Fluconazole 200mg Capsules

Document: spc-doc_PL 20395-0043 change

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 200mg of fluconazole.

For excipients, see 6.1.

3 PHARMACEUTICAL FORM

Capsule, hard.

Fluconazole 200mg Capsules have a white body and cap.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Fluconazole is indicated for the treatment of the following infections caused by fungi that are known or likely to be fluconazole susceptible.

• Genital Candidiasis	Acute or recurrent vaginal candidiasis, candidal balanitis. The treatment of partners who present with symptomatic genital candidiasis should be considered.
• Mucosal candidiasis	Oropharyngeal, oesophageal, non-invasive bronchopulmonary infections, candiduria, mucocutaneous and chronic oral atrophic candidiasis (denture sore mouth). Patients with compromised immune function may be treated.
• For verified fungal skin infections Tinea pedis, tinea corporis, tinea cruris, tinea versicolor and dermal Candida infections.	Fluconazole capsules are 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.
• Cryptococcosis	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 capsules can be used as maintenance therapy to prevent relapse of cryptococcal disease in patients with AIDS.
• Prevention of fungal infections	In immunocompromised patients considered at risk as a consequence of neutropenia following cytotoxic chemotherapy or radiotherapy, including bone marrow transplant patients.

4.2 Posology and method of administration

For oral administration.

The daily dose of Fluconazole capsules 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 recurrence of active infection. Patients with AIDS and cryptococcal meningitis usually require maintenance therapy to prevent relapse.

Use

Adults

1. Candidal vaginitis or balanitis - 150mg as a single oral dose.

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

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

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

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

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

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

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

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

6. For the prevention of fungal infections in immunocompromised patients considered at risk as a consequence of neutropenia following cytotoxic chemotherapy or radiotherapy, the dose should be 50 to 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. Fluconazole capsules administration should start several days before the anticipated onset of neutropenia, and continue for 7 days after the neutrophil count rises above 1000 cells per mm3.

Children

As with similar infections in adults, the duration of treatment is based on the clinical and mycological response. The maximum daily dose in children is 400mg as a single daily dose and this dose should not be exceeded.

The capsules are unsuitable for children who cannot take oral medication.

Also the required dose in mg/kg often cannot be achieved with capsules.

Children over 4 weeks:

Mucous membrane candidiasis: the recommended dosage of fluconazole is 3mg/kg daily. A loading dose of 6mg/kg may be used on the first day to achieve steady state levels more rapidly.

Systemic candidiasis and cryptococcal infections: 6-12 mg/kg daily, depending on the severity of disease.

Prevention of candida infections in neutropenic children: 3-12 mg/kg daily depending on the extent and duration of the neutropenia (see adult dosing).

Despite extensive data supporting the use of Diflucan in children there are limited

data available on the use of Fluconazole for genital candidiasis in children below 16 years. Use at present is not recommended unless antifungal treatment is imperative and no suitable alternative agent exists.

Children four weeks of age and younger Neonates excrete fluconazole slowly. In the first two weeks of life, the same mg/kg dosing as in older children should be used but administered every 72 hours. During weeks 3 and 4 of life, the same dose should be given every 48 hours.

A maximum dosage of 12mg/kg every 72 hours should not be exceeded in children in the first two weeks of life. For children between 3 and 4 weeks of life, 12mg/kg every 48 hours should not be exceeded.

To facilitate accurate measurement of doses less than 10mg, Fluconazole capsules should only be administered to children in hospital using the 50mg/5ml suspension orally or the intravenous infusion, 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.

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 50ml/min) the dosage schedule should be adjusted as described below.

Use in patients with impaired renal function

Fluconazole is excreted predominantly in the urine as unchanged drug. No adjustments in single dose therapy are required. In patients (including children) with impaired renal function who will receive multiple doses of Fluconazole capsules, the normal recommended dose (according to indication) should be given on day 1, followed by a daily dose based on the following table:

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

4.3 Contraindications

• Known hypersensitivity to fluconazole or to related azole compounds or any other ingredient in the formulation.

• Conditions such as hypokalaemia and hypomagnesaemia

• Congenital or acquired long QT syndromes

• Clinically relevant bradycardia, cardiac arrhythmia or severe cardiac insufficiency

Co-administration of the following medicines with fluconazole is contraindicated:

• antihistamines such as terfenadine

• antispasmodics such as cisapride

• astemizole

• medicines that prolong the QT interval such as antiarrhythmics of Class IA (eg. Disopyramide) or Class III (eg. Sotalol)

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 capsules but the clinical significance and relationship to treatment is uncertain.

Very rarely, patients who died with severe underlying disease and who had received multiple doses of Fluconazole capsules 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

which could have caused the hepatic necrosis.

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

As a causal relationship with Fluconazole cannot be excluded, patients who develop abnormal liver function tests during Fluconazole therapy should be monitored for the development of more serious hepatic injury.

Fluconazole capsules should be discontinued if clinical signs or symptoms consistent with liver disease develop during treatment with Fluconazole capsules. 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.

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.

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.

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

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

Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the Electrocardiogram. During post-marketing surveillance, there have been very rare cases of QT prolongation and torsade de pointes in patients taking fluconazole. Although the association of fluconazole and QT-prolongation has not been fully established, fluconazole should be used with caution in patients with potentially proarrythmic conditions such as:

• Congenital or documented acquired QT prolongation

• Cardiomyopathy, in particular when heart failure is present

• Sinus bradycardia

• Existing symptomatic arrythmias

• 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).

• Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia

(See Section 4.5 Interactions with other medical products and other forms of interaction)

This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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).

Cytochrome P450

Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole is also an inhibitor of CYP2C19. Diflucan 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).

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).

4.5 Interaction with other medicinal products and other forms of interaction

The following drug interactions relate to the use of multiple-dose fluconazole. The relevance to single-dose fluconazole has not yet been established.

Concomitant use of the following other medicinal products is contraindicated:

Cisapride (CYP3A4 substrate): 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 QT interval. Concomitant treatment with fluconazole and cisapride is contraindicated (see section 4.3 Contraindications).

Terfenadine (400mg or higher, CYP3A4 substrate): Because of the occurrence of serious dysrhythmias secondary to prolongation of the QTc interval in patients receiving other azole antifungals in conjunction with terfenadine, interactions 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 multiple doses of

400mg per day or greater significantly increased plasma levels of terfenadine when taken concomitantly. There have been spontaneously reported cases of

palpitations, tachycardia, dizziness, and chest pain in patients taking concomitant fluconazole and terfenadine where the relationship of the reported adverse events to drug therapy or underlying medical conditions was not clear. Because of the potential seriousness of such an interaction, the combined use of fluconazole at doses of 400

mg or greater with terfenadine is contraindicated (see section 4.3 Contraindications). The coadministration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored.

Astemizole overdoses have led to prolonged QT interval and severe ventricular arrhythmia, torsades de pointes and cardiac arrest. Concomitant administration of astemizole and fluconazole is contra-indicated due to the potential for serious, potentially fatal, cardiac effects.

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.

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)

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:

Hydrochlorothiazide: In a kinetic 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 (CYP450 inducer): Concomitant administration of fluconazole and rifampicin resulted in a 25% decrease in the AUC and 20% shorter half-life of fluconazole. In patients receiving concomitant rifampicin, an increase in the fluconazole dose should be considered.

Effect of fluconazole on the metabolism of 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. Besides the following observed interactions there is a risk of increased plasma concentrations of other medicinal products metabolised by CYP2C9 or CYP3A4 (i.e. ergot-alkaloids, HMG-CoA reductase inhibitors, quinidine) when coadministered with fluconazole. Therefore, care should always be taken when using these combinations and the patients should be carefully monitored. The effect may persist for 4-5 days after the end of fluconazole treatment due to the long fluconazole half-life.

Alfentanil: A study observed a reduction in clearance and distribution volume as well as prolongation of T/ of alfentanil following concomitant treatment with fluconazole. A possible mechanism of action is fluconazole's inhibition of CYP3A4. Dosage adjustment of alfentanil may be necessary.

Amitriptyline: Several case reports have described the development of increased amitriptyline concentrations and signs of tricyclic toxicity when amitriptyline was used in combination with fluconazole. Coadministration of fluconazole with nortriptyline, the active metabolite of amitriptyline, has been reported to result in increased nortriptyline levels. Due to the risk of amitriptyline toxicity, consideration should be given to monitoring amitriptyline levels and making dose adjustments as necessary.

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

Anticoagulants (CYP2C9 substrate): In an interaction study, fluconazole increased the prothrombin time (12%) after warfarin administration in healthy males. In postmarketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria and melaena) have been reported in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. Prothrombin time in patients receiving coumarin-type anticoagulants should be carefully monitored. Dose adjustment of warfarin may be necessary.

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

Benzodiazepines (CYP34A4 substrate): Following oral administration of midazolam, fluconazole resulted in substantial increases in midazolam concentrations and psychomotor effects. 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.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 t/ by 25-50 % due to the inhibition of metabolism of triazolam. Dosage adjustments of triazolam may be necessary.

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

Calcium channel antagonists: Certain dihydropyridine calcium channel antagonists (nifedipine, isradipine, amlodipine and felodipine) are metabolized by CYP3A4. Fluconazole has the potential to increase the systemic exposure of the calcium channel antagonists. Frequent monitoring for adverse events is recommended.

Celecoxib: During concomitant treatment with fluconazole (200 mg daily) and celecoxib (200 mg) the celecoxib Cmax and AUC increased by 68% and 134%, respectively. Half of the celecoxib dose may be necessary when combined with fluconazole.

Ciclosporin: Fluconazole significantly increases the concentration and AUC of ciclosporin. This combination may be used by reducing the dosage of ciclosporin depending on ciclosporin concentration.

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

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

Fentanyl: One fatal case of possible fentanyl fluconazole interaction was reported. The author judged that the patient died from fentanyl intoxication. Furthermore, in a randomized crossover study with twelve healthy volunteers it was shown that fluconazole delayed the elimination of fentanyl significantly. Elevated fentanyl concentration may lead to respiratory depression. Patients should be monitored closely for the potential risk of respiratory depression. Dosage adjustment of fentanyl may be necessary.

HMG-CoA: The risk of myopathy or rhabdomyolysis is increased when azole antifungals are administered concurrently with HMG-CoA reductase inhibitors such as atorvastatin. If concurrent therapy is required, patients should be monitored for signs and symptoms of myopathy or rhabdomyolysis (muscle pain, tenderness

or weakness), and creatinine kinase (CK) levels. HMG-CoA therapy should be discontinued if CK levels show a marked increase, or if myopathy or rhabdomyolysis is diagnosed or suspected.

Losartan: Due to inhibition of CYP2C9 by fluconazole, there is decreased conversion of losartan to its active metabolite (E-3174) which is responsible for most of the angiotensin II receptor antagonism that occurs with losartan therapy. The patient should be monitored for continued control of their hypertension.

Methadone: Fluconazole may enhance the serum concentration of methadone.

Dosage adjustment of methadone may be necessary.

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

82%, respectively, when fluconazole was coadministered with racemic ibuprofen (400 mg) compared to administration of racemic ibuprofen alone. Although not specifically studied, fluconazole has the potential to increase the systemic exposure of other NSAIDs that are metabolized by CYP2C9 (e.g. naproxen, lornoxicam, meloxicam, diclofenac). Frequent monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of dosage of NSAIDs may be needed.

Oral contraceptives: Two kinetic studies with combined oral contraceptives have been reported. There were no relevant effects on either hormone level in the 50mg fluconazole study, while at 200mg daily the AUCs of ethinyloestradiol 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.

In a 300 mg once weekly fluconazole study, the AUCs of ethinyl estradiol and norethindrone were increased by 24% and 13%, respectively.

Endogenous steroid Fluconazole 50mg daily does not affect endogenous steroid

levels in females: 200- 400mg daily has no clinically significant effect on endogenous steroid levels or on ACTH stimulated response in healthy male volunteers.

Phenytoin (CYP2C9 substrate and potent CYP450 inducer): Fluconazole inhibits the hepatic metabolism of phenytoin. Concomitant administration of fluconazole and phenytoin may increase the levels of phenytoin to a clinically significant degree. If it is necessary to administer both drugs concomitantly, phenytoin levels should be monitored and the phenytoin dose adjusted to maintain therapeutic levels.

Prednisone: A liver transplant recipient receiving prednisone experienced an Addisonian crisis when a threemonth course of fluconazole was discontinued. The withdrawal of fluconazole caused an increase in CYP3A4 activity leading to an increase in the degradation of prednisone and the precipitation of an Addisonian crisis. Patients on long-term treatment with fluconazole and prednisone should be carefully monitored for adrenal cortex insufficiency when fluconazole is discontinued.

Rifabutin (CYP450 inducer): There have been reports that an interaction exists when fluconazole is administered concomitantly with rifabutin, leading to increased serum levels of rifabutin. There have been reports of uveitis in patients to whom fluconazole and rifabutin were co-administered. Patients receiving rifabutin and fluconazole concomitantly should be carefully monitored.

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.

Tacrolimus and sirolimus (CYP3A4 substrates): There have been reports that an interaction exists when fluconazole is administered concomitantly with tacrolimus, leading to increased serum levels of tacrolimus.

There have been reports of nephrotoxicity in patients to whom fluconazole and tacrolimus were coadministered. Although no interaction studies have been conducted with fluconazole and sirolimus, it is recommended that sirolimus levels should be monitored because an adjustment of the dose may be required. Patients receiving tacrolimus or sirolimus and fluconazole concomitantly should be carefully monitored for increased toxicity (anaemia, leukopenia, thrombocytopenia, hypokalaemia, diarrhoea). Dose of orally administered tacrolimus should be decreased depending on tacrolimus concentration.

Sulphonyl urea drugs (CYP2C9 substrates): Fluconazole has been shown to prolong the serum half-life of concomitantly administered oral sulphonylureas (chlorpropamide, glibenclamide, glipizide and tolbutamide) in healthy volunteers.

Fluconazole and oral sulphonylureas may be co-administered to diabetic patients, but the possibility of a hypoglycaemic episode should be borne in mind. Frequent monitoring of blood glucose and appropriate reduction of sulphonylurea dose is recommended during coadministration.

Theophylline: In a placebo controlled interaction study, the administration of fluconazole 200mg for 14 days resulted in an 18% decrease in the mean plasma

clearance of theophylline. Patients who are receiving high doses of theophylline or who are otherwise at increased risk for theophylline toxicity should be observed for signs of theophylline toxicity while receiving fluconazole, and the therapy modified appropriately 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 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 AUC 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 kinetic studies resulted in increased levels of zidovudine most likely caused by the decreased conversion of zidovudine to its major metabolite. One study determined zidovudine levels in AIDS or ARC patients before and following fluconazole 200mg daily for 15 days. There was a significant increase in

zidovudine AUC (20%). A second randomised, two-period, two-treatment cross-over study examined zidovudine levels in HIV infected patients. On two occasions, 21 days apart, patients received Zidovudine 200mg every eight hours either with or without fluconazole 400mg daily for seven days. The AUC of zidovudine significantly increased (74%) during co-administration with fluconazole. Patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions. Dose reduction of zidovudine may be considered.

Fluvastatin: Up to 200% increases in the area under the curve (AUC) of fluvastatin may occur as a result of the interaction between fluconazole and fluvastatin. An individual patient using fluvastatin 80mg daily may be exposed to considerable fluvastatin concentrations if treated with high doses of fluconazole. Caution should be exercised when fluconazole or other potent cytochrome P450 2C9 (CYP2C9) inhibitors are prescribed to patients who are also taking fluvastatin. The clinical significance of increased plasma concentrations and prolonged elimination of fluvastatin remains unclear.

Didanosine: Although co-administration of didanosine and fluconazole appears to have little effect on the pharmacokinetics or efficacy of didanosine, the response to fluconazole should be monitored. It may be advantageous to administer fluconazole at some time prior to didanosine.

Trimetrexate: Medicaments such as fluconazole that inhibit the P450 enzyme system may cause interactions that increase trimetrexate plasma concentrations. If it is not possible to avoid concomitant administration, trimetrexate serum levels and toxicity (bone marrow suppression, renal and hepatic dysfunction and gastrointestinal ulceration) must be monitored carefully.

Patients receiving long term therapy should be closely monitored for signs of adrenal insufficiency when fluconazole is withdrawn.

Other Types of Interactions.

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.

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.

4.6 Pregnancy and lactation

Use during 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 being treated for 3 or more months with high dose (400-800 mg/day) fluconazole therapy for coccidioidomycosis. The relationship between fluconazole and these events is unclear.

Animal studies show teratogenic effects (see section 5.3).

Accordingly, Fluconazole Capsules should not be used in pregnancy, or in women of childbearing potential unless adequate contraception is employed.

Use during lactation

Fluconazole is found in human breast milk at concentrations similar to plasma, hence its use in nursing mothers is not recommended.

4.7 Effects on ability to drive and use machines

Experience with Fluconazole capsules indicates that therapy is unlikely to impair a patient's ability to drive or use machinery. However, when driving vehicles or operating machinery it should be taken into account that occasionally dizziness or seizures may occur.

4.8 Undesirable effects

Fluconazole is generally well tolerated.

In some patients, particularly those with serious underlying diseases such as AIDS and cancer, changes in renal and haematological function test results and hepatic abnormalities (see section 4.4 Special warnings and special precautions for use) have been observed during treatment with fluconazole and comparative agents, but the clinical significance and relationship to treatment is uncertain.

The most frequently (>1/10) reported adverse reactions are headache, abdominal pain, diarrhoea, nausea, vomiting, alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased and rash.

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
Blood and the lymphatic system disorders	Rare	Agranulocytosis, leukopenia, neutropenia, thrombocytopenia

Immune system disorders	Rare	Anaphylaxis
Metabolism and nutrition disorders	Uncommon	Decreased appetite
Metabolism and nutrition disorders	Rare	Hyp ertri glyceredaemi a, Hypercholesterol aemi a 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	Torsade de pointes, QT prolongation (see section 4.4)
Gastrointestinal disorders	Common	Abdominal pain, diarrhoea, nausea, vomiting
Gastrointestinal disorders	Uncommon	Dyspepsia, flatulence, dry mouth, constipation
Hepato-biliary disorders	Common	Alanine aminotransferase increased (see section 4.4), aspartate aminotransferase increased (see section 4.4), blood alkaline phosphatase increased (see section 4.4)
	Uncommon	Cholestasis (see section 4.4), jaundice (see section 4.4), bilirubin increased (see section 4.4)
	Rare	Hepatic failure (see section 4.4), hepatocellular necrosis (see section 4.4), Hepatitis (see section 4.4), hepatocellular damage (see section 4.4)
Skin and subcutaneous tissue disorders	Common	Rash (see section 4.4)
	Uncommon	Pruritus (see section 4.4), urticaria (see section 4.4), increased sweating , drug eruption *(see section 4.4)
	Rare	Toxic epidermal necrolysis (see section 4.4) , Stevens-Johnson syndrome (see section 4.4), acute generalised exanthematous-pustulosis (see section 4.4) , dermatitis exfoliative, angioedema, face oedema, alopecia
Musculoskeletal, connective tissue and bone disorders	Uncommon	Myalgia

General disorders and administration site conditions

Uncommon

Fatigue, malaise, asthenia, fever

*: Including fixed drug eruption.

Paediatric Population

The pattern and incidence of adverse reactions and laboratory abnormalities recorded during paediatric clinical trials, excluding the genital candidiasis indication 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 overdosage with fluconazole and in one case, a 42 year-old patient infected with human immunodeficiency virus developed hallucinations and exhibited paranoid behaviour after reportedly ingesting 8200mg of fluconazole, unverified by his physician. The patient was admitted to the hospital and his condition resolved within 48 hours.

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

As fluconazole is largely excreted in the urine, forced volume diuresis would probably increase the elimination rate. A three hour haemodialysis session decreases plasma levels by approximately 50%.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic Group: Antimycotics for Systemic Use, triazole derivatives

ATC Code: J02AC01

Fluconazole, a member of the triazole class of antifungal agents, is a potent and selective inhibitor of fungal enzymes necessary for the synthesis of ergosterol.

Fluconazole shows little pharmacological activity in a wide range of animal studies. Some prolongation of pentobarbital 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.

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 and with Paracoccidioides brasiliensis.

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. Fluconazole is highly specific for fungal cytochrome P-450 dependent enzymes.

Fluconazole 50mg daily given 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.

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 6 mg/kg/day for 6 weeks was not superior to griseofulvin administered at 11 mg/kg/day for 6 weeks. The overall success rate at 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.

Pharmacokinetic/pharmacodynamic relationship

In animal studies, there is a correlation between MIC values and efficacy against experimental mycoses due to Candidaspp. In clinical studies, there is an almost 1:1 linear relationship between the AUC and the dose of fluconazole. There is also a direct though imperfect relationship between the AUC or dose and a successful clinical response of oral candidosis and to a lesser extent candidaemia to treatment. Similarly cure is less likely for infections caused by strains with a higher fluconazole MIC.

Candida spp have developed a number of resistance mechanisms to azole antifungal agents. Fungal strains which have developed one or more of these resistance mechanisms are known to exhibit high minimum inhibitory concentrations (MICs) to fluconazole which impacts adversely efficacy in vivo and clinically.

Based on analyses of pharmacokinetic/pharmacodynamic (PK/PD) data, susceptibility in vitro and clinical response EUCAST-AFST (European Committee on Antimicrobial susceptibility Testing-subcommittee on Antifungal Susceptibility Testing) has determined breakpoints for fluconazole for Candida species (EUCAST Fluconazole rational document (2007)-version 2). These have been divided into nonspecies related breakpoints; which have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species, and species related breakpoints for those species most frequently associated with human infection. These breakpoints are given in the table below:

Antifungal

Species-related breakpoints (S</R>)

Non-species

breakpointsA

S</R>

Candida

albicans

Candida

glabrata

Candida

krusei

ida parapsilosis

Candida

tropicalis

Fluconazol

2/4

S = Susceptible, R = Resistant

A. = Non-species related breakpoints have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for use only for organisms that do not have specific breakpoints.

-- = Susceptibility testing not recommended as the species is a poor target for therapy with the medicinal product.

IE = There is insufficient evidence that the species in question is a good target for therapy with the medicinal product.

5.2 Pharmacokinetic properties

The pharmacokinetic properties of fluconazole are similar following administration by the intravenous or oral route.

After oral administration fluconazole is well absorbed and plasma levels (and systemic bioavailability) are over 90% of the levels achieved after intravenous administration. Oral absorption is not affected by concomitant food intake. Peak plasma concentrations in the fasting state occur between 0.5 and 1.5 hours postdose 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.

Administration of a loading dose (on day 1) of twice the usual daily dose enables plasma levels to approximate to 90% steady-state levels by day 2. The apparent volume of distribution approximates to total body water. Plasma protein binding is low (11-12%).

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. At a dose of 50mg once daily, the concentration of fluconazole after 12 days was 73 microgram/g and 7 days after cessation of treatment the concentration was still 5.8 microgram/g .

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.

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.

The long plasma elimination half-life provides the basis for single dose therapy for genital candidiasis and once daily dosing for other indications.

A study compared the saliva and plasma concentrations of a single fluconazole 100mg dose administration in a capsule or in an oral suspension by rinsing and retaining in mouth for 2 minutes and swallowing. The maximum concentration of fluconazole in saliva after the suspension was observed 5 minutes after ingestion, and was 182 times higher than the maximum saliva concentration after the capsule which occurred 4 hours after ingestion. After about 4 hours, the saliva concentrations of fluconazole were similar. The mean AUC (0-96) in saliva was significantly greater after the suspension compared to the capsule. There was no significant difference in the elimination rate from saliva or the plasma pharmacokinetic parameters for the two formulations.

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

11 days- 11 months	Single-IV 3mg/kg	23	110.1
9 months- 13 years	Single-Oral 2mg/kg	25.0	94.7
9 months- 13 years	Single-Oral 8mg/kg	19.5	362.5
5 years- 15 years	Multiple IV 2mg/kg	17.4¹	67.4
5 years- 15 years	Multiple IV 4mg/kg	15.2¹	139.1
5 years- 15 years	Multiple IV 8mg/kg	17.6¹	196.7
Mean Age 7 Years	Multiple Oral 3mg/kg	15.5	41.6

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 167566) 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 gg/ml and occurred at 1.3 hours post-dose. The mean AUC was 76.4 ± 20.3 ggh/ml, and the mean terminal halflife 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 hr, 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:

At 25 and 50mg/kg and higher doses, increases in foetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification were observed. At doses ranging from 80mg/kg to 320mg/kg embryolethality in rats was increased and foetal abnormalities included wavy ribs, cleft palate and abnormal cranio-facial ossification. This may be a result of known effects of lowered oestrogen on pregnancy, organogenesis and parturition as it is consistent with the inhibition of oestrogen synthesis in rats.

Carcinogenesis:

No evidence of carcinogenic potential was observed in mice and rats treated orally with fluconazole for 24 months at doses of 2.5, 5 or 10mg/kg/day. The incidence of hepatocellular adenomas was increased in male rats treated with 5 and 10mg/kg/day.

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. No evidence of chromosomal mutations was observed in cytogenetic studies in vivo (murine bone marrow cells, following oral administration of fluconazole) and in vitro (human lymphocytes exposed to fluconazole at 1000gg/ml).

Impairment of Fertility:

The fertility of male or female rats treated orally with daily doses of fluconazole at doses of 5, 10 or 20mg/kg or with parenteral doses of 5, 25 or 75mg/kg was not affected, although the onset of parturition was slightly delayed at 20mg/kg p.o. In an intravenous perinatal study in rats at 5, 20 and 40mg/kg, dystocia and prolongation of parturition were observed in a few dams at 20mg/kg and 40mg/kg, but not at 5mg/kg. The disturbances in parturition were reflected by a slight increase in the number of stillborn pups and decrease of neonatal survival at these dose levels. 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 Capsules contain:

Lactose monohydrate Maize starch Colloidal silicon dioxide Magnesium stearate Sodium lauryl sulphate Gelatin

Titanium dioxide (E171)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

The product does not require any special storage requirements within Europe.

6.5 Nature and contents of container

Fluconazole capsules are packed in opaque PVC blister packs with aluminium foil backing.

Fluconazole 200mg Capsules are supplied in packs of 7 capsules.

6.6 Instruction for use and handling

Not applicable.

In children, the following pharmacokinetic data have been reported:

Age Studied	Dose (mg/kg)	Half-life (hours)	AUC
			(microgram.h/ml)

Relonchem Limited 27 Old Gloucester Street London,

WC1 3XX United Kingdom

8. MARKETING AUTHORISATION NUMBER

PL 20395/0043

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

20/05/2010

10 DATE OF REVISION OF THE TEXT

01/12/2015

Denotes final day

In premature new-borns (gestational age around 28 weeks), intravenous administration of fluconazole of 6mg/kg was given every third day for a maximum of five doses while the premature new-borns remained in the intensive care unit. The mean half-life (hours) was 74 (range 44-185) on day 1 which decreased with