Drug Interactions between Akeega and osimertinib

MONITOR CLOSELY: Osimertinib may cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. In two premarketing studies with 411 patients, one patient (0.2%) was found to have a QTc greater than 500 msec, and 11 patients (2.7%) had an increase from baseline QTc greater than 60 msec. A pharmacokinetic/pharmacodynamic analysis performed in 210 patients from one of the studies suggested a concentration-dependent QTc interval prolongation of 14 msec at a dose of 80 mg daily. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, hypocalcemia). Moreover, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Caution is recommended if osimertinib is used in combination with other drugs that can prolong the QT interval. ECG and serum electrolytes, including potassium, magnesium and calcium, should be monitored before starting osimertinib therapy and periodically during treatment. Osimertinib should not be started if baseline QTc is greater than 500 msec. Likewise, treatment should be interrupted and adjusted in accordance with the product labeling in patients who develop QTc prolongation greater than 500 msec. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope. Permanently discontinue osimertinib in patients who develop QTc interval prolongation with life-threatening arrhythmia.

MONITOR: The concomitant use of myelosuppressive, immunosuppressive, or cytotoxic agents may potentiate and/or prolong the bone marrow toxicity associated with niraparib. Thrombocytopenia, anemia, neutropenia, and/or pancytopenia have all been observed with niraparib during clinical trials, especially during the initial phase of treatment. Additionally, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) have been reported in patients treated with niraparib. Some cases were fatal, and the duration of therapy with niraparib in patients who developed MDS/AML varied from less than 1 month to approximately 6 years. All patients had previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy.

MANAGEMENT: Caution is advised if niraparib is prescribed with other myelosuppressive, immunosuppressive, or cytotoxic agents. Do not start niraparib until patients have recovered from hematological toxicity caused by previous chemotherapy (Grade 1 or less). Complete blood counts should be monitored as recommended in the product labeling and any relevant institutional protocols. Recommendations for dose adjustments as well as treatment interruption and discontinuation can also be found in the product labeling for serious hematologic adverse reactions. If hematological toxicities have not resolved within 4 weeks after interruption, discontinue niraparib and refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue niraparib. Patients should be advised to contact their physician if they experience pale skin, weakness, fatigue, fever, weight loss, infections, shortness of breath, unusual bleeding or bruising, or blood in urine or stool.