Bayer Limited

CanOral 150mg Capsule

Each hard capsule contains Fluconazole 150 mg

Excipients: each hard capsule contains 141.0mg of lactose monhydrate.

For a full list of excipients, see section 6.1

Capsule, hard

Opaque light blue capsule (size 1) printed “CAN150”

CanOral 150mg Capsule is recommended for the treatment of acute or recurrent genital candidiasis, i.e. candidal vaginitis and candidal balanitis. The treatment of partners of patients with symptomatic genital candidiasis should also be considered.

Adults:

One capsule should be swallowed whole.

Children:

Paediatric use is not recommended.

Elderly:

There is no separate dosage schedule for the elderly.

Renal Impairment:

There is no separate dosage schedule in patients with renal impairment for single dose therapy.

Known hypersensitivity to fluconazole, related azole compounds or any of the excipients in this product.

Fluconazole should not be administered concomitantly with terfenadine or cisapride (see 4.5).

Abnormalities in haematological, hepatic, renal and other biochemical function test results have been observed in some patients during treatment with fluconazole, in particular those suffering from serious medical conditions such as AIDS and cancer. The significance of this is uncertain.

Very rarely, cases of hepatic necrosis were found during post-mortems on patients who died from severe underlying diseases and who had also been given multiple dose fluconazole. These patients were also receiving multiple concomitant treatments, some of which are known to be potentially hepatotoxic, and/or had underlying diseases, which may have caused the hepatic necrosis. No obvious relationship exists between total daily dose of fluconazole, duration of therapy, sex or age of the patient and cases of hepatotoxicity. Abnormalities are generally reversible on cessation of fluconazole treatment.

Patients who develop abnormal liver function tests whilst taking fluconazole should be monitored for the development of more serious hepatic injury since a causal relationship with fluconazole cannot be ruled out. Fluconazole treatment should be stopped if signs or symptoms indicative of liver disease occur.

Rarely, during treatment, patients have developed exfoliative cutaneous reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Patients with AIDS are more susceptible to the development of severe cutaneous reactions to many drugs.

If a patient develops a rash that may be attributed to fluconazole use, further therapy with fluconazole is not recommended.

Rarely, anaphylaxis has been reported.

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

The drug interactions listed below relate to the use of multiple dose fluconazole. The relevance of this to a single dose of fluconazole 150mg has not been established.

Anticoagulants:

Fluconazole increased the prothrombin time after warfarin administration in healthy males during an interaction study. The change was small (12%) but bleeding events such as bruising, epistaxis, gastrointestinal bleeding, hematuria and melena have been reported in association with increases in prothrombin time in patients receiving fluconazole and warfarin concomitantly. Careful monitoring of prothrombin time in patients receiving coumarin type anticoagulants is recommended.

Sulphonylureas:

In healthy volunteers, fluconazole prolonged the serum half-life of oral sulphonylureas such as chlorpropamide, glibenclamide, glipizide and tolbutamide, when co-administered. Fluconazole and oral sulphonylureas may be concomitantly administered to diabetics but the possibility of a hypoglycaemic episode should be considered.

Hydrochlorothiazide:

Co-administration of fluconazole and multiple dose hydrochlorothiazide to healthy volunteers during a kinetic interaction study, increased plasma concentrations of fluconazole by 40%. However, although the prescriber should bear this in mind, the fluconazole dose in patients receiving concomitant diuretics should not need to be altered.

Benzodiazepines:

Substantial increases in midazolam concentrations and psychomotor effects are observed when oral midazolam and fluconazole (oral or intravenous) are co-administered.

The effect on midazolam appears to be greater when fluconazole is administered orally than when fluconazole is administered intravenously. If concomitant administration of benzodiazepines and fluconazole is required then the prescriber should consider reducing the benzodiazepine dose and appropriate monitoring of the patient should be undertaken.

Phenytoin:

Levels of phenytoin may increase to a clinically significant degree during co-administration with fluconazole. Phenytoin levels should be monitored and the phenytoin dose adjusted to maintain therapeutic levels if co-administration is necessary.

Oral Contraceptives:

Studies on the use of combined oral contraceptives with multiple doses of fluconazole have been performed. No relevant effects on hormone levels occurred during a study with fluconazole 50mg, whilst the areas under the curve (AUCs) of ethinyloestradiol and levonorgestrel were increased by 40% and 24% respectively during a study with fluconazole 200mg. It is therefore considered that multiple dose fluconazole is unlikely to affect the efficacy of the combined oral contraceptive.

Rifampicin:

A 25% decrease in the AUC and 20% shorter half-life of fluconazole occurred when fluconazole and rifampicin were administered concomitantly. An increase in the fluconazole dose should be considered in patients receiving concomitant rifampicin.

Endogenous Steroid:

No effect on endogenous steroid levels was observed in females when treated with fluconazole 50mg daily. No significant effect on endogenous steroid levels or on ACTH stimulated response was observed in healthy male volunteers when treated with fluconazole 200 to 400mg daily.

Cyclosporin:

In a kinetic study it was found that fluconazole 200mg daily slowly increases cyclosporin concentrations in renal transplant patients, but a multiple dose study with fluconazole 100mg daily showed no effect on cyclosporin levels in patients with bone marrow transplants. It is therefore recommended that cyclosporin plasma concentration is monitored in patients receiving fluconazole.

Theophylline:

Use of fluconazole 200mg for 14 days showed an 18% decrease in the mean plasma clearance of theophylline. Patients who require high doses of theophylline or who may be at increased risk of theophylline toxicity should be monitored for signs of theophylline toxicity when fluconazole is co-administered. The therapy should be modified if signs of toxicity occur.

Terfenadine:

Fluconazole 200mg daily did not show a prolongation in the QTc interval. Use of fluconazole (taken in multiple doses of 400mg and 800mg per day) and terfenadine concomitantly, significantly increased plasma levels of terfenadine. Spontaneous reports of palpitations, tachycardia, dizziness and chest pains have occurred in patients taking fluconazole and terfenadine concomitantly where the relationship of the reported adverse events to drug therapy or underlying medical condition is uncertain. It is recommended that terfenadine and fluconazole should not be administered concomitantly due to the potential seriousness of such an interaction. (See 4.3).

Cisapride:

Cardiac events including torsades de pointes have been reported in patients receiving fluconazole and cisapride concomitantly.

Most of these patients appear to have been predisposed to arrhythmias or had serious underlying medical conditions, and the relationship of the reported events to a possible drug interaction is uncertain. Co-administration of cisapride is contra-indicated in patients receiving fluconazole. (See 4.3).

Zidovudine:

Zidovudine levels in AIDS or ARC patients were determined before and after daily treatment with fluconazole 200mg for 15 days. A significant increase in zidovudine AUC was observed (20%). A second study in HIV infected patients also showed a significant increase in zidovudine AUC (74%) when fluconazole was administered concomitantly. Patients received zidovudine 200mg every eight hours either with or without fluconazole 400mg for seven days on two occasions, 21 days apart. The increased zidovudine levels are most likely caused by a decrease in the conversion of zidovudine to its major metabolite. It is recommended that patients receiving fluconazole and zidovudine be monitored for zidovudine related adverse reactions.

Rifabutin:

Increased serum levels of rifabutin have been reported in patients receiving fluconazole and rifabutin concomitantly, suggesting a possible interaction. Uveitis has also been reported in patients receiving this combination. It is therefore recommended that patients are carefully monitored.

Tacrolimus:

Increased serum levels of tacrolimus have been reported in patients receiving fluconazole and tacrolimus concomitantly, suggesting a possible interaction. There have also been reports of nephrotoxicity in patients receiving this combination. It is recommended that patients receiving this combination are carefully monitored.

Astemizole or other drugs metabolised by the cytochrome P450 system taken concomitantly with fluconazole may be associated with elevations in serum levels of these drugs in patients. Fluconazole should be co-administered with caution in these circumstances and careful monitoring of patients should be undertaken.

Studies show that when fluconazole is taken orally with food, cimetidine, antacids or following total body irradiation for bone marrow transplantation, the absorption of fluconazole is not significantly impaired.

Drug – drug interaction studies with other medications have not been conducted but prescribers should be aware that such interactions may occur.

Fluconazole should not be used during pregnancy or in women of childbearing potential unless adequate contraception is being used. Fluconazole is found in breast milk so it should not be used whilst breast-feeding.

Fluconazole is unlikely to affect the ability to drive or use machinery.

The more common side effects are gastrointestinal symptoms such as nausea, abdominal pain, diarrhoea and flatulence.

Rarely, rash and headache have been reported.

Changes in renal and haematological function test results and hepatic abnormalities have been observed in some patients (in particular those with serious underlying diseases such as AIDS and cancer) during treatment with fluconazole. The significance and relationship of this to fluconazole is unclear. (See 4.4).

Cases of hepatic toxicity (including rare cases of fatalities), elevated alkaline phosphatase, elevated bilirubin, elevated Serum Glutamic Oxaloacetic Transaminase (SGOT) and elevated Serum Glutamic Pyruvic Transaminase (SGTP) have also been reported.

In addition, dizziness, seizures, alopecia, exfoliative skin disorders (including Stevens-Johnson syndrome), toxic epidermal necrolysis, dyspepsia, vomiting, leukopenia (including neutropenia and agranulocytosis), thrombocytopenia immunological anaphylaxis (including angiodema, face oedema, pruritus), hepatic failure, hepatitis, hepatocellular necrosis, jaundice, hypercholesterolaemia, hypertriglyceridaemia, hypokalaemia and taste perversion have all been reported.

Supportive measures and symptomatic treatment, with gastric lavage if necessary, may be adequate.

Fluconazole is largely excreted in the urine and therefore, forced volume diuresis would probably increase the elimination rate. Plasma levels are decreased by approximately 50% during a 3-hour haemodialysis session.

Fluconazole is a triazole antifungal. It 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 pentabarbitone 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.

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 immuno-compromised 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 immuno-compromised 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 has been shown not to affect testosterone plasma concentrations in males or steroid concentrations in females of childbearing age when given 50mg daily for up to 28 days. No clinically significant effect has been seen on endogenous steroid levels or on adrenocorticotropic hormone (ACTH) stimulated response in healthy male volunteers taking fluconazole 200 – 400mg daily. Interaction studies with antipyrine indicate that single or multiple doses of fluconazole 50mg do not affect its metabolism.

The pharmacokinetic properties of fluconazole are similar whether administered orally or by the intravenous route. After oral administration, fluconazole is well absorbed and plasma levels (and systemic bioavailability) are over 90% of the levels achieved after intravenous administration. Concomitant food intake does not affect oral absorption. In the fasting state peak plasma concentrations 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 to 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 cerebrospinal fluid (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 mg/g and 7 days after cessation of treatment the concentration was still 5.8 mg/g.

Excretion is mainly renal, with approximately 80% of the administered dose appearing in the urine as unchanged drug. Fluconazole clearance is proportional to creatine clearance. There is no evidence of circulating metabolites.

The long plasma elimination half-life provides the basis for single dose therapy for genital candidiasis.

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 the mouth for 2 minutes and swallowing. The maximum concentration of fluconazole in saliva after the suspension was observed five minutes after ingestion and was 182 times higher than maximum saliva concentration after the capsule, which occurred four hours after ingestion. After about four 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 the saliva or the plasma pharmacokinetic parameters for the two formulations.

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 1000micrograms/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.

Lactose monohydrate

Maize starch

Silica, Colloidal Anhydrous

Magnesium stearate

Sodium laurilsulfate

Capsule shells contain:

Brilliant Blue FCF (E133)

Titanium dioxide (E171)

Gelatin

Printing ink contains:

Black iron oxide (E172)

Shellac

Not applicable

3 years

This medicinal product does not require any special storage conditions

Opaque, white PVC/PVdC (60g/m²) blister with 20µm aluminium foil backing containing one capsule.

No special requirements

Bayer Limited

The Atrium

Blackthorn Road

Dublin 18

Ireland

PA 1410/41/1

Date of first authorisation: 15 April 2005

Date of next renewal: 15^th April 2010

April 2010