Consumer medicine information

Afeme Duo

Fluconazole; Clotrimazole

BRAND INFORMATION

Brand name

Afeme Duo

Active ingredient

Fluconazole; Clotrimazole

Schedule

S3

 

Consumer medicine information (CMI) leaflet

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

What is in this leaflet

This leaflet answers some common questions about AFEME 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.

What AFEME DUO is used for

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

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

AFEME DUO contains two components: AFEME DUO Fluconazole is an oral capsule which contains the active ingredient fluconazole; AFEME DUO Clotrimazole Vaginal Cream contains the active ingredient clotrimazole, both of these ingredients belong to a group of medicines called azole antifungals.

AFEME DUO Fluconazole capsule is taken by mouth and works from the inside to prevent the growth of the fungi causing your infection; AFEME DUO Clotrimazole Vaginal Cream provides soothing relief from external itching and irritation.

Ask your doctor or pharmacist if you have any questions about why AFEME DUO has been recommended for you. Your doctor or pharmacist may have recommended AFEME DUO for another reason.

AFEME DUO is not recommended for children under 18 years of age.

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

AFEME DUO is a "Pharmacist Only Medicine". It is available without a doctor's prescription but your pharmacist's advice is required.

What is vaginal thrush

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

Candida albicans is one of many organisms that live in the vagina. Your body's natural balance (immune system) normally keeps Candida albicans under control, but when this natural balance is upset, Candida albicans 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.

Before you use AFEME DUO

When you must not use it

Do not use AFEME DUO if you are allergic to medicines containing:

  • fluconazole
  • clotrimazole
  • other azole antifungals such as miconazole, ketoconazole, itraconazole, econazole; or
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • skin rash,
  • itching or hives;
  • swelling of the face, lips or tongue which may cause difficulty in swallowing or breathing;
  • wheezing or shortness of breath.

Do not use AFEME DUO if you are taking:

  • Cisapride (Prepulsid), a medicine used to treat stomach problems
  • Astemizole, a type of antihistamine
  • Pimozide, a medicine used to treat mental conditions
  • Quinidine, a medicine used to treat abnormal heart rhythm.

Combining AFEME DUO with these medicines may cause serious side effects such as an abnormal heart rhythm.

Do not use AFEME DUO if you are pregnant, suspect you may be pregnant or if you may become pregnant during treatment. AFEME DUO should not be used during pregnancy as it may affect your developing baby.

Do not use AFEME DUO if you are breastfeeding. Fluconazole passes into breast milk and may affect your baby.

Do not use AFEME DUO if the expiry date (EXP) printed on the pack has passed.

Do not use AFEME DUO if the packaging shows signs of tampering; the capsule does not look quite right or the cream tube shows signs of tampering.

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 are allergic to any other medicines, foods, dyes or preservatives.

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

  • 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 AFEME 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 them before you start using AFEME DUO.

Using the AFEME DUO Clotrimazole Vaginal Cream component of AFEME 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

If you are taking cisapride (Prepulsid), astemizole, pimozidine or quinidine, do not use AFEME DUO.

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

  • warfarin (e.g. Marevan, Coumadin), a medicine used to prevent blood clots
  • phenytoin (e.g. Dilantin), a medicine used to treat epilepsy
  • ciclosporin (eg. Neoral) or tacrolimus (e.g. 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 (e.g. Daonil, Glimel), glipizide (e.g. Minidiab, Melizide), glimepiride (e.g. Amaryl), gliclazide (e.g. Diamicron, Glyade) pioglitazone (e.g. Actos), rosiglitazone (e.g. Avandia) rifampicin (e.g. Rifadin, Rimycin) or rifabutin (e.g. Mycobutin), antibiotics used to treat infections
  • theophylline (e.g. Nuelin), a medicine used to treat asthma
  • midazolam (e.g. Hypnovel) and triazolam (e.g. Halcion), medicines used as sedatives or to treat anxiety
  • zidovudine (e.g. Retrovir), a medicine used to treat AIDS
  • hydrochlorothiazide (e.g. Dithiazide), a medicine used for treating fluid problems and high blood pressure
  • the contraceptive pill (birth control pill)
  • amphotericin B (amphotericin) (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
  • terfenadine, an antihistamine.

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

If you are not sure whether you are taking any of these medicines, check with your doctor or pharmacist. Your doctor and pharmacist have more information on medicines to be careful with or avoid while using AFEME DUO.

How to use AFEME 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.

AFEME DUO is not recommended for children under 18 years of age.

If you use too much AFEME DUO (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 you or anyone else may have used too much AFEME DUO. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

While you are using AFEME DUO

Things you must do

Before starting any new medicine, tell your doctor or pharmacist that you are using or have used AFEME DUO.

Tell all the doctors, dentists and pharmacists who are treating you that you are using or have used AFEME DUO.

Use effective contraception to prevent pregnancy while using AFEME DUO.

Immediately tell your doctor if you do become pregnant while using AFEME DUO.

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

Things you must not do

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

Do not give AFEME DUO 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 AFEME DUO. People with AIDS or a weak immune system 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 AFEME DUO.

AFEME DUO 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 this 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
  • headache
  • mild burning, stinging or irritation immediately after application
  • pruritis

The side effects listed above are common and usually mild.

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

  • unusual muscle stiffness causing poor control of movement
  • frequent infections such as fever, severe chills, sore throat or mouth ulcers
  • bleeding or bruising more easily than normal
  • 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
  • an irregular heartbeat or palpitations.

These side effects are serious and need medical attention.

Tell your doctor immediately or go to Accident and Emergency at the nearest hospital if you notice any of the following:

  • signs of an allergic reaction such as skin rash, itching or hives;
  • swelling of the face, lips or tongue which may cause difficulty in swallowing or breathing;
  • wheezing or shortness of breath
  • severe blisters and bleeding of the lips, eyes, mouth, nose and genitals
  • a severe rash with skin peeling, fever, chills and aching muscles.

These side effects are rare, but very serious and require urgent medical attention or hospitalisation.

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 AFEME DUO

Storage

Keep AFEME DUO 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 your medicine in a cool dry place where the temperature stays below 25°C.

Do not store AFEME DUO or any other medicine in the bathroom or near a sink.

Do not leave your medicine in the car or on windowsills. Heat and dampness can destroy some medicines.

Disposal

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

Product description

What AFEME DUO looks like

AFEME DUO contains two components:

AFEME DUO Fluconazole 1 capsule is a hard gelatin capsule with sky blue opaque body and cap.
Each pack contains 1 capsule.

AFEME DUO Clotrimazole Vaginal Cream is a tube with a screw-cap containing 10 g of a white cream.

Ingredients

The active ingredient in the AFEME DUO Fluconazole capsule is fluconazole 150 mg.

Each capsule also contains the following inactive ingredients:

  • gelatin
  • lactose monohydrate
  • maize starch
  • colloidal anhydrous silica
  • sodium lauryl sulfate
  • titanium dioxide
  • purified talc
  • patent blue V

The capsule contains sugars (as lactose) and traces of sulfites.

The active ingredient in AFEME DUO Clotrimazole Vaginal Cream is 10 mg clotrimazole per gram of cream as the active ingredient.

The cream also contains:

  • propylene glycol
  • cetostearyl alcohol
  • disodium edetate
  • cetomacrogol 1000
  • liquid paraffin
  • dimeticone 100
  • white soft paraffin
  • self-emulsifying glyceryl monostearate
  • benzyl alcohol
  • purified water

The cream contains benzyl alcohol 1% w/w as preservative.

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

Supplier

AFEME DUO is supplied in Australia by:

Alphapharm Pty Limited
Level 1, 30 The Bond
30 - 34 Hickson Road
Millers Point NSW 2000
www.mylan.com.au

Australian registration number:
AUST R 231084

This leaflet was prepared in January 2020.

Afeme Duo_cmi\Jan20/00

Published by MIMS March 2020

BRAND INFORMATION

Brand name

Afeme Duo

Active ingredient

Fluconazole; Clotrimazole

Schedule

S3

 

1 Name of Medicine

Fluconazole, clotrimazole.

6.7 Physicochemical Properties

Fluconazole is a bis-triazole antifungal it is a white to off-white crystalline powder, which is sparingly soluble in water and saline.
Clotrimazole is a white to pale yellow crystalline powder, practically insoluble in water, soluble in choroform and ethanol.

Fluconazole.

Chemical name: 2-(2,4-difluorophenyl)-1,3-bis (1H-1,2,4-triazol-1-yl)-2-propanol. Molecular formula: C13H12F2N6O. Molecular weight: 306.3.

Clotrimazole.

Chemical name: 1-(0-chloro-α, α-diphenylbenzyl) imidazole. Molecular formula: C22H17ClN2. Molecular weight: 344.84.

Chemical structure.


CAS number.

Fluconazole: 86386-73-4.
Clotrimazole: 23593-75-1.

2 Qualitative and Quantitative Composition

Fluconazole capsule.

The capsule contains the following active ingredient: fluconazole 150 mg.
The capsule contains sugars (as lactose) and traces of sulfites.

Clotrimazole cream.

The cream contains the following active ingredient: clotrimazole 10 mg/g.
The cream contains benzyl alcohol 1% w/w as preservative.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Fluconazole capsule.

Sky blue gelatin capsule.

Clotrimazole vaginal cream.

White, smooth semi-solid cream.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Fluconazole.

Fluconazole is a member of the bis-triazole class of antifungal agents. Fluconazole is a highly selective inhibitor of fungal cytochrome P-450 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. Fluconazole 50 mg daily given up to 28 days has been shown not to affect corticosteroid levels or 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.

Clotrimazole.

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 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.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Fluconazole.

Adults: The pharmacokinetic properties of fluconazole are similar following administration by 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 1 and 2 hours post dose with a terminal plasma elimination half-life of approximately 30 hours (range 20-50 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 level achieved with single doses. The apparent volume of distribution approximates to total body water. Plasma protein binding is low (11-12%). Fluconazole has been found to achieve good penetration into all tissues and body fluids studies. 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 is markedly affected by reduction in renal function. There is an inverse relationship between the elimination half-life and creatinine clearance. The long plasma elimination half-life provides the basis for a single dose therapy for vaginal candidiasis, once daily and once week-if required.

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.

Actions microbiology.

Fluconazole.

Fluconazole administered orally or intravenously was active in a variety of animal models of fungal infections using standard laboratory stains of fungi. Fluconazole exhibits in vitro activity against Candida spp. Activity has been demonstrated in vivo in normal and immunocompromised animals against infections with Candida spp, including systemic candidiasis. One case of cross-resistance of Candida to fluconazole in a patient (non-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.

Clotrimazole.

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.

5.3 Preclinical Safety Data

Genotoxicity.

See Section 4.4 Special Warnings and Precautions for Use.

Carcinogenicity.

See Section 4.4 Special Warnings and Precautions for Use.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of vaginal and vulvovaginal candidiasis.

4.3 Contraindications

Known sensitivity to fluconazole, clotrimazole, related azole compounds or to any of its excipients of fluconazole capsule or clotrimazole vaginal cream. Concomitant administration with cisapride is contraindicated (see Section 4.4 Special Warnings and Precautions for Use).
Coadministration of other drugs known to prolong the QT interval and which are metabolised via the enzyme CYP3A4 such as cisapride, astemizole, erythromycin, pimozide and quinidine are contraindicated (see Section 4.4 Special Warnings and Precautions for Use). 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 (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

In rare cases, as with other azoles, anaphylaxis has been reported.
Fluconazole has been associated with rare cases of serious hepatic toxicity including fatalities, primarily in patients with serious underlying medical conditions. In cases of fluconazole-associated hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, sex or age of patient has been observed. Afeme Duo should not be used again if clinical signs and symptoms consistent with liver disease develop that may be attributable to fluconazole (see Section 4.8 Adverse Effects (Undesirable Effects)).
Patients have rarely developed exfoliative cutaneous reactions, such as Stevens-Johnson Syndrome and toxic epidermal necrolysis, during treatment with fluconazole.
AIDS patients are more prone to the development of serious cutaneous reactions to many drugs. If rash which is attributable to fluconazole develops in a patient treated for a superficial fungal infection, fluconazole should not be used again. Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During post-marketing surveillance, there have been very rare cases of QT prolongation and torsade de pointes in patients taking fluconazole. These reports included seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities and concomitant medications that may have been contributory (see Section 4.8 Adverse Effects (Undesirable Effects)).
Fluconazole should be administered with caution to patients with these potentially proarrhythmic conditions (see Section 4.8 Adverse Effects (Undesirable Effects)).
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 (see Section 4.8 Adverse Effects (Undesirable Effects)).
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 Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
If evidence of local intolerance develops when using the cream, consider withdrawal of the medicine and institution of appropriate therapy.
Use of clotrimazole vaginal cream may reduce the effectiveness and safety of latex products, e.g. condoms and diaphragms. This effect is temporary and occurs only during treatment. Clotrimazole vaginal cream is not intended for ophthalmic use.

Use in the elderly.

No data available.

Paediatric use.

No data available.

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 2-7 x 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 4 strains of Salmonella typhimurium and in mouse lymphoma system. Cytogenetic studies in vivo and in vitro showed no evidence of chromosomal mutations.
Clotrimazole vaginal cream has shown no observed carcinogenicity or mutagenicity in animal studies.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

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 fluconazole.
Fluconazole is an inhibitor of the cytochrome P450 system, particularly the CYP2C and to a lesser extent the CYP3A isoforms. There are possibilities that other drugs may affect the metabolism of fluconazole and that fluconazole may affect the metabolism of other drugs. In vitro studies conducted in human hepatic microsomes demonstrate that the extent of inhibition of CYP3A isoforms is lowest with fluconazole, when compared with ketoconazole and itraconazole.

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. An effect of this magnitude should not necessitate a change in the fluconazole dose regimen in subjects receiving diuretics, although the prescriber should bear it in mind.

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.

Cisapride.

Cardiac events including torsades de pointes have been reported in patients receiving fluconazole and cisapride concomitantly. A controlled study found that concomitant fluconazole 200 mg once daily and cisapride four times a day yielded a significant increase in cisapride plasma levels and prolongation of QTc interval.
Coadministration of cisapride is contraindicated in patients receiving fluconazole (see Section 4.3 Contraindications).

Ciclosporin.

A pharmacokinetic study in renal transplant patients found fluconazole 200 mg daily slowly increased ciclosporin concentrations. However, in another multiple dose study with 100 mg daily, fluconazole did not affect ciclosporin levels in patients with bone marrow transplants. Ciclosporin plasma concentration monitoring in patients, with or without impaired renal function, receiving fluconazole is recommended.

Oral contraceptives.

Fluconazole at a dose of 50 mg for ten days decreased the AUC for ethinylestradiol by 16%, but values for levonorgestrel were unchanged.

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. 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. The possibility of a hypoglycaemic episode should be borne in mind.

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.

Non-steroidal anti-inflammatory drugs (NSAIDs).

The Cmax and AUC of flurbiprofen were increased by 23% and 81%, respectively, when coadministered with fluconazole compared to administration of flurbiprofen alone. Similarly, the Cmax and AUC of the pharmacologically active isomer [S-(+)-ibuprofen] were increased by 15% and 82%, respectively, when fluconazole was administered with racemic ibuprofen (400 mg) compared to administration of racemic ibuprofen alone. Although not specifically studied, fluconazole has the potential to increase the systemic exposure of other NSAIDs that are metabolised by CYP2C9 (e.g. naproxen, lornoxicam, meloxicam, diclofenac). Frequent monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of NSAID dosage may be needed.

Short acting benzodiazepines.

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.

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 coadministered. 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 coadministered. 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 and therapy 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.

The AUC of zidovudine significantly increased (74%) during coadministration with fluconazole. Patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions.

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.

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 (amphotericin).

Concurrent administration of fluconazole and amphotericin B (amphotericin) 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.

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 Section 4.3 Contraindications).

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%.

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.

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.

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.

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.

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-31 74) 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.

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 Section 4.3 Contraindications).

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.

Quinidine.

Although not studied in vitro or in vivo, concomitant administration of fluconazole with quinidine may result in inhibition of quinidine metabolism. Use of quinidine has been associated with QT prolongation and rare occurrences of torsades de pointes. Coadministration of fluconazole and quinidine is contraindicated (see Section 4.3 Contraindications).

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.

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 Section 4.3 Contraindications).

Tofacitinib.

Exposure is increased when tofacitinib is coadministered with medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19.

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.

Voriconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor).

Concurrent administration of oral voriconazole (400 mg Q12h for 1 day, then 200 mg Q12h for 2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg Q24h for 4 days) to 6 healthy male subjects resulted in an increase in C, and AUC, of voriconazole by an average of 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. In a follow-on clinical study involving 8 healthy male subjects, reduced dosing and/or frequency of voriconazole and fluconazole did not eliminate or diminish this effect. Concomitant administration of voriconazole and fluconazole at any dose is not recommended.

Other.

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

4.6 Fertility, Pregnancy and Lactation

Effects 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 p.o. 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 mg/kg 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 the dose levels. The effects of parturition in rats are consistent with the species specific oestrogen-lowering properties produced by high doses of fluconazole. Such a hormone change has not been observed in women treated with fluconazole (see Section 5.1 Pharmacodynamic Properties).
(Category D)
Australian categorization definition of Category D: Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human foetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.
There have been reports of spontaneous abortion and congenital abnormalities in infants whose mothers were treated with 150 mg of fluconazole as a single or repeated dose in the first trimester.
There are no adequate and well-controlled studies in pregnant women. There have been reports of multiple congenital abnormalities in infants whose mothers were being treated for 3 or more months with high dose (400 to 800 mg/day) fluconazole therapy 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.
Fluconazole should not be used in women who are pregnant, or in women of childbearing potential unless adequate contraception is employed. Effective contraceptive measures should continue throughout the treatment period and for approximately 1 week (5 to 6 half-lives) after the final dose.
Controlled clinical studies for clotrimazole vaginal 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.
 Fluconazole has been found in human breast milk at concentrations similar to plasma. Systemic absorption of clotrimazole following topical or vaginal administration is low, however there is no information on whether or not clotrimazole is excreted in breast milk. Hence, the use of Afeme Duo in breast-feeding women is not recommended.

4.8 Adverse Effects (Undesirable Effects)

Fluconazole and clotrimazole are generally well tolerated.

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

Nervous system.

Headache.

Gastrointestinal.

Nausea, abdominal pain, diarrhoea, dyspepsia.

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

Dermatological.

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

Nervous system.

Dizziness, flushing, dry mouth, vertigo, hyperkinesia, hypertonia, taste perversion.

Gastrointestinal.

Constipation, anorexia, flatulence, vomiting, loose stools.

Metabolic.

Thirst.

Psychiatric.

Insomnia, nervousness, female sexual dysfunction.

Reproductive.

Intermenstrual bleeding, dysmenorrhoea, leucorrhoea, menorrhagia, uterine spasm, vaginal disorder.

Respiratory.

Pharyngitis.

Special senses.

Abnormal vision, visual field defect.

Urinary.

Polyuria, renal pain.

General.

Fatigue, hot flushes, malaise, back pain, herpes simplex, pain, rigors.
The following adverse events have occurred during experience with overall fluconazole use.

Blood and lymphatic system.

Leucopenia including neutropenia and agranulocytosis, thrombocytopenia.

Cardiovascular.

QT prolongation, torsade de pointes (see Section 4.4 Special Warnings and Precautions for Use).

Nervous system.

Seizures.

Immune system disorders.

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

Metabolic.

Hypercholesterolaemia, hypertriglyceridaemia and hypokalaemia.

Hepatobiliary disorders.

Hepatic failure, hepatitis, hepatocellular necrosis, jaundice.

Skin and subcutaneous tissue disorders.

Alopecia, exfoliative skin disorders including Steven-Johnson syndrome and toxic epidermal necrolysis.
Clotrimazole vaginal cream is generally well tolerated after local application. The following have been reported infrequently: erythema, stinging, blistering, peeling, oedema, pruritus, urticaria and general irritation.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Adults 18 years and over.

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 or three times daily until symptoms clear.
Afeme Duo is not recommended for use in children under 18 years.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.9 Overdose

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 8,200 mg of fluconazole. The patient was admitted to hospital, and his condition resolved within 48 hours. There have been no reports of overdosage with clotrimazole vaginal cream.

Treatment.

In the event of overdosage, symptomatic treatment (with supportive measures) should be undertaken. 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%.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S3.

6 Pharmaceutical Particulars

6.1 List of Excipients

Fluconazole capsule contains the following excipients.

Lactose monohydrate, maize starch, colloidal anhydrous silica, purified talc and sodium lauryl sulfate, gelatin, titanium dioxide, patent blue V.

Clotrimazole cream contains the following excipients.

propylene glycol, disodium edetate, cetomacrogol 1000, cetostearyl alcohol, liquid paraffin, dimeticone 100, white soft paraffin, self-emulsifying glyceryl monostearate, benzyl alcohol and purified water.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Afeme Duo fluconazole 150 mg capsule blister pack and clotrimazole 10 mg/g cream tube composite pack.
Fluconazole capsule: Capsule, fluconazole 150 mg (sky blue gelatin capsule). 1 capsule.
Clotrimazole vaginal cream: Cream, clotrimazole 10 mg/g (1%). 10 g tube.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking it to your local pharmacy.

Summary Table of Changes