GIVINOSTAT Drug Interactions: What You Need to Know

INTERACTIONS Closely monitor when DUVYZAT is used in combination with an oral CYP3A4 sensitive substrate or a sensitive substrate of the OCT2 transporter, for which a small change in substrate plasma concentration may lead to serious toxicities. ( 7.1 ) Avoid concomitant use with other drugs that prolong the QTc interval; monitor ECG if concomitant use cannot be avoided. ( 7.2 )

7.1 Effect of DUVYZAT on Other Drugs CYP3A4 Sensitive Substrates Givinostat is a weak intestinal CYP3A4 inhibitor <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . 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.

7.2 Effect of Other Drugs on DUVYZAT Drugs that Prolong the QTc Interval 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4) ]</span> . Withhold DUVYZAT if the QTc interval is &gt; 500 ms or the change from baseline is &gt; 60 ms <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) ]</span> . DUVYZAT causes QTc interval prolongation <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2) ]</span> . 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4) ]</span> .

None. None. ( 4 )

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 )

5.1 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, at month 3, and then 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2) ]</span> . 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) ]</span> , concomitant use of other medicinal products known to cause QT prolongation <span class="opacity-50 text-xs">[see Drug Interactions (7.2) ]</span> . 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) ]</span> .