Givinostat Hydrochloride
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alara Ece Dagsali, M.D.
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Overview
Givinostat Hydrochloride is an inhibits class I and class II histone deacetylases (HDACs) and several pro-inflammatory cytokines that is FDA approved for the treatment of of Duchenne muscular dystrophy (DMD) in patients 6 years of age and older.. Common adverse reactions include *Hematological Changes
- Increased Triglycerides
- Gastrointestinal Disturbances
- QTc Prolongation.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
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 The recommended dosage of DUVYZAT is based on body weight and administered orally twice daily with food
- Platelet count <150 x 109/L verified in two assessments one week apart
or
- Moderate or severe diarrhea
or
- Fasting triglycerides >300 mg/dL verified by two assessments one week apart
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Givinostat Hydrochloride in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Givinostat Hydrochloride in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Givinostat Hydrochloride FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Givinostat Hydrochloride in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Givinostat Hydrochloride in pediatric patients.
Contraindications
None.
Warnings
- Hematological Changes:
DUVYZAT can cause dose-related thrombocytopenia and other signs of myelosuppression, including decreased hemoglobin and neutropenia.
In Study 1 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
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.
- Increased Triglycerides
DUVYZAT can cause elevations in triglycerides. In Study 1 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/dLTreatment with DUVYZAT should be discontinued if triglycerides remain elevated despite adequate dietary intervention and dosage adjustment.
- 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 Modify the dosage of DUVYZAT in patients with moderate or severe diarrhea, and treatment should be discontinued if significant symptoms persist
- QTc Prolongation:
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 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
Adverse Reactions
Clinical Trials Experience
- Hematological Changes
- Increased Triglycerides
- Gastrointestinal Disturbances
- QTc Prolongation
Postmarketing Experience
There is limited information regarding Givinostat Hydrochloride Postmarketing Experience in the drug label.
Drug Interactions
- Effect of DUVYZAT on Other Drugs:
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 DUVYZAT 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.
- Effect of Other Drugs on DUVYZAT:
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 Withhold DUVYZAT if the QTc interval is > 500 ms or the change from baseline is > 60 ms Concomitant use of DUVYZAT 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
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Givinostat Hydrochloride in women who are pregnant.
Pregnancy Category (AUS):
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.
Labor and Delivery
There is no FDA guidance on use of Givinostat Hydrochloride during labor and delivery.
Nursing Mothers
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.
Pediatric Use
The safety and effectiveness of DUVYZAT in children aged 6 years and older have been established
Geriatic Use
DMD is largely a disease of children and young adults; therefore, there is no experience with DUVYZAT in geriatric DMD patients.
Gender
There is no FDA guidance on the use of Givinostat Hydrochloride with respect to specific gender populations.
Race
There is no FDA guidance on the use of Givinostat Hydrochloride with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Givinostat Hydrochloride in patients with renal impairment.
Hepatic Impairment
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
Females of Reproductive Potential and Males
No human data are available on the effect of DUVYZAT on reproductive potential.
Animal studies indicate possible adverse effects on reproduction
Immunocompromised Patients
There is no FDA guidance one the use of Givinostat Hydrochloride in patients who are immunocompromised.
Administration and Monitoring
Administration
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 The recommended dosage of DUVYZAT is based on body weight and administered orally twice daily with food
- Platelet count <150 x 109/L verified in two assessments one week apart
or
- Moderate or severe diarrhea
or
- Fasting triglycerides >300 mg/dL verified by two assessments one week apart
Monitoring
There is limited information regarding Givinostat Hydrochloride Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Givinostat Hydrochloride and IV administrations.
Overdosage
There is limited information regarding Givinostat Hydrochloride overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Givinostat Hydrochloride Pharmacology in the drug label.
Mechanism of Action
DUVYZAT is a histone deacetylase inhibitor. The precise mechanism by which DUVYZAT exerts its effect in patients with DMD is unknown.
Structure
There is limited information regarding Givinostat Hydrochloride Structure in the drug label.
Pharmacodynamics
- 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 1
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). 02
Pharmacokinetics
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.
Nonclinical Toxicology
Carcinogenesis
Studies to assess the carcinogenic potential of givinostat have not been conducted.
Mutagenesis
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.
Impairment of Fertility
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.
Clinical Studies
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 1; NCT02851797). 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 appliedThe 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 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.
How Supplied
DUVYZAT (givinostat) oral suspension is a white to off-white or faintly pink, peach-cream flavored suspension. It is supplied in an amber polyethylene terephthalate bottle closed with a high-density polyethylene child-resistant, screw cap with low-density polyethylene syringe adapter, containing 140 mL of oral suspension (NDC 11797-110-01). Each mL contains 8.86 mg of givinostat.
Storage
Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Do not freeze. Store upright.
Discard any unused DUVYZAT remaining after 60 days of first opening of the bottle.
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
- Shake DUVYZAT oral suspension well before measuring out each dose.
- Administer using the provided graduated oral syringe to measure the appropriate volume of suspension corresponding to the prescribed dose for the patient.
- Take DUVYZAT with food.
- Discard any unused DUVYZAT oral suspension remaining after 60 days of first opening the bottle
Precautions with Alcohol
Alcohol-Givinostat Hydrochloride interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
DUVYZAT
Look-Alike Drug Names
There is limited information regarding Givinostat Hydrochloride Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.