Drug Interactions between fluconazole and gefitinib

Cutaneous reactions, in some cases severe, have been reported with the use of EGFR inhibitors. Monitor patients who develop dermatologic or soft tissue toxicities while receiving these agents for the development of inflammatory or infectious sequelae. It is recommended to withhold treatment, and appropriate measures should be instituted as appropriate or discontinue the use of these agents for dermatologic or soft tissue toxicity associated with severe or life-threatening inflammatory or infectious complications. Advise patients to wear sunscreen and hats and limit sun exposure while receiving therapy with these agents as exposure to sunlight can exacerbate dermatologic toxicities.

The use of some EGFR inhibitors may be associated with gastrointestinal perforation and fatal cases have been reported. Patients receiving concomitant anti-angiogenic agents, corticosteroids, NSAIDs, or taxane-based chemotherapy, or who have prior history of peptic ulceration or diverticular disease may be at increased risk of perforation. Permanently discontinue these agents in patients who develop gastrointestinal perforation.

The use of certain EGFR 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, permanently discontinue these agents and institute appropriate measures.

The use of some EGFR inhibitors may be associated with gastrointestinal perforation and fatal cases have been reported. Patients receiving concomitant anti-angiogenic agents, corticosteroids, NSAIDs, or taxane-based chemotherapy, or who have prior history of peptic ulceration or diverticular disease may be at increased risk of perforation. Permanently discontinue these agents in patients who develop gastrointestinal perforation.

The use of some EGFR inhibitors may be associated with gastrointestinal perforation and fatal cases have been reported. Patients receiving concomitant anti-angiogenic agents, corticosteroids, NSAIDs, or taxane-based chemotherapy, or who have prior history of peptic ulceration or diverticular disease may be at increased risk of perforation. Permanently discontinue these agents in patients who develop gastrointestinal perforation.

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.

Gefitinib undergoes extensive hepatic metabolism. Obtain periodic liver function testing and withhold gefitinib for up to 14 days in patients with worsening liver function (Grade 2 or higher for ALT and/or AST elevations) and resume treatment when the adverse reaction fully resolves or improves to NCI CTCAE Grade 1. Permanently discontinue therapy in patients with severe hepatic impairment. Monitor adverse reactions when gefitinib is administered to patients with moderate and severe hepatic impairment.

Some epidermal growth factor receptor (EGFR) inhibitors should be administered cautiously in patients with ocular disorders such as primary keratitis, ulcerative keratitis, or conjunctivitis. It is recommended to interrupt or discontinue treatment with these agents if patients present with acute or worsening ocular disorders.

The use of certain EGFR 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, permanently discontinue these agents and institute appropriate measures.

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.

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.

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.

Less than four percent (<4%) of gefitinib and its metabolites are excreted via the kidney. Population pharmacokinetic analyses suggest that creatinine clearance (above 20 mL/min) has no clinically meaningful effect on predicted steady state trough concentration of gefitinib. No clinical studies were conducted with gefitinib in patients with severe renal impairment.