Drug Interactions between Akeega and treprostinil

MONITOR: Coadministration with inhibitors of CYP450 2C8 may increase the plasma concentrations of treprostinil, which is primarily metabolized by the isoenzyme. Coadministration of the potent CYP450 2C8 inhibitor gemfibrozil (600 mg twice daily) with oral treprostinil (treprostinil diolamine) in healthy adults resulted in a doubling of both the systemic exposure (AUC) and peak plasma concentration (Cmax) of treprostinil. However, it has not been determined if the safety and efficacy of treprostinil administered parenterally (e.g., subcutaneously, intravenously, via inhalation) are altered by this interaction.

MANAGEMENT: Pharmacologic response to treprostinil should be monitored more closely whenever a CYP450 2C8 inhibitor is added to or withdrawn from therapy, and the treprostinil dosage adjusted as necessary. Patients starting on oral treprostinil who are already on a CYP450 2C8 inhibitor should use a lower starting dose of 0.125 mg twice daily and titrate in 0.125 mg twice daily increments, not more frequently than every 3 to 4 days. If a CYP450 2C8 inhibitor is started during therapy with treprostinil, patients should be advised to notify their physician if they experience excessive adverse effects of treprostinil such as headache, dizziness, lightheadedness, flushing, diarrhea, edema, and unusual bleeding or bruising. Abrupt cessation of a CYP450 2C8 inhibitor should be avoided where possible due to the potential of worsening pulmonary arterial hypertension symptoms.

MONITOR: Coadministration of niraparib and drugs that interfere with platelet function or coagulation may potentiate the risk of bleeding complications. In pooled safety population data of patients (n=1,314) with advanced ovarian, fallopian tube, or primary peritoneal cancer treated with niraparib monotherapy, thrombocytopenia was reported in 60% of patients. Two niraparib clinical trials reported greater than or equal to Grade 3 thrombocytopenia in 29% to 39% of patients with niraparib discontinuation due to thrombocytopenia occurring in approximately 3% to 4% of patients. The MAGNITUDE study, which included an evaluation of niraparib in combination with abiraterone for breast cancer gene (BRCA)-mutated metastatic castration-resistant prostate cancer (mCRPC) reported Grade 3 or more thrombocytopenia in 8% of patients.

MANAGEMENT: Concomitant use of anticoagulants or other medications known to reduce platelet count should be approached with caution. Recommendations for holding, adjusting the dose of, or discontinuing niraparib can be found in the manufacturer's labeling. If the patient has additional risk factors for bleeding, such as coadministration with an anticoagulant or antiplatelet, it may be advisable to consider a platelet transfusion at a higher platelet count. For hematologic adverse reactions requiring transfusion, withhold niraparib and consider interrupting any drugs that interfere with platelet function or coagulation. Niraparib may be resumed at a reduced dose per manufacturer recommendations. If hematologic toxicity does not resolve within 28 days following interruption, discontinue niraparib and consider referral to a hematologist. Blood counts should be monitored as recommended by the manufacturer. Patients should be advised to promptly report any signs or symptoms of bleeding to their primary care provider.