Drug Interactions between Ascomp with Codeine and niraparib

GENERALLY AVOID: Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants (e.g., nonbenzodiazepine sedatives/hypnotics, anxiolytics, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol) may result in profound sedation, respiratory depression, coma, and death. The risk of hypotension may also be increased with some CNS depressants (e.g., alcohol, benzodiazepines, phenothiazines).

MANAGEMENT: The use of opioids in conjunction with benzodiazepines or other CNS depressants should generally be avoided unless alternative treatment options are inadequate. If coadministration is necessary, the dosage and duration of each drug should be limited to the minimum required to achieve desired clinical effect, with cautious titration and dosage adjustments when needed. Patients should be monitored closely for signs and symptoms of respiratory depression and sedation, and advised to avoid driving or operating hazardous machinery until they know how these medications affect them. Cough medications containing opioids (e.g., codeine, hydrocodone) should not be prescribed to patients using benzodiazepines or other CNS depressants including alcohol. For patients who have been receiving extended therapy with both an opioid and a benzodiazepine and require discontinuation of either medication, a gradual tapering of dose is advised, since abrupt withdrawal may lead to withdrawal symptoms. Severe cases of benzodiazepine withdrawal, primarily in patients who have received excessive doses over a prolonged period, may result in numbness and tingling of extremities, hypersensitivity to light and noise, hallucinations, and epileptic seizures.

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.

One study has reported that coadministration of caffeine and aspirin lead to a 25% increase in the rate of appearance and 17% increase in maximum concentration of salicylate in the plasma. A significantly higher area under the plasma concentration time curve of salicylate was also reported when both drugs were administered together. The exact mechanism of this interaction has not been specified. Physicians and patients should be aware that coadministration of aspirin and caffeine may lead to higher salicylate levels faster.

Coadministration with niraparib may decrease the plasma concentrations of drugs that are substrates of the CYP450 1A2 isoenzyme. At high concentrations, niraparib is able to weakly induce CYP450 1A2. If niraparib is used in combination with substrates of CYP450 1A2, particularly those with a narrow therapeutic range (e.g., clozapine, theophylline, ropinirole), then monitoring for signs and symptoms of reduced exposure to the CYP450 1A2 substrate should be considered.