Drug Interaction Report

MONITOR CLOSELY: Coadministration of inotersen and drugs that interfere with platelet function or coagulation may potentiate the risk of serious, potentially life-threatening bleeding complications, including spontaneous intracranial and intrapulmonary hemorrhage. Inotersen causes reductions in platelet count that may result in sudden and unpredictable thrombocytopenia. In a premarketing clinical trial, platelet counts below 100 x 10^9/L and 75 x 10^9/L occurred in 25% and 14% of patients receiving inotersen, respectively, versus 2% and none of the patients receiving placebo, respectively. Thirty-nine percent of inotersen-treated patients with a baseline platelet count below 200 x10^9/L had a nadir platelet count below 75 x 10^9/L, compared to 6% of patients with baseline platelet counts 200 x10^9/L or higher. Three inotersen-treated patients (3%) developed sudden severe thrombocytopenia (i.e., platelet count below 25 x 10^9/L), all of whom had treatment-emergent antiplatelet IgG antibodies detected shortly before or at the time of the severe thrombocytopenia. In 2 patients, platelet clumping caused uninterpretable platelet measurements that delayed the diagnosis and treatment of severe thrombocytopenia. Platelet clumping can be caused by a reaction between antiplatelet antibodies and ethylenediaminetetraacetic acid (EDTA). In the clinical trial, 23% of inotersen-treated patients had at least one uninterpretable platelet count caused by platelet clumping, compared to 13% of placebo-treated patients.

MANAGEMENT: Caution is advised when inotersen is prescribed with antiplatelet agents, anticoagulants, or other medications that commonly cause thrombocytopenia or bleeding. A platelet count should be obtained prior to initiation of inotersen and regularly during and for at least 8 weeks after treatment in accordance with the product labeling. Inotersen should not be administered in patients with a platelet count below 100 x 10^9/L or in patients who are unable to adhere to the recommended laboratory monitoring and management guidelines. Patients or their caregivers should be apprised of the signs and symptoms of thrombocytopenia and to seek medical attention if they occur, including any unusual or prolonged bleeding (e.g., petechiae, easy bruising, hematoma, subconjunctival bleeding, gingival bleeding, epistaxis, hemoptysis, irregular or heavier than normal menstrual bleeding, hematemesis, hematuria, hematochezia, melena), neck stiffness, or atypical severe headache. If thrombocytopenia is suspected, obtain a platelet count as soon as possible and withhold further inotersen dosing until platelet count is confirmed to be acceptable. A prompt recheck of the platelet count is necessary if a platelet measurement is not interpretable (e.g., clumped sample). The manufacturer recommends glucocorticoid therapy in patients with a platelet count below 50 x 10^9/L and in patients with suspected immune-mediated thrombocytopenia. Additionally, consideration should be given to discontinuing any concomitant medications that may be contributing to the thrombocytopenia and/or bleeding complication, if clinically feasible.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of panobinostat. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Increased exposure to panobinostat may increase the risk of adverse effects such as nausea, vomiting, diarrhea, anorexia, peripheral edema, cardiotoxicity, ECG abnormalities, electrolyte disturbances, bleeding complications, hepatotoxicity, and myelosuppression.

Food may delay the rate of absorption of panobinostat, but does not significantly affect the overall extent of absorption. When a single oral dose of panobinostat was administered to 36 patients with advanced cancer 30 minutes after a high-fat meal, panobinostat peak plasma concentration (Cmax) and systemic exposure (AUC) were approximately 44% and 16% lower, respectively, compared to administration under fasting conditions. The median time to maximum concentration (Tmax) was prolonged by 2.5 hours.

MANAGEMENT: Patients should avoid consumption of grapefruit or grapefruit juice during treatment with panobinostat. The manufacturer also recommends avoiding star fruit, Seville oranges, pomegranate, and pomegranate juice. Panobinostat may be administered with or without food.