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SUMMARY OF PRODUCT CHARACTERISTICS

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 in adults for the treatment of the following conditions:

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

•    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.

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

•    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.

•    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.

•    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.

•    Coccidioidomycosis

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 (see section 4.4).

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.

4.2 Posology and method of administration

Method of administration Fluconazole is administered orally.

Posology

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

Indications		Posology	Duration of treatment
Cryptococcosis	- Treatment of cryptococcal meningitis.	Loading dose: 400 mg on Day 1 Subsequent dose: 200 mg to 400 mg daily	Usually at least 6 to 8 weeks. In life threatening infections the daily dose can be increased to 800 mg
	- Maintenance therapy to prevent relapse of cryptococcal meningitis in patients with high risk of recurrence.	200 mg daily	Indefinitely at a daily dose of 200 mg
Coccidioidomycosis		200 mg to 400 mg	11 months up to 24 months or longer depending on the patient. 800 mg daily may be considered for some infections and especially for meningeal disease
Invasive candidiasis		Loading dose: 800 mg on Day 1 Subsequent dose: 400 mg daily	In general, the recommended duration of therapy for candidemia is for 2 weeks after first

			negative blood culture result and resolution of signs and symptoms attributable to candidemia.
Treatment of mucosal candidiasis	- Oropharyngeal candidiasis	Loading dose: 200 mg to 400 mg on Day 1 Subsequent dose: 100 mg to 200 mg daily	7 to 21 days (until oropharyngeal candidiasis is in remission). Longer periods may be used in patients with severely compromised immune function
	- Oesophageal candidiasis	Loading dose: 200 mg to 400 mg on Day 1 Subsequent dose: 100 mg to 200 mg daily	14 to 30 days (until oesophageal candidiasis is in remission). Longer periods may be used in patients with severely compromised immune function
	- Candiduria	200 mg to 400 mg daily	7 to 21 days. Longer periods may be used in patients with severely compromised immune function.
	- Chronic atrophic candidiasis	50 mg daily	14 days
	- Chronic mucocutaneous candidiasis	50 mg to 100 mg daily	Up to 28 days. Longer periods depending on both the severity of infection or underlying immune compromisation and infection
Prevention of relapse of mucosal candidiasis in patients infected with HIV who are at high risk of experiencing relapse	- Oropharyngeal candidiasis	100 mg to 200 mg daily or 200 mg 3 times per week	An indefinite period for patients with chronic immune suppression
	- Oesophageal candidiasis	100 mg to 200 mg daily or 200 mg 3 times per week	An indefinite period for patients with chronic immune suppression
Genital candidiasis	-    Acute vaginal candidiasis -    Candidal balanitis	150 mg	Single dose

	- Treatment and prophylaxis of recurrent vaginal candidiasis (4 or more episodes a year).	150 mg every third day for a total of 3 doses (day 1, 4, and 7) followed by 150 mg once weekly maintenance dose	Maintenance dose: 6 months.
Dermatomycosis	-    tinea pedis, -    tinea corporis, -    tinea cruris, -    Candida infections	150 mg once weekly or 50 mg once daily	2 to 4 weeks, tinea pedis may require treatment for up to 6 weeks
	- tinea versicolor	300 mg to 400 mg once weekly	1 to 3 weeks
		50 mg once daily	2 to 4 weeks
	- tinea unguium(onychomycosis)	150 mg once weekly	Treatment should be continued until infected nail is replaced (uninfected nail grows in). Regrowth of fingernails and toenails normally requires 3 to 6 months and 6 to 12 months, respectively. However, growth rates may vary widely in individuals, and by age. After successful treatment of long-term chronic infections, nails occasionally remain disfigured.
Prophylaxis of candidal infections in patients with prolonged neutropenia		200 mg to 400 mg	Treatment should start several days before the anticipated onset of neutropenia and continue for 7 days after recovery from neutropenia after the neutrophil count rises above 1000 cells per mm3.

Paediatric population

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.

A maximum of 400mg daily should not be exceeded.

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):

Indication    Posology    Recommendations

Dose: 6 mg/kg daily    Depending on the severity

of the disease

Dose: 3 to 12 mg/kg daily Depending on the extent and duration

of the induced neutropenia (see Adults posology)

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.

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):

(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.

Special Populations 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 > 50	Percent of recommended dose 100 %
50 (no dialysis)	50 %
Patients receiving regular	100% after each dialysis

Patients on regular dialysis should receive 100% of the recommended dose after each dialysis; 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 (see sections 4.4 and 4.8).

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 (seesection 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, quinidine and erythromycin 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 warning and precautions for use

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.

Hepatobiliary

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 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.

Dermatological

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.

Terfenadine

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).

Hypersensitivity

In rare cases, as with other azoles, anaphylaxis has been reported.

Cardiovascular System

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. Coadministration of other medicinal products known to prolong the QT interval and which are metabolised via the cytochrome P450 (CYP) 3A4 are contraindicated (see sections 4.3 and 4.5).

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 (see section 4.5).

Renal System

Fluconazole should be administered with caution to patients with renal dysfunction (see also 4.2).

Cytochrome P450

Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole is also an inhibitor of CYP2C19. Fluconazole treated patients who are concomitantly treated with drugs with a narrow therapeutic window metabolised through CYP2C9, CYP2C19 and CYP3A4, should be monitored (see section 4.5 Interaction with Other Medicaments and Other Forms of Interaction).

Excipients

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 Interactions 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 (see section 4.3).

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 (see section 4.3).

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

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.

This combination should be avoided.

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 (see section 4.3).

Concomitant use of the following other medicinal products cannot be recommended:

Halofantrine: Fluconazole can increase halofantrine plasma concentration due to an inhibitory effect on CYP3A4. Concomitant use of fluconazole and halofantrine has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsades de pointes) and consequently sudden heart death. This combination should be avoided (see section 4.4).

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, co-administration 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 in the fluconazole dose should be considered.

Interaction studies have shown that when oral fluconazole is co-administered with food, cimetidine, antacids or following total body irradiation for bone marrow transplantation, no clinically significant impairment of fluconazole absorption occurs

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. Fluconazole is also an inhibitor of the isozyme CYP2C19. In addition to the observed/documented interactions mentioned below, there is a risk of increased plasma concentration of other compounds 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. During concomitant treatment with fluconazole (400mg) and intravenous alfentanil (20ug/kg) in healthy volunteers the alfentanil AUC10 increased 2-fold, probably through inhibition of CYP3A4.

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. During concomitant treatment with fluconazole and warfarin the prothrombin time was prolonged up to 2-fold, probably due to an inhibition of the warfarin metabolism through CYP2C9. 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 azithromycin. There was no significant pharmacokinetic interaction between fluconazole and azithromycin.

Benzodiazepines (Short Acting) i.e., midazolam, triazolam: Following oral administration of midazolam, fluconazole resulted in substantial increases in midazolam concentrations and psychomotor effects. Concomitant intake of fluconazole 200mg and midazolam 7.5mg orally increased the midazolam AUC and half-life 3.7-fold and 2.2-fold, respectively. Fluconazole 200mg daily given concurrently with triazolam 0.25mg orally increased the triazolam AUC and half-life 4.4-fold and 2.3-fold, respectively. Potentiated and prolonged effects of triazolam have been observed at concomitant treatment with fluconazole. 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 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 verapamil and felodipine) are metabolized by CYP3A4.

Fluconazole has the potential to increase the systemic exposure of the calcium channel antagonists. Frequent monitoring for adverse events is recommended.

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.

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.

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. Patients should be monitored closely for the potential risk of respiratory depression. Dosage adjustment of Fentanyl may be necessary.

Concomitant use of the following medicinal product cannot be recommended:

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.

Immunosuppresors (i.e. ciclosporin, everolimus, sirolimus and tacrolimus):

Ciclosporin: Fluconazole significantly increases the concentration and AUC of ciclosporin. During concomitant treatment with fluconazole 20mg daily and ciclosporin (2.7mg/kg/day) there was a 1.8-fold increase in ciclosporin AUC. This combination may be used by reducing the dosage of ciclosporin depending on ciclosporin concentration.

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

Sirolimus: Fluconazole increases plasma concentrations of sirolimus presumably by inhibiting the metabolism of sirolimus via CYP3A4 and P-glycoprotein. This combination may be used with a dosage adjustment of sirolimus depending on the effect/concentration measurements.

Tacrolimus: Fluconazole may increase the serum concentrations of orally administered tacrolimus up to 5 times due to inhibition of tacrolimus metabolism through CYP3A4 in the intestines. No significant pharmacokinetic changes have been observed when tacrolimus is given intravenously. Increased tacrolimus levels have been associated with nephrotoxicity.

Dosage of orally administered tacrolimus should be decreased depending on tacrolimus concentration.

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. Concomitant repeated administration of 200mg fluconazole and 250mg phenytoin intravenously, caused an increase of the phenytoin AUC24 by 75% and Cmin by 128%. With coadministration, serum phenytoin concentration levels should be monitored in order to avoid phenytoin toxicity.

Prednisone: There was a case report that a liver-transplanted patient treated with prednisone developed acute adrenal cortex insufficiency when a three month therapy with fluconazole was discontinued. The discontinuation of fluconazole presumably caused an enhanced

CYP3A4 activity which led to increased metabolism of prednisone. Patients on long-term treatment with fluconazole and prednisone should be carefully monitored for adrenal cortex insufficiency when fluconazole is discontinued.

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. Interaction with saquinavir/ritonavir has not been studied and might be more marked. Dosage adjustment of saquinavir may be necessary.

Sulfonylureas: Fluconazole has been shown to prolong the serum half-life of concomitantly administered oral sulfonylureas (e.g., chlorpropamide, glibenclamide, glipizide, tolbutamide) in healthy volunteers. Frequent monitoring of blood glucose and appropriate reduction of sulfonylurea dosage is recommended during coadministration.

Theophylline: In a placebo controlled interaction study, the administration of fluconazole 200 mg for 14 days resulted in an 18% decrease in the mean plasma clearance rate of theophylline. Patients who are receiving high dose theophylline or who are otherwise at increased risk for theophylline toxicity should be observed for signs of theophylline toxicity while receiving fluconazole. Therapy should be modified if signs of toxicity develop.

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): Co-administration 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 AUCt of voriconazole by an average of 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. The reduced dose and/or frequency of voriconazole and fluconazole that would eliminate this effect have not been established. Monitoring for voriconazole associated adverse events is recommended if voriconazole is used sequentially after fluconazole.

Zidovudine: Fluconazole increases Cmax and AUC of zidovudine by 84% and 74%, respectively, due to an approx. 45% decrease in oral zidovudine clearance. The half-life of zidovudine was likewise prolonged by approximately 128% following combination therapy with fluconazole. Patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions. Dosage reduction of zidovudine may be considered.

Ivacaftor: Co-administration with ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, increased ivacaftor exposure by 3-fold and hydroxymethyl-ivacaftor (M1) exposure by 1.9-fold. A reduction of the ivacaftor dose to 150 mg once daily is recommended for patients taking concomitant moderate CYP3A inhibitors, such as fluconazole and erythromycin.

Interaction studies have shown that when oral fluconazole is co-administered with food, cimetidine, antacids or following total body irradiation for bone marrow transplantation, no clinically significant impairment of fluconazole absorption occurs.

4.6    Fertility,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.

Breast-feeding

Fluconazole is found in human breast milk at concentrations lower to those in to plasma, hence its use in nursing mothers is not recommended. Breast-feeding may be maintained after a single use of a standard dose 200 mg fluconazole or less. Breast-feeding is not recommended after repeated use or after high dose fluconazole.

Fertility

Fluconazole did not affect the fertility of male or female rates (see section 5.3)

4.7    Effect on ability to drive and use machines

No studies have been performed on the effects of Fluconazole on the ability to drive or use machines.

Taking Fluconazole 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 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	Decreased appetite
	Rare	Hypertriglyceridaemia, Hypercholesterolaemia, Hypokalaemia
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	Constipation, 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	Uncommon	Myalgia
General disorders and administration site	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

0/

%.

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 14 -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
Organism	S	R
Candida albicans,	2	4
Candida parapsilosis,
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.

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

Absorpton

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.

Distribution

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%).

Biotransformation

Fluconazole is metabolised only to a minor extent. Of a radioactive dose, only 11% is excreted in a changed form in the urine. Fluconazole is a selective inhibitor of the isozymes CYP2C9 and CYP3A4 (see section 4.5). Fluconazole is also an inhibitor of the isozyme CYP2C19.

Elimination

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 (30 hours) makes it possible to administer a single dose in the treatment of genital candidiasis and a daily dose in the treatment of other indications.

Pharmacokinetics in renal impairment

In patients with severe renal insufficiency, (GFR< 20 ml/min) half-life increased from 30 to 98 hours. Consequently, reduction of the dose is needed. Fluconazole is removed by haemodialysis and to a lesser extent by peritoneal dialysis. After three hours of haemodialysis session, around 50% of fluconazole is eliminated from blood.

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 one study were not interpretable due to changes in formulation pathway through the study. Additional data were available from a compassionate use study.

After administration of 2-8 mg/kg fluconazole to children between the ages of 9 months to 15 years, an AUC of about 38 ^gh/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 completed the protocol; a maximum of five 6 mg/kg intravenous infusions of fluconazole were administered every 72 hours. The mean half-life (hours) was 74 (range 44-185) on day 1 which decreased, with time to a mean of 53 (range 30-131) on day 7 and 47 (range 27-68) on day 13. The area under the curve (microgram.h/ml) was 271 (range 173-385) on day 1 and increased with a mean of 490 (range 292-734) on day 7 and decreased with a mean of 360 (range 167-566) on day 13. The volume of distribution (ml/kg) was 1183 (range 1070-1470) on day 1 and increased, with time, to a mean of 1184 (range 510- 2130) on day 7 and 1328 (range 1040-1680) on day 13.

Pharmacokinetics in elderly

A pharmacokinetic study was conducted in 22 subjects, 65 years of age or older receiving a single 50 mg oral dose of fluconazole. Ten of these patients were concomitantly receiving diuretics. The Cmax was 1.54

pg/ml and occurred at 1.3 hours post-dose. The mean AUC was 76.4 ± 20.3 pg*h/ml, and the mean

terminal half-life was 46.2 hours. These pharmacokinetic parameter values are higher than analogous

values reported for normal young male volunteers. Coadministation of diuretics did not significantly alter AUC or Cmax. In addition, creatinine clearance (74 ml/min), the percent of medicinal product recovered unchanged in urine (0-24 h, 22%) and the fluconazole renal clearance estimates (0.124 ml/min/kg) for the elderly were generally lower than those of younger volunteers. Thus, the alteration of fluconazole disposition in the elderly appears to be related to reduced renal function characteristics of this group

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 g/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 effects 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 pregelatinized 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

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

18^th May 2004

10    DATE OF REVISION OF THE TEXT

15/09/2015