PLIVA Thrush Duo

Fluconazole 150mg Capsule

Paramed Fluconazole 150mg Capsule

Morrisons Fluconazole 150mg Capsule

Sainsbury's Fluconazole 150mg Capsule

Boots Pharmacy Thrush Capsule (Fluconazole 150mg)

Boots Pharmacy Thrush Duo

Boots Thrush Fluconazole 150mg Capsule

Boots Thrush Duo

Asda Fluconazole 150mg Capsule

Lloyds Pharmacy Thrush Duo

Teva Thrush Duo

Vantage Thrush Duo

Each capsule contains 150mg of fluconazole.

For excipients, see 6.1.

Capsules, hard.

Fluconazole 150mg Capsules have a blue body and a blue cap, with imprint FLUCO 150.

Fluconazole 150mg capsule is indicated for the treatment of the following conditions:

Vaginal candidiasis, acute or recurrent; or candidal balanitis associated with vaginal candidiasis.

In Adults aged 16 - 60 years

Vaginal candidiasis or candidal balanitis – 150mg single oral dose.

In Children

Fluconazole is not recommended for use in children and adolescents under the age of 16 years, unless antifungal treatment is imperative, and no suitable alternative agent exists, due to insufficient safety and efficacy (see section 5.2).

Use in Elderly

No dosage adjustment required in single dose therapy.

Use in Renal Impairment

Fluconazole is excreted predominantly in the urine as unchanged drug. No adjustments in single dose therapy are required.

Use in patients with hepatic insufficiency

Fluconazole should only be administered with special care and under careful monitoring in patients with liver insufficiency (see section 4.4).

Fluconazole capsules should not be used in patients with known hypersensitivity to fluconazole or to related azole compounds or any of the excipients.

Co-administration of other drugs known to prolong the QT interval and which are metabolised via the enzyme CYP3A4 such as cisapride, astemizole, pimozide and quinidine is contra-indicated in patients receiving fluconazole (see sections 4.4 and 4.5).

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

Fluconazole has been associated with rare cases of serious hepatic toxicity including fatalities, primarily in patients with serious underlying medical conditions. In cases of fluconazole-associated hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, sex or age of patient has been observed. Fluconazole hepatotoxicity has usually been reversible on discontinuation of therapy. The benefits of the treatment should be evaluated against the risks of developing serious liver damage if therapy is repeated in patients whose liver enzyme values rise during fluconazole treatment.

The dose of fluconazole must be reduced when creatinine clearance is below 50 ml/min.

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

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

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

Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, there have been very rare cases of QT prolongation and torsade de pointes in patients taking fluconazole. These reports included seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities and concomitant medications that may have been contributory.

Even though a connection between fluconazole and prolonged QT-interval has not been formally confirmed, fluconazole should be administered with caution to patients with these potentially proarryhthmic conditions, such as:

• Congenital or documented acquired QT prolongation

• Cardiomyopathy, particularly in the presence of heart failure

• Clinically significant (including sinus) bradycardia

• Symptomatic arrhythmias

• Electrolyte disturbances

• Concomitant administration of medicinal products known to prolong the QT-interval (see section 4.5).

For single dose use in patients with renal dysfunction, no dose adjustment is required (see section 4.2).

Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole-treated patients who are concomitantly treated with drugs which have a narrow therapeutic window (e.g. warfarin and phenytoin) and which are metabolised through CYP2C9 and CYP3A4 should be monitored (see sections 4.3 and 4.5).

The product intended for pharmacy availability without prescription will carry a leaflet which will advise the patient:

“Do not use Fluconazole 150mg capsule without first consulting your doctor:

If you are under 16 or over 60 years of age

If you are allergic to any of the ingredients in fluconazole 150mg capsule or other antifungals, such as ketoconazole and itraconazole, or and other thrush treatments

If you are taking any medicine other than the Pill

If you are taking astemizole (for allergies) or the prescription medicine cisapride (used to treat heartburn and to lower stomach acid)

If you have had thrush more than twice in the last six months

If you have any disease or illness affecting your liver or have had unexplained jaundice

If you suffer from any other chronic disease or illness

If you or your partner have had exposure to a sexually transmitted disease

If you are unsure about the cause of your symptoms

If you are taking pimozide (used in psychosis)

If you are taking quinidine (an antiarrhythmic, used to treat an irregular heartbeat).

Women only:

If you are pregnant, suspect you might be pregnant or are breast feeding

If you have any abnormal or irregular vaginal bleeding or a blood stained discharge

If you have vulval or vaginal sores, ulcers or blisters

If you are having lower tummy pain or burning on passing urine.

Men only:

If your sexual partner does not have thrush

If you have penile sores, ulcers or blisters

If you have an abnormal penile discharge (leakage)

If your penis has started to smell

If you have pain on passing urine.”

The product should never be used again if the patient experiences a rash or anaphylaxis follows the use of the drug.

Recurrent use (men and women): patients should be advised to consult their physician if the symptoms have not been relieved within one week of taking fluconazole 150mg capsule. Fluconazole 150mg capsule can be used if the candidal infection returns after 7 days. However, if the candidal infection recurs more than twice within six months, patients should be advised to consult their physician.

Fluconazole capsules contain lactose and should not be given to patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

The following drug interactions relate to the use of multiple-dose fluconazole and the relevance to single-dose 150mg fluconazole has not yet been established.

Concomitant use of the following other medicinal products is contraindicated:

Astemizole

Concomitant administration of fluconazole with astemizole may decrease the clearance of astemizole. Resulting increased plasma concentrations of astemizole can lead to QT prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and astemizole is contraindicated.

Cisapride

There have been reports of cardiac events including torsades de pointes in patients to whom fluconazole and cisapride were co-administered. In most of these cases, the patients appear to have been predisposed to arrhythmias or had serious underlying illnesses, and the relationship of the reported events to a possible fluconazole-cisapride drug interaction is unclear. 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. Because of the potential seriousness of such an interaction, co-administration of cisapride is contra-indicated in patients receiving fluconazole (see section 4.3).

Pimozide

Although not studied in vitro or in vivo, concomitant administration of fluconazole with pimozide may result in inhibition of pimozide metabolism. Increased pimozide plasma concentrations can lead to QT prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and pimozide is contraindicated.

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

Erythromycin

Concomitant use of fluconazole and erythromycin has the potential to increase the risk of cardiotoxicity (prolonged QT interval, Torsades de Pointes) and consequently sudden heart death. This combination should be avoided.

Concomitant use of the following other medicinal products lead to precautions and dose adjustments:

The effect of other medicinal products on fluconazole

Hydrochlorothiazide

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

The effect of fluconazole on other medicinal products

Fluconazole is a potent inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and a moderate inhibitor of CYP3A4. In addition to the observed /documented interactions mentioned below, there is a risk of increased plasma concentration of other compounds metabolized by CYP2C9 and CYP3A4 co-administered with fluconazole. Therefore caution should be exercised when using these combinations and the patients should be carefully monitored. The enzyme inhibiting effect of fluconazole persists 4- 5 days after discontinuation of fluconazole treatment due to the long half-life of fluconazole (see section 4.3).

Alfentanil

A study observed a reduction in clearance and distribution volume as well as prolongation of T_½ of alfentanil following concomitant treatment with fluconazole. A possible mechanism of action is fluconazole's inhibition of CYP3A4. Dosage adjustment of alfentanil may be necessary.

Amitriptyline, nortriptyline

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

Amphotericine B

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

Anticoagulants

In an interaction study, fluconazole increased the prothrombin time (12%) after warfarin administration in healthy males. In post-marketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, haematuria 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 (short acting)

Following oral administration of midazolam, fluconazole resulted in substantial increases in midazolam concentrations and psychomotor effects. This effect on midazolam appears to be more pronounced following oral administration of fluconazole than with fluconazole administered intravenously. If concomitant benzodiazepine therapy is necessary in patients being treated with fluconazole, consideration should be given to decreasing the benzodiazepine dosage and the patients should be appropriately monitored

Fluconazole increases the AUC of triazolam (single dose) by approximately 50%, C_max with 20-32% and increases t_½ by 25-50% due to the inhibition of metabolism of triazolam. Dosage adjustments of triazolam may be necessary.

Calcium Channel Blockers

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

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.

Celecoxib

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

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

Cyclophosphamide

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

Fentanyl

One fatal case of possible fentanyl fluconazole interaction was reported. The author judged that the patient died from fentanyl intoxication. Furthermore, in a randomized crossover study with twelve healthy volunteers it was shown that fluconazole delayed the elimination of fentanyl significantly. Elevated fentanyl concentration may lead to respiratory depression.

Halofantrine

Fluconazole can increase halofantrine plasma concentration due to an inhibitory effect on CYP3A4. and can cause a prolongation of the QT interval. The concomitant use of fluconazole and halofantrine is not recommended.

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. The combination may require dose reduction of the HMG-CoA reductase inhibitors. HMG-CoA reductase inhibitors should be discontinued if a marked increase in creatinine kinase is observed or myopathy/rhabdomyolysis is diagnosed or suspected.

Losartan

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

Methadone

Fluconazole may enhance the serum concentration of methadone. Dosage adjustment of methadone may be necessary.

Non-steroidal anti-inflammatory drugs

The C_max and AUC of flurbiprofen were increased by 23% and 81%, respectively, when coadministered with fluconazole compared to administration of flurbiprofen alone. Similarly, the C_max 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 performed using multiple doses of fluconazole. There were no relevant effects on either hormone level in the 50mg fluconazole study, while at 200mg daily the AUCs of ethinylestradiol and levonorgestrel were increased 40% and 24% respectively. Thus multiple dose use of fluconazole at these doses is unlikely to have an effect on the efficacy of the combined oral contraceptive.

Phenytoin

Fluconazole inhibits the hepatic metabolism of phenytoin. With coadministration, serum phenytoin levels should be monitored in order to avoid phenytoin toxicity, and the phenytoin dose adjusted to maintain therapeutic levels.

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 co-administered. In combination therapy, symptoms of rifabutin toxicity should be taken into consideration, and patients receiving rifabutin and fluconazole concomitantly should be carefully monitored.

Saquinavir

Fluconazole increases the AUC of saquinavir with approximately 50%, C_max with approximately 55% and decreases clearance of saquinavir with approximately 50% due to inhibition of saquinavir's hepatic metabolism by CYP3A4 and inhibition of P-glycoprotein. Dosage adjustment of saquinavir may be necessary.

Sirolimus

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

Sulphonylureas

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 frequent monitoring of blood glucose and appropriate reduction of sulfonylurea dosage is recommended during coadministration.

Tacrolimus

Fluconazole may increase the serum concentrations of orally administered tacrolimus up to 5 times, due to inhibition of tacrolimus metabolism through CYP3A4 in the intestines. No significant pharmacokinetic changes have been observed when tacrolimus is given intravenously. Increased tacrolimus levels have been associated with nephrotoxicity. Patients receiving tacrolimus and fluconazole concomitantly should be carefully monitored. Dosage of orally administered tacrolimus should be decreased depending on tacrolimus concentration.

Terfenadine

Because of the occurrence of serious cardiac 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 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 multiple doses of 400 mg 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. The coadministration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored.

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 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.

Zidovudine

Fluconazole increases C_max of zidovudine by 85%, due to an approx. 45% decrease in oral zidovudine clearance. The half-life of zidovudine was likewise prolonged by approximately 128% following combination therapy with fluconazole. Patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions. Dosage reduction of zidovudine may be considered.

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

Physicians should be aware that drug-drug interaction studies with other medications have not been conducted, but that such interactions may occur.

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) but the potential risk to humans is unknown.

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

Lactation

Fluconazole is secreted in human breast milk at concentrations lower than those in plasma. Breast feeding may be continued after a single dose of Fluconazole 150 mg Capsules. Breast-feeding is not recommended after repeated use, or after high-dose fluconazole.

When driving vehicles or operating machines it should be taken into account that occasionally dizziness or seizures may occur.

Fluconazole is generally well tolerated.

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

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 form the available data).

Adverse reactions were reported more frequently in HIV infected patients (21%) than in non-HIV infected patients (13%). However, the patterns of adverse reactions in HIV infected and non-HIV infected patients were similar.

Paediatric Population

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

In most patients overdose results in gastrointestinal complaints and skin reactions (itch, rash, etc.). There has been a report of an overdose with fluconazole where 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 hospital and his condition resolved within 48 hours.

Treatment

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

As fluconazole is largely excreted in the urine, forced volume diuresis would probably increase the elimination rate. No data are available on the effect of forced diuresis. A three hour haemodialysis session decreases plasma levels by approximately 50%.

Pharmacotherapeutic category:

Antimycotics for systemic use, triazole derivates.

ATC code: J02A C01.

Mechanism of action

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, which leads to defects in the cell membrane. Fluconazole is very specific for fungal cytochrome P450 enzymes.

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

Both orally and intravenously administered fluconazole is 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.

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.

Mechanism of resistance

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

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

(ii) increasing drug efflux, and

(iii) altering the ergosterol biosynthetic pathways.

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

Breakpoints

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

The antimycotic spectrum of fluconazole includes a number of pathogens including the species Candida albicans, non-Candida albicans, Cryptococcus and dermatophytes.

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

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

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

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.

Absorption

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%. Oral absorption is not affected by concomitant food intake. Peak plasma concentrations in the fasting state occur between 0.5 and 1.5 hours post-dose with a plasma elimination half-life of approximately 30 hours. Plasma concentrations are proportional to dose. Ninety percent steady-state levels are reached by day 4 -5 with multiple once daily dosing.

The plasma concentration is proportional to the dose. After administration of 200 mg fluconazole, C_max is approx. 4.6 mg/l and the plasma steady-state concentrations after 15 days are about 10 mg/l. After administration of 400 mg fluconazole, C_max is approx. 9 mg/l and the plasma steady-state concentrations after 15 days are about 18 mg/l. Taking a double dose on day 1 leads to plasma concentrations of approx. 90% of the plasma steady-state concentrations on day 2.

Distribution

Administration of 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 µg/g and 7 days after cessation of treatment the concentration was still 5.8 µg /g.

Biotransformation

Fluconazole is broken down to a modest extent. Only 11% of a radioactive dose is excreted in the form of metabolites in the urine.

Elimination

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

The mean half-life in the plasma is approximately 30 hours. The long plasma elimination half-life provides the basis for single dose therapy for genital candidiasis and once daily dosing for other indications.

Reproductive toxicity Increases in foetal anatomical variants and delays in ossification were observed at 25 and 50mg/kg and higher doses. At doses ranging from 80mg/kg (approximately 20-60x the recommended human dose) to 320mg/kg embryolethality in rats was increased and foetal abnormalities included wavy ribs, cleft palate and abnormal cranio-facial ossification. These effects are consistent with the inhibition of oestrogen synthesis in rats and may be a result of known effects of lowered oestrogen on pregnancy, organogenesis and parturition.

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

Mutagenesis Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in 4 strains of S.typhimurium and in the mouse lymphoma L5178Y system. Cytogenetic studies in vivo and in vitro showed no evidence of chromosomal mutations.

Impairment of fertility Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5, 10 or 20mg/kg or with parenteral doses of 5, 25 or 75mg/kg, 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 still-born 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.

Lactose monohydrate

Maize starch

Sodium laurilsulfate

Colloidal anhydrous silica

Magnesium stearate

Capsule shells contain titanium dioxide (E171), gelatin and patent blue V (E131).

Ink contains shellac glaze, black iron oxide (E172), industrial methylated spirit 74 OP, n-butyl alcohol, propylene glycol (E1520), and isopropyl alcohol.

Not applicable.

24 months.

Do not store above 25ºC.

PVC/ Aluminium blister containing 1 capsule.

Lloyds Pharmacy Thrush Duo pack only: Aluminium tube with polypropylene screw-on cap containing 20g of cream and PVC/Aluminium blisters containing 1 capsule.

There are no special instructions for use and handling.

Teva UK Limited

Brampton Road

Hampden Park

Eastbourne

East Sussex

BN22 9AG

PL 00289/1477

08/02/2005 / 11/11/2009

01/06/2011