Drug Interactions between abemaciclib and Provenge

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of abemaciclib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. The interaction has not been studied with grapefruit juice, but has been reported for other CYP450 3A4 inhibitors. According to the product labeling, abemaciclib systemic exposure (AUC) is predicted to increase by up to 16-fold when administered with the potent CYP450 3A4 inhibitor ketoconazole. Itraconazole, another potent inhibitor, is predicted to increase the relative potency-adjusted unbound AUC of abemaciclib plus its active metabolites by 2.2-fold. In cancer patients, administration of a single 50 mg dose of abemaciclib (one-third the approved recommended dose of 150 mg) with clarithromycin 500 mg twice daily increased the relative potency-adjusted unbound AUC of abemaciclib plus its active metabolites by 2.5-fold relative to abemaciclib administered alone. The moderate CYP450 3A4 inhibitors, diltiazem and verapamil, are predicted to increase the relative potency-adjusted unbound AUC of abemaciclib plus its active metabolites by 2.4-fold and 1.6-fold, respectively. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Increased exposure to abemaciclib may increase adverse effects such as nausea, vomiting, diarrhea, stomatitis, venous thromboembolism, hepatotoxicity, anemia, neutropenia, and thrombocytopenia.

Food has modest effects on the pharmacokinetics of abemaciclib. A high-fat, high-calorie meal (800 to 1000 calories; 150 calories from protein, 250 calories from carbohydrate, and 500 to 600 calories from fat) administered to healthy subjects increased the Cmax and AUC of abemaciclib plus its active metabolites by 26% and 9%, respectively.

MANAGEMENT: Abemaciclib may be administered with or without food. Patients should avoid consumption of grapefruit and grapefruit juice during treatment with abemaciclib.

The dosing frequency of abemaciclib should be reduced to once daily when it is administered to patients with severe hepatic impairment (Child-Pugh C). No dosage adjustments are necessary for patients with mild or moderate hepatic impairment (Child-Pugh A or B). Hepatotoxicity has been reported with the use of abemaciclib. It is recommended to monitor liver function tests prior to the start of therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, dose discontinuation, or delay in starting treatment cycles is recommended for patients who develop persistent or recurrent Grade 2, or Grade 3 or 4, hepatic transaminase elevation.

Vascular disorders that include, cerebrovascular and cardiovascular events have occurred with the use of sipuleucel-T. It is recommended to exercise caution when using this agent in patients with risk factors for vascular disorders such as, hemorrhagic and ischemic strokes, and myocardial infarctions. Close monitoring is recommended.

Diarrhea, sometimes associated with dehydration and infection, has occurred in patients receiving abemaciclib. Diarrhea incidence was greatest during the first month of abemaciclib dosing. Care should be exercised when treating patients with symptoms of diarrhea. Treatment discontinuation may be required for Grade 3 or 4 diarrhea, or diarrhea that requires hospitalization. Resume treatment at the next lower dose once toxicity resolves to <= Grade 1 diarrhea.

Diarrhea, sometimes associated with dehydration and infection, has occurred in patients receiving abemaciclib. Diarrhea incidence was greatest during the first month of abemaciclib dosing. Care should be exercised when treating patients with symptoms of diarrhea. Treatment discontinuation may be required for Grade 3 or 4 diarrhea, or diarrhea that requires hospitalization. Resume treatment at the next lower dose once toxicity resolves to <= Grade 1 diarrhea.

Neutropenia, including febrile neutropenia has occurred in patients receiving abemaciclib. Care should be exercised when prescribing this agent to patients with preexisting neutropenia. It is recommended to monitor complete blood counts prior to the start of therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.

Diarrhea, sometimes associated with dehydration and infection, has occurred in patients receiving abemaciclib. Diarrhea incidence was greatest during the first month of abemaciclib dosing. Care should be exercised when treating patients with symptoms of diarrhea. Treatment discontinuation may be required for Grade 3 or 4 diarrhea, or diarrhea that requires hospitalization. Resume treatment at the next lower dose once toxicity resolves to <= Grade 1 diarrhea.

Patients treated with abemaciclib have reported severe, life-threatening, or fatal interstitial lung disease (ILD) and/or pneumonitis. It is recommended to monitor patients for pulmonary symptoms indicative of ILD/pneumonitis such as, hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams. Dose interruption or dose reduction is recommended for patients who develop persistent or recurrent Grade 2 ILD/pneumonitis. Permanently discontinue therapy in all patients with Grade 3 or 4 ILD or pneumonitis.

Vascular disorders that include, cerebrovascular and cardiovascular events have occurred with the use of sipuleucel-T. It is recommended to exercise caution when using this agent in patients with risk factors for vascular disorders such as, hemorrhagic and ischemic strokes, and myocardial infarctions. Close monitoring is recommended.

Neutropenia, including febrile neutropenia has occurred in patients receiving abemaciclib. Care should be exercised when prescribing this agent to patients with preexisting neutropenia. It is recommended to monitor complete blood counts prior to the start of therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.

The use of certain multikinase inhibitors has been associated with pulmonary toxicity. Serious cases of interstitial lung disease (ILD), including fatal cases and interstitial pneumonitis or pulmonary fibrosis have been reported. Caution is recommended when using these agents in patients with a history of interstitial pneumonitis or pulmonary fibrosis or those patients presenting with acute onset of new or progressive unexplained pulmonary symptoms such as dyspnea, cough, and fever pending diagnostic evaluation. If ILD is confirmed, these agents should be permanently discontinued and appropriate measures should be instituted. Treatment should be immediately withheld in patients diagnosed with ILD/pneumonitis and permanently discontinued if no other potential causes of ILD/pneumonitis have been identified.

The use of sipuleucel-T can cause thromboembolism, including deep venous thrombosis and pulmonary embolism. It is recommended to exercise caution when using this agent in patients with risk factors for thromboembolic events. Close monitoring is recommended.

Venous thromboembolic events have been reported with the use of abemaciclib. Care should be exercised when using this agent in patients with risk factors or history of venous thromboembolic events. It is recommended to monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate.