1. Name Of The Medicinal Product
Fluconazole 200 mg capsules, hard
2. Qualitative And Quantitative Composition
Each capsule, hard contains 200 mg fluconazole.
Excipient: 202.24 mg lactose/hard capsule
For a full list of excipients, see section 6.1
3. Pharmaceutical Form
Capsules, hard
Size '0' hard gelatin capsule filled with white to off-white powder and imprinted with 'E' on white to off-white opaque cap and '98' on white to off-white opaque body with yellow ink.
4. Clinical Particulars
4.1 Therapeutic Indications
Acute or recurrent vaginal candidiasis when systemic therapy is considered appropriate.
Mucosal candidal infection. These include oropharyngeal, oesophageal, mucocutaneous and non-invasive bronchopulmonary candidiasis and candiduria, in patients with compromised immune function.
Systemic candidiasis in non-neutropenic patients.
Acute cryptococcal meningitis in adults. Fluconazole can be used as maintenance therapy to prevent relapse of cryptococcal disease in patients with AIDS.
Prophylaxis of deep-seated candida infections (particularly Candida albicans) in patients with neutropenia due to bone marrow transplantation.
Consideration should be given to official guidance on the appropriate use of antifungal agents.
Paediatric use
Not all indications are applicable for paediatric patients; see details in section 4.2.
Fluconazole should not be used for tinea captis.
4.2 Posology And Method Of Administration
Oral use, capsules should be swallowed whole, independent of food intake.
The dose is depending on the type and severity of the fungal infection. The treatment of infections requiring multiple dosing must be continued until clinical parameters or laboratory results show that the active fungal infection has declined. An insufficient treatment period may lead to recurrence of the active infection.
Depending on the severity of the disease and the clinical state of the patients intravenous administration may be required. It is not necessary to change the daily dose of fluconazole when changing the route of administration from intravenous to oral.
Adults:
Vaginal candidiasis: 150 mg as a single dose.
Mucous membrane candidiasis:
Oropharyngeal candidiasis: Normal daily dose: 50-100 mg for 7-14 days. Duration of treatment depends on clinical response.
Oesophageal mucocutaneous, non-invasive bronchopulmonary candidiasis and candiduria: Normal dose is 50 mg daily for 14-30 days. In severe and particular recurrent cases the dose can be increased to 100 mg.
Systemic candidiasis:
The dose in candidaemia and other invasive Candida infections is 400-800 mg on the first day and 200-400 mg daily thereafter. The dose depends on the type and severity of the infection. In most cases a loading dose of 800 mg on the first day followed by 400 mg daily thereafter may be preferable. The duration of treatment, often up to several weeks, is determined by the clinical response.
Prevention of candida infections in neutropenic patients:
400 mg once daily. Prophylaxis with fluconazole should begin in time before the appearance of expected neutropenia. Treatment should be continued for 7 days after the neutrophil counts have increased to > 1x109/ l.
Cryptococcal meningitis in immunosuppressed patients: For infections with cryptococcal meningitis the usual dose is 400 mg on the first day followed by 200-400 mg once daily. Duration of treatment for cryptococcal infections depends on the clinical response, but is usually at least 6-8 weeks for cryptococcal meningitis.
For the prevention of relapse of cryptococcal meningitis in patients with AIDS, fluconazole may be administered at a daily dose of 200 mg.
Duration of maintenance treatment in AIDS patients should be carefully justified, because of the increased risk of resistance to fluconazole.
Paediatric use:
As with similar infections in adults, the duration of treatment is based on the clinical and mycological response. Fluconazole is administered as a single daily dose.
The capsules formulation may be unsuitable for children younger than 5-6 years.
For children with impaired renal function, see dosing in “Use in patients with impaired renal function”.
Children over four weeks of age:
The recommended dose of fluconazole for mucosal candidiasis is 3 mg/kg daily. A loading dose of 6 mg/kg may be used on the first day to achieve steady state levels more rapidly.
For the treatment of systemic candidiasis and cryptococcal infection, the recommended dosage is 6 - 12 mg/kg daily, depending on the severity of the disease.
For the prevention of fungal infections in immunocompromised patients considered at risk as a consequence of neutropenia following cytotoxic chemotherapy or radiotherapy, the dose should be 3 - 12 mg/kg daily, depending on the extent and duration of the induced neutropenia (see adult dosing).
A maximum dosage of 400 mg daily should not be exceeded in children.
Children four weeks of age and younger:
Neonates excrete fluconazole slowly. In the first two weeks of life the same mg/kg dosing as in older children should be used but administered every 72 hours. During weeks 3 - 4 of life the same dose should be given every 48 hours. There are few PK data to support this Posology in term newborn babies (see section 5.2).
A maximum dosage of 12 mg/kg every 72 hours should not be exceeded in children below two weeks of life. For children between 3 - 4 weeks of life 12 mg/kg every 48 hours should not be exceeded.
The pharmacokinetics of fluconazole has not been studied in children with renal insufficiency.
Use in the elderly
The normal dose should be used if there is no evidence of renal impairment. In patients with renal impairment (creatinine clearance less than 50 ml/min) the dosage schedule should be adjusted as described below.
Use in patients (adults and paediatric) with impaired renal function
Fluconazole is excreted predominantly in the urine as unchanged drug. No adjustments in single dose therapy are required. In patients with impaired renal function who will receive multiple doses of fluconazole, the normal recommended dose (according to indication) should be given on day 1 and 2, followed by a daily dose based on the following table:
Creatinine clearance (ml/min.)
|
Percentage of recommended dose
|
>50
|
100%
|
|
50%
|
Regular dialysis
|
100% after each dialysis
|
The pharmacokinetics of fluconazole has not been studied in children with renal insufficiency.
4.3 Contraindications
• Hypersensitivity to fluconazole or to related azole compounds or to any of the excipients.
• Co-administration of terfenadine is contra-indicated 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, pimozide and quinidine are contra-indicated in patients receiving fluconazole (see sections 4.4 and 4.5).
4.4 Special Warnings And Precautions For Use
Fluconazole should be administered with caution to patients with liver dysfunction (see also section 4.2).
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 should be monitored for the development of more serious hepatic injury. Fluconazole should be discontinued if clinical signs or symptoms consistent with liver disease develop that may be attributable to fluconazole.
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 drugs. If a rash, which is considered attributable to fluconazole, develops in a patient treated for a superficial fungal infection, further therapy with this agent 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.
The coadministration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored (see sections 4.3 and 4.5).
In rare cases, as with other azoles, anaphylaxis has been reported.
Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, there have been very rare cases of QT prolongation and torsade 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 medications that may have been contributory.
Fluconazole should be administered with caution to patients with these potentially proarryhthmic conditions.
Fluconazole should be administered with caution to patients with renal dysfunction (see also 4.2).
Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole treated patients who are concomitantly treated with drugs with a narrow therapeutic window metabolised through CYP2C9 and CYP3A4, should be monitored (see section 4.5).
This medicinal product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
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 co-administered. 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 QT interval. Concomitant treatment with fluconazole and Cisapride is contra-indicated (see section 4.3).
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 (see section 4.3). 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 torsade 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 torsade de pointes. Coadministration of fluconazole and pimozide is contraindicated.
Concomitant use of the following other medicinal products cannot be recommended:
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. This combination should be avoided.
Concomitant use of the following other medicinal products lead to precautions and dose adjustments:
The effect of other medicinal products on fluconazole
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, although the prescriber should bear it in mind.
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.
The effect of fluconazole on other medicinal products
Fluconazole is a potent inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and a moderate inhibitor of CYP3A4. In addition to the observed /documented interactions mentioned below, there is a risk of increased plasma concentration of other compounds metabolized by CYP2C9 and CYP3A4 co-administered 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 (See section 4.3).
Alfentanil: A study observed a reduction in clearance and distribution volume as well as prolongation of T½ 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.
Amitriptyline, nortriptyline: Fluconazole increases the effect of amitriptyline and nortriptyline. 5- nortriptyline and/or S-amitnptyline may be measured at initiation of the combination therapy and after one week. Dosage of amitriptyline/nortriptyline should be adjusted, if necessary
Amphotericine 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 drugs in systemic infection with A. fumigatus. The clinical significance of results obtained in these studies is unknown.
Anticoagulants: In an interaction study, fluconazole increased the prothrombin time (12%) after warfarin administration in healthy males. 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. Prothrombin time in patients receiving coumarin-type anticoagulants should be carefully monitored. Dose adjustment of warfarin may be necessary.
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.
Benzodiazepines (Short Acting): Following oral administration of midazolam, fluconazole resulted in substantial increases in midazolam concentrations and psychomotor effects. This effect on midazolam appears to be more pronounced following oral administration of fluconazole than with fluconazole administered intravenously. If concomitant benzodiazepine therapy is necessary in patients being treated with fluconazole, consideration should be given to decreasing the benzodiazepine dosage, and the patients should be appropriately monitored.
Fluconazole increases the AUC of triazolam (single dose) by approximately 50%, Cmax with 20-32% and increases t½ by 25-50 % due to the inhibition of metabolism of triazolam. Dosage adjustments of triazolam may be necessary.
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.
Calcium Channel Blockers: Certain dihydropyridine calcium channel antagonists (nifedipine, isradipine, amlodipine 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.
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.
Ciclosporin: Fluconazole significantly increases the concentration and AUC of ciclosporin. This combination may be used by reducing the dosage of ciclosporin depending on ciclosporin concentration.
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 possible fentanyl fluconazole interaction was reported. The author judged that the patient died from fentanyl intoxication. Furthermore, in a randomized crossover study with twelve healthy volunteers it was shown that fluconazole delayed the elimination of fentanyl significantly. Elevated fentanyl concentration may lead to respiratory depression.
Halofantrine: Fluconazole can increase halofantrine plasma concentration due to an inhibitory effect on CYP3A4.
HMG-CoA reductase inhibitors: The risk of myopathy and rhabdomyolysis increases when fluconazole is coadministered with HMG-CoA reductase inhibitors metabolised through CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin. 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.
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.
Methadone: Fluconazole may enhance the serum concentration of methadone. Dosage 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 metabolized by CYP2C9 (e.g. naproxen, lornoxicam, meloxicam, diclofenac). Frequent monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of dosage of NSAIDs may be needed.
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.
Phenytoin: Fluconazole inhibits the hepatic metabolism of phenytoin. 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 of saquinavir with approximately 50%, Cmax with approximately 55% and decreases clearance of saquinavir with approximately 50% due to inhibition of saquinavir's hepatic metabolism by CYP3A4 and inhibition of P-glycoprotein. Dosage adjustment of saquinavir may be necessary.
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 dosage adjustment of sirolimus depending on the effect/concentration measurements.
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 dosage is recommended during coadministration.
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. Dosage of orally administered tacrolimus should be decreased depending on tacrolimus concentration.
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.
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.
Zidovudine: Fluconazole increases Cmax and AUC of zidovudine by 85% and 75%, 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. Dosage reduction of zidovudine may 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.
4.6 Pregnancy And Lactation
Pregnancy
Data from several hundred pregnant women treated with standard doses (<200 mg/day) of fluconazole, administered as a single or repeated dosage in the first trimester, show no undesired effects in the foetus.
There have been reports of multiple congenital abnormalities 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.
Animal studies show teratogenic effects (see section 5.3).
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.
Lactation
Fluconazole is found in human breast milk at concentrations similar to plasma, hence its use in nursing mothers is not recommended.
4.7 Effects On Ability To Drive And Use Machines
Fluconazole has no or negligible influence on the ability to drive and use machines.
However when driving vehicles or operating machines it should be taken into account that occasionally dizziness or seizures may occur.
4.8 Undesirable Effects
Fluconazole is generally well tolerated.
In some patients, particularly those with serious underlying diseases such as AIDS and cancer, changes in renal and hematological function test results and hepatic abnormalities (see section 4.4) have been observed during treatment with fluconazole and comparative agents, but the clinical significance and relationship to treatment is uncertain.
The following frequency data are used in the evaluation of undesirable effects:
Very common: (
Common: (
Uncommon: (
Rare (
Very rare (< 1/10,000, not known (cannot be estimated from the available data)
System Organ Class
|
Frequency
|
Undesirable effects
|
Blood and the lymphatic system disorders
|
Rare
|
Agranulocytosis, leukopenia, neutropenia, thrombocytopenia
|
Immune system disorders
|
Rare
|
Anaphylaxis
|
Metabolism and nutrition disorders
|
Uncommon
|
Hypokalaemia
|
Rare
|
Hypertriglyceredaemia, hypercholesterolaemia
|
|
Psychiatric disorders
|
Uncommon
|
Insomnia, somnolence
|
Nervous system disorders
|
Common
|
Headache
|
Uncommon
|
Seizures, dizziness, paraesthesia, taste perversion
|
|
|
Rare
|
Tremor
|
Ear and labyrinth disorders
|
Uncommon
|
Vertigo
|
Cardiac disorders
|
Rare
|
Torsade de pointes, QT prolongation
|
Gastrointestinal disorders
|
Common
|
Abdominal pain, diarrhoea, nausea, vomiting
|
Uncommon
|
Dyspepsia, flatulence, dry mouth
|
|
Hepato-biliary disorders
|
Common
|
Alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased
|
Uncommon
|
Cholestasis, jaundice, bilirubin increased
|
|
Rare
|
Hepatic failure, hepatocellular necrosis, hepatitis, hepatocellular damage
|
|
Skin and subcutaneous tissue disorders
|
Common
|
Rash
|
Uncommon
|
Pruritus, urticaria, increased sweating, drug eruption
|
|
Rare
|
Toxic epidermal necrolysis , Stevens-Johnson syndrome, acute generalised exanthematous-pustulosis, dermatitis exfoliative, angioedema, face oedema, alopecia
|
|
Musculoskeletal, connective tissue and bone disorders
|
Uncommon
|
Myalgia
|
General disorders and administration site conditions
|
Uncommon
|
Fatigue, malaise, asthenia, fever
|
Pediatric population: The pattern and incidence of side effects and laboratory abnormalities recorded during paediatric use are comparable to those seen in adults.
4.9 Overdose
Symptoms:
There have been reports of overdose with fluconazole and hallucination and paranoid behaviour have been concomitantly reported.
Treatment:
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 hemodialysis session decreases plasma levels by approximately 50%.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic Group: Antimycotics for systemic use, Triazole derivatives;
ATC code: J02AC01.
Type of action
Fluconazole is a substance, which belongs to the triazole derivative class of drugs. The agent is particularly effective against Candida species and cryptococci.
Mechanism of action
Fluconazole has a highly specific effect on cytochrome-P450-dependent fungal enzymes and is a potent and specific inhibitor of fungal sterol synthesis.
Spectrum of activity
Fluconazole has a wide spectrum of antimycotic activity. In various in-vivo animal activity studies (p.o. and i.v.), fluconazole is active in superficial and systemic infections with Candida, Cryptococcus and various dermatophytes.
Candida krusei is resistant to fluconazole. The susceptibility of Candida glabrata is variable. Candida dubliniensis is not primarily resistant but shows a high tendency towards resistance, mainly during therapy. Fluconazole has little of no activity against Aspergillus, Mucor, Microsporum and Trichophyton species.
In animal experimental models of endemic mycosis, fluconazole was shown to be effective, including in infections with Blastomyces dermatitidis, Coccidioides immitis and Histoplasma capsulatum in normal and immunosuppressed animals. As with other azoles, due to the lack of a standardised procedure, the results of in-vitro tests are of lesser significance in terms of predicting clinical efficacy than the results of in-vivo studies.
In volunteers, 200-400 mg fluconazole daily have no clinically relevant effect on endogenous serum steroid concentrations or ACTH-stimulated cortisol release.
The efficacy of fluconazole in tinea captis has been studied in 2 randomised controlled trials in a total of 878 patients, comparing fluconazole with griseofulvin. Fluconazole at 6 mg/kg/day for 6 weeks was not superior to griseofulvin administered at 11 mg/kg/day for 6 weeks. The overall success rate at 6 weeks was low (fluconazole 6 weeks: 18.3%; fluconazole 3 weeks: 14.7%; griseofulvin: 17.7%) across all the treatment groups. These findings are not inconsistent with the natural history of tinea capitis without therapy.
5.2 Pharmacokinetic Properties
Absorption:
Fluconazole is well absorbed after oral intake. The absolute bioavailability is above 90%. The oral absorption is not affected by concomitant food intake. The maximum fasting plasma concentration is reached 0.5 - 1.5 hours after dose intake.. 90% of the steady-state level is reached 4-5 days after dosing once daily.
Plasma concentration is proportional to the dose. After administration of 200 mg fluconazole, Cmax is around 4.6 mg/l and plasma concentrations at steady-state after 15 days are around 10 mg/l. After administration of 400 mg of fluconazole, Cmax is around 9 mg/l and plasma concentrations at steady state after 15 days are around 18 mg/l.
Intake of a double dose on day 1 results in plasma concentrations of approximate 90% of steady-state on day 2.
Distribution:
The volume of distribution corresponds to the total body water. The protein binding in plasma is low (11-12%).
The concentration in saliva corresponds to the plasma concentration. In patients with fungal meningitis the concentration of fluconazole in the cerebrospinal fluid is approximately 80% of the corresponding plasma concentration.
In stratum corneum, epidermis-dermis and in exocrine sweat higher concentrations of fluconazole are reached compared to those in serum. Fluconazole is accumulated in the stratum corneum. At a dose of 150 mg once weekly the concentration of fluconazole in stratum corneum was after 2 doses 23.4 µg/g and seven days after the second dosing it was still 7.1 µg/g..
Elimination:
Fluconazole is mainly renally excreted. Approximately 80% of the administered dose is excreted in the urine in non-metabolized form. Fluconazole clearance is proportional to the creatinine clearance. Circulating metabolites have not been demonstrated.
The half-life in plasma is approximately 30 hours.
Pharmacokinetics in Children
Pharmacokinetic data were assessed for 113 paediatric patients from 5 studies; 2 single dose studies, 2 multiple dose studies and a study in premature neonates. Data from 1 study were not interpretable due to changes in formulation partway through the study. Additional data were available from a compassionate use study.
In children, the following pharmacokinetic data have been reported:
Age Studied
|
Dose (mg/kg)
|
Half-life (hours)
|
AUC (μg.h/ml)
|
11 days - 11 months
|
Single IV
3 mg/kg
|
23
|
110.1
|
9 months - 13 years
|
Single - oral
2 mg/kg
|
25.0
|
94.7
|
9 months - 13 years
|
Single - oral
8 mg/kg
|
19.5
|
362.5
|
5 years - 15 years
|
Multiple IV
2 mg/kg
|
17.4*
|
67.4
|
5 years - 15 years
|
Multiple IV
4 mg/kg
|
15.2*
|
139.1
|
5 years - 15 years
|
Multiple IV
8 mg/kg
|
17.6*
|
196.7
|
Mean age 7 years
|
Multiple oral
3 mg/kg
|
15.5
|
41.6
|
*Denotes final day
After administration of 2 - 8 mg/kg fluconazole to children between the ages of 9 months to 15 years, an AUC of about 38 pg.h/ml was found per 1 mg/kg dose units. The average fluconazole plasma elimination half-life varied between 15 and 18 hours and the distribution volume was approximately 880 ml/kg after multiple doses. A higher fluconazole plasma elimination half-life of approximately 24 hours was found after a single dose. This is comparable with the fluconazole plasma elimination half-life after a single administration of 3 mg/kg i.v. to children of 11 days-11 months old. The distribution volume in this age group was about 950 ml/kg.
Experience with fluconazole in neonates is limited to pharmacokinetic studies in premature newborns. The mean age at first dose was 24 hours (range 9-36 hours) and mean birth weight was 0.9 Kg (range 0.75-1.10 Kg) for 12 pre-term neonates of average gestation around 28 weeks. Seven patients complet
