DUVYZAT Oral suspension Ref.[109306] Active ingredients: Givinostat

5.1 Hematological Changes

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

In Study 1 [see Clinical Studies (14)], 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.

Monitor blood counts every 2 weeks for the first 2 months of treatment, then monthly for the first 3 months, and every 3 months thereafter. Modify the dosage of DUVYZAT for confirmed thrombocytopenia [see Dosage and Administration (2.3)]. Treatment should be permanently discontinued if the abnormalities worsen despite dose modification. If a patient develops signs or symptoms of thrombocytopenia, obtain a platelet count as soon as possible, and hold dosing until platelet count is confirmed.

5.2 Increased Triglycerides

DUVYZAT can cause elevations in triglycerides. In Study 1 [see Clinical Studies (14)], 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 300 mg/dL) resulted in discontinuation and led to dosage modification in 2% and 8%, respectively, of patients treated with DUVYZAT. Monitor triglycerides at 1 month, 3 months, 6 months, and then every 6 months thereafter.

Modify the dosage if fasting triglycerides are verified >300 mg/dL [see Dosage and Administration (2.3)]. Treatment with DUVYZAT should be discontinued if triglycerides remain elevated despite adequate dietary intervention and dosage adjustment.

5.3 Gastrointestinal Disturbances

Gastrointestinal disturbances, including diarrhea, nausea/vomiting, and abdominal pain were common adverse reactions in DUVYZAT clinical trials in DMD. In Study 1, diarrhea was reported in 37% of patients treated with DUVYZAT (with 1 severe case reported) compared to 20% of patients on placebo. Diarrhea 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 [see Warnings and Precautions (5.4)]. Modify the dosage of DUVYZAT in patients with moderate or severe diarrhea, and treatment should be discontinued if significant symptoms persist [see Dosage and Administration (2.3)].

5.4 QTc Prolongation

DUVYZAT can cause prolongation of QTc interval [see Clinical Pharmacology (12.2)]. 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 [see Warnings and Precautions (5.3)], concomitant use of other medicinal products known to cause QT prolongation [see Drug Interactions (7.2)]. Obtain ECGs prior to initiating treatment with DUVYZAT in patients with underlying cardiac disease or in patients who are taking concomitant medications that cause QT prolongation [see Dosage and Administration (2.1)].

The following clinically significant adverse reactions are described below and elsewhere in the labeling:

• Hematological Changes [see Warnings and Precautions (5.1)]
• Increased Triglycerides [see Warnings and Precautions (5.2)]
• Gastrointestinal Disturbances [see Warnings and Precautions (5.3)]
• QTc Prolongation [see Warnings and Precautions (5.4)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In controlled and uncontrolled trials in patients with confirmed DMD, 222 male patients aged 6 years and older were treated with DUVYZAT, including 210 patients treated for ≥6 months, 187 patients for ≥12 months, and 105 patients for ≥24 months.

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 (Study 1) [see Clinical Studies (14)]. The dosage in Study 1 was weightbased [see Dosage and Administration (2.2)]. Patients were excluded from the study if they had the following abnormalities at the screening visit: platelet, white blood cell, or hemoglobin counts less than the lower limit of normal, triglycerides >300 mg/dL (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.

Adverse reactions reported in >5% of DUVYZAT-treated patients at a frequency at least 5% greater than that of the placebo group are presented in Table 3 below.

Table 3. Adverse Reactions Reported in >5% of DUVYZAT-Treated Patients and at Least 5% Greater than Placebo in Study 1:

¹ Thrombocytopenia includes platelet count decreased and thrombocytopenia.

Less Common Adverse Reactions in Study 1

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.

7.1 Effect of Givinostat on Other Drugs

CYP3A4 Sensitive Substrates

Givinostat is a weak intestinal CYP3A4 inhibitor. Closely monitor when DUVYZAT is used in combination with orally administered CYP3A4 sensitive substrates for which a small change in substrate plasma concentration may lead to serious toxicities.

OCT2 Sensitive Substrates

Givinostat is a weak inhibitor of the renal uptake transporter OCT2. Closely monitor when givinostat is used in combination with drugs known as a sensitive substrate of the OCT2 transporter for which a small change in substrate plasma concentration may lead to serious toxicities.

7.2 Effect of Other Drugs on givinostat

Drugs that Prolong the QTc Interval

Avoid concomitant use of givinostat 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. Withhold givinostat if the QTc interval is >500 ms or the change from baseline is >60 ms.

Givinostat causes QTc interval prolongation. Concomitant use of givinostat with other products that prolong the QTc interval may result in a greater increase in the QTc interval and adverse reactions associated with QTc interval prolongation, including Torsade de pointes, other serious arrythmias, and sudden death.

Risk Summary

DUVYZAT is indicated for the treatment of DMD, which is a disease of predominantly young male patients. Therefore, there are no adequate data available to assess the use of DUVYZAT in pregnant women. In animal studies, oral administration of givinostat during organogenesis resulted in decreased fetal body weight and increased structural variations; oral administration during pregnancy and lactation resulted in increased embryofetal and offspring mortality and neurobehavioral changes in the offspring. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

Oral administration of givinostat (0, 40, 80, or 160 mg/kg/day) to pregnant rats throughout organogenesis resulted in reduced fetal body weight at the highest dose tested and increases in the incidence of skeletal and visceral variations at the mid and high doses. The no-effect dose (40 mg/kg/day) for adverse effects on embryofetal development was associated with maternal plasma exposures (AUC) lower than that in humans at the maximum recommended human dose (MRHD) of 53.2 mg twice daily.

Oral administration of givinostat (0, 40, 80, or 160 mg/kg/day) to pregnant rabbits throughout organogenesis resulted in maternal death at the highest dose tested, resulting in too few fetuses to evaluate. No adverse effects on embryofetal development were observed at the low and mid doses. Plasma exposures (AUC) at the higher no-effect dose (80 mg/kg) for adverse effects on embryofetal development were approximately 4 times that in humans at the MRHD.

Oral administration of givinostat (0, 40, 80, or 160 mg/kg/day) to rats throughout pregnancy and lactation resulted in increases in embryofetal mortality, stillbirths, and offspring mortality at the highest dose tested. When offspring were tested postweaning (postnatal day 49), adverse effects on behavior (decreased open field activity) were observed at all doses. A no-effect dose for adverse developmental effects was not identified; plasma exposures (AUC) at the lowest dose tested were lower than that in humans at the MRHD.

Risk Summary

There are no human or animal data to assess the effect of DUVYZAT or its metabolites on milk production, the presence of givinostat in milk, or the effects on the breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for DUVYZAT and any potential adverse effects on the breastfed infant from DUVYZAT or from the underlying maternal condition.

No human data are available on the effect of DUVYZAT on reproductive potential.

Animal studies indicate possible adverse effects on reproduction [see Nonclinical Toxicology (13.1)].

The safety and effectiveness of DUVYZAT in children aged 6 years and older have been established [see Clinical Studies (14)]. Safety and effectiveness in pediatric patients below the age of 6 years have not been established.

Juvenile Animal Data

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.

DMD is largely a disease of children and young adults; therefore, there is no experience with DUVYZAT in geriatric DMD patients.

A dedicated clinical study was not conducted to evaluate the pharmacokinetics of DUVYZAT in subjects with hepatic impairment, and no recommendation for dosage adjustment can be made for patients with hepatic impairment. Because DUVYZAT is eliminated mainly through hepatic metabolism, hepatic impairment is expected to increase the exposure of givinostat [see Clinical Pharmacology (12.3)].