Consumer medicine information

Femazole Duo Combination pack

Fluconazole; Clotrimazole

BRAND INFORMATION

Brand name

Femazole Duo Combination pack

Active ingredient

Fluconazole; Clotrimazole

Schedule

S3

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Femazole Duo Combination pack.

What is in this leaflet

Please read this leaflet carefully before you start using FEMAZOLE DUO.

This leaflet answers some common questions about FEMAZOLE DUO.

It does not contain all of the available information.

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

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

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine.

You may need to read it again.

What FEMAZOLE DUO is used for

FEMAZOLE DUO is used to treat a certain fungal infection called vaginal thrush.

FEMAZOLE DUO contains two components: FEMAZOLE ONE CAPSULE is an oral capsule which contains the active ingredient Fluconazole. FEMAZOLE DUO CREAM is a cream and contains the active ingredient clotrimazole. Both actives belongs to a group of medicines called azole antibiotics.

FEMAZOLE DUO CAPSULE is taken by the mouth and is used to treat vaginal thrush. FEMAZOLE DUO CREAM is for external use and provides soothing relief from external itching and irritation.

If this is the first time you have had these symptoms, talk to your doctor before using any treatment.

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

Your doctor or pharmacist may have recommended FEMAZOLE DUO for another reason.

What is vaginal thrush

Vaginal thrush is a common infection caused by an overgrowth of yeast-like fungus called Candida albicans. This yeast lives naturally in the bowel and in small numbers in the vagina. It is mostly harmless, but thrush symptoms can develop if yeast numbers increase.

The following situations can influence the overgrowth of thrush:

  • Diabetes
  • Obesity
  • Illness
  • Fatigue
  • Hormonal fluctuations (pregnancy, menstrual cycle, oral contraceptive pill, HRT)
  • Prolonged use of antibiotics or steroids

Common symptoms of vaginal thrush include:

  • itching, burning or soreness around the vagina
  • vaginal discharge with a ‘cottage cheese’ appearance and yeasty smell
  • swelling or irritation of the infected area

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

  • wear clean cotton underwear and avoid wearing tight-fitting pants and synthetic underwear
  • wash regularly, but do not wash and dry yourself harshly
  • Wipe your bottom from front to back after going to the toilet. This will prevent the spread of Candida albicans from the anus to the vagina.
  • Avoid using soap to wash the genital area. Soap substitutes can be used.
  • Avoid using perfumed products, antiseptics, douches or perfumed sprays in the genital area.

Before you take FEMAZOLE DUO

When you must not take it

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

  • any medicine containing Fluconazole and clotrimazole
  • medicines related to fluconazole such as miconazole, ketoconazole or itraconazole
  • any of the ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.

FEMAZOLE DUO should not be given if you are taking cisapride (a medicine used to treat stomach problems).

Do not take this medicine if the expiry date (EXP) printed on the packaging has passed 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 taking this medicine, talk to your doctor.

Before you start to take it

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

Tell your doctor if you have any other health problems, including:

  • liver problems
  • heart problems
  • kidney problems.
  • diabetes
  • unexplained jaundice
  • HIV or AIDS

If you are unsure about the cause of your symptoms, and if you have had thrush more than twice in the last six months.

If you have not told your doctor about any of the above, tell them before you start taking FEMAZOLE DUO.

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

  • fever or chills
  • abnormal or irregular vaginal bleeding or blood-stained discharge
  • foul smelling and/or unsuaual coloured discharge
  • vulval or vaginal sores, ulcer or blisters
  • lower abdominal pain or burning when passing urine.

Using the clotrimazole cram component of Femazole 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

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

Some medicines may be affected by FEMAZOLE DUO, or may affect how well it works. These include:

  • some medicines for diabetes such as glipizide, tolbutamide or glibenclamide
  • some antibiotics and antiviral drugs such as rifampicin, rifabutin or zidovudine
  • some drugs used in problems with the immune system, such as cyclosporin or tacrolimus
  • warfarin (used to stop blood clots)
  • phenytoin (used to treat epilepsy)
  • theophylline (used to treat asthma)
  • some benzodiazepines such as midazolam
  • hydrochlorothiazide (used for treating fluid problems).

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking FEMAZOLE DUO.

How to use FEMAZOLE DUO

How to use it

Femazole Duo Capsule:

Adults
Swallow whole one capsule by mouth with a glass of water.

Only a single dose (1 capsule) is needed.

The capsule can be taken with or without food.

Femazole Duo Cream:

Wash your hands thoroughly before applying the cream. Apply gently to the irritated area of the skin outside the vagina, 2-3 times daily until symptoms are relieved, usually not more than 3 days. For external use only.

FEMAZOLE DUO is not recommended for use in children under 18 years of age.

If you tuse too much FEMAZOLE DUO (overdose)

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

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking FEMAZOLE DUO

Things you must do

If the symptoms of your infection do not improve within 3 days, or if they become worse, tell your doctor.

If you become pregnant while using FEMAZOLE DUO, tell your doctor immediately.

Before starting any new medicine, tell your doctor or pharmacist that you are taking FEMAZOLE DUO.

Tell all the doctors, dentists and pharmacists who are treating you that you are using FEMAZOLE DUO.

Things you must not do

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

Do not use FEMAZOLE DU0 to treat any other medical complaints unless your doctor tells you to.

Things to be careful of

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

If you suffer from HIV or have a weakened immune system you may be more prone to serious side effects of the skin.

Side effects

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

FEMAZOLE DUO helps most people with vaginal thrush, but it may have a few unwanted 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 attention if you get some of the side effects.

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

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

You may not experience any of them.

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

  • nausea or feeling sick, vomiting
  • headache
  • stomach pain, indigestion, diarrhoea

The clotrimazole cream component of Femazole Duo may cause mild burning, stinging or irritation immediately after applications. If you are concerned about any of these reactions, stop treatment and tell your doctor or pharmacist.

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

If you notice any of the following while taking FEMAZOLE DU0, stop taking it and tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing (allergic reactions)
  • shortness of breath, difficulty with breathing, wheezing, asthma (allergic reactions)
  • sudden or severe itching, skin rash, hives (allergic reactions)
  • flaking of the skin
  • yellowing of the skin or eyes, also called jaundice
  • bleeding or bruising more easily than normal, reddish or purplish blotches under the skin
  • fast or irregular heart beat
  • severe abdominal cramps
  • watery and severe diarrhoea,
  • signs of frequent or worrying infections such as fever, severe chills, sore throat or mouth ulcers.

These are very serious side effects. You may need urgent medical attention or hospitalisation. All of these side effects are usually rare.

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

This is not a complete list of all possible side effects. Others may also occur in some people and there may be some side effects not yet known.

After using FEMAZOLE DU0

Storage

Keep this medicine 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.

Keep FEMAZOLE DUO in a cool, dry place where it stays below 25°C.

Do not store FEMAZOLE DUO in the bathroom or near a sink.

Do not leave FEMAZOLE DUO in the car or on window sills.

Heat and dampness can destroy some medicines.

Disposal

If your doctor tells you to stop taking this medicine, or it has passed its expiry date, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

FEMAZOLE DUO contains two components:

  • FEMAZOLE DUO CAPSULE contains a single hard blue gelatin capsule, filled with a white to off-white powder. .
  • FEMAZOLE DUO CREAM contains a white opaque cream in a 10g tube.

Ingredients

The active ingredient in FEMAZOLE DUO capsule is Fluconazole 150 mg.

The capsules also contain:

  • lactose
  • pregelatinised maize starch
  • sodium lauryl sulfate
  • colloidal anhydrous silica
  • magnesium stearate
  • purified talc.

The capsule shells contain

  • gelatin
  • sodium lauryl sulfate
  • titanium dioxide (E171)
  • brilliant blue FCF (E133)

The capsule does not contain gluten, sucrose, tartrazine or any other azo dyes.

The ingredient in FEMAZOLE DUO CREAM is clotrimazole 10 mg/g

The cream also contains:

  • Propylene glycol
  • Cetomacrogol 1000
  • Cetostearyl alcohol
  • Paraffin – liquid and soft white
  • Dimethicone 100
  • Self-emulsifying Glyceryl monostearate
  • Benzyl alcohol
  • Disodium edetate
  • Purified water

Sponsor

Sigma Pharmaceuticals (Australia) Pty Ltd
96 Merrindale Drive
Croydon Vic 3136
Tel: 03 - 9839 2800

The Australian Registration Numbers for FEMAZOLE DU0 is AUST R 174773.

Date of preparation
Oct 2009

BRAND INFORMATION

Brand name

Femazole Duo Combination pack

Active ingredient

Fluconazole; Clotrimazole

Schedule

S3

 

Name of the medicine

Capsule: fluconazole. Cream: clotrimazole.

Excipients.

Capsule.

Lactose, pregelatinised maize starch, sodium lauryl sulfate, colloidal anhydrous silica, magnesium stearate and purified talc. The capsule shells contain: gelatin, sodium lauryl sulfate, titanium dioxide (E171), brilliant blue FCF (E133) and erythrosine (E127) (50 mg and 200 mg capsule shells only). The capsules are gluten free.

Cream.

Propylene glycerol, disodium edetate, cetomacrogol 1000, cetostearyl alcohol, liquid paraffin, dimethicone 100, white soft paraffin, glyceryl monostearate S.E., benzyl alcohol and water-purified.

Description

Fluconazole.

The chemical name of fluconazole is 2-(2,4 -difluorophenyl)-1,3-bis (1H-1,2,4-triazol- 1yl)-2-propanol. C13H12F2N6O. Molecular weight: 306.3. CAS No.: 86386-73-4.
Fluconazole is a white to off-white crystalline powder which is sparingly soluble in water and saline.
Femazole Duo Capsule contains 150 mg of fluconazole.
The capsule also contains the following excipients: lactose, pregelatinised maize starch, sodium lauryl sulfate, colloidal anhydrous silica, magnesium stearate and purified talc. The capsule shells contain: gelatin, sodium lauryl sulfate, titanium dioxide (E171), brilliant blue FCF (E133) and erythrosine (E127) (50 mg and 200 mg capsule shells only). The capsules are gluten free.

Clotrimazole.

The chemical name of clotrimazole is 1-[(2- Chlorophenyl) diphenylmethyl]-1H imidazole. C22H17ClN2. Molecular weight: 344.8. CAS No.: 23593-75-1.
Clotrimazole is a white to pale yellow crystalline powder, practically insoluble in water, soluble in chloroform and ethanol.
Femazole Duo Cream contains 10 mg/g of clotrimazole.
The cream also contains propylene glycerol, disodium edetate, cetomacrogol 1000, cetostearyl alcohol, liquid paraffin, dimethicone 100, white soft paraffin, glyceryl monostearate S.E, benzyl alcohol and water - purified.

Pharmacology

Microbiology.

Fluconazole administered orally 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 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. In Candida albicans, clotrimazole inhibits transformation of blastospores into invasive mycelial form.

Pharmacology.

Fluconazole is a member of the bis-triazole class of antifungal agents. It is a highly selective inhibitor of fungal cytochrome P450 sterol C-14 alpha-demethylation. Mammalian cell demethylation is much less sensitive to fluconazole inhibition. The subsequent loss of normal sterols correlates with the accumulation of 14 alpha-methyl sterols in fungi and may be responsible for the fungistatic activity of fluconazole.
Clotrimazole has a broad antimycotic spectrum of action in vitro and in vivo, which includes dermatophytes, yeasts and moulds.
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 infections. In vitro activity is limited to proliferating fungal elements; fungal spores are only slightly sensitive.
In addition to this antimycotic action, clotrimazole also acts as Trichomonas vaginalis gram positive microorganisms (Streptococci/Staphylococci) and gram negative microorganisms (Bacteroids/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.

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 after the dose with a terminal plasma elimination half-life of approximately 30 hours (range 20 to 50 hours). 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. The levels of fluconazole in saliva and sputum are similar to plasma levels.
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, however no adjustment in single dose is necessary.
Oral administration is not affected by concomitant food intake.
The long plasma elimination half-life provides the basis for single dose therapy for vaginal candidiasis.
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 in adults.

Clotrimazole.

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

Treatment of vaginal and vulvovaginal candidiasis.

Contraindications

Known sensitivity to fluconazole, clotrimazole related azole compounds or any of the excipients of Femazole Duo capsule or cream.
Concomitant administration with cisapride is contraindicated (see Precautions).

Precautions

Anaphylaxis has been reported in rare instances.
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 liver injury. Femazole Duo capsule should not be used again if clinical signs and symptoms consistent with liver disease develop that may be attributable to fluconazole (see Adverse Effects).
Patients have rarely developed exfoliative cutaneous reactions, e.g. Stevens-Johnson syndrome and toxic epidermal necrolysis, during treatment with fluconazole. AIDS patients are more prone to the development of serious cutaneous reactions to many drugs. If a rash that is attributable to fluconazole develops, fluconazole should not be used again.
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, such as structural heart disease, electrolyte abnormalities and concomitant medications that may have been contributory. Fluconazole should be administered with caution to patients with these potentially pro-arrhythmic conditions (see Adverse Effects).
If evidence of local intolerance develops when using Femazole Duo Cream, discontinue use of the cream and institute appropriate therapy.
Use of Femazole Duo Cream may reduce the effectiveness and safety of latex products, such as condoms and diaphragms. This effect is temporary and occurs only during treatment.
Femazole Duo Cream is not intended for ophthalmic use.

Carcinogenesis, mutagenesis, impairment of fertility.

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.
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).
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 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. Controlled clinical studies for clotrimazole cream in pregnant women do not exist, however epidemiological investigations give no indication that harmful effects on the mother and child shoud be anticipated when used during pregnancy.
Femazole Duo should not be used in women who are pregnant or in women of childbearing potential unless adequate contraception is employed.

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, there is no information on whether clotrimazole is excreted in breast milk.
Therefore, Femazole Duo is not recommended for use in breastfeeding women.

Interactions

Drug interactions to single dose of Fluconazole are unknown. Patients taking other medications should seek advice from a doctor or pharmacist prior the use of Femazole Duo.
Fluconazole is an inhibitor of the cytochrome P450 system, particularly the CYP2C and to a lesser extent the CYP3A isoforms. Co-administration 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.

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 ten days in normal volunteers resulted in an increase of 41% in Cmax and an increase of 43% in area under the curve (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 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 medicines.

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 co-administration of fluconazole and cisapride is contraindicated (see Contraindications).

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 increases in midazolam concentrations and psychomotor effects following oral administration of midazolam 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 interaction between fluconazole and triazolam 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 the patients should be appropriately monitored.

Cyclosporin.

A kinetic study in renal transplant patients found fluconazole 200 mg daily slowly increased cyclosporin concentrations. However, in another multiple dose study with 100 mg daily, fluconazole did not affect cyclosporin levels in patients with bone marrow transplants. Cyclosporin plasma concentration should be monitored in all patients receiving concomitant fluconazole.

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 seven 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. When fluconazole and sulfonylureas are co-administered, blood glucose concentrations should be monitored carefully and the dose of the sulfonylurea adjusted accordingly.

Phenytoin.

Concomitant administration of oral fluconazole 200 mg with phenytoin at steady-state resulted in average increase of 75% of phenytoin AUC values in normal volunteers. Careful monitoring of phenytoin concentrations in patients receiving fluconazole and phenytoin is recommended.

Rifabutin.

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

Tacrolimus.

There have been reports that an interaction exists when fluconazole is administered concomitantly with tacrolimus, leading to increased serum levels of tacrolimus. There have been reports of nephrotoxicity in patients to whom fluconazole and tacrolimus were co-administered. Patients receiving tacrolimus and fluconazole concomitantly should be carefully monitored.

Theophylline.

In a placebo controlled interaction study, the administration of fluconazole 200 mg for 14 days resulted in an 18% decrease in the mean plasma clearance of theophylline. Patients who are receiving high doses of theophylline, or who are otherwise at increased risk of theophylline toxicity, should be observed for signs of theophylline toxicity while receiving fluconazole. Therapy should be modified appropriately if signs of toxicity develop.

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.

Two kinetic studies resulted in increased levels of zidovudine, most likely caused by the decreased conversion of zidovudine to its major metabolite. One study determined zidovudine levels in acquired immune deficiency syndrome (AIDS) or AIDS related complex (ARC) patients before and following fluconazole 200 mg daily for 15 days. There was a significant increase in zidovudine AUC (20%). A second randomised, two period, two treatment crossover study examined zidovudine levels in HIV infected patients. On two occasions, 21 days apart, patients received zidovudine 200 mg every eight hours either with or without fluconazole 400 mg for seven days. The AUC of zidovudine significantly increased (74%) during co-administration with fluconazole. Patients receiving this combination should be monitored for the development of zidovudine related adverse reactions.

Interaction of fluconazole with the following agent may not require 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 ten days in ten healthy women. There was no significant difference in ethinyloestradiol or levonorgestrol AUC after the administration of fluconazole 50 mg. The mean increase in ethinyloestradiol AUC was 6% (range:-47 to 108%) and levonorgestrol AUC increased 17% (range: -33 to 141%).
In a second study, 25 normal females received daily doses of fluconazole 200 mg tablets 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 levonorgestrol and ethinyloestradiol were administered on the final treatment day (day 10) of both cycles. Following administration of fluconazole 200 mg, the mean percentage increase in AUC for levonorgestrol 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 weekly doses of fluconazole 300 mg and single doses of ethinyloestradiol 35 microgram and norethindrone 0.5 mg. AUC of ethinyloestradiol was increase 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 oral dose of azithromycin 1,200 mg on the pharmacokinetics of a single oral dose of fluconazole 800 mg as well as the effects of fluconazole on the pharmacokinetics of azithromycin. The estimated ratio of the mean AUC of fluconazole co-administered with azithromycin to fluconazole administered alone was 101%. The estimated ratio of the mean AUC of azithromycin co-administered with fluconazole to azithromycin administered alone was 107%. The estimated ratio of the mean Cmax of fluconazole co-administered with azithromycin to fluconazole administered alone was 104%. The estimated ratio of the mean Cmax of azithromycin co-administered with fluconazole to azithromycin administered alone was 82%. See Table 1.

Others.

Doctors should be alert to the potential for interactions between fluconazole and other drugs, for which pharmacokinetic drug-drug interaction studies have not been conducted.
There have been no reported drug interactions with topical clotrimazole cream.

Adverse Effects

Fluconazole and clotrimazole are generally well tolerated.
Adverse reactions observed with Fluconazole during vaginal candidiasis clinical trains and associated with fluconazole include the following. Frequencies are categorised as follows: very common ≥ 10%; 1% ≤ common < 10%; 0.1% ≤ uncommon < 1%; 0.01% < rare < 0.1%.

Gastrointestinal.

Common: nausea, abdominal pain, diarrhoea, dyspepsia.
Uncommon: vomiting, dry mouth, constipation, flatulence, loose stools.

Central nervous system.

Common: headache. Uncommon: dizziness, vertigo, hyperkinesia, hypertonia, taste perversion.

Autonomic nervous system.

Uncommon: flushing, hot flushes.

Dermatological.

Uncommon: pruritus, genital pruritus, rash, erythematous rash, dry skin, abnormal skin odour, urticaria.

General.

Uncommon: thirst, fatigue, malaise, rigors.

Infections or infestations.

Uncommon: pharyngitis, herpes simplex.

Metabolic.

Uncommon: anorexia.

Musculoskeletal.

Uncommon: back pain.

Ophthalmic.

Uncommon: abnormal vision, visual field defect.

Psychiatric.

Uncommon: insomnia, nervousness.

Reproductive.

Uncommon: intermenstrual bleeding, dysmenorrhoea, leucorrhoea, menorrhagia, uterine spasm, vaginal disorder, female sexual dysfunction.

Urinary.

Uncommon: polyuria, renal pain.
The following adverse events have occurred during experience with overall fluconazole use.

Cardiovascular.

QT prolongation, torsades de pointes (see Precautions).

Central nervous system.

Dizziness, seizures.

Dermatological.

Alopecia, exfoliative skin disorders including Stevens-Johnson syndrome and toxic epidermal necrolysis.

Haemopoietic and lymphatic.

Leucopenia including neutropenia and agranulocytosis, thrombocytopenia.

Hepatobiliary.

Hepatocellular damage, jaundice, elevation of transaminase greater than two to three times the upper limit of normal.

Immunological.

Anaphylaxis (including face oedema, angioedema, urticaria and pruritus).

Metabolic.

Hypercholesterolaemia, hypertriglyceridaemia and hypokalaemia.

Dosage and Administration

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

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 reporting to have ingested fluconazole 8,200 mg. The patient was admitted to hospital, and his condition resolved within 48 hours.
In the event of overdosage, symptomatic treatment with supportive measures should be undertaken. Contact the Poisons Information Centre on 131 126 for advice on management.
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 clotrimazole cream.
In the event of overdosage, symptomatic treatment (with supportive measures and gastric lavage if necessary) should be undertaken.

Presentation

Femanazole Duo containing:

Capsules.

Blue, opaque, hard gelatin capsules. Blister packs of 1.

Cream.

White, opaque, cream. Tube of 10 g.

Storage

Store below 25°C.

Poison Schedule

S3.