Canesten^® Oral Capsule (also available in the combination product Canesten Oral & Cream Duo)

Fluconazole 150mg

For excipients, see 6.1

Hard capsule

Opaque light blue capsule (size 1) with “Canesten^®” printed in black between two black lines.

Canesten Oral Capsule is recommended for the treatment of candidal vaginitis, acute or recurrent. It should also be used for the treatment of partners with associated candidal balanitis.

Adults (16 to 60):

One capsule should be swallowed whole.

Children (under 16):

Paediatric use is not recommended.

Elderly:

Not recommended in patients over 60.

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, cisapride or ergot-derivatives (see 4.5).

The product available from pharmacies without prescription will include a leaflet that advises the patient - Do not use Canesten Oral 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 Canesten Oral Capsule or other antifungals and other thrush treatments (see section “After Taking Canesten Oral Capsule”).

If you are taking any other medicine other than the Pill.

If you are taking the antihistamine terfenadine or the prescription medicine cisapride

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

If you have any disease or illness affecting your liver or kidneys 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 of the cause of your symptoms.

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 experiencing lower abdominal pain or burning sensation on passing water.

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

Fluconazole must be taken with particular care in patients with congenital or acquired QT prolongation and torsades de pointes or a history thereof, known cardiomyopathy, sinus bradycardia, cardiac arrhythmia, or are treated with a co-medication potentially leading to QT prolongation (see 4.5).

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

Fluconazole, like other azoles, may interfere with the metabolism of some drugs if given concomitantly, mainly through inhibition of the cytochrome P450 isoenzymes CYP3A4 and CYP2C9. The vast majority of formal interaction studies and case reports are related to multiple dose fluconazole use, therefore, the magnitude of the effect of this inhibition on an individual patient after a single dose of fluconazole is hard to predict, particularly in light of the individual variability in the activity of the isoenzymes. Nonetheless, single dose pharmacokinetic studies have demonstrated that the inhibitory action of fluconazole is immediate and leads, dose-dependently, to increased plasma concentrations of the interacting agents. Given fluconazole's long plasma elimination half-life of approximately 30 hours and substantially longer tissue bioavailability (see section 5.2 Pharmacokinetic Properties), these interactions may be clinically relevant following coadministration with drugs that have both a narrow therapeutic window and also act on vital organ systems like the heart and brain or are involved with glucose metabolism.

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 an 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.

Anti-arrhythmic drugs

Cases of QTc prolongation and/or torsades de pointes may occur after concomitant use of fluconazole with Class I, Class Ia, and all Class III anti-arrhythmic agents. Even though no formal drug interaction studies have been done, concomitant use of these anti-arrhythmic agents and drugs known to prolong the QT interval is not recommended.

Pharmacodynamic interactions

Medicinal products that prolong QT interval: Case reports indicate that fluconazole might have the potential to induce QT prolongation leading to serious cardiac arrhythmia. Patients treated concomitantly with fluconazole and other drugs that prolong QT interval should be carefully monitored, since an additive effect cannot be excluded.

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.

Carbamazepine, Phenobarbital, Phenytoin, Rifapentine

Concurrent administration of fluconazole and carbamazepine, phenobarbital, phenytoin or rifapentine results in enhanced metabolism of fluconazole, potentially reducing fluconazole effective inhibitory serum concentrations. An increase in the fluconazole dose should be considered in patients receiving concomitant carbamazepine, phenobarbital, phenytoin or rifapentine.

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 AUCs of ethinylestradiol 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.

Ergot derivatives

Because of the potential for serious toxicity including vasospasm that can occur with increased plasma concentrations of ergot derivatives (dihydroergotamine, ergoloid mesylates, ergonovine, ergotamine, methylergonovine, methysergide) the concurrent use of fluconazole and ergot derivatives is contraindicated (see Contraindications). Fluconazole and ergot derivatives are both metabolized by cytochrome P450 3A4 enzymes, and the competition for metabolism could result in a rapid onset of increased plasma concentration of the ergot derivative.

Losartan

CYP2C9 and CYP3A4 are involved in the metabolism of losartan to its active carboxylic acid metabolite E-3174 that is responsible for most of the angiotensin II receptor antagonism that occurs with losartan therapy. Fluconazole was shown to significantly inhibit the conversion of losartan to this metabolite. Monitoring of patients for continued control of their hypertension is recommended.

Ciclosporin:

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

Fentanyl, Methadone

Coadministration of fluconazole may cause decreased clearance of fentanyl or methadone and subsequent increased or prolonged opioid effects (CNS depression, respiratory depression). Dosage adjustment of the opioid may be necessary.

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, Sirolimus:

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. Patients receiving tacrolimus or sirolimus and fluconazole concomitantly should be 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.

No studies on the effect on the ability to drive and use machines have been performed. However, undesirable effects such as dizziness have been observed. If dizziness occurs, patients should not drive or operate machines.

The listed undesirable effects are based on spontaneous reports, thus an organisation according to CIOMS III categories of frequency is not possible.

Blood and lymphatic system disorders

Leukopenia, neutropenia, agranulocytosis, thrombocytopenia.

Cardiac disorders

Torsades de pointes/QT prolongation.

Gastrointestinal disorders

Nausea, diarrhea, vomiting, gastrointestinal and abdominal pains, abdominal distension, flatulence.

Hepatobiliary disorders

Most events were observed when a multiple treatment was used: mild transient elevations in transaminases, hepatitis (non infective), jaundice, cholestasis and acute hepatic failure, including fatalities.

Immune System Disorders

Allergic reaction, anaphylactic reaction, anaphylactic shock.

Hypersensitivity reactions including symptoms such as rash, urticaria, oedema, pruritus, cardio-respiratory distress.

Investigations

Electrocardiogram QT prolonged, electrocardiogram QT corrected interval prolonged, hypercholesterolemia, hypertriglyceridemia, hypokalemia.

Nervous system disorders

Seizures, dizziness, headache, dysgeusia.

Skin and subcutaneous tissue disorders

Rash, pruritus, alopecia, exfoliative skin reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis.

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.

Pharmacotherapeutic group: Fluconazole is a triazole antifungal, ATC-Code: J02AC01

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 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 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 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.

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). Data derived from in vitro studies (human lymphocytes exposed to fluconazole) are not consistent.

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

Colloidal silicon dioxide

Magnesium stearate

Sodium lauryl sulphate

Capsule shells contain:

Brilliant blue FCF (E133)

Titanium dioxide (E171)

Gelatine

Printing ink contains:

Shellac

Black iron oxide (E172)

Propylene glycol

Not applicable

3 years

No special precautions for storage

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

The capsule is also available with a 10g tube of Canesten Thrush Cream as Canesten Oral & Cream Duo (Legal Category P).

Not applicable.

Bayer plc

Bayer House

Strawberry Hill

Newbury

Berkshire

RG14 1JA

U.K.

Trading as Bayer plc, Consumer Care Division

PL 00010/0282

25 September 2002

20 February 2012

P