Consumer medicine information

Canesoral Duo

Fluconazole; Clotrimazole

BRAND INFORMATION

Brand name

Canesoral Duo Combination pack

Active ingredient

Fluconazole; Clotrimazole

Schedule

S3

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Canesoral Duo.

What is in this leaflet

This leaflet answers some common questions about CANESORAL DUO.

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor or pharmacist has weighed the risks of you using this medicine against the benefits expected for you.

If you have any concerns about using this medicine, talk to your doctor or pharmacist.

Keep this leaflet with your medicine.

You may need to read it again.

The information in this leaflet relates only to CANESORAL DUO. It is not to be used in relation to any other product, which may also contain the same active ingredients.

What CANESORAL DUO is used for

CANESORAL DUO is used to treat a type of fungal infection called vaginal thrush.

CANESORAL DUO contains two components: CANESORAL is an oral capsule which contains the active ingredient fluconazole; CANESTEN CLOTRIMAZOLE CREAM contains the active ingredient clotrimazole. Both of these ingredients belong to a group of medicines called azole antifungals.

CANESORAL is taken by mouth and works from the inside to prevent the growth of the fungi causing your infection; CANESTEN CLOTRIMAZOLE CREAM is applied to the irritated area and provides soothing relief from external itching and irritation.

What is vaginal thrush

Vaginal thrush is a common name for vaginal candidiasis, an infection caused by a yeast-like fungus called Candida.

Candida is one of many organisms that live in the vagina. Your body’s natural balance (immune system) normally keeps Candida under control, but when this natural balance is upset, Candida can multiply and can cause thrush symptoms.

Common symptoms of vaginal thrush include:

  • itching, burning or soreness around the vagina
  • cottage-cheese like discharge
  • swelling or irritation of the infected area.

Things that may help you to avoid thrush in the future:

  • wear cotton briefs, stockings and loose-fitting clothing rather than tight synthetic clothing
  • wash regularly, but do not wash and dry yourself harshly
  • avoid perfumed soaps, bath additives and vaginal deodorants.

Your doctor or pharmacist may have more information on things you can do to avoid thrush in the future.

Ask your doctor or pharmacist if you have any questions about why this medicine has been recommended for you.

Your doctor or pharmacist may have recommended it for another reason.

There is no evidence that either component in CANESORAL DUO is addictive.

CANESORAL DUO is a “Pharmacist Only Medicine”. It is available without a doctor’s prescription but your pharmacist’s advice is required.

CANESORAL DUO is not recommended for children under 18 years of age except under doctor supervision.

Before you use CANESORAL DUO

When you must not use it

Do not use CANESORAL DUO if you have an allergy to:

  • any medicine containing fluconazole
  • any medicine containing clotrimazole
  • any other azole antifungals related to fluconazole or clotrimazole such as miconazole (e.g. Daktarin), ketoconazole (e.g. Nizoral) or itraconazole (e.g. Sporanox)
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty in breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Do not use CANESORAL DUO if you are taking:

  • cisapride (Prepulsid), a medicine used to treat stomach problems
  • astemizole
  • pimozide
  • quinidine.

Combining CANESORAL DUO with the above medicines may cause serious side effects such as an abnormal heart rhythm.

Do not use CANESORAL DUO if you are pregnant, suspect you may be pregnant or if you may become pregnant during treatment.

It may affect your developing baby if you use it during pregnancy.

Do not use CANESORAL DUO if you are breastfeeding.

The active ingredient fluconazole passes into breast milk and there is a possibility that your baby may be affected.

Do not use this medicine after the expiry date printed on the pack, or if the packaging is torn or shows signs of tampering.

If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start using this medicine, talk to your doctor or pharmacist.

Before you start to use it

Tell your doctor or pharmacist if you have allergies to any other medicines, foods, dyes or preservatives.

Tell your doctor or pharmacist if you have or have had any of the following medical conditions:

  • thrush more than twice in the last six months
  • liver problems
  • kidney problems
  • heart problems
  • HIV infection or AIDS
  • diabetes.

Your doctor or pharmacist may want to take special care if you have any of these conditions.

Tell your doctor or pharmacist before using CANESORAL DUO if you are taking warfarin (eg. Marevan, Coumadin) as bleeding or bruising may occur.

Tell your doctor or pharmacist if you are experiencing any of the following:

  • abnormal or irregular vaginal bleeding or blood stained discharge
  • foul smelling or unusual coloured discharge
  • vulval or vaginal sores, ulcers or blisters
  • lower abdominal pain or burning when passing urine
  • fever or chills.

If you have not told your doctor or pharmacist about any of the above, tell him/her before you start using CANESORAL DUO.

Using the CANESTEN CLOTRIMAZOLE CREAM component of CANESORAL DUO may reduce the effectiveness and safety of latex products, such as condoms and diaphragms. This effect is temporary and occurs only during treatment.

Taking other medicines

Do not use CANESORAL DUO if you are taking

  • cisapride (Prepulsid), a medicine used to treat stomach problems
  • astemizole
  • pimozide
  • quinidine.

Tell your doctor or pharmacist if you are taking any other medicines, including any that you buy without a prescription from a pharmacy, supermarket or health food shop.

Some medicines and CANESORAL DUO may interfere with each other. These include:

  • warfarin (eg. Marevan, Coumadin), a medicine used to prevent blood clots
  • phenytoin (eg. Dilantin) or carbamazepine (eg. Tegretol), medicines used to treat epilepsy
  • cyclosporin (eg. Neoral), sirolimus (eg. Rapamune) or tacrolimus (eg. Prograf), medicines used to prevent organ transplant rejection or to treat certain problems with the immune system
  • certain medicines use to treat diabetes such as:
    - glibenclamide (eg. Daonil, Glimel), glipizide (eg. Minidiab, Melizide), glimepiride (eg. Amaryl), gliclazide (eg. Diamicron, Glyade)
    - pioglitazone (eg. Actos), rosiglitazone (eg. Avandia)
  • rifampicin (eg. Rifadin, Rimycin) or rifabutin (eg. Mycobutin), antibiotics used to treat infections
  • theophylline (eg. Nuelin), a medicine used to treat asthma
  • midazolam (eg. Hypnovel) and triazolam (eg. Halcion), medicines used as sedatives or to treat anxiety
  • zidovudine (eg. Retrovir), saquinavir (eg. Invirase), medicines used to treat AIDS patients
  • hydrochlorothiazide (eg. Dithiazide), a medicine used for treating fluid problems and high blood pressure
  • the contraceptive pill (birth control pill)
  • amphotericin B (eg. Fungilin), a medicine used to treat fungal infection
  • erythromycin (eg. E-Mycin) and azithromycin (eg. Zithromax), antibiotics used to treat certain types of bacterial infections
  • anticancer drugs such as cyclophophamide, vincristine and vinblastine, medicines used to treat certain types of cancers
  • carbamazepine (eg. Tegretol), a medicine used in the treatment of epilepsy and bipolar disorder
  • NSAIDS such as naproxen, diclofenac and celecoxib (eg. Celebrex)
  • opioid pain killers such as alfentanil, fentanyl and methadone
  • losartan, a medicine used to treat high blood pressure
  • calcium channel blockers, such as nifedipine, amlodipine and felodipine used in relieving high blood pressure and certain heart conditions
  • statins such as atorvastatin, simvastatin and fluvastatin, used to control high cholesterol levels
  • antidepressants such as amitriptyline (eg. Endep) and nortriptyline.

Talk to your doctor about the need for an additional method of contraception while using CANESORAL DUO.

It may decrease the effectiveness of some birth control pills.

Your doctor can tell you what to do if you are taking any of these medicines.

These medicines may be affected by CANESORAL DUO or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while using this medicine.

How to use CANESORAL DUO

Follow all directions given to you by your doctor and pharmacist carefully.

They may differ from the information contained in this leaflet.

If you do not understand the instructions on the pack, ask your doctor or pharmacist for help.

How to use it

For vaginal thrush in adults, only a single dose (1 capsule) is needed.

Swallow the capsule whole with a glass of water.

The capsule can be taken with or without food.

Use the cream on the external irritated area 2-3 times a day to relieve the symptoms for as long as they last, usually not more than 3 days.

Do not give CANESORAL DUO to children under 18 years of age except under doctor supervision.

If you use too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have used too much CANESORAL DUO.

Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

While you are using CANESORAL DUO

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are using CANESORAL DUO.

Tell any other doctors, dentists and pharmacists who treat you that you are using this medicine.

Use effective contraception to prevent pregnancy while using CANESORAL DUO.

If you become pregnant while using this medicine, tell your doctor immediately.

If your symptoms do not improve after 3 days, tell your doctor or pharmacist.

Things you must not do

Do not use CANESORAL DUO to treat any other complaints unless your doctor or pharmacist tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Things to be careful of

Tell your doctor immediately if you develop a rash while using CANESORAL DUO.

People with HIV, AIDS or a weak immune system may be more prone to serious side effects of the skin.

Be careful when driving vehicles or operating machinery as occasional dizziness or seizures may occur.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using CANESORAL DUO.

This medicine helps most people and is generally well tolerated. However it may have unwanted side effects in some people.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Do not be alarmed by the following list of possible side effects.

You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • nausea (feeling sick), vomiting
  • stomach pain, indigestion
  • diarrhoea
  • acne
  • headache
  • rash
  • itching.

The above list includes the more common side effects of your medicine. They are usually mild and short-lived.

Tell your doctor as soon as possible if you notice any of the following:

  • unusual muscle stiffness causing poor control of movement
  • signs of frequent or worrying infections such as fever, severe chills, sore throat or mouth ulcers
  • swelling of the face, lips or tongue which may cause difficulty in swallowing or breathing
  • asthma, wheezing, shortness of breath
  • sudden or severe itching, skin rash, hives
  • fainting, seizures or fits
  • flaking of the skin
  • bleeding or bruising more easily than normal, reddish or purplish blotches under the skin
  • passing more urine than normal, kidney pain (pain on the sides of the body)
  • symptoms of liver disease such as yellowing of the skin or eyes; dark urine, pale stools; loss of appetite; unusual tiredness
  • irregular heart beat or palpitations
  • increased sweating.

The above list includes serious side effects that may require medical attention. Serious side effects are rare.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are very rare.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

After using CANESORAL DUO

Storage

Keep your capsule and cream in the pack until it is time to use them.

If you take the capsule or cream out of the pack it may not keep well.

Keep your capsule and cream in a cool dry place where the temperature stays below 25°C.

Do not store CANESORAL DUO or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car.

Heat and dampness can destroy some medicines.

Keep it where children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor or pharmacist tells you to stop using this medicine or its expiry date has passed, ask your pharmacist what to do with it.

Product description

What CANESORAL DUO looks like

CANESORAL DUO contains two components:

  • CANESORAL is a hard white gelatin capsule, marked with “G” and “FC 150” in black ink.
    Each pack contains 1 capsule.
  • CANESTEN CLOTRIMAZOLE CREAM is an aluminium tube with a screw-cap containing 10 g of a white opaque cream.

Ingredients

The active ingredient in the CANESORAL capsule is fluconazole 150 mg.

Each capsule also contains the following inactive ingredients:

  • gelatin
  • lactose
  • maize starch
  • silicon dioxide
  • magnesium stearate
  • sodium lauryl sulfate
  • titanium dioxide (E171)
  • TekPrint SW-9008 Black Printing Ink
  • TekPrint SW-9009 Black Printing Ink.

The active ingredient in CANESTEN CLOTRIMAZOLE CREAM is 10 mg clotrimazole per gram of cream as the active ingredient.

The cream also contains:

  • sorbitan monostearate
  • polysorbate 60
  • cetyl palmitate
  • cetostearyl alcohol
  • octyldodecanol
  • benzyl alcohol
  • purified water.

This medicine does not contain sucrose, gluten, tartrazine or any other azo dyes.

Supplier

CANESORAL DUO is supplied in Australia by:
Bayer Australia Limited
Consumer Care
875 Pacific Highway
Pymble NSW 2073
Toll Free: 1800 023 884
www.canesten.com.au

AUST R 163461

This leaflet was prepared in June 2011.

BRAND INFORMATION

Brand name

Canesoral Duo Combination pack

Active ingredient

Fluconazole; Clotrimazole

Schedule

S3

 

Name of the medicine

Capsule: fluconazole. Cream: clotrimazole.

Excipients

Capsule.

Gelatin, lactose, maize starch, silicon dioxide, magnesium stearate, sodium lauryl sulfate, titanium dioxide, Tekprint SW-9008 black printing ink and Tekprint SW-9009 black printing ink.

Cream.

Sorbitan monostearate, polysorbate 60, cetyl palmitate, cetostearyl alcohol, octyldodecanol, benzyl alcohol and purified water.

Description

Fluconazole.

Chemical name: 2-(2,4-difluorophenyl)-1,3-bis (1H-1,2,4-triazol-1-yl)-2-propanol. Molecular formula: C13H12F2N6O. MW: 306.3. CAS: 86386-73-4. Fluconazole is a white to off white crystalline powder, which is sparingly soluble in water and saline.

Clotrimazole.

Chemical name: 1-(o-chloro-α,α-diphenylbenzyl) imidazole. Molecular formula: C22H17ClN2. MW: 344.84. Melting point: 141 to 145°C. CAS: 23593-75-1. Clotrimazole is a colourless, crystalline, weakly alkaline substance, soluble in acetone, chloroform and ethanol and practically insoluble in water. It forms stable salts with both organic and inorganic acids. It is not photosensitive but is slightly hygroscopic, and may be hydrolysed in acid media.

Pharmacology

Fluconazole.

Pharmacodynamics.

Fluconazole is a member of the bistriazole class of antifungal agents. Fluconazole is a highly selective inhibitor of fungal cytochrome P450 sterol C-14 α-demethylation. Mammalian cell demethylation is much less sensitive to fluconazole inhibition. The subsequent loss of normal sterols correlates with the accumulation of 14 α-methyl sterols in fungi and may be responsible for the fungistatic activity of fluconazole. Fluconazole 50 mg daily given up to 28 days has been shown not to affect corticosteroid levels or adrenocorticotrophic hormone (ACTH) stimulated response in healthy female volunteers. Plasma oestradiol levels and urinary free cortisol levels were decreased with little effect on plasma testosterone levels. Interaction studies with antipyrine indicate that single or multiple doses of fluconazole 50 mg do not affect its metabolism.

Pharmacokinetics and metabolism.

Adults.

The pharmacokinetic properties of fluconazole are similar following administration by the intravenous or oral routes. In normal volunteers, the bioavailability of orally administered fluconazole is over 90% compared with intravenous administration. In fasted normal volunteers, peak plasma concentrations occur between one and two hours postdose with a terminal plasma elimination half-life of approximately 30 hours (range 20 to 50 hours). Plasma concentrations are proportional to dose and steady-state levels are reached within 5-10 days with oral doses of 50-400 mg once daily. Steady-state levels are approximately 2.5 times the levels achieved with single doses. 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 to 12%).
Fluconazole has been found to achieve good penetration into all tissues and body fluids studied. See Table 1.
The major route of excretion is renal, with approximately 80% of the administered dose appearing in the urine as unchanged drug. About 11% of the dose is excreted in the urine as metabolites. The pharmacokinetics of fluconazole are markedly affected by reduction in renal function. There is an inverse relationship between the elimination half-life and creatinine clearance. The dose of fluconazole may need to be reduced in patients with impaired renal function (see Dosage and Administration). A 3 hour haemodialysis session reduces plasma concentration by about 50%.
The long plasma elimination half-life provides the basis for single dose therapy for vaginal candidiasis.

Children.

There are differences in the pharmacokinetics of fluconazole between adults and children, with children, after the neonatal period, generally having a faster elimination rate and larger volume of distribution than adults.

Microbiology.

Fluconazole administered orally or intravenously was active in a variety of animal models of fungal infections using standard laboratory strains of fungi.
Fluconazole exhibits in vitro activity against Cryptococcus neoformans and Candida species. Activity has been demonstrated in vivo in normal and immunocompromised animals against infections with Candida sp., including systemic candidiasis, and in normal animals with Cryptococcus neoformans, including intracranial infections. One case of cross resistance of Candida to fluconazole in a patient [not infected with human immunodeficiency virus (HIV)] previously treated with ketoconazole has been reported. The efficacy of fluconazole in vivo is greater than would be apparent from in vitro testing against the above mentioned fungi.
Concurrent administration of fluconazole and amphotericin B in infected normal and immunocompromised mice showed antagonism of the two drugs in systemic infection with Aspergillus fumigatus. The clinical significance of results obtained in these studies is unknown.

Clotrimazole.

Microbiology.

Clotrimazole is an imidazole derivative with a broad spectrum antimycotic activity.
Clotrimazole acts against fungi by inhibiting ergosterol synthesis. Inhibition of ergosterol synthesis leads to structural and functional impairment of the cytoplasmic membrane.

Pharmacodynamics.

Clotrimazole has a broad antimycotic spectrum of action in vitro and in vivo, which includes dermatophytes, yeasts, moulds etc.
Under appropriate test conditions, the mean inhibitory concentration (MIC) values for these types of fungi are in the region of less than 0.062-4 (-8) microgram/mL substrate. The mode of action of clotrimazole is fungistatic or fungicidal depending on the concentration of clotrimazole at the site of infection. In vitro activity is limited to proliferating fungal elements; fungal spores are only slightly sensitive.
In addition to its antimycotic action, clotrimazole also acts on Trichomonas vaginalis, gram positive microorganisms (Streptococci/ Staphylococci) and gram negative microorganisms (Bacteroides/ Gardnerella vaginalis).
In vitro clotrimazole inhibits the multiplication of Corynebacteria and gram positive cocci (with the exception of Enterococci) in concentrations of 0.5 to 10 microgram/mL substrate and exerts a trichomonacidal action at 100 microgram/mL.
Primarily resistant variants of sensitive fungal species are very rare; the development of secondary resistance by sensitive has so far only been observed in very isolated cases under therapeutic conditions.

Pharmacokinetics.

Pharmacokinetic investigations after dermal application have shown that only a small amount of clotrimazole (< 2% of the dose) is absorbed. The resulting peak plasma concentrations of the active ingredient are < 10 nanogram/mL (i.e. below the detection limit) and do not lead to measurable systemic effects or side effects.

Indications

Canesoral Duo is indicated for the Treatment of vaginal and vulvovaginal candidiasis.

Contraindications

Known sensitivity to fluconazole, clotrimazole, to related azole compounds or to any of its excipients.
Coadministration of terfenadine is contraindicated in patients receiving fluconazole at multiple doses of 400 mg per day or higher based upon results of a multiple dose interaction study.
Coadministration 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 contraindicated in patients receiving fluconazole (see Interactions with Other Medicines).

Precautions

Anaphylaxis.

Anaphylaxis has been reported in rare instances.

Hepatic impairment.

Fluconazole should be administered with caution to patients with liver dysfunction. Fluconazole has been associated with rare cases of serious hepatic toxicity, including fatalities, primarily in patients with serious underlying medical conditions. In cases of fluconazole associated hepatoxicity, no obvious relationship to total daily dose, duration of therapy, sex or age of the patient has been observed.
Patients who develop abnormal liver function tests during fluconazole therapy should be monitored for the development of more severe hepatic injury. Canesoral Duo should be discontinued if clinical signs and symptoms consistent with liver disease develop that may be attributable to fluconazole (see Adverse Effects).

Renal impairment.

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

Elderly patients with renal impairment.

Dosage should be adjusted for elderly patients with renal impairment (see Dosage and Administration).

Skin and subcutaneous tissue disorders.

Patients have rarely developed exfoliative cutaneous reactions, e.g. Stevens-Johnson syndrome and toxic epidermal necrolysis, during treatment with fluconazole. Acquired immune deficiency syndrome (AIDS) patients are more prone to the development of serious cutaneous reactions to many drugs. If rash which is attributable to fluconazole develops in a patient treated for a superficial fungal infection, Canesoral should be discontinued. If patients with invasive/ systemic fungal infections develop rashes, they should be monitored closely and Canesoral discontinued if bullous lesions or erythema multiforme develop (see Adverse Effects).

QT interval prolongation.

Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During postmarketing surveillance, there have been very rare cases of QT prolongation and torsades de pointes in patients taking fluconazole. These reports included seriously ill patients with multiple confounding risk factors, e.g. structural heart disease, electrolyte abnormalities and concomitant medications that may have been contributory. Fluconazole should be administered with caution to patients with these potentially proarrhythmic conditions (see Adverse Effects).
If evidence of local intolerance develops when using the cream, consider withdrawal of the medicine and institution of appropriate therapy.
Use of Canesten clotrimazole cream may reduce the effectiveness and safety of latex products, e.g. condoms and diaphragms. This effect is temporary and occurs only during treatment.
Canesten clotrimazole cream is not intended for ophthalmic use.

CYP2C9 and CYP3A4 interactions.

Fluconazole is a potent CYP2C9 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole treated patients who are concomitantly treated with drugs with a narrow therapeutic window metabolized through CYP2C9 and CYP3A4 should be monitored (see Interactions with Other Medicines).

Effect on fertility.

Fluconazole did not affect the fertility of male or female rats treated orally with daily doses of 5, 10 or 20 mg/kg or with parenteral doses of 5, 25 or 75 mg/kg, although the onset of parturition was slightly delayed at 20 mg/kg given orally. In an intravenous perinatal study in rats at 5, 20 and 40 mg/kg, dystocia and prolongation of parturition were observed in a few dams at 20 and 40 mg/kg, but not at 5 mg/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 (see Pharmacology, Pharmacodynamics).
Canesten clotrimazole cream has shown no observed carcinogenicity or mutagenicity in animal studies.

Use in pregnancy.

(Category D)
There are no adequate and well controlled studies of fluconazole use in pregnant women. There have been reports of multiple congenital abnormalities in infants whose mothers were being treated for three or more months with high dose fluconazole therapy (400 to 800 mg/day) for coccidiomycosis. The relationship between fluconazole use and these events is unclear. Adverse foetal effects have been seen in animals only at high dose levels associated with maternal toxicity. These findings are not considered relevant to fluconazole used at therapeutic doses. Use in pregnancy should be avoided except in patients with severe or potentially life threatening fungal infections in whom fluconazole may be used if the anticipated benefit outweighs the possible risk to the foetus. Controlled clinical studies for Canesten clotrimazole cream in pregnant women do not exist, however, epidemiological investigations give no indication that harmful effects on the mother and child should be anticipated when used during pregnancy.

Use in lactation.

Fluconazole has been found in human breast milk at concentrations similar to those in plasma. Although systemic absorption of clotrimazole following topical or vaginal administration is low, caution should be exercised when clotrimazole is administered to breastfeeding mothers as there is no information on whether or not clotrimazole is excreted in breast milk. Hence, the use of Canesoral Duo in breastfeeding women is not recommended.

Carcinogenicity and mutagenicity.

Fluconazole showed no evidence of carcinogenic potential in mice and rats treated orally for 24 months at doses of 2.5, 5 or 10 mg/kg/day (approximately two to seven times the recommended human dose). Male rats treated with 5 and 10 mg/kg/day had an increased incidence of hepatocellular adenomas.
Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in four strains of Salmonella typhimurium and in the mouse lymphoma system. Cytogenetic studies in vivo and in vitro showed no evidence of chromosomal mutations.

Effects on driving and using machinery.

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

Interactions

Fluconazole is an inhibitor of the cytochrome P450 system, particularly the CYP2C and to a lesser extent the CYP3A isoforms. Coadministration of fluconazole with some other drugs metabolised primarily by these P450 isoforms may result in altered plasma concentrations of these drugs that could change therapeutic effects and/or adverse event profiles.
Clinically or potentially significant drug interactions have been observed between fluconazole and the following agents: short acting benzodiazepines, cisapride, coumarin type anticoagulants, cyclosporin, hydrochlorothiazide, oral hypoglycaemics, phenytoin, rifampicin, rifabutin, tacrolimus and theophylline. These are described in greater detail below.
The relevance of the following drug interactions to single dose fluconazole is unknown. Patients on other medications should be advised to consult their doctor or pharmacist before starting Canesoral.

Effects of other medicinal products on fluconazole.

The exposure to fluconazole is significantly increased by the concomitant administration of the following agent.

Hydrochlorothiazide.

Concomitant oral administration of fluconazole 100 mg and hydrochlorothiazide 50 mg for 10 days in normal volunteers resulted in an increase of 41% in Cmax and an increase of 43% in AUC of fluconazole, compared to fluconazole given alone. Overall the plasma concentrations of fluconazole were approximately 3.26 to 6.52 micromol/L higher with concomitant diuretic. These changes are attributable to a mean net reduction of approximately 20% in renal clearance of fluconazole.
The exposure to fluconazole is significantly decreased by the concomitant administration of the following agent.

Rifampicin.

Administration of a single oral dose of fluconazole 200 mg after chronic rifampicin administration resulted in a 25% decrease in AUC and a 20% shorter half-life of fluconazole in normal volunteers. Depending on clinical circumstances, an increase of the dose of fluconazole should be considered when it is administered with rifampicin.
Minor or no significant pharmacokinetic interactions that require no dosage adjustment.

Gastrointestinal drugs.

In fasted normal volunteers, absorption of orally administered fluconazole does not appear to be affected by agents that increase gastric pH. Single dose administration of fluconazole (100 mg) with cimetidine (400 mg) resulted in a 13% reduction in AUC and a 21% reduction in Cmax of fluconazole. Administration of an antacid containing aluminium and magnesium hydroxides immediately prior to a single dose of fluconazole (100 mg) had no effect on the absorption or elimination of fluconazole.

Effects 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 metabolised by CYP2C9 and CYP3A4 coadministered with fluconazole. Therefore caution should be exercised when using these combinations and the patients should be carefully monitored. The enzyme inhibiting effect of fluconazole persists 4-5 days after discontinuation of fluconazole treatment due to the long half-life of fluconazole.

Alfentanil.

A study observed a reduction in clearance and distribution volume as well as prolongation of t1/2 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-amitriptyline may be measured at initiation of the combination therapy and after one week. Dosage of amitriptyline/ nortriptyline should be adjusted, if necessary.

Amphotericin B.

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

Cisapride.

Fluconazole 200 mg daily increased the AUC and Cmax of cisapride (20 mg four times daily) both after a single dose (AUC increased 101% and Cmax increased 91%) and multiple doses (AUC increased 192% and Cmax increased 154%). A significant prolongation in QTc interval was recorded. Cardiac events including torsades de pointes have been reported in patients receiving fluconazole and cisapride concomitantly. In most of these cases, the patients appear to have been predisposed to arrhythmias or had serious underlying illness. The coadministration of fluconazole and cisapride is contraindicated (see Contraindications).

Terfenadine.

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

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 (see Contraindications).

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 (see Contraindications).
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, torsade de pointes) and consequently sudden heart death. This combination should be avoided.
Interaction of fluconazole with the following agents may result in increased exposure to these drugs. Careful monitoring and/or dosage adjustment should be considered.

Benzodiazepines (short acting).

Studies in human subjects have reported changes in midazolam pharmacokinetics and clinical effects that are dependent on dosage and route of administration. Single doses of fluconazole 150 mg resulted in modest increases in midazolam concentrations and psychomotor effects following oral administration of 10 mg that may not be clinically significant. At doses used to treat systemic mycoses, fluconazole resulted in substantial increase in midazolam concentrations and psychomotor effects following oral administration of 7.5 mg, but only modest increases that are not likely to be clinically significant following intravenous infusion of midazolam 0.05 mg/kg. This effect on midazolam appears to be more pronounced following oral administration of fluconazole than with fluconazole administered intravenously. There have been reports of sleepiness and disturbed consciousness in patients taking fluconazole for systemic mycoses and triazolam. However, in most of these cases the patients had serious underlying illnesses and/or concomitant therapies that could have contributed to the reported events and a true fluconazole triazolam interaction has not been established. If concomitant benzodiazepine therapy is necessary in patients being treated with fluconazole, consideration should be given to decreasing the benzodiazepine dosage and monitoring the patient's response. Fluconazole increases the AUC of triazolam (single dose) by approximately 50% Cmax with 20-32% and increases the half life 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.

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.

Cyclosporin.

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

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.

Losartan.

Fluconazole inhibits the metabolism of losartan to its active metabolite (E-3174) which is responsible for most of the angiotensin II receptor antagonism that 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.

Nonsteroidal anti-Inflammatory drugs (NSAIDs).

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 hypoglycaemic agents.

The effects of fluconazole on the pharmacokinetics of the sulfonylurea oral hypoglycaemic agents tolbutamide, glipizide and glibenclamide were examined in three placebo controlled crossover studies in normal volunteers. All subjects received the sulfonylurea alone and following treatment with fluconazole 100 mg as a single daily oral dose for 7 days. Fluconazole administration resulted in significant increases in Cmax and AUC of the sulfonylurea. Several subjects in these three studies experienced symptoms consistent with hypoglycaemia. In the glibenclamide study, several volunteers required oral glucose treatment. As fluconazole is a potent inhibitor CYP2C8 and CYP2C9, it may also interact with other sulfonylureas (e.g. glimepiride and gliclazide) and the thiazolidinediones (e.g. pioglitazone and rosiglitazone), which are metabolised by these enzymes. When fluconazole and sulfonylureas or thiazolidinediones are coadministered, blood glucose concentrations should be monitored carefully and the dose of the sulfonylurea adjusted accordingly.

Phenytoin.

Fluconazole inhibits the hepatic metabolism of phenytoin. With coadministration, serum phenytoin concentration levels should be monitored in order to avoid phenytoin toxicity.

Prednisone.

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

Rifabutin.

There have been reports that an interaction exists when fluconazole is administered concomitantly with rifabutin, leading to increased serum levels of rifabutin up to 80%. There have been reports of uveitis in patients to whom fluconazole and rifabutin were coadministered. Patients receiving rifabutin and fluconazole concomitantly should be carefully monitored.

Saquinavir.

Fluconazole increases the AUC of saquinavir and decreases clearance of saquinavir 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.

Sulfonylureas.

Fluconazole has been shown to prolong the serum half-life of concomitantly administered oral sulfonylureas (e.g. chlorpropamide, glibenclamide, glipizide, tolbutamide) in healthy volunteers. 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. Dosage of orally administered tacrolimus should be decreased depending on tacrolimus concentration.

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 of theophylline toxicity should be observed for signs of theophylline toxicity while receiving fluconazole and 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 alltrans-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.

Warfarin.

A single dose of warfarin 15 mg given to normal volunteers, following 14 days of orally administered fluconazole 200 mg resulted in a 12% increase in the prothrombin time response (area under the prothrombin time-time curve). One in 13 subjects experienced a twofold increase in prothrombin time response. In postmarketing 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. Careful monitoring of prothrombin time in patients receiving fluconazole and coumarin type anticoagulants is recommended.

Zidovudine.

Fluconazole increases Cmax and AUC of zidovudine, respectively, due to decrease in oral zidovudine clearance. The half-life of zidovudine was likewise prolonged 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.

Carbamazepine.

Azole antifungals may raise carbamazepine plasma concentrations. Since high plasma concentrations of carbamazepine and/or carbamazepine-10, 11-epoxy may result in adverse effects (e.g. dizziness, drowsiness, ataxia, diplopia), the dosage of carbamazepine should be adjusted accordingly and/or plasma concentrations monitored when used concomitantly with fluconazole.
Minor or no significant pharmacokinetic interactions that require no dosage adjustment.

Oral contraceptives.

Oral contraceptives were administered as a single dose both before and after oral administration of fluconazole 50 mg once daily for 10 days in 10 healthy women. There was no significant difference in ethinyloestradiol or levonorgestrel AUC after the administration of 50 mg of fluconazole. The mean increase in ethinyloestradiol AUC was 6% (range: -47 to 108%) and levonorgestrel AUC increased 17% (range: -33 to 141%).
In a second study, twenty five normal females received daily doses of 200 mg fluconazole or placebo for two, ten day periods. The treatment cycles were one month apart with all subjects receiving fluconazole during one cycle and placebo during the other. Single doses of an oral contraceptive tablet containing levonorgestrel and ethinyloestradiol were administered on the final treatment day (day 10) of both cycles. Following administration of 200 mg of fluconazole, the mean percentage increase in AUC for levonorgestrel compared to placebo was 25% (range: -12 to 82%) and the mean percentage increase for ethinyloestradiol compared to placebo was 38% (range: -11 to 101%). Both of these increases were statistically significantly different from placebo.
In a third study 21 healthy women received 300 mg weekly doses of fluconazole and single doses of ethinyloestradiol 35 microgram and norethindrone 0.5 mg. AUC of ethinyloestradiol was increased by 24% (range: 3 to 59%) and AUC of norethindrone was increased by 13% (range: -5 to 36%).
Multiple doses of fluconazole may increase exposure to hormone levels in women taking oral contraceptives and are unlikely to result in decreased efficacy of the oral contraceptive.

Two way interactions.

Minor or no significant pharmacokinetic interactions that require no dosage adjustment.

Azithromycin.

An open label, randomised, three way cross 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. The estimated ratio of the mean AUC of fluconazole coadministered with azithromycin to fluconazole administered alone was 101%. The estimated ratio of the mean AUC of azithromycin coadministered with fluconazole to azithromycin administered alone was 107%. The estimated ratio of the mean Cmax of fluconazole coadministered with azithromycin to fluconazole administered alone was 104%. The estimated ratio of the mean Cmax of azithromycin coadministered with fluconazole to azithromycin administered alone was 82%.
See Table 2.
There have been no reported drug interactions with Canesten clotrimazole cream.

Adverse Effects

Fluconazole and clotrimazole are generally well tolerated.

Common adverse events (> 1% and < 10%) observed during vaginal candidiasis clinical trials and associated with fluconazole.

Nervous system disorders.

Headache.

Gastrointestinal disorders.

Nausea, abdominal pain, diarrhoea, dyspepsia.

Hepatobiliary disorders.

Alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased.

Uncommon adverse events (> 0.1% and < 1%) observed during vaginal candidiasis clinical trials associated with fluconazole.

Eye disorders.

Abnormal vision.

Skin and subcutaneous tissue disorders.

Pruritus, genital pruritus, rash, erythematous rash, dry skin, abnormal skin odour, urticaria.

Nervous system disorders.

Dizziness, vertigo, hyperkinesia, hypertonia, taste perversion, visual field defect.

Gastrointestinal.

Constipation, dry mouth, flatulence, vomiting, loose stools.

Infections and infestations.

Pharyngitis, herpes simplex.

Metabolism and nutrition disorders.

Anorexia.

Psychiatric disorders.

Insomnia, nervousness.

Reproductive system and breast disorders.

Intermenstrual bleeding, dysmenorrhoea, leucorrhoea, menorrhagia, uterine spasm, vaginal disorder, female sexual dysfunction.

Vascular disorders.

Flushing, hot flushes.

Hepatobiliary disorders.

Cholestasis, jaundice, bilirubin increased.

Renal and urinary disorders.

Polyuria, renal pain.

General disorders and administration site conditions.

Fatigue, hot flushes, malaise, back pain, herpes simplex, pain, rigors, thirst, asthenia, fever.

Musculoskeletal and connective tissue disorders

Back pain, myalgia.

Rare adverse events (> 0.01% and < 0.1%) observed during vaginal candidiasis clinical trials associated with fluconazole.

Hepatobiliary disorders.

Hepatic toxicity, including rare cases of fatalities. Hepatic failure, hepatocellular necrosis, hepatitis, hepatocellular damage.

Cardiac disorders.

Torsade de pointes, QT prolongation.

Postmarketing experience.

Cardiac disorders.

Torsade de pointes (see Precautions).

Gastrointestinal disorders.

Dyspepsia, vomiting.

Hepatobiliary disorders.

Hepatocellular necrosis.

Immune system disorders.

Anaphylaxis (including face oedema, angioedema and pruritus).

Investigations.

QT prolongation (see Precautions).

Metabolism and nutrition disorders.

Hypercholesterolaemia, hypertriglyceridaemia and hypokalaemia.

Nervous system disorders

Dizziness.
Canesten clotrimazole cream is generally well tolerated after local application. The following have been reported infrequently: erythema, stinging, blistering, peeling, oedema, pruritus, urticaria and general irritation.

Dosage and Administration

Adults.

Capsule.

Swallow 1 capsule with water, with or without food. Take once only, at any time of the day.

Cream.

Apply gently to the irritated area (for external use only). Use two to three times daily until symptoms clear.

Overdosage

The minimal lethal human dose has been not established. There have been reports of overdosage with fluconazole, and in one case a 42 year old patient infected with HIV developed hallucinations and exhibited paranoid behaviour after reportedly ingesting fluconazole 8,200 mg. The patient was admitted to hospital and his condition resolved within 48 hours.
Signs and symptoms are likely to be an extension of those under Adverse Effects.
There is no specific antidote. Treatment is symptomatic and supportive, including respiratory and cardiovascular function. Monitor for hypokalaemia and elevated liver enzymes; and obtain a full blood count to monitor for possible thrombocytopenia and agranulocytosis.
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%.
There have been no reports of overdosage with Canesten clotrimazole cream.
Contact the Poisons Information Centre on 131 126 for advice on the management of an overdose.

Presentation

Canesoral.

Capsule, fluconazole 150 mg (white, opaque, hard gelatin, size 1, marked in black ink FC 150 and G): 1's (blister pack).

Canesten.

Cream, clotrimazole 10 mg/g (1%) (vanishing base): 10 g (tube).

Storage

Store below 25°C.

Poison Schedule

S3.