Fluconazole intravenous

Drug Interactions: (See CONTRAINDICATIONS .) Fluconazole is a moderate CYP2C9 and CYP3A4 inhibitor. Fluconazole is also a strong inhibitor of CYP2C19. Patients treated with Fluconazole in Sodium Chloride Injection, who are also concomitantly treated with drugs with a narrow therapeutic window metabolized through CYP2C9 and CYP3A4, should be monitored for adverse reactions associated with the concomitantly administered drugs. In addition to the observed/documented interactions mentioned below, there is a risk of increased plasma concentration of other compounds metabolized by CYP2C9, CYP2C19, and CYP3A4 coadministered with fluconazole.

Therefore, caution should be exercised when using these combinations and the patients should be carefully monitored. The enzyme inhibiting effect of fluconazole persists 4 to 5 days after discontinuation of fluconazole treatment due to the long half-life of fluconazole.

Clinically or potentially significant drug interactions between fluconazole and the following agents/classes have been observed and are described in greater detail below: Abrocitinib : Drug interaction studies indicate that when co-administered with fluconazole (strong inhibitor of CYP2C19; moderate inhibitor of CYP2C9 and CYP3A4), the systemic exposure of abrocitinib and its active metabolites increased (See CLINICAL PHARMACOLOGY ). Avoid concomitant use of abrocitinib with fluconazole. Refer to the abrocitinib Prescribing Information for additional details.

Alfentanil: A study observed a reduction in clearance and distribution volume as well as prolongation of t ½ of alfentanil following concomitant treatment with fluconazole. A possible mechanism of action is fluconazole’s inhibition of CYP3A4. Dosage adjustment of alfentanil may be necessary. Amiodarone : Concomitant administration of fluconazole with amiodarone may increase QT prolongation. Caution must be exercised if the concomitant use of fluconazole and amiodarone is necessary, notably with high-dose fluconazole (800 mg). Amitriptyline, nortriptyline: Fluconazole increases the effect of amitriptyline and nortriptyline.

5-Nortriptyline and/or S-amitriptyline may be measured at initiation of the combination therapy and after 1 week. Dosage of amitriptyline/nortriptyline should be adjusted, if necessary. Amphotericin B: Concurrent administration of fluconazole and amphotericin B in infected normal and immunosuppressed mice showed the following results: a small additive antifungal effect in systemic infection with Candida albicans , no interaction in intracranial infection with Cryptococcus neoformans , and antagonism of the two drugs in systemic infection with A. fumigatus . The clinical significance of results obtained in these studies is unknown.

Azithromycin : An open-label, randomized, three-way crossover study in 18 healthy subjects assessed the effect of a single 1200 mg oral dose of azithromycin on the pharmacokinetics of a single 800 mg oral dose of fluconazole as well as the effects of fluconazole on the pharmacokinetics of azithromycin. There was no significant pharmacokinetic interaction between fluconazole and azithromycin. Calcium channel blockers : Certain calcium channel antagonists (nifedipine, isradipine, amlodipine, verapamil, and felodipine) are metabolized by CYP3A4. Fluconazole has the potential to increase the systemic exposure of the calcium channel antagonists.

Frequent monitoring for adverse events is recommended. Carbamazepine : Fluconazole inhibits the metabolism of carbamazepine and an increase in serum carbamazepine of 30% has been observed. There is a risk of developing carbamazepine toxicity. Dosage adjustment of carbamazepine may be necessary depending on concentration measurements/effect. Celecoxib : During concomitant treatment with fluconazole (200 mg daily) and celecoxib (200 mg), the celecoxib C max and AUC increased by 68% and 134%, respectively. Half of the celecoxib dose may be necessary when combined with fluconazole.

Coumarin-type anticoagulants : Prothrombin time may be increased in patients receiving concomitant fluconazole and coumarin-type anticoagulants. In post-marketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena) have been reported in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. Careful monitoring of prothrombin time in patients receiving fluconazole and coumarin-type anticoagulants is recommended. Dose adjustment of warfarin may be necessary.

(See CLINICAL PHARMACOLOGY: Drug Interaction Studies .) Cyclophosphamide : Combination therapy with cyclophosphamide and fluconazole results in an increase in serum bilirubin and serum creatinine. The combination may be used while taking increased consideration to the risk of increased serum bilirubin and serum creatinine. Cyclosporine : Fluconazole significantly increases cyclosporine levels in renal transplant patients with or without renal impairment. Careful monitoring of cyclosporine concentrations and serum creatinine is recommended in patients receiving fluconazole and cyclosporine.

(See CLINICAL PHARMACOLOGY: Drug Interaction Studies .) This combination may be used by reducing the dosage of cyclosporine depending on cyclosporine concentration. Fentanyl : One fatal case of possible fentanyl-fluconazole interaction was reported. The author judged that the patient died from fentanyl intoxication. Furthermore, in a randomized crossover study with 12 healthy volunteers, it was shown that fluconazole delayed the elimination of fentanyl significantly. Elevated fentanyl concentration may lead to respiratory depression.

HMG-CoA reductase inhibitors : The risk of myopathy and rhabdomyolysis increases when fluconazole is co-administered with HMG-CoA reductase inhibitors metabolized through CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin (decreased hepatic metabolism of the statin). If concomitant therapy is necessary, the patient should be observed for symptoms of myopathy and rhabdomyolysis and creatinine kinase should be monitored. HMG-CoA reductase inhibitors should be discontinued if a marked increase in creatinine kinase is observed or myopathy/rhabdomyolysis is diagnosed or suspected. Dose reduction of statins may be needed.

Refer to the statin-specific prescribing information for details. Hydrochlorothiazide : In a pharmacokinetic interaction study, coadministration of multiple-dose hydrochlorothiazide to healthy volunteers receiving fluconazole increased plasma concentrations of fluconazole by 40%. An effect of this magnitude should not necessitate a change in the fluconazole dose regimen in subjects receiving concomitant diuretics. Ibrutinib : Moderate inhibitors of CYP3A4 such as fluconazole may increase plasma ibrutinib concentrations and increase risk of adverse reactions associated with ibrutinib.

If ibrutinib and fluconazole are concomitantly administered, reduce the dose of ibrutinib as instructed in ibrutinib prescribing information and the patient should be frequently monitored for any adverse reactions associated with ibrutinib. Ivacaftor and fixed dose ivacaftor combinations (e.g., tezacaftor/ivacaftor and ivacaftor/tezacaftor/elexacaftor): Coadministration with ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, increased ivacaftor exposure by 3-fold.

If used concomitantly with a moderate inhibitor of CYP3A4, such as fluconazole, a reduction in the dose of ivacaftor (or ivacaftor combination) is recommended as instructed in the ivacaftor (or ivacaftor combination) prescribing information. Lemborexant: Concomitant administration of fluconazole increased lemborexant C max and AUC by approximately 1.6- and 4.2-fold, respectively which is expected to increase risk of adverse reactions, such as somnolence. Avoid concomitant use of fluconazole with lemborexant.

Losartan : Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74) which is responsible for most of the angiotensin Il-receptor antagonism which occurs during treatment with losartan. Patients should have their blood pressure monitored continuously. Lurasidone : Concomitant use of moderate inhibitors of CYP3A4 such as fluconazole may increase lurasidone plasma concentrations. If concomitant use cannot be avoided, reduce the dose of lurasidone as instructed in the lurasidone prescribing information. Methadone : Fluconazole may enhance the serum concentration of methadone. Dosage adjustment of methadone may be necessary.

Non-steroidal anti-inflammatory drugs: The C max and AUC of flurbiprofen were increased by 23% and 81%, respectively, when coadministered with fluconazole compared to administration of flurbiprofen alone. Similarly, the C max and AUC of the pharmacologically active isomer [S-(+)-ibuprofen] were increased by 15% and 82%, respectively, when fluconazole was…

Pregnancy Teratogenic Effects Potential for Fetal Harm: Use in pregnancy should be avoided except in patients with severe or potentially life-threatening fungal infections in whom fluconazole may be used if the anticipated benefit outweighs the possible risk to the fetus. A few published case reports describe a pattern of distinct congenital anomalies in infants exposed in utero to high dose maternal fluconazole (400 to 800 mg/day) during most or all of the first trimester. These reported anomalies are similar to those seen in animal studies.

Effective contraceptive measures should be considered in women of child-bearing potential who are being treated with Fluconazole 400 to 800 mg/day and should continue throughout the treatment period and for approximately 1 week (5 to 6 half-lives) after the final dose. If fluconazole is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be informed of the potential hazard to the fetus. Spontaneous abortions and congenital abnormalities have been suggested as potential risks associated with 150 mg of fluconazole as a single or repeated dose in the first trimester of pregnancy based on retrospective epidemiological studies.

There are no adequate and well-controlled studies of fluconazole in pregnant women. (See WARNINGS: Potential for Fetal Harm .) Human Data Case reports describe a distinctive and rare pattern of birth defects among infants whose mothers received high-dose (400 to 800 mg/day) fluconazole during most or all of the first trimester of pregnancy. The features seen in these infants include brachycephaly, abnormal facies, abnormal calvarial development, cleft palate, femoral bowing, thin ribs and long bones, arthrogryposis, and congenital heart disease. These effects are similar to those seen in animal studies.

Epidemiological studies suggest a potential risk of spontaneous abortion and congenital abnormalities in infants whose mothers were treated with 150 mg of fluconazole as a single or repeated dose in the first trimester, but these epidemiological studies have limitations and these findings have not been confirmed in controlled clinical trials. Animal Data Fluconazole was administered orally to pregnant rabbits during organogenesis in two studies at doses of 5 mg/kg, 10 mg/kg, and 20 mg/kg and at 5 mg/kg, 25 mg/kg, and 75 mg/kg, respectively.

Maternal weight gain was impaired at all dose levels (approximately 0.25 to 4 times the 400 mg clinical dose based on body surface area [BSA] comparison), and abortions occurred at 75 mg/kg (approximately 4 times…

Nursing Mothers Fluconazole was present in low levels in breast milk following administration of a single 150 mg dose, based on data from a study in 10 breastfeeding women who temporarily or permanently discontinued breastfeeding 5 days to 19 months postpartum. The estimated daily infant dose of fluconazole from breast milk (assuming mean milk consumption of 150 mL/kg/day) based on the mean peak milk concentration (2.61 mcg/mL [range: 1.57 to 3.65 mcg/mL] at 5.2 hours post-dose) was 0.39 mg/kg/day, which is approximately 13% of the recommended pediatric dose for oropharyngeal candidiasis.

(Labeled pediatric dose is 6 mg/kg/day on the first day followed by 3 mg/kg/day; estimated infant dose is 13% of 3 mg/kg/day maintenance dose). There are no data on fluconazole levels in milk after repeated use or after high-dose fluconazole. A published survey of 96 breastfeeding women who were treated with fluconazole 150 mg every other day (average of 7.3 capsules [range 1 to 29 capsules]) for lactation-associated candida of the breasts reported no serious adverse reactions in infants. Caution should be exercised when Fluconazole is administered to a nursing woman.