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  • Diflucan
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    Active Ingredient
    Fluconazole 50 mg / 5 ml

    Status in Israel
    RX

    Presentation and Status in Health Basket

    Presentation Basket Yarpa Pharmasoft

    Powder

    35 ml

    partial basket chart 76478 4182

    Related information


    Dosage

    The dose should be based on the nature and severity of the fungal infection. Treatment of infections requiring multiple dosing should be continued until clinical parameters or laboratory tests indicate that active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection.
    Adults: For adults dosing please refer to table 1 at the attached doctor’s leaflet.
    Elderly: Dosage should be adjusted based on the renal function (see “Renal impairment”).
    Renal impairment: Fluconazole is predominantly excreted in the urine as unchanged active substance. No adjustments in single dose therapy are necessary. In patients (including paediatric population) with impaired renal function who will receive multiple doses of fluconazole, an initial dose of 50 mg to 400 mg should be given, based on the recommended daily dose for the indication. After this initial loading dose, the daily dose (according to indication) should be based on the following:
    Creatinine clearance (ml/min)>50: Percent of recommended dose- 100%.
    Creatinine clearance (ml/min)≤50 (no haemodialysis): Percent of recommended dose- 50%.
    Haemodialysis: Percent of recommended dose- 100% after each haemodialysis.
    Patients on haemodialysis should receive 100% of the recommended dose after each haemodialysis; on non-dialysis days, patients should receive a reduced dose according to their creatinine clearance.
    Hepatic impairment: Limited data are available in patients with hepatic impairment, therefore fluconazole should be administered with caution to patients with liver dysfunction.
    Paediatric population: A maximum dose of 400 mg daily should not be exceeded in paediatric population.
    As with similar infections in adults, the duration of treatment is based on the clinical and mycological response. Fluconazoleis administered as a single daily dose.
    For paediatric patients with impaired renal function, see dosing in “Renal impairment”. The pharmacokinetics of fluconazole has not been studied in paediatric population with renal insufficiency (for “Term newborn infants” who often exhibit primarily renal immaturity please see below).
    Infants, toddlers and children (from 28 days to 11 years old): Please refer to table 2 at the attached doctor’s leaflet.
    Adolescents (from 12 to 17 years old): Depending on the weight and pubertal development, the prescriber would need to assess which posology (adults or children) is the most appropriate. Clinical data indicate that children have a higher fluconazole clearance than observed for adults. A dose of 100, 200 and 400 mg in adults corresponds to a 3, 6 and 12 mg/kg dose in children to obtain a comparable systemic exposure.
    Safety and efficacy for genital candidiasis indication in paediatric population has not been established. Current available safety data for other paediatric indications are described in section 4.8. If treatment for genital candidiasis is imperative in adolescents (from 12 to 17 years old), the posology should be the same as adults posology.
    Term newborn infants (0 to 27 days): Neonates excrete fluconazole slowly. There are few pharmacokinetic data to support this posology in term newborn infants. Please refer to table 3 at the attached doctor’s leaflet.
    Method of administration: Fluconazole may be administered either orally (Capsules and Powder for Oral Suspension) or by intravenous infusion (Solution for Infusion), the route being dependent on the clinical state of the patient. On transferring from the intravenous to the oral route, or vice versa, there is no need to change the daily dose.
    The physician should prescribe the most appropriate pharmaceutical form and strength according to age, weight and dose. The capsule formulation is not adapted for use in infants and small children. Oral liquid formulations of fluconazole are available that are more suitable in this population.
    Diflucan can be taken with or without food.
    See prescribing information for full details.


    Indications

    Fluconazole is indicated in adults for the treatment of:
    • Cryptococcal meningitis.
    • Coccidioidomycosis.
    • Invasive candidiasis.
    • Mucosal candidiasis including oropharyngeal, oesophageal candidiasis, candiduria and chronic mucocutaneous candidiasis.
    • Chronic oral atrophic candidiasis (denture sore mouth) if dental hygiene or topical treatment are insufficient.
    • Vaginal candidiasis, acute or recurrent; when local therapy is not appropriate.
    • Candidal balanitis when local therapy is not appropriate.
    • Dermatomycosis including tinea pedis, tinea corporis, tinea cruris, tinea versicolor and dermal candida infections when systemic therapy is indicated.
    • Tinea unguinium (onychomycosis) when other agents are not considered appropriate.
    Fluconazole is indicated in adults for the prophylaxis of:
    • Relapse of cryptococcal meningitis in patients with high risk of recurrence.
    • Relapse of oropharyngeal or oesophageal candidiasis in patients infected with HIV who are at high risk of experiencing relapse.
    • To reduce the incidence of recurrent vaginal candidiasis (4 or more episodes a year).
    • Prophylaxis of candidal infections in patients with prolonged neutropenia (such as patients with haematological malignancies receiving chemotherapy or patients receiving Hematopoietic Stem Cell Transplantation (see section 5.1)).
    Fluconazole is indicated in term newborn infants, infants, toddlers, children, and adolescents aged from 0 to 17 years old:
    Fluconazole is used for the treatment of mucosal candidiasis (oropharyngeal, oesophageal), invasive candidiasis, cryptococcal meningitis and the prophylaxis of candidal infections in immunocompromised patients. Fluconazole can be used as maintenance therapy to prevent relapse of cryptococcal meningitis in children with high risk of reoccurrence.
    Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly.
    Consideration should be given to official guidance on the appropriate use of antifungals.


    Contra-Indications

    Fluconazole should not be used in patients with known hypersensitivity to the drug, any of the inert ingredients or to related triazole compounds. Coadministration of terfenadine is contraindicated in patients receiving fluconazole at multiple doses of 400 mg per day or higher based upon results of a multiple dose interaction study. Co-administration of other drugs known to prolong the QT interval and which are metabolised via the enzyme CYP3A4 such as cisapride, astemizole, erythromycin, pimozide and quinidine are contraindicated in patients receiving fluconazole.


    Special Precautions

    Tinea capitis: Fluconazole has been studied for treatment of tinea capitis in children. It was shown not to be superior to griseofulvin and the overall success rate was less than 20%. Therefore, fluconazole should not be used for tinea capitis.
    Cryptococcosis: The evidence for efficacy of fluconazole in the treatment of cryptococcosis of other sites (e.g. pulmonary and cutaneous cryptococcosis) is limited, which prevents dosing recommendations.
    Deep endemic mycoses: The evidence for efficacy of fluconazole in the treatment of other forms of endemic mycoses such as paracoccidioidomycosis, lymphocutaneous sporotrichosis and histoplasmosis is limited, which prevents specific dosing recommendations.
    Renal system: Fluconazole should be administered with caution to patients with renal dysfunction.
    Adrenal insufficiency: Ketoconazole is known to cause adrenal insufficiency, and this could also although rarely seen be applicable to fluconazole. Adrenal insufficiency relating to concomitant treatment with prednisone.
    Hepatobiliary system: Fluconazole should be administered with caution to patients with liver dysfunction.
    Fluconazole has been associated with rare cases of serious hepatic toxicity including fatalities, primarily in patients with serious underlying medical conditions. In cases of fluconazole associated hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, sex or age of patient has been observed. Fluconazole hepatotoxicity has usually been reversible on discontinuation of therapy.
    Patients who develop abnormal liver function tests during fluconazole therapy must be monitored closely for the development of more serious hepatic injury.
    The patient should be informed of suggestive symptoms of serious hepatic effect (important asthenia, anorexia, persistent nausea, vomiting and jaundice). Treatment of fluconazole should be immediately discontinued and the patient should consult a physician.
    Cardiovascular system: Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. Fluconazole causes QT prolongation via the inhibition of Rectifier Potassium Channel current (Ikr). The QT prolongation caused by other medicinal products (such as amiodarone) may be amplified via the inhibition of cytochrome P450 (CYP) 3A4. During post-marketing surveillance, there have been very rare cases of QT prolongation and torsades de pointes in patients taking fluconazole. These reports included seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities and concomitant treatment that may have been contributory. Patients with hypokalemia and advanced cardiac failure are at an increased risk for the occurrence of life threatening ventricular arrhythmias and torsades de pointes.
    Fluconazole should be administered with caution to patients withpotentially proarrhythmic conditions.
    Coadministration of other medicinal products known to prolong the QT interval and which are metabolised via the cytochrome P450 (CYP) 3A4 are contraindicated.
    Halofantrine: Halofantrine has been shown to prolong QTc interval at the recommended therapeutic dose and is a substrate of CYP3A4. The concomitant use of fluconazole and halofantrine is therefore not recommended.
    Dermatological reactions: Patients have rarely developed exfoliative cutaneous reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, during treatment with fluconazole. Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported. AIDS patients are more prone to the development of severe cutaneous reactions to many medicinal products. If a rash, which is considered attributable to fluconazole, develops in a patient treated for a superficial fungal infection, further therapy with this medicinal product should be discontinued. If patients with invasive/systemic fungal infections develop rashes, they should be monitored closely and fluconazole discontinued if bullous lesions or erythema multiforme develop.
    Hypersensitivity: In rare cases anaphylaxis has been reported.
    Cytochrome P450: Fluconazole is a moderate CYP2C9 and CYP3A4 inhibitor. Fluconazole is also a strong inhibitor of CYP2C19. Fluconazole treated patients who are concomitantly treated with medicinal products with a narrow therapeutic window metabolised through CYP2C9, CYP2C19 and CYP3A4, should be monitored.
    Terfenadine: The coadministration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored.
    Candidiasis:
    Studies have shown an increasing prevalence of infections with Candida species other than C. albicans. These are often inherently resistant (e.g. C. krusei and C. auris) or show reduced susceptibility to fluconazole (C. glabrata). Such infections may require alternative antifungal therapy secondary to treatment failure. Therefore, prescribers are advised to take into account the prevalence of resistance in various Candida species to fluconazole.
    Excipients: Diflucan powder for oral suspension contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose/galactose malabsorption and sucrase-isomaltase insufficiency should not take this medicine. Doses of 10 ml contain 5.5 g or more of sugar. This should be taken into account in patients with diabetes mellitus.
    The medicinal product may be harmful to teeth if used for periods of longer than 2 weeks.
    Diflucan powder for oral suspension contains sodium benzoate. The 60 ml capacity bottle contains 83 mg of sodium benzoate per bottle which is equivalent to 2.37 mg/ml.
    Sodium benzoate may increase jaundice (yellowing of the skin and eyes) in newborn babies (up to 4 weeks old).
    When reconstituted, Diflucan 10 mg/ml powder for oral suspension contains 1.13 mg sodium per ml. This is equivalent to 4.5% of the WHO recommended maximum daily intake of 2 g sodium for an adult.


    Side Effects

    Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported in association with fluconazole treatment.
    The most frequently (>1/10) reported adverse reactions are headache, abdominal pain, diarrhoea, nausea, vomiting, alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased and rash.
    See prescribing information for full details.


    Drug interactions

    Concomitant use of the following other medicinal products is contraindicated:
    Cisapride: There have been reports of cardiac events including torsades de pointes in patients to whom fluconazole and cisapride were coadministered. A controlled study found that concomitant fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant increase in cisapride plasma levels and prolongation of QTc interval. Concomitant treatment with fluconazole and cisapride is contraindicated.
    Terfenadine: Because of the occurrence of serious cardiac dysrhythmias secondary to prolongation of the QTc interval in patients receiving azole
    antifungals in conjunction with terfenadine, interaction studies have been performed. One study at a 200 mg daily dose of fluconazole failed to demonstrate a prolongation in QTc interval. Another study at a 400 mg and 800 mg daily dose of fluconazole demonstrated that fluconazole taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. The combined use of fluconazole at doses of 400 mg or greater with terfenadine is contraindicated. The coadministration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored.
    Astemizole: Concomitant administration of fluconazole with astemizole may
    decrease the clearance of astemizole. Resulting increased plasma concentrations of astemizole can lead to QT prolongation and rare occurrences of torsades de pointes. Coadministration of fluconazole and astemizole is contraindicated.
    Pimozide: Although not studied in vitro or in vivo, concomitant administration
    of fluconazole with pimozide may result in inhibition of pimozide metabolism.
    Increased pimozide plasma concentrations can lead to QT prolongation and rare
    occurrences of torsades de pointes. Coadministration of fluconazole and
    pimozide is contraindicated.
    Quinidine: Although not studied in vitro or in vivo, concomitant administration of fluconazole with quinidine may result in inhibition of quinidine metabolism. Use of quinidine has been associated with QT prolongation and rare occurrences of torsades de pointes. Coadministration of fluconazole and quinidine is contraindicated.
    Erythromycin: Concomitant use of fluconazole and erythromycin has the
    potential to increase the risk of cardiotoxicity (prolonged QT interval, torsades de pointes) and consequently sudden heart death. Coadministration of fluconazole and erythromycin is contraindicated.
    Concomitant use of the following other medicinal products cannot be recommended:
    Halofantrine: Fluconazole can increase halofantrine plasma concentration due to an inhibitory effect on CYP3A4. Concomitant use of fluconazole and halofantrine has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsades de pointes) and consequently sudden heart death. This combination should be avoided.
    Concomitant use that should be used with caution:
    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).
    Concomitant use of the following other medicinal products lead to precautions and dose adjustments:
    The effect of other medicinal products on fluconazole:
    Rifampicin:
    Concomitant administration of fluconazole and rifampicin resulted in a 25% decrease in the AUC and a 20% shorter half-life of fluconazole. In patients receiving concomitant rifampicin, an increase of the fluconazole dose should be considered.
    Interaction studies have shown that when oral fluconazole is coadministered with food, cimetidine, antacids or following total body irradiation for bone marrow transplantation, no clinically significant impairment of fluconazole absorption occurs.
    Hydrochlorothiazide: In a pharmacokinetic interaction study, coadministration of multiple-dose hydrochlorothiazide to healthy volunteers receiving fluconazole increased plasma concentration of fluconazole by 40%. An effect of this magnitude should not necessitate a change in the fluconazole dose regimen in subjects receiving concomitant diuretics.
    The effect of fluconazole on other medicinal products:
    Fluconazole is a moderate inhibitor of cytochrome P450 (CYP) isoenzymes 2C9 and 3A4. Fluconazole is also a strong inhibitor of the isozyme CYP2C19. In addition to the observed/documented interactions mentioned below, there is a risk of increased plasma concentration of other compounds metabolised 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 4-5 days after discontinuation of fluconazole treatment due to the long half-life of fluconazole.
    Abrocitinib: Fluconazole (inhibitor of CYP2C19, 2C9, 3A4) increased exposure of abrocitinib active moiety by 155%. If co-administered with fluconazole, adjust the dose of abrocitinib as instructed in the abrocitinib prescribing information.
    Alfentanil: During concomitant treatment with fluconazole (400 mg) and intravenous alfentanil (20 μg/kg) in healthy volunteers, the alfentanil AUC 10 increased 2-fold, probably through inhibition of CYP3A4.
    Dose adjustment of alfentanil may be necessary.
    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 one week. Dose 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 C. albicans, no interaction in intracranial infection with Cryptococcus neoformans, and antagonism of the two medicinal products in systemic infection with Aspergillus fumigatus. The clinical significance of results obtained in these studies is unknown.
    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. During concomitant treatment with fluconazole and warfarin, the prothrombin time was prolonged up to 2-fold, probably due to an inhibition of the warfarin metabolism through CYP2C9. In patients receiving coumarin-type or indanedione anticoagulants concurrently with fluconazole, the prothrombin time should be carefully monitored. Dose adjustment of the anticoagulant may be necessary.
    Benzodiazepines (short-acting), i.e. midazolam, triazolam: If concomitant benzodiazepine therapy is necessary in patients being treated with fluconazole, consideration should be given to decreasing the benzodiazepine dose, and the patients should be appropriately monitored. See prescribing information for full details.
    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. Dose adjustment of carbamazepine may be necessary depending on concentration measurements/effect.
    Calcium channel blockers: Certain calcium channel antagonists (nifedipine, isradipine, amlodipine, verapamil and felodipine) are metabolised by CYP3A4. Fluconazole has the potential to increase the systemic exposure of the calcium channel antagonists. Frequent monitoring for adverse events is recommended.
    Celecoxib: During concomitant treatment with fluconazole (200 mg daily) and celecoxib (200 mg), the celecoxib Cmax and AUC increased by 68% and 134%, respectively. Half of the celecoxib dose may be necessary when combined with fluconazole.
    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.
    Fentanyl: One fatal case of fentanyl intoxication due to possible fentanyl-fluconazole interaction was reported. Furthermore, it was shown in healthy volunteers that fluconazole delayed the elimination of fentanyl significantly. Elevated fentanyl concentration may lead to respiratory depression. Patients should be monitored closely for the potential risk of respiratory depression. Dosage adjustment of fentanyl may be necessary.
    HMG-CoA reductase inhibitors: The risk of myopathy and rhabdomyolysis increases (dose-dependent) when fluconazole is coadministered with HMG-CoA reductase inhibitors metabolised 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 creatine kinase should be monitored. HMG-CoA reductase inhibitors should be discontinued if a marked increase in creatine kinase is observed or myopathy/rhabdomyolysis is diagnosed or suspected. Lower doses of HMG-CoA reductase inhibitors may be necessary as instructed in the statins prescribing information.
    Ibrutinib: Moderate inhibitors of CYP3A4 such as fluconazole increase plasma ibrutinib concentrations and may increase risk of toxicity. If the combination cannot be avoided, reduce the dose of ibrutinib to 280 mg once daily (two capsules) for the duration of the inhibitor use and provide close clinical monitoring.
    Ivacaftor (alone or combined with drugs in the same therapeutic class): Co-administration with ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, increased ivacaftor exposure by 3-fold and hydroxymethyl-ivacaftor (M1) exposure by 1.9-fold. A reduction of the ivacaftor (alone or combined) dose is necessary as instructed in the ivacaftor (alone or combined) prescribing information.
    Olaparib: Moderate inhibitors of CYP3A4 such as fluconazole increase olaparib plasma concentrations; concomitant use is not recommended. If the combination cannot be avoided, limit the dose of olaparib to 200 mg twice daily.
    Immunosuppressors (i.e. ciclosporin, everolimus, sirolimus and tacrolimus):
    Ciclosporin: Fluconazole significantly increases the concentration and AUC of ciclosporin. During concomitant treatment with fluconazole 200 mg daily and ciclosporin (2.7 mg/kg/day) there was a 1.8-fold increase in ciclosporin AUC. This combination may be used by reducing the dose of ciclosporin depending on ciclosporin concentration.
    Everolimus: Although not studied in vivo or in vitro, fluconazole may increase serum concentrations of everolimus through inhibition of CYP3A4.
    Sirolimus: Fluconazole increases plasma concentrations of sirolimus presumably by inhibiting the metabolism of sirolimus via CYP3A4 and P-glycoprotein. This combination may be used with a dose adjustment of sirolimus depending on the effect/concentration measurements.
    Tacrolimus: Fluconazole may increase the serum concentrations of orally administered tacrolimus up to 5 times due to inhibition of tacrolimus metabolism through CYP3A4 in the intestines. No significant pharmacokinetic changes have been observed when tacrolimus is given intravenously. Increased tacrolimus levels have been associated with nephrotoxicity. Dose of orally administered tacrolimus should be decreased depending on tacrolimus concentration.
    Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74), which is responsible for most of the angiotensin II-receptor antagonism which occurs during treatment with losartan. Patients should have their blood pressure monitored continuously.
    Lurasidone: 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. Dose adjustment of methadone may be necessary.
    Non-steroidal anti-inflammatory drugs: The Cmax and AUC of flurbiprofen was increased by 23% and 81%, respectively, when coadministered with fluconazole compared to administration of flurbiprofen alone. Similarly, the Cmax and AUC of the pharmacologically active isomer [S-(+)-ibuprofen] was increased by 15% and 82%, respectively, when fluconazole was coadministered with racemic ibuprofen (400 mg) compared to administration of racemic ibuprofen alone. Although not specifically studied, fluconazole has the potential to increase the systemic exposure of other NSAIDs that are metabolised by CYP2C9 (e.g. naproxen, lornoxicam, meloxicam, diclofenac). Frequent monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of dose of NSAIDs may be needed.
    Phenytoin: Fluconazole inhibits the hepatic metabolism of phenytoin. Concomitant repeated administration of 200 mg fluconazole and 250 mg phenytoin intravenously, caused an increase of the phenytoin AUC24 by 75% and Cmin by 128%. With coadministration, serum phenytoin concentration levels should be monitored in order to avoid phenytoin toxicity.
    Prednisone: There was a case report that a liver-transplanted patient treated with prednisone developed acute adrenal cortex insufficiency when a three-month therapy with fluconazole was discontinued. The discontinuation of fluconazole presumably caused an enhanced CYP3A4 activity which led to increased metabolism of prednisone. Patients on long-term treatment with fluconazole and prednisone should be carefully monitored for adrenal cortex insufficiency when fluconazole is discontinued.
    Rifabutin: Fluconazole increases serum concentrations of rifabutin, leading to increase in the AUC of rifabutin up to 80%. There have been reports of uveitis in patients to whom fluconazole and rifabutin were coadministered. In combination therapy, symptoms of rifabutin toxicity should be taken into consideration.
    Saquinavir: Fluconazole increases the AUC and Cmax of saquinavir with approximately 50% and 55% respectively, due to inhibition of saquinavir’s hepatic metabolism by CYP3A4 and inhibition of P-glycoprotein. Interaction with saquinavir/ritonavir has not been studied and might be more marked. Dose adjustment of saquinavir may be necessary.
    Sulfonylureas: Fluconazole has been shown to prolong the serum half-life of concomitantly administered oral sulfonylureas (e.g., chlorpropamide, glibenclamide, glipizide, tolbutamide) in healthy volunteers. Frequent monitoring of blood glucose and appropriate reduction of sulfonylurea dose is recommended during coadministration.
    Theophylline: In a placebo-controlled interaction study, the administration of fluconazole 200 mg for 14 days resulted in an 18% decrease in the mean plasma clearance rate of theophylline. Patients who are receiving high-dose theophylline or who are otherwise at increased risk for theophylline toxicity should be observed for signs of theophylline toxicity while receiving fluconazole. Therapy should be modified if signs of toxicity develop.
    Tofacitinib: Exposure of tofacitinib is increased when tofacitinib is co-administered with medications that result in both moderate inhibition of CYP3A4 and strong inhibition of CYP2C19 (e.g., fluconazole).Therefore, it is recommended to reduce tofacitinib dose to 5 mg once daily when it is combined with these drugs.
    Tolvaptan: Exposure to tolvaptan is significantly increased (200% in AUC; 80% in Cmax) when tolvaptan, a CYP3A4 substrate, is co-administered with fluconazole, a moderate CYP3A4 inhibitor, with risk of significant increase in adverse reactions particularly significant diuresis, dehydration and acute renal failure. In case of concomitant use, the tolvaptan dose should be reduced as instructed in the tolvaptan prescribing information and the patient should be frequently monitored for any adverse reactions associated with tolvaptan.
    Vinca alkaloids: Although not studied, fluconazole may increase the plasma levels of the vinca alkaloids (e.g. vincristine and vinblastine) and lead to neurotoxicity, which is possibly due to an inhibitory effect on CYP3A4.
    Vitamin A: Based on a case-report in one patient receiving combination therapy with all-trans-retinoid acid (an acid form of vitamin A) and fluconazole, CNS-related undesirable effects have developed in the form of pseudotumour cerebri, which disappeared after discontinuation of fluconazole treatment. This combination may be used but the incidence of CNS-related undesirable effects should be borne in mind.
    Voriconazole: (CYP2C9, CYP2C19 and CYP3A4 inhibitor): Coadministration of oral voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg Q24h for 4 days) to 8 healthy male subjects resulted in an increase in Cmax and AUCτ of voriconazole by an average of 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. The reduced dose and/or frequency of voriconazole and fluconazole that would eliminate this effect have not been established. Monitoring for voriconazole-associated adverse events is recommended if voriconazole is used sequentially after fluconazole.
    Zidovudine: Fluconazole increases Cmax and AUC of zidovudine by 84% and 74%, respectively, due to an approx. 45% decrease in oral zidovudine clearance. The half-life of zidovudine was likewise prolonged by approximately 128% following combination therapy with fluconazole. Patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions. Dose reduction of zidovudine may be considered.
    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.
    Oral contraceptives: Two pharmacokinetic studies with a combined oral contraceptive have been performed using multiple doses of fluconazole. There were no relevant effects on hormone level in the 50 mg fluconazole study, while at 200 mg daily, the AUCs of ethinyl estradiol and levonorgestrel were increased 40% and 24%, respectively. Thus, multiple dose use of fluconazole at these doses is unlikely to have an effect on the efficacy of the combined oral contraceptive.


    Pregnancy and Lactation

    Pregnancy: An observational study has suggested an increased risk of spontaneous abortion in women treated with fluconazole during the first trimester.
    Data from several thousand pregnant women treated with a cumulative dose of ≤ 150 mg of fluconazole, administered in the first trimester, show no increase in the overall risk of malformations in the foetus. In one large observational cohort study, first trimester exposure to oral fluconazole was associated with a small increased risk of musculoskeletal malformations, corresponding to approximately 1 additional case per 1000 women treated with cumulative doses ≤ 450 mg compared with women treated with topical azoles and to approximately 4 additional cases per 1000 women treated with cumulative doses over 450 mg. The adjusted relative risk was 1.29 (95% CI 1.05 to 1.58) for 150 mg oral fluconazole and 1.98 (95% CI 1.23 to 3.17) for doses over 450 mg fluconazole.
    There have been reports of multiple congenital abnormalities (including brachycephalia, ears dysplasia, giant anterior fontanelle, femoral bowing and radio-humeral synostosis) in infants whose mothers were treated for at least three or more months with high doses (400-800 mg daily) of fluconazole for coccidioidomycosis. The relationship between fluconazole use and these events is unclear.
    Studies in animals have shown reproductive toxicity.
    Before becoming pregnant a washout period of approximately 1 week (corresponding to 5-6 half-lives) is recommended after a single-dose or discontinuation of a course of treatment.
    Fluconazole in standard doses and short-term treatments should not be used in pregnancy unless clearly necessary.
    Fluconazole in high dose and/or in prolonged regimens should not be used during pregnancy except for potentially life-threatening infections.
    Lactation: Fluconazole passes into breast milk to reach concentrations similar to those in plasma. Breast-feeding may be maintained after a single dose of 150 mg fluconazole. Breast-feeding is not recommended after repeated use or after high dose fluconazole. The developmental and health benefits of breast-feeding should be considered along with the mother’s clinical need for Fluconazole and any potential adverse effects on the breast-fed child from Fluconazole or from the underlying maternal condition.


    Overdose

    There have been reports of overdose with fluconazole. Hallucination and paranoid behaviour have been concomitantly reported.In the event of overdose, symptomatic treatment (with supportive measures and gastric lavage if necessary) may be adequate.
    Fluconazole is largely excreted in the urine; forced volume diuresis would probably increase the elimination rate. A three-hour haemodialysis session decreases plasma levels by approximately 50%.


    Manufacturer
    Fareva Amboise, Poce-sur-Cisse, France
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