Givinostat (Monograph)

Brand name: Duvyzat
Drug class: Other Miscellaneous Therapeutic Agents

Introduction

Givinostat is a histone deacetylase inhibitor.¹

Uses for Givinostat

Givinostat has the following uses:

Givinostat is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients 6 years of age and older.¹

Givinostat Dosage and Administration

General

Givinostat hydrochloride is available in the following dosage form(s) and strength(s):

Oral suspension: 8.86 mg of givinostat per mL.¹

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Obtain and evaluate baseline platelet counts and triglycerides prior to initiation of givinostat.¹ Do not initiate givinostat in patients with a platelet count less than 150 x 10⁹/L.¹

The dosage of givinostat is based on patient’s body weight (see Table 1).¹ Administer oral suspension twice daily with food.¹ See Full Prescribing Information for additional details on preparation and administration of the drug.¹

Dosage modifications may be needed for decreased platelet counts, diarrhea, increased triglycerides, or QTc prolongation.¹ See Full Prescribing Information for additional details.¹

Cautions for Givinostat

Contraindications

None.¹

Warnings/Precautions

Hematological Changes

Givinostat can cause dose-related thrombocytopenia and other signs of myelosuppression, including decreased hemoglobin and neutropenia. ¹

In the principal efficacy study, thrombocytopenia occurred in 33% of patients treated with givinostat compared to no patients on placebo.¹ The maximum decrease in platelets occurred within the first 2 months of therapy and remained low throughout the course of therapy.¹ In a few patients, thrombocytopenia was associated with bleeding events including epistaxis, hematoma or contusions.¹ Low platelet counts resulted in givinostat dose reduction in 28% of patients.¹ Patients with baseline platelet counts below the lower limit of normal were excluded from the study.¹

Decreased hemoglobin and decreased neutrophils were also observed in patients treated with givinostat compared to placebo.¹

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.¹ Modify the dosage of givinostat for confirmed thrombocytopenia.¹ Treatment should be permanently discontinued if the abnormalities worsen despite dose modification.¹ 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.¹

Increased Triglycerides

Givinostat can cause elevations in triglycerides.¹ In the principal efficacy study, hypertriglyceridemia occurred in 23% of patients treated with givinostat (one of whom had familial hypertriglyceridemia) compared to 7% of patients on placebo.¹ 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 givinostat.¹

Monitor triglycerides at 1 month, 3 months, 6 months, and then every 6 months thereafter.¹ Modify the dosage if fasting triglycerides are verified > 300 mg/dL.¹ Treatment with givinostat should be discontinued if triglycerides remain elevated despite adequate dietary intervention and dosage adjustment.¹

GI Disturbances

GI disturbances, including diarrhea, nausea/vomiting, and abdominal pain were common adverse reactions in givinostat clinical trials in DMD.¹ In the principal efficacy study, diarrhea was reported in 37% of patients treated with givinostat (with 1 severe case reported) compared to 20% of patients on placebo.¹ Diarrhea usually occurred within the first few weeks of initiation of treatment with givinostat.¹

Vomiting and nausea, sometimes severe and usually occurring within the first 2 months of treatment, occurred in 32% of patients treated with givinostat compared to 18% of patients on placebo.¹ Abdominal pain occurred in 34% of patients treated with givinostat compared to 25% of patients on placebo.¹ One case of abdominal pain was serious.¹

Antiemetics or antidiarrheal medications may be considered during treatment with givinostat.¹ Fluid and electrolytes should be replaced as needed to prevent dehydration.¹ Modify the dosage of givinostat in patients with moderate or severe diarrhea, and treatment should be discontinued if significant symptoms persist.¹

QT Prolongation

Givinostat can cause prolongation of the QTc interval.¹ Avoid use of givinostat 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.¹ Obtain ECGs prior to initiating treatment with givinostat in patients with underlying cardiac disease or in patients who are taking concomitant medications that cause QT prolongation.¹

Specific Populations

Pregnancy

Givinostat is indicated for the treatment of DMD, which is a disease of predominantly young male patients.¹ Therefore, there are no adequate data available to assess the use of givinostat in pregnant women.¹ 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.¹ 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.¹

Lactation

There are no human or animal data to assess the effect of givinostat or its metabolites on milk production, the presence of givinostat in milk, or the effects on the breastfed infant.¹ The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for givinostat and any potential adverse effects on the breastfed infant from givinostat or from the underlying maternal condition.¹

Females and Males of Reproductive Potential

No human data are available on the effect of givinostat on reproductive potential.¹

Animal studies indicate possible adverse effects on reproduction.¹

Pediatric Use

The safety and effectiveness of givinostat in children 6 years of age and older have been established.¹ Safety and effectiveness in pediatric patients younger than 6 years of age have not been established.¹

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 92.¹ 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.¹ 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.¹ Persistent decreases in bone density were observed at all doses tested.¹ 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.¹

Geriatric Use

DMD is largely a disease of children and young adults; therefore, there is no experience with givinostat in geriatric DMD patients.¹

Hepatic Impairment

A dedicated clinical study was not conducted to evaluate the pharmacokinetics of givinostat in subjects with hepatic impairment, and no recommendation for dosage adjustment can be made for patients with hepatic impairment.¹ Because givinostat is eliminated mainly through hepatic metabolism, hepatic impairment is expected to increase drug exposure.¹

Common Adverse Effects

Most common adverse reactions (≥10% in givinostat-treated patients) are diarrhea, abdominal pain, thrombocytopenia, nausea/vomiting, hypertriglyceridemia, and pyrexia.¹

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

• Closely monitor when givinostat is used in combination with an oral cytochrome P-450 (CYP) 3A4 sensitive substrate or a sensitive substrate of the OCT2 transporter, for which a small change in substrate plasma concentration may lead to serious toxicities.¹

• Avoid concomitant use with other drugs that prolong the QTc interval; monitor ECG if concomitant use cannot be avoided.¹

Actions

Mechanism of Action

Givinostat is a histone deacetylase inhibitor.¹ The precise mechanism by which givinostat exerts its effect in patients with DMD is unknown.¹

Advice to Patients

• Advise patients to read the FDA-approved patient labeling. ¹

• Instruct patients or caregivers to shake givinostat oral suspension well before measuring out each dose.¹

• Instruct patients or caregivers to administer givinostat using the provided graduated oral syringe to measure the appropriate volume of suspension corresponding to the prescribed dose for the patient.¹

• Instruct patients or caregivers to take givinostat with food.¹

• Instruct patients or caregivers to discard any unused givinostat oral suspension remaining after 60 days of first opening the bottle.¹

• Inform patients and/or caregivers that givinostat can cause hematological changes including a decrease in platelet counts (thrombocytopenia), anemia, and a decrease in neutrophils (neutropenia).¹ Advise patients to notify their healthcare provider if they have any signs or symptoms of these adverse reactions (e.g., easy bruising, excessive bleeding from cuts, blood in the stool, fatigue).¹ Instruct patients to adhere to the testing recommended to monitor for these adverse reactions.¹ Inform patients that their dosage may need to be changed or their treatment may need to be stopped depending on the results of their test for platelet counts.¹

• Inform patients and/or caregivers that givinostat can cause an increase in triglycerides.¹ Instruct patients to adhere to the testing recommended to monitor for this adverse reaction.¹ Inform patients that their dosage may need to be changed or their treatment may need to be stopped depending on the results of their test for triglycerides.¹

• Inform patients and/or caregivers that givinostat can cause diarrhea and vomiting, which may require medication for treatment.¹ Advise patients to maintain hydration if diarrhea or vomiting occurs and contact their healthcare provider if the symptoms persist or become moderate to severe.¹ Inform patients that their dosage may need to be changed or their treatment may need to be stopped depending on the severity of diarrhea.¹

• Inform patients and/or caregivers that givinostat can cause prolongation of the QTc interval.¹ Instruct patients to notify their healthcare provider if they have or develop any symptoms of significant QTc prolongation (e.g., dizziness, lightheadedness, syncope) or new cardiac issues and before taking any over-the-counter (e.g., diphenhydramine), herbal (e.g., echinacea), or prescription medications (e.g., antibiotics).¹

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Medical Disclaimer