Other drugs for disorders of the musculo-skeletal system

Duvyzat

Approved 21 Mar 2024OralSuspension

Indications

DUVYZAT is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients 6 years of age and older. DUVYZAT is a histone deacetylase inhibitor indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients 6 years of age and older. ( 1 )

Contraindications

None. None. ( 4 )

Warnings and precautions

Hematological Changes: DUVYZAT can cause dose-related thrombocytopenia and other signs of myelosuppression, including anemia and neutropenia. Monitor platelets; dosage adjustment or discontinuation may be needed. ( 2.3 , 5.1 ) Increased Triglycerides: An increase in triglycerides can occur; dosage modification may be needed. Discontinuation may be needed. ( 2.3 , 5.2 ) Gastrointestinal Disturbances: Adjust dosage if moderate or severe diarrhea occurs.

Antiemetics or antidiarrheal medications may be considered during treatment with DUVYZAT. Discontinue DUVYZAT if the symptoms persist. ( 2.3 , 5.3 ) QTc Prolongation: Avoid use of DUVYZAT in patients who are at an increased risk for ventricular arrhythmias. ( 2.1 , 5.4 , 7.2 )

5.1Hematological 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, at month 3, and then every 3 months thereafter. Modify the dosage of DUVYZAT for confirmed thrombocytopenia [see Dosage and Administration (2.3) ] .

Warnings and precautions

5.1Hematological Changes

Pregnancy and breastfeeding

8.1Pregnancy 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.

Adverse reactions

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) ] Most common adverse reactions (≥10% in DUVYZAT-treated patients) are diarrhea, abdominal pain, thrombocytopenia, nausea/vomiting, hypertriglyceridemia, and pyrexia.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact ITF Therapeutics, LLC. at 1-833-582-4312 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical Trials Experience

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 weight-based [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 Adverse Reaction DUVYZAT N=118 % Placebo N=61 % Diarrhea 37 20 Abdominal pain 34 25 Thrombocytopenia Thrombocytopenia includes platelet count decreased and thrombocytopenia 33 0 Nausea/Vomiting 32 18 Hypertriglyceridemia 23 7 Pyrexia 13 8 Myalgia 9 3 Rash 9 2 Arthralgia 8 2 Fatigue 8 0 Constipation 7 2 Decreased appetite 7 0 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.

Duvyzat

Indications

Contraindications

Warnings and precautions

5.1Hematological Changes

Two medicines in one question?

Duvyzat

Indications

Contraindications

Warnings and precautions

5.1Hematological Changes

Two medicines in one question?

5.2Increased Triglycerides

5.3Gastrointestinal Disturbances

5.4QTc Prolongation

Interactions

7.1Effect of

7.2Effect of Other Drugs on

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Adverse reactions

6.1Clinical Trials Experience

Composition

Official product information

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