3% were Asian, 3% were Black.

The primary endpoint was the change from baseline to Month 18 in 4-stair climb (4SC) time for Duvyzat compared to placebo. The 4SC is a measure of muscle function that tests the time it takes to climb 4 stairs. A secondary efficacy endpoint was change from baseline to Month 18 in physical function as assessed by the North Star Ambulatory Assessment (NSAA).

The primary analysis population was based on a prespecified range of baseline muscle fat fraction as determined by MR spectroscopy. Patients treated with Duvyzat showed statistically significant less decline in the 4-stair climb compared to placebo (see Table 4). Patients treated with givinostat experienced less worsening on the NSAA compared to placebo, which was nominally significant but not statistically significant based on the prespecified multiplicity adjustment.

Table 4 – Change from Baseline to Month 18 on 4SC Compared to Placebo*

*Givinostat or placebo were administered in addition to a stable dose of corticosteroids throughout the study

Non ambulatory patients

The pivotal Study 48 was conducted in ambulatory patients only. Givinostat has not been studied in patients that commence treatment in the non-ambulatory phase. Conditional Marketing Authorisation (CMA) was given at this stage while waiting for confirmatory clinical results for non-ambulatory population.

For this reason, a randomized, placebo-controlled study to evaluate the efficacy and safety of givinostat in paediatric non-ambulant patients has recently commenced as part of the PIP MHRA-101094-23-M01 (Study DSC/14/2357/50).

The expected date for availability of final study report DSC/14/2357/50 is October 2026. The results of this study should provide evidence of efficacy of Givinostat in the non-ambulatory patients population.

Givinostat exhibits linear kinetics with the studied dose range. Systemic exposure to givinostat was dose-proportional across the therapeutic dose range. Steady-state concentrations are achieved within 5 to 7 days after twice daily dosing. An accumulation of less than 2-fold was observed for givinostat after twice daily administration.

Absorption

Absolute bioavailability was not determined but a physiologically based pharmacokinetic analysis, including healthy volunteer data, predicted an oral bioavailability in humans of more than 50% after single oral administration at the dose range of 44.3 to 177.2 mg. The time to maximum plasma concentrations is about 2 to 3 hours after both single and repeated oral administration.

Effect of Food

A high fat standard meal resulted in an increase in the exposure (about 40% increase in area under the plasma concentration-time curve [AUC] and about 23% increase in maximum plasma concentration [C_max]) and a delay in time to maximum concentration (T_max) from 2 to 3 hours (see section 4.2).

Distribution

Givinostat is approximately 96% bound to human plasma proteins and is slightly partitioned into red blood cells (blood to plasma ratio = 1.3).

Biotransformation

In vitro studies with human enzymatic preparations together with animal metabolism showed that givinostat is extensively metabolized forming several metabolites. The main reactions involve the hydroxamic acid group and the carbamic bond, while those involving the tertiary amine have a minor impact on givinostat clearance. CYP450 and UGTs are not involved in the main metabolic reactions. The enzymes forming the primary metabolites have only been partially identified. Four major metabolites have been characterized in humans and animal species, although with differences in quantitative amounts. The major metabolites of givinostat showed no significant HDAC inhibition.

Elimination

In plasma, apparent elimination half-life of givinostat is about 6 hours.

The elimination of givinostat is likely dependent on metabolism followed by renal and biliary excretion of the resulting metabolites as suggested by the mass balance study in the rat. Urinary excretion of givinostat in humans is minimal (<3% of the dose).

Linearity/non-linearity

The pharmacokinetics of givinostat is linear, since the AUC_∞ obtained after single administration is comparable to that with repeated o.d. administration, with a possible minimal apparent drug accumulation over time (range of accumulation ratios found 1.0 - 1.7). Linearity was tested after single administration of doses 44.3 to 354.4 mg and multiple administration of doses 44.3 to 177.2 mg.

Characteristics in specific groups

The population PK analyses show that the PK of givinostat can be affected by body weight, while age has no effects on the pharmacokinetics of givinostat.

Hepatic Impairment

The pharmacokinetics and safety of givinostat have not been studied in patients with hepatic impairment. Givinostat is highly metabolized and therefore the impact of hepatic impairment on the exposure of givinostat cannot be excluded.

Renal Impairment

The pharmacokinetics and safety of givinostat have not been studied in patients with renal impairment. However, renal impairment is not expected to impact the exposure of givinostat because renal excretion is not a significant route of givinostat elimination.

Drug Interaction Studies

In Vitro

Givinostat is not a substrate of cytochrome P450 (CYP450) enzymes and uridine diphosphate glucuronosyltransferase (UGT). Therefore, coadministration of drugs that are inducers or inhibitors of major metabolizing enzymes will not significantly affect the systemic exposure of givinostat.

Givinostat and its metabolites ITF2374, ITF2375, ITF2440, and ITF2563 were investigated as inhibitors of the main CYP450 subfamilies, and the results indicated no inhibition is expected of CYP1A2, 2C9, 2C19, 2D6, 2B6, 2C8, and 3A4. Givinostat showed induction of CYP1A2, 2B6, and CYP3A4.

In vitro studies indicate that givinostat is a substrate of the intestinal transporters: P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Givinostat showed the potential to inhibit the intestinal transporter P-gp (MDR1) and BCRP based on in vitro results. However, these interactions are not expected to be clinically meaningful.

In Vivo

A weak inhibition of the renal uptake transporter OCT2 by givinostat was seen in clinical trials by creatinine (OCT2 substate) measurements (see section 4.5).

A clinical drug interaction study was conducted in healthy volunteers to assess the effects of coadministration of givinostat with other drugs and results indicated that:

• givinostat has a weak inhibition of the intestinal CYP3A4 enzyme based on the exposure of a CYP3A4 substrate, midazolam (see section 4.5).

• givinostat does not likely inhibit P-gp transporters based on the exposure of dabigatran.

• strong P-gp inhibitors have a weak effect on givinostat based on exposure of clarithromycin, which had an increase in C_max by about 40% without a significant change of AUC.

The effect of BCRP inhibitors on givinostat PK was not studied in a clinical study. However, the effect of BCRP inhibitors on givinostat PK is expected to be smaller than P-gp inhibitors based on the comparison of the two transporters mediated efflux ratios determined in the in vitro cell models.

Genotoxicity and carcinogenicity

Studies to assess the carcinogenic potential of givinostat have not been conducted.

Givinostat was positive in a bacterial reverse mutation (Ames) assay, and negative in an in vitro mammalian cell (mouse lymphoma) mutation assay, an in vitro chromosomal aberration assay in mammalian (human lymphocytes) cells, and an in vivo gene mutation assay (with Pig-a endpoints) in Big Blue transgenic rats.

Reproductive and developmental toxicity

Oral administration of givinostat (0, 40, 80, or 160 mg/kg) prior to and throughout mating in male and female rats and continuing to gestation day 7 in females, resulted in no adverse effects on fertility. However, there was an increase in corpora lutea at the mid and high doses and increased pre- and postimplantation loss at all doses. A no-effect dose for adverse effects on early embryonic development was not identified; plasma exposures (AUC) at the lowest dose tested were lower than that in humans at the maximum recommended human dose of 53.2 mg twice daily.

Juvenile toxicity

In a study in juvenile male and female rats, givinostat was orally administered at doses of 0, 10, 20, or 40 mg/kg on postnatal days (PND) 7 to 27, doses of 0, 15, 30, or 60 mg/kg/day on PNDs 28 to 48, and doses of 0, 15, 45, or 90 mg/kg/day on PNDs 49 to 92. Adverse effects on behavior (increased locomotor activity and decreased auditory startle prepulse inhibition) were observed at the high dose at the end of the dosing period. Adverse effects on locomotor activity, but not prepulse inhibition, were observed at the end of the recovery period primarily at the mid and high doses. Persistent decreases in bone density were observed at all doses tested. A no-effect dose for adverse effects on postnatal development was not identified; the lowest dose tested was associated with plasma exposures (AUC) less than that in humans at the MRHD.

Polysorbate 20 (E432)

Glycerol (E422)

Tragacanth Gum (E413)

Sodium Benzoate (E211)

Peach flavour: natural flavouring substances, flavouring substances, propylene glycol (E1520)

Cream flavour: natural flavouring substances, flavouring substances, propylene glycol (E1520)

Saccharin Sodium (E954)

Liquid Sorbitol (E420)

Tartaric Acid (E334)

Sodium Hydroxide (E524)

Purified Water

Not applicable.

3 years.

After first opening: 60 days.

This medicinal product does not require any special temperature storage conditions.

For storage conditions after first opening of the medicinal product, see section 6.3.

Amber polyethylene terephthalate bottle containing 140 mL oral suspension closed with a high-density polyethylene child-resistant closure with low-density polyethylene syringe adapter.

Each pack contains one bottle and one graduated oral syringe of 5 mL.

The syringe of 5 mL is graduated from 1 to 5 mL by increments of 0.5 mL.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.