VORINOSTAT Drug Interactions: What You Need to Know

INTERACTIONS Coumarin-derivative anticoagulants: Prolongation of prothrombin time and International Normalized Ratio (INR) have been observed with concomitant use. Monitor INR frequently. ( 7.1 )

7.1 Coumarin-Derivative Anticoagulants Prolongation of prothrombin time (PT) and International Normalized Ratio (INR) were observed in patients receiving ZOLINZA concomitantly with coumarin-derivative anticoagulants. Physicians should monitor PT and INR more frequently in patients concurrently administered ZOLINZA and coumarin derivatives.

7.2 Other HDAC Inhibitors Severe thrombocytopenia and gastrointestinal bleeding have been reported with concomitant use of ZOLINZA and other HDAC inhibitors (e.g., valproic acid). Monitor platelet count every 2 weeks for the first 2 months <span class="opacity-50 text-xs">[see Warnings and Precautions (5.6) ]</span>.

None. None ( 4 )

AND PRECAUTIONS Thromboembolism: Monitor for pertinent signs and symptoms of pulmonary embolism and deep vein thrombosis. ( 5.1 ) Myelosuppression: Thrombocytopenia and anemia may require dose modification or discontinuation. Monitor blood counts every 2 weeks during the first 2 months of therapy and monthly thereafter. ( 2.2 , 5.2 , 6 )

Gastrointestinal

Toxicity: Nausea, vomiting and diarrhea; patients may require antiemetics, antidiarrheals, and fluid and electrolyte replacement to prevent dehydration. ( 5.3 , 6 ) Hyperglycemia: Monitor blood glucose every 2 weeks during the first 2 months of therapy and monthly thereafter. ( 5.4 )

Clinical Chemistry

Abnormalities: Measure and correct abnormal electrolytes, creatinine, magnesium and calcium at baseline. Monitor every 2 weeks during the first 2 months of therapy and at least monthly during treatment. ( 5.5 )

Severe

Thrombocytopenia with Concomitant Use of other HDAC Inhibitors: Severe thrombocytopenia with gastrointestinal bleeding has been reported with concomitant use of ZOLINZA and other HDAC inhibitors (e.g., valproic acid). Monitor platelet counts more frequently. ( 5.6 , 7.2 ) Embryo-Fetal Toxicity: Fetal harm can occur when administered to a pregnant woman. Women should be apprised of the potential harm to the fetus. ( 5.7 )

5.1 Thromboembolism Pulmonary embolism occurred in 5% (4/86) of patients receiving ZOLINZA, and deep vein thrombosis has also been reported. Monitor for signs and symptoms of these events, particularly in patients with a prior history of thromboembolic events <span class="opacity-50 text-xs">[see Adverse Reactions (6) ]</span> .

5.2 Myelosuppression Treatment with ZOLINZA can cause dose-related thrombocytopenia and anemia. Monitor blood counts every 2 weeks during the first 2 months of therapy and monthly thereafter. Adjust dosage or discontinue treatment with ZOLINZA as clinically appropriate <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) , Warnings and Precautions (5.6) and Adverse Reactions (6) ]</span>.

5.3 Gastrointestinal Toxicity Gastrointestinal disturbances, including nausea, vomiting and diarrhea, have been reported <span class="opacity-50 text-xs">[see Adverse Reactions (6) ]</span> and may require the use of antiemetic and antidiarrheal medications. Fluid and electrolytes should be replaced to prevent dehydration <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Pre-existing nausea, vomiting, and diarrhea should be adequately controlled before beginning therapy with ZOLINZA.

5.4 Hyperglycemia Hyperglycemia has been observed in patients receiving ZOLINZA and was severe in 5% (4/86) of patients <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Monitor serum glucose every 2 weeks during the first 2 months of therapy and monthly thereafter.

5.5 Clinical Chemistry Abnormalities Obtain chemistry tests, including serum electrolytes, creatinine, magnesium, and calcium, every 2 weeks during the first 2 months of therapy and monthly thereafter. Correct hypokalemia and hypomagnesemia prior to administration of ZOLINZA. Monitor potassium and magnesium more frequently in symptomatic patients (e.g., patients with nausea, vomiting, diarrhea, fluid imbalance or cardiac symptoms).

5.6 Severe Thrombocytopenia when Combined with Other Histone Deacetylase (HDAC)

Inhibitors

Severe thrombocytopenia leading to gastrointestinal bleeding has been reported with concomitant use of ZOLINZA and other HDAC inhibitors (e.g., valproic acid). Monitor platelet counts more frequently [see Drug Interactions (7.2) ] .

5.7 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, ZOLINZA can cause fetal harm when administered to a pregnant woman. There are insufficient data on ZOLINZA use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal reproduction studies, vorinostat crossed the placenta and caused adverse developmental outcomes at exposures approximately 0.5 times the human exposure based on AUC 0-24 hours . Advise females of reproductive potential to use effective contraception during treatment and for at least 6 months after the last dose. Advise males with female sexual partners of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 , 8.3) and Clinical Pharmacology (12.1) ]</span> .