Drug Interactions between fluconazole and rucaparib

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 Treatment should be withdrawn if persistent elevations or worsening of liver enzyme levels occur.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.

Cases of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) have been reported with the use of rucaparib. Rucaparib should not be started until patients have recovered from hematological toxicity caused by previous chemotherapy (grade 1 or less). It is recommended to monitor complete blood counts for cytopenia at baseline and monthly thereafter for clinically significant changes during therapy. For hematologic toxicities exceeding 4 weeks, rucaparib should be interrupted or the dosage reduced according to the manufacturer product information; blood counts should be monitored weekly until recovery. If levels have not recovered to grade 1 or less after 4 weeks or if MDS/AML is suspected, the patient should be referred to a hematologist for further investigations (including bone marrow analysis and blood sample for cytogenetics). If MDS/AML is confirmed, rucaparib should be discontinued.

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.

No dose adjustment is recommended for patients with mild to moderate liver dysfunction (total bilirubin up to 3 times the upper limit of normal [3 x ULN] or AST greater than ULN). Caution should be exercised when using this agent in patients with severe liver dysfunction (total bilirubin greater than 3 x ULN and any AST) as rucaparib has not been studied in these patients.

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.

No dose adjustment is recommended for patients with mild to moderate renal dysfunction (CrCl between 30 and 89 mL/min [as estimated by Cockcroft-Gault method]). Caution should be exercised when using this agent in patients with severe renal dysfunction (CrCl less than 30 mL/min) or patients on dialysis as rucaparib has not been studied in these patients.