SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Fluconazole 50mg/5ml Powder for Oral Suspension

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5ml of oral suspension contains 50mg of fluconazole

For a full list of excipients see section 6.1.

3 PHARMACEUTICAL FORM

Powder for oral suspension.

The powder is almost white. A whitish suspension is obtained after its reconstitution with water.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Fluconazole is indicated in the treatment of mycoses caused by Candida, Cryptococcus and other susceptible yeast, in particular:

1. Mucosal candidiasis: These include oropharyngeal candidiasis, oesophageal, non-invasive bronchopulmonary infections, candiduria, mucocutaneous candidiasis and chronic atrophic oral candidiasis (denture sore mouth). Both normal hosts and immunocompromised patients may be treated.

2    Systemic candidiasis (including disseminated    deep infections    and peritonitis).

3.    Acute cryptococcal meningitis in    adults,    including    patients    with    AIDS,

transplanted

patients or other patients with other causes of immunosuppression.

4.    Genital candidiasis. Acute or recurrent vaginal candidiasis. Candida balanitis. The treatment of partners who present with symptomatic genital candidiasis should be considered.

5.    Prevention of fungal infections in patients predisposed to such infections as a result of chemotherapy or radiotherapy, including bone transplant patients.

6. Dermatomycosis, including infections such as Tinea pedis, Tinea corporis, Tinea cruris, Tinea versicolor. Fluconazole is not indicated for nail infections and tinea capitis.

Use in children

Fluconazole should not be used for tinea capitis.

Consideration should be given to official guidance on the appropriate use of antimycotic agents. Before initiating treatment, samples should be taken for microbiological analysis and the suitability of the therapy should be subsequently confirmed (see sections 4.2 and 5.1)

In some patients with severe crytococcoal meningitis, the mycological response during fluconazole treatment may be slower that during other treatments (see section 4.4)

4.2 Posology and method of administration

The daily dose of fluconazole will depend on the nature and severity of the fungal infection. Most cases of vaginal candidiasis respond to a single dose treatment. The treatment of those types of infection requiring multiple doses of the drug should be continued until the clinical parameters or laboratory tests indicate that the active fungal infection has subsided.

An inadequate treatment period may cause relapses of the active infection. Patients with AIDS and cryptococcal meningitis or recurrent oral candidiasis usually require maintenance treatment to prevent relapses.

Adults

Indications		Posology	Duration of Treatment
Candidal vaginitis or balantis		150mg	single oral dose
Mucosal Candidiasis	Oropharyngeal candidiasis	50mg once daily*	7-14 days. Treatment should not normally exceed 14 days except in severely immunocompromised patients.
	Atopic oral condidiasis associated with dentures	50mg once daily*	14 days administered concomitantly with local antiseptic measures to the dentures.

Indications		Posology	Duration of Treatment
	Other candidal infections for mucosa (except genital candidiasis see above) e.g. oesophagitis, noninvasive broncopulmonary infections, candiduria, mucocutaneous candidiasis etc.	50mg daily*	14-30 days
Dermatomycosis	-    tinea pedis -    tinea corporis -    tinea crusis -    tinea versicolor -    dermal Candida infections	50mg once daily	Normally 2 to 4 weeks**
—Candidaemia —Disseminated candidiasis —Other invasive candidal infections		Loading dose: 400mg on Day 1 Subsequent dose: 200mg daily (depending on clinical response, may be increased to 400mg daily)	Based upon the clinical response.
Cryptococcosis	Treatment of cryptococcal meningitis and cryptococcal infections at other sites	Loading dose: 400mg on Day 1 Subsequent dose: 200mg - 400mg once daily	Dependant on the clinical and mycological response. Usually 6-8 weeks for cryptococcal meningitis.
	Prevention of relapse of crytococcal meningitis in patients with AIDS	100mg - 200mg daily	Indefinitely at a daily dose of 100-200 mg.

Indications		Posology	Duration of Treatment
Prevention of fungal infections	Immunocompromised patients considered at risk as a consequence of neutropenia following cytotoxic chemotherapy or radiotherapy	50 to 400mg 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 400mg once daily.	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 mm
* In unusually difficult cases of mucosal candial infections, the dose may be increased to 100mg daily. ** tinea pedis may require treatment for up to 6 weeks. Duration of treatment should not exceed 6 weeks.

Use in the elderly

The normal dose should be used if there is no evidence of renal impairment. In patients with renal impairment (creatinine clearance less than 50 ml/min) the dosage schedule should be adjusted as below.

Use in patients with impaired renal function

Fluconazole is excreted primarily in the urine as unchanged drug. No adjustments in single dose therapy are required. In patients (including paediatric population) with impaired renal functions 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 in the following table:

Creatinine clearance (ml/min)	Percentage of dose recommended
> 50	100%
< 50 (no dialysis)	50%
Regular dialysis	100% after each dialysis

Paediatric Population

A maximum dosage of 400mg daily should not be exceeded in 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.

The pharmacokinetics of fluconazole has not been studied in children with renal insufficiency. For children with impaired renal function, see dosing in ‘Use in patients with impaired renal function’.

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

To facilitate accurate measurement of doses less than 10mg, fluconazole should only be administered to children in hospital using the 50mg/5ml suspension orally or the intraveneous injection, depending on the clinical condition of the child. A suitable measuring device should be used for administration of the suspension. Once reconstituted, the suspension should not be further diluted.

Infants, toddlers, children and adolescents (from 28 days to 17 years)

Indication	Posology	Recommendations
Mucosal candidiasis	3 mg/kg daily	A leading dose of 6mg/kg may be used on the first day to achieve steady state levels more rapidly.
Systemic candidiasis, Cryptococcal infections	6-12 mg/kg daily	Dosage dependant on the severity of the disease
Prevention of fungal infections in immunocompromised patients considered at risk as a consequence of neutropenia following cytotoxic chemotherapy or radiotherapy	3-12 mg/kg daily	Dosage dependant on the extent and duration of the induced neutopenia (see adult dosing).

Term newborn infants (0 to 27 days): Neonates excrete fluconazole slowly.

Age group	Posology	Recommendations
Term newborn infants (0 to 14 days)	The same mg/kg dosing as in older children should be used but administered every 72 hours	A maximum dosage of 12 mg/kg every 72 hours should not be exceeded
Term newborn infants (from 15 to 27 days)	The same mg/kg dosing as in older children should be used but administered every 48 hours	A maximum dosage of 12mg/kg every 48 hours should not be exceeded

4.3. Contra-Indications

Hypersensitivity to the active substance, to related azole substances, or to any of the excipients listed in section 6.1.

Coadministration of terfenadine is contraindicated in patients receiving fluconazole at multiple doses of 400 mg per day or higher based upon results of a multiple dose interaction study. Co-administration of other medicinal products known to prolong the QT interval and which are metabolised via the cytochrome P450 (CYP) 3A4 such as cispride, astimizole, pimozide, quinidine and erythromycin are contraindicated in patients receiving fluconazole (see sections

4.4 and 4.5).

4.4 Special warnings and precautions for use

In some patients, particularly those with serious underlying diseases such as AIDS and cancer, abnormalities in haematological, hepatic, renal and other biochemical function test results have been observed during treatment with fluconazole but the clinical significance and relationship to treatment is uncertain.

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

There is some evidence that in some patients with cryptococcal meningitis, the mycological response during fluconazole treatment may be slower compared with treatment with amphotericin B in combination with flucytosine. This should be taken into account for the treatment choice of patients with severe cryptococcal meningitis.

The evidence for efficacy of fluconazole in the treatment of cryptococcosis of other sites (e.g. pulmonary and cutaneous cryptococcosis) is limited, which prevents dosing recommendations.

Deep endemic mycoses

The evidence for efficacy of fluconazole in the treatment of other forms of endemic mycoses such as paracoccidioidomycosis, lymphocutaneous sporotrichosis and histoplasmosis is limited, which prevents specific dosing recommendations.

Renal system

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

Adrenal insufficiency

Ketoconazole is known to cause adrenal insufficiency, and this could also although rarely seen be applicable to fluconazole.

Adrenal insufficiency relating to concomitant treatment with Prednisone is described in section 4.5

Hepatobiliary System

Fluconazole should be administered with caution to patients with liver dysfunction.

Fluconazole has been associated with rare cases of serious hepatic toxicity including fatalities, primarily in patients with serious underlying medical conditions.

Patients who died with severe underlying diseases and who have received multiple dose of fluconazole had post-mortem findings which included hepatic necrosis. These patients were receiving multiple concomitant medications, some known to be potentially hepatotoxic and/or had underlying diseases that could have caused hepatic necrosis.

In cases of fluconazole-associated hepatotoxicity, no obvious relationship to the total daily dose, duration of therapy, sex or age of patient has been observed. Fluconazole hepatotoxicity has usually been reversible on discontinuation of fluconazole therapy.

Patients who develop abnormal liver function tests during fluconazole therapy must be closely monitored for 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). Fluconazole should be immediately discontinued if clinical signs or symptoms consistent with liver disease develop during treatment with fluconazole and the patient should consult a physician.

Cardiovascular System

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

Some azoles, including fluconazole, have been associated with the prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, there have been very rare cases of QT prolongation and torsade de pointes in patients taking fluconazole. These reports included seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities and concomitant treatment that may have been contributory. Although the association of fluconazole and QT prolongation has not been fully established, fluconazole should be used with caution in the following patients with potentially proarrythmic conditions such as:

•    Congenital or documented acquired QT prolongation

•    Cardiomyopathy in particular where heart failure is present

•    Sinus bradycardia

•    Existing symptomatic arrhythmias

•    Electrolye disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia.

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).

Dermatological reactions

Patients have rarely developed exfoliative cutaneous reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, during treatment with fluconazole. AIDS patients are more prone to the development of severe cutaneous reactions to many medicinal products. If a rash, which is considered attributable to fluconazole, develops in a patient treated for a superficial fungal infection, further therapy with this medicinal product should be discontinued. If patients with invasive/systemic fungal infections develop rashes, they should be monitored closely and fluconazole discontinued if bullous lesions or erythema multiforme develop.

Hypersensitivity

In rare cases anaphylaxis has been reported (see section 4.3).

Cytochrome P450

Fluconazole is a potent CYP2C9 and CYP2C19 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole treated patients who are concomitantly treated with medicinal products with a narrow therapeutic window metabolised through CYP2C9, CYP2C19 and CYP3A4, should be monitored (see section 4.5).

Terfenadine

The coadministration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored (see sections 4.3 and 4.5).

Excipients

Fluconazole 50 mg/5 ml powder for oral suspension contains respectively 2881 mg/5 ml of sucrose as an excipient. Patients with rare hereditary problems to fructose intolerance, glucose/galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine. This medicinal product contains less than 1 mmol sodium (23 mg) per 5ml, i.e. essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant use of the following other medicinal products is contraindicated:

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

Terfenadine: Because of the occurrence of serious cardiac dysrhythmias secondary to prolongation of the QTc interval in patients receiving azole antifungals in conjunction with terfenadine, interaction studies have been performed. One study at a 200 mg daily dose of fluconazole failed to demonstrate a prolongation in QTc interval. Another study at a 400 mg and 800 mg daily dose of fluconazole demonstrated that fluconazole taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. The combined use of fluconazole at doses of 400 mg or greater with terfenadine is contraindicated (see section 4.3). The coadministration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored.

Astemizole: As fluconazole inhibits cytochrome p450 isoenzyme 3A4, concomitant administration of fluconazole with astemizole may increase the serum levels / decrease the clearance of astemizole. Resulting increased plasma concentrations of astemizole can lead to QT prolongation, potentially fatal arrhythmias (including 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 torsades de pointes. Coadministration of fluconazole and pimozide is contraindicated (see section 4.3).

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).

Erythromycin: Concomitant use of fluconazole and erythromycin has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsades de pointes) and consequently sudden heart death. Coadministration of fluconazole and erythromycin is contraindicated (see section 4.3).

Amiodarone: Concomitant administration of fluconazole with amiodarone may increase QT prolongation. Therefore, caution should be made when both drugs are combined, notably with high dose fluconazole (800mg).

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

Rifampicin (Rifampin): Concomitant administration of fluconazole and rifampicin resulted in a 25% decrease in the AUC and a 20% shorter half life of fluconazole. In patients receiving concomitant rifampicin, an increase of the fluconazole dose should be considered.

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

Hydrochlorothiazide: In a pharmacokinetic interaction study, co-administration of multiple-dose hydrochlorothiazide to healthy volunteers receiving fluconazole increased plasma concentration of fluconazole by 40%. An effect of this magnitude should not necessitate a change in the fluconazole dose regimen in subjects receiving concomitant diuretics¹, although the prescriber will have to take this into account.

¹ Mesure R. Protocol 245. An open placebo-controlled crossover study to determine any effect of concomitant diuretic treatment on fluconazole pharmacokinetics in healthy volunteers.

The effect of fluconazole on other medicinal products

Fluconazole is a potent inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and 2C19, 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, CYP2C19 and CYP3A4 (inc. HIV protease inhibitors such as ritonavir and indinavir) coadministered with fluconazole. Therefore caution should be exercised when using these combinations and the patients should be carefully monitored. The enzyme inhibiting effect of fluconazole persists 4-5 days after discontinuation of fluconazole treatment due to the long half-life of fluconazole (see section 4.3).

Alfentanil: In a placebo-controlled and crossover interaction study on healthy volunteers, the administration of doses of 400 mg of oral or intravenous fluconazole prior to the intravenous administration of alfentanil 20 g/kg caused a 55% reduction in alfentanil clearance by inhibiting its metabolism (probably through inhibition of CYP3A4), thus its effects may be extended. If concurrent treatment with alfentanil is necessary in patients who are being treated with fluconazole, decreasing the dose of alfentanil should be considered, and the patients must be appropriately monitored.

Amitriptyline, nortriptyline: Fluconazole increases the effect of amitriptyline and nortriptyline. 5 nortriptyline and/or S amitriptyline may be measured at initiation of the combination therapy and after one week. Dose of amitriptyline/nortriptyline should be adjusted, if necessary.

Amphotericin B: Concurrent administration of fluconazole and amphotericin B in infected normal and immunosuppressed mice showed the following results: a small additive antifungal effect in systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus neoformans, and antagonism of the two medicinal products in systemic infection with A. fumigatus. The clinical significance of results obtained in these studies is unknown.

Anticoagulants: In post-marketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena) have been reported, in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. During concomitant treatment with fluconazole and warfarin the prothrombin time was prolonged up to 2 fold, probably due to an inhibition of the warfarin metabolism through CYP2C9. In patients receiving coumarin-type or indanedione anticoagulants concurrently with fluconazole the prothrombin time should be carefully monitored. Dose adjustment of the anticoagulant may be necessary.

Benzodiazepines (short acting), i.e. midazolam, lorazepam, oxazepam, temazepam, Lormetazepam, triazolam: Following oral administration of midazolam, fluconazole resulted in substantial increases in midazolam concentrations and psychomotor effects. This effect on midazolam seems greater following oral administration of fluconazole than with intravenous administration. Concomitant intake of fluconazole 200 mg and midazolam 7.5 mg orally increased the midazolam AUC and half-life 3.7 fold and 2.2 fold, respectively. Fluconazole 200 mg daily given concurrently with triazolam 0.25 mg 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. If concomitant benzodiazepine therapy is necessary in patients being treated with fluconazole, consideration should be given to decreasing the benzodiazepine dose, and the patients must be appropriately monitored.

Carbamazepine: Fluconazole inhibits the metabolism of carbamazepine and an increase in serum carbamazepine of 30% has been observed. There is a risk of developing carbamazepine toxicity. Dose adjustment of carbamazepine may be necessary depending on concentration measurements/effect.

Calcium channel blockers: Certain calcium channel antagonists (nifedipine, isradipine, amlodipine, verapamil and felodipine) are 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.

Cyclophosphamide: Combination therapy with cyclophosphamide and fluconazole results in an increase in serum bilirubin and serum creatinine. The combination may be used while taking increased consideration to the risk of increased serum bilirubin and serum creatinine.

Fentanyl: One fatal case of fentanyl intoxication due to possible fentanyl fluconazole interaction was reported. Furthermore, it was shown in healthy volunteers that fluconazole delayed the elimination of fentanyl significantly. Elevated fentanyl concentration may lead to respiratory depression. Patients should be monitored closely for the potential risk of respiratory depression. Dosage adjustment of fentanyl may be necessary.

HMG CoA reductase inhibitors: The risk of myopathy and rhabdomyolysis increases when fluconazole is coadministered with HMG-CoA reductase inhibitors metabolised through CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin. If concomitant therapy is necessary, the patient should be observed for symptoms of myopathy and rhabdomyolysis and creatinine kinase should be monitored. HMG-CoA reductase inhibitors should be discontinued if a marked increase in creatinine kinase is observed or myopathy/rhabdomyolysis is diagnosed or suspected.

Immunosuppresors (i.e. ciclosporin, everolimus, sirolimus and tacrolimus): Ciclosporin: Fluconazole significantly increases the concentration and AUC of ciclosporin. During concomitant treatment with fluconazole 200 mg daily and ciclosporin (2.7 mg/kg/day) there was a 1.8 fold increase in ciclosporin AUC. However, in another multiple dose study using 100mg daily of fluconazole, ciclosporin levels were not affected in bone marrow transplant patients. Therefore monitoring the plasma concentration of ciclosporin is recommended in patients receiving fluconazole and dose reduction of ciclosporin may be required depending on ciclosporin concentration.

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

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

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

Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E 31 74) which is responsible for most of the angiotensin Il receptor antagonism which occurs during treatment with losartan. Patients should have their blood pressure monitored continuously.

Methadone: Fluconazole may enhance the serum concentration of methadone. Dose adjustment of methadone may be necessary.

Non-steroidal anti-inflammatory drugs (NSAIDs): The Cmax and AUC of flurbiprofen was increased by 23% and 81%, respectively, when coadministered with fluconazole compared to administration of flurbiprofen alone. Similarly, the Cmax and AUC of the pharmacologically active isomer [S (+) ibuprofen] was increased by 15% and 82%, respectively, when fluconazole was coadministered with racemic ibuprofen (400 mg) compared to administration of racemic ibuprofen alone.

Although not specifically studied, fluconazole has the potential to increase the systemic exposure of other NSAIDs that are metabolized by CYP2C9 (e.g. naproxen, lornoxicam, meloxicam, diclofenac). Frequent monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of dose of NSAIDs may be needed.

Phenytoin: Fluconazole inhibits the hepatic metabolism of phenytoin and the conconcomitant administration of fluconazole and phenytoin may increase phenytoin levels to a clinically significant degree. Concomitant repeated administration of 200 mg fluconazole and 250 mg phenytoin intravenously, caused an increase of the phenytoin AUC24 by 75% and Cmin by 128%. If it is necessary to administer both drugs concomitantly, serum phenytoin concentration levels should be monitored and the phenytoin dose adjusted to maintain therapeutic levels and avoid phenytoin toxicity.

Prednisone: There was a case report that a liver-transplanted patient treated with prednisone developed acute adrenal cortex insufficiency when a three month therapy with fluconazole was discontinued. The discontinuation of fluconazole presumably caused an enhanced CYP3A4 activity which led to increased metabolism of prednisone. Patients on long-term treatment with fluconazole and prednisone should be carefully monitored for adrenal cortex insufficiency when fluconazole is discontinued.

Rifabutin: Fluconazole increases serum concentrations of rifabutin, leading to increase in the AUC of rifabutin up to 80%. There have been reports of uveitis in patients to whom fluconazole and rifabutin were coadministered. In combination therapy, symptoms of rifabutin toxicity should be taken into consideration.

Saquinavir: Fluconazole increases the AUC and C max of saquinavir with approximately 50% and 55% respectively, due to inhibition of saquinavir’s hepatic metabolism by CYP3A4 and inhibition of P glycoprotein. Interaction with saquinavir/ritonavir has not been studied and might be more marked. Dose adjustment of saquinavir may be necessary.

Sulfonylureas: Fluconazole has been shown to prolong the serum half-life of concomitantly administered oral sulfonylureas (e.g., chlorpropamide, glibenclamide, glipizide, tolbutamide) in healthy volunteers. Fluconazole and sulphonylureas may be concurrently administered to diabetic patients, but the possibility of a hypoglycaemic episode must be considered therefore frequent monitoring of blood glucose and appropriate reduction of sulfonylurea dose is recommended.

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

Vinca alkaloids: Although not studied, fluconazole may increase the plasma levels of the vinca alkaloids (e.g. vincristine and vinblastine) and lead to neurotoxicity, which is possibly due to an inhibitory effect on CYP3A4.

Vitamin A: Based on a case-report in one patient receiving combination therapy with all trans retinoid acid (an acid form of vitamin A) and fluconazole, CNS related undesirable effects have developed in the form of pseudotumour cerebri, which disappeared after discontinuation of fluconazole treatment. This combination may be used but the incidence of CNS related undesirable effects should be borne in mind.

Voriconazole: (CYP2C9, CYP2C19 and CYP3A4 inhibitor): Coadministration of oral voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg Q24h for 4 days) to 8 healthy male subjects resulted in an increase in Cmax and 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: Two pharmacokinetic studies have exhibited increases in zidovudine levels, probably caused by the decrease in zidovudine conversion into its main metabolite. One study determined zidovudine levels in patients with AIDS or ARC before and after the administration of 200 mg of fluconazole daily for 15 days. A significant increase of the AUC for zidovudine was observed (20%). A second randomised, two periods, crossover, two treatment study studied the zidovudine levels in patients infected with HIV. In two occasions, with an interval of 21 days, the patients received 200 mg of zidovudine every 8 hours with or without 400 mg of fluconazole daily for 7 days. The Cmax and AUC of zidovudine increased significantly (84% and 74% respectively) during the combined administration with fluconazole, 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. Those patients receiving this association must be monitored regarding the occurrence of zidovudine-related undesirable effects. Dose reduction of zidovudine may be considered.

Azithromycin: An open label, randomized, three way crossover study in 18 healthy subjects assessed the effect of a single 1200 mg oral dose of azithromycin on the pharmacokinetics of a single 800 mg oral dose of fluconazole as well as the effects of fluconazole on the pharmacokinetics of azithromycin. There was no significant pharmacokinetic interaction between fluconazole and azithromycin.

Oral contraceptives: Two pharmacokinetic studies with a combined oral contraceptive have been performed using multiple doses of fluconazole. There were no relevant effects on hormone level in the 50 mg fluconazole study, while at 200 mg daily, the area under the curve (AUC)s 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.

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.

Although no interaction studies have been performed with other drugs, the possible occurrence of other similar pharmacological interactions is not rejected.

4.6 Fertility, pregnancy and lactation

Pregnancy

There have been reports of multiple congenital abnormalities (including brachycephalia, ears dysplasia, giant anterior fontanelle, femoral bowing and radio-humeral synostosis) in infants whose mothers were treated for at least three or more months with high doses (400-800mg daily) of fluconazole for coccidioidomycosis. The relationship between fluconazole and these incidents is unclear.

Studies in animals have shown reproductive toxicity (see section 5.3).

Data from several hundred pregnant women treated with standard doses (<200 mg/day) of fluconazole, administered as a single or repeated dose in the first trimester, show no increased risk of undesirable effects in the foetus.

Fluconazole at standard doses and short-term treatment should not be used in pregnancy unless clearly necessary. Fluconazole in high doses and/or in prolonged regimens should not be used during pregnancy except for potentially life threatening infections.

Breast-feeding

Fluconazole passes into breast milk to reach concentrations lower than those in plasma. 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.

4.7 Effects on ability to drive and use machines

Experience with fluconazole indicates that treatment with this drug is unlikely to affect the patient's ability to drive or use machines.

4.8 Undesirable effects

Adverse reactions associated with fluconazole observed in clinical trials and postmarketing studies are listed below:

Frequencies are defined as:

Very common (>1/10)

Common (>1/100 to <1/10)

Uncommon (>1/1000 to <1/100)

Rare (>1/10,000 to <1/1000)

Very rare (<1/10,000)

Not known (cannot be estimated from the available data)

Within each frequency group, undesirable effects are presented in order of decreasing seriousness. Adverse events with very common frequency (>1/10) until now have not been recognised.

System organ class	Common (>1/100 to <1/10)	Uncommon (>1/1000 to <1/100)	Rare (>1/10,000 to <1/1000)	Very rare (<1/10,000)	Not known
Infections and infestations					infection due to resistance microorganisms
Blood and lymphatic system disorders		anaemia	agranulocytosis, leucopenia, neutropenia, thrombocytopenia
Immune system disorders			anaphylaxis	angiodemia, face oedema
Metabolism and nutrition disorders		decreased appetite	hypercholesterolemia, hypertriglyceridemia, hypokalaemia
Psychiatric disorders		insomnia, somnolence
Nervous system disorders	headache	seizures, convulsions, dizziness, paraesthesia, taste perversion, tremor, vertigo
Cardiac disorders			ventricular arrhythmia (QT prolongation, torsades de pointes) -see section 4.4
Gastrointestinal disorders	vomiting, nausea, abdominal pain, diarrhoea	dyspepsia, flatulence, anorexia, constipation, dry mouth
Hepatobiliary disorders	increase in the serum activities of liver-derived enzymes such as blood alkaline phosphatase (ALP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST)	cholestasis, bilirubin increased, jaundice, hepatotoxicity	hepatitis, hepatocellular necrosis, hepatic failure with isolated fatalities. The appropriate laboratory values should be very closely monitored (see section 4.4)
Skin and subcutaneous tissue disorders	maculopapular erythema, rash	urticaria, pruritus, increased	exfoliative skin disorders (Stevens-Johnson syndrome),	exfoliative skin disorders

		sweating, drug eruption*	acute generalised exanthematous pustulosis, dermatitis exfoliative, angioderma, face oedema, alopecia	(toxic epidermal necrolysis or Lyell syndrome)
Musculoskeletal and connective tissue disorders		myalgia
Renal and urinary disorders		changes in renal function tests
General disorders and administration site conditions		fatigue, malaise, asthenia, fever
* = including fixe<	l drug eruptions

Paediatric population

The pattern and incidence of side-effects and laboratory abnormalities recorded during paediatric use 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

Cases of overdose with fluconazole have been reported and one case of a 42-year old patient infected with the human immunodeficiency virus who exhibited hallucinations and paranoid behaviour after reporting that he had taken 8,200 mg of fluconazole. The patient was hospitalised and the symptoms resolved in 48 hours.

Symptomatic treatment may be suitable in the event of an overdose, with maintenance of vital signs and gastric lavage if necessary.

Fluconazole is eliminated mainly through urine; therefore, forced diuresis will very probably increase the elimination rate. A three-hour haemodialysis session reduces plasma levels to approximately 50%.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antimycotic (triazole derivatives)

ATC code: J02 AC 01

General properties

Fluconazole is a bis-triazole antifungal drug that belongs to the new class of triazole antifungal drugs.

Mode of action

Fluconazole is a powerful and specific inhibitor of the fungal synthesis of sterols. It acts by inhibiting cytochrome P450 14^ demethylase in susceptible fungi which converts lanosterol into ergosterol, an essential lipid component of the fungal membrane.

Fluconazole is highly specific for cytochrome P-450-dependent fungal enzymes. A daily dose of 50 mg of fluconazole, administered for a maximum period of up to 28 days, has demonstrated not to affect plasma concentrations of testosterone in males or steroid concentrations in women of child-bearing age.

A daily dose of 200-400 mg of fluconazole does not have a clinically significant effect upon the levels of endogenous steroids or on their response to ACTH stimulation in healthy volunteers. Interaction studies with antipyrine indicate that fluconazole, at single or multiple doses of 50 mg, does not affect its metabolism.

Most fungi show in vivo a clear sensitivity to fluconazole greater than the sensitivity they show in vitro. This is a common problem to all azole antifungal drugs

Fluconazole, both orally and intravenously, has demonstrated to be active in a wide variety of animal fungal infection models. Said activity has been demonstrated in opportunist mycoses, such as infections by Candida spp., including systemic candidiasis in immunocompromised animals; infections by Cryptococcus neoformans , including intracranial infections; infections by Microsporum spp., and infections by Trichophyton spp.

Fluconazole has demonstrated to be active in endemic mycosis animal models, including infections by Blastomyces dermatitidis; infections by Coccidioides immitis, including intracranial infection; and infections by Histoplasma capsulatum in normal and immunocompromised animals.

Mechanism of resistance

Occasional isolates of fluconazole-resistant Candida albicans have been reported in patients receiving prolonged AIDS treatments. As with amphotericin B and any other antiinfectious drug, isolates that are resistant to a specific treatment may occur especially in immunocompromised patients receiving treatment with that drug.

Breakpoints

	Species related breakpoints					Non-species related breakpoint*
	Candida	Candida	Candida	Candida	Candida

PK/PD data and are independent of MIC distributions of specific species. They are for use only with organisms that do not have specific breakpoints - Susceptibility testing not recommended as specires is a poor target for therapy with the drug.

IE - there is insufficient evidence that the species in question is a good target for therapy with the drug

Susceptibility

The prelevance 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 local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable

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 6 weeks was low (fluconazole 6 weeks: 18.3%; fluconazole 3 weeks: 14.7%; griseofulvin: 17.7%) across all the treatment groups. These findings are not inconsistent with the natural history of tinea capitis without therapy.

5.2 Pharmacokinetic properties

Absorption

The pharmacokinetic properties of fluconazole are similar following its oral or intravenous administration. Fluconazole is well absorbed orally, with plasma levels (and systemic bioavailability) of more than 90% with respect to the levels reached following intravenous administration. Oral absorption is not affected by the combined administration of food. Peak plasma concentrations are obtained between 0.5 and 1.5 hours post-dose, with an elimination half-life of approximately 30 hours.

Distribution

Plasma concentrations are proportional to the doses. 90% of the equilibrium state levels are reached 4 or 5 days following multiple doses once daily. The administration of a higher dose on the first day, double the usual daily dose, increases plasma levels to 90% of the equilibrium state levels on the second day. The apparent distribution volume is close to the total body water. Binding to plasma proteins is low (11-12%).

Fluconazole penetration in all the body fluids studied is high. Fluconazole levels in saliva and sputum are similar to plasma levels. In patients with fungal meningitis, the fluconazole concentration in cerebrospinal fluid is approximately 80% of the plasma concentration.

High concentrations of fluconazole are reached in the stratum corneum, dermis and epidermis and in eccrine sweat, higher than serum concentrations. Fluconazole accumulates in the stratum corneum. At a dose of 50 mg once daily, the fluconazole concentration after twelve days was 73 g/g, and seven days after discontinuation of the treatment, it was still 5.8 g/g. At a dose of 150 mg once a week, the fluconazole concentration in the stratum corneum on day seven was 23.4 g/g and seven days after the second dose it was still 7.1 pg/g.

The concentration of fluconazole in the nails after four months of administration of 150 mg once a week, was 4.05 g/g in healthy nails and 1.8 pg/g in affected nails. Fluconazole could still be measured in nail samples taken six months after treatment completion.

Metabolism-Elimination

Its elimination is preferably renal, 80% of the dose appearing in urine without modification. Fluconazole clearance is proportional to creatinine clearance. There is no evidence of circulating metabolites.

Its long elimination half-life allows administration of a single dose in the treatment of genital candidiasis and of a daily dose or a weekly dose in the treatment of any other mycoses it is indicated for.

One study compared the plasma and saliva concentrations after a single dose of 100 mg of fluconazole administered in oral suspension (by rinsing and keeping in the mouth for two minutes and swallowing) or in a capsule. The maximum concentration of fluconazole in saliva with the suspension was observed five minutes after swallowing, and was 182 times greater than the maximum concentration in saliva after capsule administration, reached four hours after swallowing. After approximately four hours, fluconazole concentrations in saliva were similar. The mean AUC (0-96) in saliva was significantly higher following administration of the suspension compared to the capsule. There were no significant differences in the elimination rate from saliva or in the pharmacokinetic parameters for both formulations.

Pharmacokinetics in children

Pharmacokinetic data were assessed for 113 paediatric patients from 5 studies; 2 single dose studies, 2 multiple dose studies and a study in premature neonates. Data from 1 study were not interpretable due to changes in formulation partway through the study. Additional data were available from a compassionate use study.

After administration of 2 - 8mg/kg fluconazole to children between ages of 9 months to 15 years, a AUC of about 38 pg.h/ml was found per 1 mg/kg dose units. The average fluconazole plasma elimination half-life varied between 15 and 18 hours and the distribution volume was approximately 880ml/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 950ml/kg.

5.3 Preclinical safety data

Preclinical data for conventional studies on repeat-dose/general toxicity, genotoxicity or carcinogenicity indicate no special hazard for humans not already considered in other sections of the SPC.

In reproduction toxicity studies in rats, an increased incidence of hydronephrosis and extension of renal pelvis was reported and embryonal lethality was increased. An increase in anatomical variations and delayed ossification was noted as prolonged delivery and dystocia. In reproduction toxicity studies in rabbits, abortions were recorded.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sucrose colloidal silica titanium dioxide xanthan gum sodium citrate anhydrous citric acid monohydrate sodium benzoate (E-211)

orange flavour (containing maltodextrin and arabic gum)

6.2 Incompatibilities

None known.

6.3 Shelf life

Unopened bottle: 2 years

Reconstituted suspension: The reconstituted oral suspension has a shelf life of 14 days after reconstitution.

6.4 Special precautions for storage

Unopened bottle: No special storage conditions for the unopened medicinal product.

Reconstituted suspension: Do not freeze the reconstituted suspension. Do not store above 30°C.

6.5 Nature and contents of container

Topaz type III glass bottle with polyethylene cap and polyethylene seal for 35 ml of suspension. A polypropylene dosing cup is included to measure 5 and 10ml. Pack sizes of 1 and 10 bottles (hospital use).

6.6 Special precautions for disposal

INSTRUCTIONS FOR RECONSTITUTION

Turn the bottle upside down and tap it gently until all the powder moves freely. Add 23ml of potable water and shake vigorously. Shake again before use. A whitish suspension is obtained after its reconstitution with water. Dilution is not appropriate.

Any unused product should be disposed of in accordance with local requirements.

7    MARKETING AUTHORISATION HOLDER

Genus Pharmaceuticals Limited

T/A Genus Pharmaceuticals

Linthwaite

Huddersfield

HD75QH

UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 06831/0220

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 15/06/2011

DATE OF REVISION OF THE TEXT

13/03/2016