Presentation and Status in Health Basket
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.
Fluconazole is indicated in adults for the treatment of:
• Cryptococcal meningitis.
• 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.
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.
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. 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.
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.
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.
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.
See prescribing information for full details.
Pregnancy and Lactation
Pregnancy: An observational study has suggested an increased risk of spontaneous abortion in women treated with fluconazole during the first trimester.
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.
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.
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%.