Drug Interactions between axitinib and fluconazole

Do not consume grapefruit or grapefruit juice during treatment with axitinib unless directed otherwise by your doctor. Grapefruit juice can increase the blood levels of axitinib. This may increase the risk and/or severity of side effects such as high blood pressure, diarrhea, nausea, vomiting, constipation, decreased appetite, weight loss, and rash, itching or peeling of skin on the hands and feet. You may also be more likely to experience less common but more severe side effects such as blood clots (depending on location, can lead to complications such as stroke, heart attack, breathing difficulties, and vision abnormalities); bleeding; liver problems; thyroid problems; tearing (perforation) in the stomach or intestinal wall; and a rare nervous system condition known as reversible posterior leukoencephalopathy syndrome (RPLS). You should seek immediate medical attention if you develop signs and symptoms of these conditions including chest pain or pressure; pain in the arms, back, neck or jaw; swelling; shortness of breath; numbness or weakness on one side of the body; headache; vision changes; seizures, unusual bleeding or bruising; red or black stools; coughing up or vomiting blood or blood clots; and severe stomach or abdominal pain. It is important to tell your doctor about all other medications you use, including vitamins and herbs. Do not stop using any medications without first talking to your doctor.

Fatal hemorrhagic events, including cerebral hemorrhage, hematuria, hemoptysis, lower gastrointestinal hemorrhage, and melena have been reported with the use of axitinib. Therapy with axitinib has not been studied in patients who have evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in these patients. If any bleeding requires medical intervention, it is recommended to temporarily interrupt the axitinib dose and to stop treatment at least 24 hours prior to scheduled surgery. The decision to resume therapy after surgery should be based on clinical judgment of adequate wound healing.

The use of fluconazole has been rarely associated with hepatotoxicity. Reversible idiosyncratic hepatitis, cholestasis and fatal fulminant hepatic failure have been reported, the latter occurring primarily in patients with serious underlying medical conditions and taking multiple concomitant medications. Liver function tests should be performed periodically in patients with preexisting hepatic abnormalities, particularly during prolonged therapy. Treatment should be withdrawn if persistent elevations or worsening of liver enzyme levels occur.

Some azole antifungals have been associated with prolongation of the QT interval on the ECG. Rare cases of QT prolongation and torsade de pointes have been reported during postmarketing experience; such reports usually involved seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities, and concomitant medications. These drugs should be administered with caution to patients with potentially proarrhythmic conditions, such as congenital/acquired QT prolongation, cardiomyopathy (especially when heart failure is present), sinus bradycardia, and existing symptomatic arrhythmias. Concomitant use with other medications that have potential to increase the risk of cardiotoxicity should be avoided.

Arterial and venous thromboembolic events, including transient ischemic attack, cerebrovascular accident, myocardial infarction, pulmonary embolism, deep vein thrombosis, retinal occlusion, vein thrombosis, and deaths have been reported with the use of axitinib. Use with caution in patients who are at risk for, or who have a history of, these events. The use of axitinib has not been studied in patients who had an arterial or venous thromboembolic event within the previous 12 months. It is recommended to monitor closely for signs and symptoms of thromboembolism.

Cardiac failure, including fatal events have been reported in patients receiving axitinib. It is recommended to monitor for signs or symptoms of cardiac failure throughout treatment. Management of cardiac failure may require permanent discontinuation of therapy. Care should be taken when using this agent in patients at risk.

Therapy with axitinib should be used with caution in patients who may be at increased risk for gastrointestinal perforation, such as those with a history of diverticulitis. Patients presenting with new onset of abdominal symptoms should be evaluated promptly for early identification of gastrointestinal perforation. It is recommended to monitor for symptoms of gastrointestinal perforation or fistula periodically throughout the treatment.

Therapy with axitinib should be used with caution in patients who may be at increased risk for gastrointestinal perforation, such as those with a history of diverticulitis. Patients presenting with new onset of abdominal symptoms should be evaluated promptly for early identification of gastrointestinal perforation. It is recommended to monitor for symptoms of gastrointestinal perforation or fistula periodically throughout the treatment.

Fluconazole is substantially removed by hemodialysis. Plasma levels of fluconazole has been shown to reduce by 50% following 3 hours of dialysis. Fluconazole should be administered after hemodialysis.

Arterial and venous thromboembolic events, including transient ischemic attack, cerebrovascular accident, myocardial infarction, pulmonary embolism, deep vein thrombosis, retinal occlusion, vein thrombosis, and deaths have been reported with the use of axitinib. Use with caution in patients who are at risk for, or who have a history of, these events. The use of axitinib has not been studied in patients who had an arterial or venous thromboembolic event within the previous 12 months. It is recommended to monitor closely for signs and symptoms of thromboembolism.

Arterial and venous thromboembolic events, including transient ischemic attack, cerebrovascular accident, myocardial infarction, pulmonary embolism, deep vein thrombosis, retinal occlusion, vein thrombosis, and deaths have been reported with the use of axitinib. Use with caution in patients who are at risk for, or who have a history of, these events. The use of axitinib has not been studied in patients who had an arterial or venous thromboembolic event within the previous 12 months. It is recommended to monitor closely for signs and symptoms of thromboembolism.

The use of axitinib may causes hypertension. Blood pressure should be well-controlled prior to initiating axitinib and treated as needed with standard anti-hypertensive therapy. It is recommended to reduce the dose in case of persistent hypertension despite use of anti-hypertensive medications and to discontinue therapy if hypertension is severe and persistent despite these measures. Discontinuation of therapy should be considered if there is evidence of hypertensive crisis. Close monitoring is recommended.

Thyroid level fluctuations that include hypothyroidism and hyperthyroidism have been reported with the use of axitinib. It is recommended to monitor thyroid function before initiation of, and periodically throughout treatment and to maintain euthyroid state according to standard medical practice.

Thyroid level fluctuations that include hypothyroidism and hyperthyroidism have been reported with the use of axitinib. It is recommended to monitor thyroid function before initiation of, and periodically throughout treatment and to maintain euthyroid state according to standard medical practice.

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.

Arterial and venous thromboembolic events, including transient ischemic attack, cerebrovascular accident, myocardial infarction, pulmonary embolism, deep vein thrombosis, retinal occlusion, vein thrombosis, and deaths have been reported with the use of axitinib. Use with caution in patients who are at risk for, or who have a history of, these events. The use of axitinib has not been studied in patients who had an arterial or venous thromboembolic event within the previous 12 months. It is recommended to monitor closely for signs and symptoms of thromboembolism.

The systemic exposure to axitinib is higher in subjects with moderate hepatic impairment. Dose adjustment is recommended in patients with moderate hepatic impairment. No dose adjustment is required in patients with mild hepatic impairment. The use of axitinib has not been studied in subjects with severe hepatic impairment. It is recommended to monitor liver enzymes and bilirubin before the start of therapy and periodically thereafter.

Reversible posterior leukoencephalopathy syndrome (RPLS) has been reported in patients receiving axitinib. Consider this syndrome in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. It is recommended to discontinue therapy in patients developing RPLS. The safety of reinitiating therapy in patients previously experiencing RPLS is not known. Care and close monitoring should be considered in these patients.

Proteinuria has been reported in patients taking axitinib. It is recommended to monitor for proteinuria before initiation of therapy, and periodically thereafter. Reduce dose or temporarily interrupt therapy in patients who develop moderate to severe proteinuria.

Arterial and venous thromboembolic events, including transient ischemic attack, cerebrovascular accident, myocardial infarction, pulmonary embolism, deep vein thrombosis, retinal occlusion, vein thrombosis, and deaths have been reported with the use of axitinib. Use with caution in patients who are at risk for, or who have a history of, these events. The use of axitinib has not been studied in patients who had an arterial or venous thromboembolic event within the previous 12 months. It is recommended to monitor closely for signs and symptoms of thromboembolism.

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.

Based on population pharmacokinetic analyses no starting dose adjustment is needed for patients with mild to severe renal impairment. It is recommended to take caution in patients with end-stage renal disease.

Fluconazole is primarily eliminated by the kidney. Patients with renal impairment may be at greater risk for adverse effects from fluconazole due to decreased drug clearance. Dosage adjustments are recommended for patients with moderate to severe renal impairment (CrCl <= 50 mL/min) receiving multiple doses of the drug.

Arterial and venous thromboembolic events, including transient ischemic attack, cerebrovascular accident, myocardial infarction, pulmonary embolism, deep vein thrombosis, retinal occlusion, vein thrombosis, and deaths have been reported with the use of axitinib. Use with caution in patients who are at risk for, or who have a history of, these events. The use of axitinib has not been studied in patients who had an arterial or venous thromboembolic event within the previous 12 months. It is recommended to monitor closely for signs and symptoms of thromboembolism.