Version October 2024
Dosage guidance:
Safety: Do not initiate if platelets <150 × 109 L.
Dosing: Dosing based on actual body weight.
Duchenne muscular dystrophy:
Oral:
40 to <60 kg: 44.3 mg (5 mL) twice daily.
≥60 kg: 53.2 mg (6 mL) twice daily.
There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).
There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); however, givinostat is cleared hepatically, so it may accumulate in cases of hepatic impairment.
Signs or symptoms of thrombocytopenia: Perform platelet count and hold treatment until platelet count is confirmed.
Platelet count <150 × 109/L (2 assessments, 1 week apart), moderate to severe diarrhea, OR fasting triglycerides >300 mg/dL (2 assessments, 1 week apart):
40 kg to <60 kg: Reduce dose to 31 mg (3.5 mL) twice daily; if symptoms persist on the 31 mg dose, reduce dose to 26.6 mg (3 mL) twice daily; if symptoms persist on the 26.6 mg dose, discontinue treatment.
≥60 kg: Reduce dose to 39.9 mg (4.5 mL) twice daily; if symptoms persist on the 39.9 mg dose, reduce dose to 35.4 mg (4 mL) twice daily; if symptoms persist on the 35.4 mg dose, discontinue treatment.
QTc >500 msec or change from baseline is >60 msec: Withhold treatment.
Refer to adult dosing.
(For additional information see "Givinostat: Pediatric drug information")
Dosage guidance:
Safety: Obtain baseline platelet count; do not initiate treatment unless baseline platelet count ≥150 × 109/L.
Duchenne muscular dystrophy: Note: Dose based on actual body weight.
Children ≥6 years and Adolescents:
10 to <20 kg: Oral: 22.2 mg twice daily.
20 to <40 kg: Oral: 31 mg twice daily.
40 to <60 kg: Oral: 44.3 mg twice daily.
≥60 kg: Oral: 53.2 mg twice daily.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Dosing adjustment for toxicity:
Platelets <150 × 109/L on 2 assessments 1 week apart, moderate to severe diarrhea, or fasting triglycerides >300 mg/dL on 2 assessments 1 week apart: Consider treatment interruption prior to dosage modification based on severity of adverse drug reaction. For initial dosage modification, follow recommendations for first dosage modification; if adverse reaction persists after first dosage modification, follow recommendations for second dosage modification. Treatment should be permanently discontinued if adverse drug reaction worsens despite dosage modification or if adverse reaction continues after second dosage modification.
First dosage modification: Note: Dose based on actual body weight:
Children ≥6 years and Adolescents:
10 to <20 kg: Oral: 17.7 mg twice daily.
20 to <40 kg: Oral: 22.2 mg twice daily.
40 to <60 kg: Oral: 31 mg twice daily.
≥60 kg: Oral: 39.9 mg twice daily.
Second dosage modification: Note: Dose based on actual body weight:
Children ≥6 years and Adolescents:
10 to <20 kg: Oral: 13.3 mg twice daily.
20 to <40 kg: Oral: 17.7 mg twice daily.
40 to <60 kg: Oral: 26.6 mg twice daily.
≥60 kg: Oral: 35.4 mg twice daily.
QT prolongation: Children ≥6 years and Adolescents: QTc interval >500 ms or the change is >60 ms from baseline: Hold givinostat.
There are no dosing adjustments provided in the manufacturer's labeling (has not been studied); renal excretion is not a significant route of elimination and should not affect drug exposure.
There are no dosing adjustments provided in the manufacturer's labeling (has not been studied). Givinostat is primarily eliminated via hepatic metabolism; increased exposure is expected in patients with liver impairment.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Endocrine & metabolic: Hypertriglyceridemia (23%)
Gastrointestinal: Abdominal pain (34%), diarrhea (37%), nausea and vomiting (32%)
Hematologic & oncologic: Thrombocytopenia (33%)
Miscellaneous: Fever (13%)
1% to 10%:
Dermatologic: Skin rash (9%)
Endocrine & metabolic: Hypothyroidism (≤5%), increased thyroid stimulating hormone level (≤5%)
Gastrointestinal: Constipation (7%), decreased appetite (7%)
Nervous system: Fatigue (8%)
Neuromuscular & skeletal: Arthralgia (8%), myalgia (9%)
Frequency not defined: Hematologic & oncologic: Decreased hemoglobin, decreased neutrophils
There are no contraindications listed in the manufacturer's labeling.
Concerns related to adverse effects:
• Cardiac abnormalities: May prolong the QT interval. Avoid in those at risk for ventricular arrhythmias (eg, congenital long QT syndrome, coronary artery disease, electrolyte abnormalities, concomitant use of other QT-prolonging medications).
• GI effects: Can cause diarrhea, nausea, vomiting, and abdominal pain. In studies, symptoms generally occurred within the first 2 month of treatment. Treat with antiemetics, antidiarrheal medications, fluid, and electrolytes.
• Hematological changes: Can cause dose-related thrombocytopenia, decreased Hb, and neutropenia. In studies, the maximum decrease in platelets occurred within the first 2 months of therapy.
• Increased triglycerides: Can cause elevated triglycerides.
Duvyzat: FDA approved March 2024; availability anticipated in 3rd quarter of 2024.
Oral: Administer with food. Shake for 30 seconds before use. Measure dose using the provided graduated oral syringe.
Oral: Shake suspension for ≥30 seconds by inverting bottle by 180 degrees before use. Administer with food. Administer with graduated oral syringe provided; do not use a household teaspoon (overdosage may occur).
Missed dose: Do not take a double or extra doses.
Duchenne muscular dystrophy: Treatment of Duchenne muscular dystrophy in patients ≥6 years of age.
Givinostat may be confused with Givosiran.
Substrate of BCRP/ABCG2, P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors): Givinostat may increase the serum concentration of CYP3A4 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Haloperidol: QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of Haloperidol. Risk C: Monitor therapy
Levoketoconazole: QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of Levoketoconazole. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
OCT2 Substrates (Clinically Relevant with Inhibitors): Givinostat may increase the serum concentration of OCT2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Adverse events were observed in animal reproduction studies.
It is not known if givinostat is present in breast milk.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.
CBC (baseline and every 2 weeks during first 2 months of treatment, then monthly for the next 3 months, then every 3 months thereafter); triglycerides (baseline, at 1 month, 3 months, 6 months, and then every 6 months thereafter); ECG (if underlying cardiac disease or on concomitant medications that prolong QT) (baseline and as clinically appropriate).
Givinostat is a histone deacetylase inhibitor; exact mechanism in Duchenne muscular dystrophy is unknown. The precise mechanism by which givinostat exerts its effect in patients with Duchenne muscular dystrophy is unknown.
Absorption: High-fat meals increase absorption; ~40% increase in AUC, ~23% increase in Cmax, and delay in time to peak by 2 to 3 hours.
Protein binding: ~96%.
Metabolism: Hepatic to inactive metabolites.
Half-life elimination: ~6 hours.
Time to peak: 2 to 3 hours.
Excretion: Urine: <3%.
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