Drug Interactions between fluconazole and temsirolimus

If you are receiving therapy with temsirolimus you should avoid grapefruits and grapefruit juice. Grapefruit can raise the levels of temsirolimus in your body and lead to dangerous side effects. Do not increase or decrease the amount of grapefruit products in your diet without first talking to your doctor.

Hypersensitivity/infusion reactions, including but not limited to flushing, chest pain, dyspnea, hypotension, apnea, loss of consciousness, hypersensitivity and anaphylaxis, have been associated with the administration of temsirolimus. Caution should be exercised during the infusion and appropriate supportive care should be available. For patients who develop hypersensitivity reaction during the infusion, it is recommended to stop the infusion and close observation with the possibility of resuming therapy at a slower rate should be contemplated at the discretion of the physician. Temsirolimus infusion should be interrupted in all patients with severe infusion reactions and appropriate medical therapy administered. A benefit-risk assessment should be done prior to the continuation of therapy in patients with severe or life-threatening reactions.

Hypersensitivity/infusion reactions, including but not limited to flushing, chest pain, dyspnea, hypotension, apnea, loss of consciousness, hypersensitivity and anaphylaxis, have been associated with the administration of temsirolimus. Caution should be exercised during the infusion and appropriate supportive care should be available. For patients who develop hypersensitivity reaction during the infusion, it is recommended to stop the infusion and close observation with the possibility of resuming therapy at a slower rate should be contemplated at the discretion of the physician. Temsirolimus infusion should be interrupted in all patients with severe infusion reactions and appropriate medical therapy administered. A benefit-risk assessment should be done prior to the continuation of therapy in patients with severe or life-threatening reactions.

Cases of fatal bowel perforation occurred in patients who received temsirolimus. Therapy with temsirolimus should be administered 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 or worsening of abdominal symptoms or blood in the stools should be evaluated promptly for early identification of 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.

Temsirolimus is contraindicated in patients with bilirubin >1.5×ULN. Caution is recommended when treating patients with mild hepatic impairment and a dose reduction may be needed depending on AST and bilirubin levels. Dosage adjustment is needed based on hepatic function; therefore, assessment of AST and bilirubin levels is recommended before initiation of therapy and periodically thereafter.

Cases of renal failure, including acute renal failure and elevations of serum creatinine and proteinuria, some with a fatal outcome, have been observed in patients treated with inhibitors of mTOR (mammalian target of rapamycin). Therapy with these agents should be administered cautiously in patients with renal dysfunction, in particularly where patients have additional risk factors that may further impair renal function. Renal impairment is not expected to influence drug exposure, and no dosage adjustment is recommended in patients with renal impairment. Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein, or serum creatinine, is recommended prior to the start of therapy and periodically thereafter.

The administration of live vaccines should be avoided during therapy with inhibitor of mTOR (mammalian target of rapamycin). It is recommended that close contact with individuals who have received live vaccines should be avoided because of the potential risk for shedding from the household contact and transmission to patient. It is recommended to be up-to-date with all required immunizations, as recommended by current immunization guidelines, before initiating therapy with these agents.

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.

Inhibition of mTOR activity results in delays of wound healing and increases the occurrence of wound-related complications, which might require surgical intervention. Patients with central nervous system tumors (primary CNS tumor or metastases) and/or receiving anticoagulation therapy may be at an increased risk of developing intracerebral bleeding (including fatal outcomes). Caution is recommended when using these agents, particularly in the perioperative period.

Inhibition of mTOR activity results in delays of wound healing and increases the occurrence of wound-related complications, which might require surgical intervention. Patients with central nervous system tumors (primary CNS tumor or metastases) and/or receiving anticoagulation therapy may be at an increased risk of developing intracerebral bleeding (including fatal outcomes). Caution is recommended when using these agents, particularly in the perioperative period.

Elevations in serum blood glucose levels have been reported in patients taking inhibitors of mTOR (mammalian target of rapamycin). Monitoring of fasting serum glucose levels is recommended prior to the start of therapy and periodically thereafter. Clinicians should achieve control of glucose levels before initiating therapy with these agents.

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.

Elevations in cholesterol and triglyceride levels have been reported in patients taking inhibitors of mTOR (mammalian target of rapamycin). Monitoring of fasting lipid profile is recommended prior to the start of therapy and periodically thereafter. Clinicians should achieve control of lipid levels before initiating therapy with these agents.

The immunosuppressant effect of inhibitors of mTOR (mammalian target of rapamycin) may decrease host resistance to infectious agents and may predispose patients to bacterial, fungal, viral, or protozoal infections, infections with opportunistic pathogens, and reactivation of viral infections. Therapy with these agents should be administered with caution in patients with an infection, particularly active infections or any untreated systemic fungal, bacterial, parasitic, or viral infection. It is recommended to complete the treatment of preexisting invasive fungal infections prior to starting treatment and if a diagnosis of invasive systemic fungal infection is made during treatment, discontinue and treat with appropriate antifungal therapy.

Cases of interstitial lung disease, some resulting in death, occurred in patients who received temsirolimus. It is recommended that patients undergo baseline radiographic assessment by lung computed tomography scan or chest radiograph prior to the initiation of therapy. Close monitoring for the occurrence of any new or worsening respiratory symptoms is advisable and if clinically significant respiratory symptoms develop, consider withholding administration until after recovery of symptoms and improvement of radiographic findings related to pneumonitis.

Cases of interstitial lung disease, some resulting in death, occurred in patients who received temsirolimus. It is recommended that patients undergo baseline radiographic assessment by lung computed tomography scan or chest radiograph prior to the initiation of therapy. Close monitoring for the occurrence of any new or worsening respiratory symptoms is advisable and if clinically significant respiratory symptoms develop, consider withholding administration until after recovery of symptoms and improvement of radiographic findings related to pneumonitis.

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.