This information is intended for use by health professionals

1. Name of the medicinal product

Fluconazole 50 mg Capsules

2. Qualitative and quantitative composition

Each capsule contains 50 mg fluconazole.

Excipients with known effect: Lactose Monohydrate

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Capsules, hard.

Fluconazole 50 mg Capsules are green-white capsules.

4. Clinical particulars
4.1 Therapeutic indications

Therapy may be started before the results of the cultures and other laboratory studies are known; however, once results become available, anti-infective therapy should be adjusted accordingly.

Fluconazole is indicated for the treatment of the following conditions:

1. Genital candidiasis. Vaginal candidiasis, acute or recurrent. Candidal balanitis. The treatment of partners who present with symptomatic genital candidiasis should be considered.

2. Mucosal candidiasis. These include oropharyngeal, oesophageal, non-invasive bronchopulmonary infections, candiduria, mucocutaneous and chronic oral atrophic candidiasis (denture sore mouth). Normal hosts and patients with compromised immune function may be treated.

3. Tinea pedis, tinea corporis, tinea cruris, tinea versicolor and dermal Candida infections. Fluconazole is not indicated for nail infections.

4. Systemic candidiasis including candidaemia, disseminated candidiasis and other forms of invasive candidal infection. These include infections of the peritoneum, endocardium and pulmonary and urinary tracts. Candidal infections in patients with malignancy, in intensive care units or those receiving cytotoxic or immunosuppressive therapy may be treated.

5. Cryptococcus, including cryptococcal meningitis and infections of other sites (e.g. pulmonary, cutaneous). Normal hosts and patients with AIDS, organ transplants or other causes of immunosuppression may be treated. Fluconazole can be used as maintenance therapy to prevent relapse of cryptococcal disease in patients with AIDS.

6. For the prevention of fungal infections in immunocompromised patients considered at risk as a consequence of neutropenia following cytotoxic chemotherapy or radiotherapy, including bone marrow transplant patients.

4.2 Posology and method of administration

Fluconazole is administered orally.

The daily dose of fluconazole should be based on the nature and severity of the fungal infection. Most cases of vaginal candidiasis respond to single dose therapy. Therapy for those types of infections requiring multiple dose treatment should be continued until clinical parameters or laboratory tests indicate that active fungal infection has subsided. An inadequate period of treatment may lead to the recurrence of active infection. Patients with AIDS and cryptococcal meningitis usually require maintenance therapy to prevent relapse.

Adults

1. Candidal vaginitis or balanitis – 150 mg single oral dose.

2. Mucosal candidiasis

• Oropharyngeal candidiasis – the usual dose is 50 mg once daily for 7 – 14 days. Treatment should not normally exceed 14 days except in severely immunocompromised patients.

• Atrophic oral candidiasis associated with dentures – the usual dose is 50 mg once daily for 14 days administered concurrently with local antiseptic measures to the denture.

• For other candidal infections of mucosa (except genital candidiasis see above), e.g. oesophagitis, non-invasive bronchopulmonary infections, candiduria, mucocutaneous candidiasis etc., the usual effective dose is 50 mg daily, given for 14 – 30 days.

• In unusually difficult cases of mucosal candidal infections the dose may be increased to 100 mg daily.

3. For tinea pedis, corporis, cruris, vesicular and dermal Candidal infections the recommended dosage is 50 mg once daily. Duration of treatment is normally 2 to 4 weeks but tinea pedis may require treatment for up to 6 weeks. Duration of treatment should not exceed 6 weeks.

4. For candidaemia, disseminated candidiasis and other invasive candidal infections the usual dose is 400 mg on the first day followed by 200 mg daily. Depending on the clinical response the dose may be increased to 400 mg daily. Duration of treatment is based upon the clinical response.

5. For cryptococcal meningitis and cryptococcal infections at other sites, the usual dose is 400 mg on the first day followed by 200 – 400 mg once daily. Duration of treatment for cryptococcal infections will depend on the clinical and mycological response, but is usually at least 6 – 8 weeks for cryptococcal meningitis.

6. For the prevention of relapse of cryptococcal meningitis in patients with AIDS, after the patient receives a full course of primary therapy, fluconazole may be administered indefinitely at a daily dose of 100 – 200 mg.

7. 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 50 to 400 mg once daily, based on the patient's risk for developing fungal infection. For patients at high risk of systemic infection e.g. patients who are anticipated to have profound or prolonged neutropenia such as during bone marrow transplantation, the recommended dose is 400 mg once daily. Fluconazole administration should start several days before the anticipated onset of neutropenia, and continue for 7 days after the neutrophil count rises above 1000 cells per mm3.

Children

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 each day.

Children over four weeks of age

Mucosal candidiasis: The recommended dose of fluconazole for 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.

Invasive candidal infections (including candidaemia and disseminated candidiasis) and cryptococcal infection: The recommended dosage is 6 – 12 mg/kg daily, depending on the severity of the disease.

A maximum of 400mg daily should not be exceeded.

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.

Despite extensive data supporting the use of fluconazole in children there are limited data available on the use of fluconazole for genital candidiasis in children below 16 years. Use at present is not recommended unless antifungal treatment is imperative and no suitable alternative agent exists.

Children below 4 weeks of age

(capsule form not suitable for this age group)

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 2 – 4 of life the same dosing as in older children should be used but administered every 48 hours.

A maximum dosage of 12 mg/kg every 72 hours should not be exceeded in children in the first two weeks of life. For children between 2 – 4 weeks of life 12 mg/kg every 48 hours should not be exceeded.

For children with impaired renal function the daily dose should be reduced in accordance with the guidelines given for adults.

To facilitate accurate measurement of doses less than 10 mg, fluconazole should only be administered to children in hospital using preparations available as oral suspension or intravenous infusion, depending on the clinical condition of the child.

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 renal impairment

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, followed by a daily dose based on the following table:

Creatinine clearance (ml/min)

Percent of recommended dose

> 50

100 %

≤ 50 (no dialysis)

50 %

Patients receiving regular dialysis

100% after each dialysis

4.3 Contraindications

Fluconazole should not be used in patients with known hypersensitivity to fluconazole or to related azole compounds or to any other ingredient within the formulation (see section 6.1.).

Co-administration with terfenadine is contra-indicated in patients receiving fluconazole at multiple doses of 400mg per day or higher based on 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 contraindicated in patients receiving fluconazole (See section 4.4 Special warnings and precautions for use and section 4.5 'Interactions with other medicinal products and other forms of interaction).

Fluconazole should not be used in patients with Porphyria.

4.4 Special warnings and precautions for use

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 of fluconazole, duration of therapy, sex or age of the patient has been observed; the abnormalities have usually been reversible on discontinuation of fluconazole 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 during treatment with 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 more 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 400mg per day with terfenadine should be carefully monitored (see sections 4.3 Contraindications and 4.5 Interactions with Other Medicaments and Other Forms of Interaction).

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 including 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 Interaction with Other Medicaments and Other Forms of Interaction).

This product contains lactose. 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 medicinal products is contraindicated:

Cisapride: There have been reports of cardiac events including Torsade de Pointes in patients to whom fluconazole and cisapride were coadministered. A controlled study found that concomitant fluconazole 200mg once daily and cisapride 20mg four times a day yielded a significant increase in cisapride plasma levels and prolongation of QT interval. Concomitant treatment with fluconazole and cisapride is contraindicated (see section 4.3 Contraindications).

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 200mg daily dose of fluconazole failed to demonstrate a prolongation in QTc interval. Another study at a 400mg and 800mg daily dose of fluconazole demonstrated that fluconazole taken in doses of 400mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. The combined use of fluconazole at doses of 400mg or greater with terfenadine is contraindicated (see section 4.3 Contraindications). The coadministration of fluconazole at doses lower than 400mg 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 torsade de pointes. Coadministration of fluconazole and pimozide is contraindicated.

Sertindole: Possible increased risk of ventricular arrhythmias when triazoles given with sertindole- avoid concomitant use.

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 T1/2 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-amitriptyline may be measured at initiation of the combination therapy and after one 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 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 patient receiving coumarin-type anticoagulants should be carefully monitored. Dose adjustment of warfarin may be necessary.

Artemether and Lumefantrine: Avoidance of fluconazole is advised by the manufacturers of artemether and lumefantrine.

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 azifhromycin. 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 t1/2 by 25-50 % due to the inhibition of metabolism of triazolam. Dosage adjustments of triazolam may be necessary.

Bosentan: Fluconazole may increase levels of bosentan since both are metabolized by cytochrome P450.

Carbamazepine: Fluconazole inhibits the metabolism of carbamazepine and an increase in serum of 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 /effects.

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.

Citalopram: Fluconazole may increase levels of citalopram since both are metabolized by the cytochrome P450.

Cyclophoshamide: 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.

Eplerenone: Fluconazole increases plasma concentration of eplerenone (reduce dose of eplerenone)

Ergotamine and Methysergide: Increased risk of ergotism when triazoles given with ergotamine and methysergide – avoid concomitant use.

Everolimus: Although not studied in vivo or in vitro, fluconazole may increase serum concentrations of everolimus through inhibition of CYP3A4.

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. 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.

HMG-CoA reductase inhibitors: The risk of myopathy and rhabdomyolysis increases when fluconazole is coadministered with HMG-CoA reductase inhibitors metabolized 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 rnyopathy/rhabdomyolysis is diagnosed or suspected.

Ivabradine: Fluconazole increases plasma concentrations of ivabradine – reduce initial dose of ivabradine.

Losartan: Fluconazole inhibits the metabolism of losartan to its active metabotite (E-31 74) which is responsible for most of the angiotensin ll-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.

Nateglinide: Fluconazole may increase levels of nateglinide since both are metabolized by cytochrome P450.

Nevirapine: Fluconazole may increase levels of nevirapine since both are metabolized by cytochrome P450.

Nisoldipine: Avoidance of fluconazole is advised by the manufacturer of nisoldipine.

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 NSAlDs 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 NSAlDs 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.

Parecoxib: Fluconazole may increase levels of parecoxib since both are metabolized by cytochrome P450.

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.

Quetiapine: Triazoles possibly increase plasma concentration of quetiapine (reduce dose of quetiapine).

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.

Ritonavir: Fluconazole increase plasma concentration of ritonavir.

Rofecoxib: Fluconazole may increase plasma levels of rofecoxib since both are metabolized by cytochrome P450.

Saquinavir: Fluconazole increases the AUC of saquinavir by approximately 50%, Cmax by approximately 55% and decreases clearance of saquinavir by 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.

Tipranavir: Fluconazole increases plasma concentration of tipranavir.

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 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 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 (400-800mg daily) of fluconazole for coccidioidomycosis. The relationship between fluconazole use and these events in 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 foetus.

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

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 haematological function test results and hepatic abnormalities have been observed during treatment with fluconazole and comparative agents, but the clinical significance and relationship to treatment is uncertain. (See Section 4.4., 'Special warning and precautions for use'.)

The following undesirable effects have been observed and reported during treatment with fluconazole with the following frequencies: Very common (>1/10); common (≥1/100 to <1/10); uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000) and very rare (≥1/10000), not known (cannot be estimated from the available data).

System Organ Class

Frequency

Undesirable effects

Blood and the lymphatic system disorders

Uncommon

Anaemia

Rare

Angranulocytosis, Leukopenia, neutropenia, thrombocytopenia

Immune system disorders

Rare

Anaphylaxis

Metabolism and nutrition disorders

Uncommon

Hypokalaemia, Decreased appetite

Rare

Hypertriglyceridaemia, 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

Torsades de pointes, QT prolongation

Gastrointestinal disorders

Common

Abdominal pain, diarrhoea, nausea, vomiting

Uncommon

Dyspepsia, flatulence, dry mouth

Hepato- biliary disorders

Common

Alanine aminotranserase increased, aspartate aminotransferance increased, blood alkaline phosphate increased

Uncommon

Cholestasis, jaundice, bilirubin increased

Rare

Hepatic failure, hepatocellular necrosis hepatitis, hepatocellular damage

Skin and subcutaneous tissue disorders

Common

Rash

Uncommon

Pruritis, urticaria, increased sweating, drug eruption

Rare

Toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthermatous-pustulosis, dermatitis exfoliative, angiodema, face oedema, alopecia

Musculoskeletal, connective tissue and bone disorders

Uncommon

Myalgia

General disorders and administration site conditions

Uncommon

Fatigue, malaise, asthenia, fever

Paediatric Population

The pattern and incidence of side effects and laboratory abnormalities recorded during paediatric clinical trials are comparable to those seen in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the yellow card scheme at www.mhra.gov.uk/yellowcard

4.9 Overdose

There have been reports of overdose with fluconazole and hallucination and paranoid behaviour have been concomitantly reported.

In the event of overdosage, supportive measures and symptomatic treatment, with gastric lavage if necessary, may be adequate.

As 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 %.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic category:

Antimycotics for systemic use, triazole derivatives.

ATC code: J02A C01

Mechanism of action and pharmacodynamic effects

Fluconazole is a member of the triazole class of antifungal agents. It is a potent and selective inhibitor of fungal enzymes necessary for the synthesis of ergosterol. Lack of ergosterol leads to defects in the cell membrane. Fluconazole is very specific for fungal cytochrome P450 enzymes.

Mechanism of resistance

Depending on the yeast species involved, the principal mechanisms of resistance to fluconazole, in common with other azole antifungal agents, involve impairing the accumulation of the drug in the cell by:

i) altering the amino acid composition of lanosterol 14α-demethylase,

ii) increasing drug efflux, and

iii) altering the ergosterol biosynthetic pathways.

In Candida albicans, blockage of the ergosterol synthetic pathways is thought to primarily arise from blockage of sterol C5, 6-desaturase which is encoded by ERG3. In the more resistant species, Candida glabrata, the predominant pathway has not been fully elucidated but is thought to arise from upregulation of CDR genes (CDR1, CDR2 and MMDR1) responsible for efflux of the drug substance from the cells. Resistance to fluconazole therefore usually confers resistance to other azole antifungal agents. In Cryptococcus neoformans the studies have demonstrated that the same principle mechanisms of resistance exist in this species, and that these may be affected by prior exposure to azole antifungal agents. Similar careful consideration of the benefits of the proposed dose versus the risk of development of resistance must therefore be applied with fluconazole as for any other antimichrobial chemotherapy.

Breakpoints

According to EUCAST, the following clinical breakpoints apply for fluconazole:

EUCAST Breakpoints ( μg/ml)

Organism

S ≤

R ≥

Candida albicans, Candida parapsilosis, Candida tropicalis

2

4

Non-species related breakpoints

2

4

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

Commonly susceptible species

C.albicans

C. kefyr

C. lusitaniae

C. parapsilosis

Species for which acquired resistance may be a problem

C. dubliniensis

C. famata

C. guillermondii

C. pelliculosa

C. tropicalis

Inherently resistant organisms

C. glabrata

C. krusei

Resistant isolates of Candida albicans have been found in AIDS patients who have undergone long-term treatment with fluconazole.

There have been reports of cases of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to fluconazole (e.g. Candida krusei). Such cases may require alternative antifungal therapy.

Infections resulting from Aspergillus species, Zygomycetes including Mucor and Rhizopus, Microsporum, Trychophyton species should not be treated with fluconazole since fluconazole has little or no activity against these fungi.

Both orally and intravenously administered fluconazole was active in a variety of animal fungal infection models. Activity has been demonstrated against opportunistic mycoses, such as infections with Candida spp. including systemic candidiasis in immunocompromised animals; with Cryptococcus neoformans, including intracranial infections; with Microsporum spp. and with Trichophyton spp. Fluconazole has also been shown to be active in animal models of endemic mycoses, including infections with Blastomyces dermatitides; with Coccidoides immitis, including intracranial infection and with Histoplasma capsulatum in normal and immunosuppressed animals.

Clinical efficacy and safety

Fluconazole is highly specific for fungal cytochrome P-450 dependent enzymes. Fluconazole 50mg daily given for up to 28 days has been shown not to affect testosterone plasma concentrations in males or steroid concentrations in females of child-bearing age. Fluconazole 200-400mg daily has no clinically significant effect on endogenous steroid levels or on ACTH stimulated response in healthy male volunteers. Interaction studies with antipyrine indicate that single or multiple doses of fluconazole 50mg do not affect its metabolism.

Fluconazole shows little pharmacological activity in a wide range of animal studies. Some prolongation of pentobarbitone sleeping times in mice (p.o.), increased mean arterial and left ventricular blood pressure and increased heart rate in anaesthetised cats (i.v.) occurred. Inhibition of rat ovarian aromatase was observed at high concentrations.

The efficacy of fluconazole in tinea capitis has been studied in 2 randomised controlled trials in a total of 878 patients comparing fluconazole with griseofulvin. Fluconazole at 6mg/kg/day for 6 weeks was not superior to griseofulvin administered at 11mg/kg/day for 6 weeks. The overall success rate at week 6 was low (fluconazole 6 weeks: 18.3%; fluconazole 3 weeks: 14.7%; griseofulvin:17.7%) across all treatment groups. These findings are not inconsistent with the natural history of tinea capitis without therapy.

5.2 Pharmacokinetic properties

The pharmacokinetic properties of fluconazole are similar following administration by the intravenous or oral route. After oral administration fluconazole is well absorbed and plasma levels (and systemic bioavailability) are over 90% of the levels achieved after intravenous administration. Oral administration is not affected by concomitant food intake. Peak plasma concentrations in the fasting state occur between 0.5 – 1.5 hours post-dose with a plasma elimination half-life of approximately 30 hours. Plasma concentrations are proportional to dose. Ninety percent steady-state levels are reached by day 4 – 5 with multiple once daily dosing.

The administration of a higher dose on the first day, double that of the normal daily dose, raises plasma levels to approximate to 90% steady-state levels by the second day.

The apparent volume of distribution approximates to total body water. Fluconazole achieves good penetration in all body fluids studied. The levels of fluconazole in saliva and sputum are similar to plasma levels. In patients with fungal meningitis, fluconazole levels in the CSF are approximately 80% of the corresponding plasma levels. High skin concentrations of fluconazole, above serum concentrations, are achieved in the stratum corneum, epidermis-dermis and eccrine sweat. Fluconazole accumulates in the stratum corneum. Plasma protein binding is low (11-12%).

The major route of excretion is renal, with approximately 80% of the administered dose appearing in the urine as unchanged drug. Fluconazole clearance is proportional to creatinine clearance. There is no evidence of circulating metabolites.

Its long clearance plasma elimination half-life makes it possible to administer a single dose in the treatment of genital candidiasis and a daily dose in the treatment of other indications.

5.3 Preclinical safety data

Reproductive toxicity: Increases in foetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 and 50 mg/kg and higher doses. At doses from 80 mg/kg to 320 mg/kg embryolethality in rats was increased and foetal abnormalities included wavy ribs, cleft palate and abnormal cranio-facial ossification.

Carcinogenesis: Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for 24 months at doses of 2.5, 5 or 10 mg/kg/day. Male rats treated with 5 and 10mg/kg/day had an increased incidence of hepatocellular adenomas.

Mutagenesis: Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in 4 strains of S. typhimurium and in the mouse lymphoma L5178Y system. Cytogenetic studies in vivo (murine bone marrow cells, following oral administration of fluconazole) and in vitro (human lymphocytes exposed to fluconazole at 1000 μg/ml) showed no evidence of chromosomal mutations.

Impairment of fertility: Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5, 10 or 20 mg/kg or with parenteral doses of 5, 25 or 75 mg/kg, although the onset of parturition was slightly delayed at 20 mg/kg p.o. In an intravenous perinatal study in rats at 5, 20 and 40 mg/kg, dystocia and prolongation of parturition were observed in a few dams at 20 mg/kg and 40 mg/kg, but not at 5 mg/kg. The disturbances in parturition were reflected by a slight increase in the number of still-born pups and decrease of neonatal survival at these doses. The affects on parturition in rats are consistent with the species specific oestrogen-lowering property produced by high doses of fluconazole. Such a hormone change has not been observed in women treated with fluconazole.

6. Pharmaceutical particulars
6.1 List of excipients

Fluconazole 50 mg capsules contain:

Lactose monohydrate

Microcrystalline cellulose

Pregelatinised maize starch

Colloidal anhydrous silica

Magnesium stearate

Sodium lauryl sulphate

The capsule shells contain:

Titanium dioxide E171

Quinoline yellow E104

Yellow iron oxide E172

Patent blue V E131

Gelatin

6.2 Incompatibilities

Not applicable

6.3 Shelf life

36 months

6.4 Special precautions for storage

No special precautions for storage

6.5 Nature and contents of container

PVC/ Aluminium blisters containing 7 capsules.

6.6 Special precautions for disposal and other handling

Not applicable

7. Marketing authorisation holder

Athlone Pharmaceuticals Limited,

Ballymurray,

Co.Roscommon

Ireland

8. Marketing authorisation number(s)

PL 30464/0146

9. Date of first authorisation/renewal of the authorisation

18th May 2004

10. Date of revision of the text

06/12/2013