Consumer medicine information

APOHealth Thrush Treatment Duo

Fluconazole; Clotrimazole

BRAND INFORMATION

Brand name

APOHealth Thrush Treatment Duo

Active ingredient

Fluconazole; Clotrimazole

Schedule

S3

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APOHealth Thrush Treatment Duo.

SUMMARY CMI

APOHEALTH THRUSH TREATMENT DUO

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

1. Why am I using this medicine?

APOHEALTH THRUSH TREATMENT DUO contains two components: APOHEALTH Fluconazole One capsule is an oral capsule which contains the active ingredient fluconazole. APOHEALTH Clotrimazole Cream contains the active ingredient clotrimazole, both ingredients belong to a group of medicines called azole antifungals.

For more information, see Section 1. Why am I using this medicine? in the full CMI.

2. What should I know before I use this medicine?

Do not use if you have ever had an allergic reaction to Fluconazole or clotrimazole or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use this medicine? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with this medicine and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use this medicine?

  • For vaginal thrush in adults, only a single dose (1 capsule) is needed.
  • Swallow the capsule whole with a glass of water. The capsule can be taken with or without food.
  • Use the cream on the external irritated area 2-3 times a day to relieve the symptoms for as long as they last, usually not more than 3 days.
  • Do not give APOHEALTH THRUSH TREATMENT DUO to children under 18 years of age except under doctor supervision.

More instructions can be found in Section 4. How do I use this medicine? in the full CMI.

5. What should I know while using this medicine?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using APOHEALTH THRUSH TREATMENT DUO.
  • Use effective contraception to prevent pregnancy while using APOHEALTH THRUSH TREATMENT DUO.
  • Immediately tell your doctor if you do become pregnant while using APOHEALTH THRUSH TREATMENT DUO.
Things you should not do
  • Do not use APOHEALTH THRUSH TREATMENT DUO to treat any other conditions unless your doctor or pharmacist tells you to.
  • Do not give APOHEALTH THRUSH TREATMENT DUO to anyone else, even if they have the same condition as you.
Looking after your medicine
  • Store it in a cool dry place away from moisture, heat or sunlight where the temperature stays below 25°C.

For more information, see Section 5. What should I know while using this medicine? in the full CMI.

6. Are there any side effects?

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using APOHEALTH THRUSH TREATMENT DUO. APOHEALTH THRUSH TREATMENT DUO helps most people and is generally well tolerated. However, it may have unwanted side effects in some people.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

APOHEALTH THRUSH TREATMENT DUO

Active ingredient(s): Fluconazole & Clotrimazole

Consumer Medicine Information (CMI)

This leaflet provides important information about using this medicine. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using this medicine.

Where to find information in this leaflet:

1. Why am I using this medicine?
2. What should I know before I use this medicine?
3. What if I am taking other medicines?
4. How do I use this medicine?
5. What should I know while using this medicine?
6. Are there any side effects?
7. Product details

1. Why am I using this medicine?

APOHEALTH THRUSH TREATMENT 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.

APOHEALTH THRUSH TREATMENT DUO contains two components: APOHEALTH Fluconazole One capsule is an oral capsule which contains the active ingredient fluconazole.

APOHEALTH Clotrimazole Cream contains the active ingredient clotrimazole, both ingredients belong to a group of medicines called azole antifungals.

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

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

APOHEALTH THRUSH TREATMENT DUO is not recommended for children under 18 years of age except under doctor supervision.

There is no evidence that either component in APOHEALTH THRUSH TREATMENT DUO is addictive.

APOHEALTH THRUSH TREATMENT 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.

2. What should I know before I use this medicine?

Warnings

Do not use this medicine if:

  • you are allergic to fluconazole, clotrimazole, other azole antifungals such as miconazole, ketoconazole, itraconazole, econazole or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.

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 APOHEALTH THRUSH TREATMENT DUO if you are taking cisapride (Prepulsid), a medicine used to treat stomach problems. Combining APOHEALTH THRUSH TREATMENT DUO with cisapride may cause serious side effects such as an abnormal heart rhythm.

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

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

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

Do not use APOHEALTH THRUSH TREATMENT 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.

Check with your doctor if you:

  • are allergic to any other medicines, foods, dyes or preservatives.
  • take any medicines for any other condition

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 APOHEALTH THRUSH TREATMENT DUO if you are taking warfarin (e.g. 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 APOHEALTH THRUSH TREATMENT DUO

Using the APOHEALTH Clotrimazole Cream component of APOHEALTH THRUSH TREATMENT DUO may reduce the effectiveness and safety of latex products, such as condoms and diaphragms. This effect is temporary and occurs only during treatment.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

3. What if I am taking other medicines?

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

If you are taking cisapride (Prepulsid), a medicine used to treat stomach problems, do not use APOHEALTH THRUSH TREATMENT DUO.

Some medicines may interfere with this medicine and affect how it works.

  • warfarin (e.g. Marevan, Coumadin), a medicine used to prevent blood clots
  • phenytoin (e.g. Dilantin), a medicine used to treat epilepsy
  • cyclosporin (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 used 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).

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

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect this medicine.

4. How do I use this medicine?

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.

How to use

  • For vaginal thrush in adults, only a single dose (1 capsule) is needed.
  • Swallow the capsule whole with a glass of water. The capsule can be taken with or without food.
  • Use the cream on the external irritated area 2-3 times a day to relieve the symptoms for as long as they last, usually not more than 3 days.
  • Do not give APOHEALTH THRUSH TREATMENT DUO to children under 18 years of age except under doctor supervision.
  • Follow the instructions provided and use this medicine until your doctor tells you to stop.

If you forget to use this medicine

this medicine should be used regularly at the same time each day, week or month.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose you missed.

If you use too much this medicine

If you think that you have used too much this medicine, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26 - Aust. or 0800 764 766 - N.Z.), or
  • contact your doctor, or
  • go to the Accident and Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using this medicine?

Things you should do

Call your doctor straight away if you:

  • Before starting any new medicine, tell your doctor or pharmacist that you are using or have used APOHEALTH THRUSH TREATMENT DUO.
  • Tell all the doctors, dentists and pharmacists who are treating you that you are using or have used APOHEALTH THRUSH TREATMENT DUO.
  • Use effective contraception to prevent pregnancy while using APOHEALTH THRUSH TREATMENT DUO.
  • Immediately tell your doctor if you do become pregnant while using APOHEALTH THRUSH TREATMENT DUO.
  • If your symptoms do not improve after 3 days, tell your doctor or pharmacist.

Remind any doctor, dentist or pharmacist you visit that you are using this medicine.

Things you should not do

  • Do not use APOHEALTH THRUSH TREATMENT DUO to treat any other conditions unless your doctor or pharmacist tells you to.
  • Do not give APOHEALTH THRUSH TREATMENT 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 APOHEALTH THRUSH TREATMENT DUO. People with AIDS or a weak immune system may be more prone to serious side effects of the skin..

Looking after your medicine

Keep APOHEALTH THRUSH TREATMENT 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.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight where the temperature stays below 25°C; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.
  • Heat and dampness can destroy some medicines.

Keep it where young children cannot reach it.

When to discard your medicine (as relevant)

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

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

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

APOHEALTH THRUSH TREATMENT 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. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
  • nausea (feeling sick), vomiting
  • stomach pain, indigestion
  • diarrhoea
  • headache
  • mild burning, stinging or irritation immediately after application
  • pruritis
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • 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.
Call your doctor straight away or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Very Serious side effects

Very Serious side effectsWhat to do
  • 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.
Call your doctor straight away or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.
These side effects are rare, but very serious and require urgent medical attention or hospitalization.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What this medicine contains

APOHEALTH Fluconazole One capsule
Active ingredient
(main ingredient)		One 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
Potential allergensOne capsule also contains sugars (as lactose) and sulfites (from gelatin).
APOHEALTH Clotrimazole Cream
Active ingredient
(main ingredient)		10 mg clotrimazole per gram of cream as the active ingredient.
Other ingredients
(inactive ingredients)
  • Propylene glycol
  • Cetostearyl alcohol
  • Disodium edetate
  • Cetomacrogol 1000
  • Liquid paraffin
  • Dimethicone 100
  • White soft paraffin
  • Self-emulsifying glyceryl monostearate
  • Benzyl alcohol
  • Purified water
Potential allergensThis medicine does not contain sucrose, gluten, tartrazine or any other azo dyes.

Do not take this medicine if you are allergic to any of these ingredients.

What this medicine looks like

APOHEALTH THRUSH TREATMENT DUO contains two components:

  • APOHEALTH Fluconazole One capsule is a hard gelatin capsule with sky blue opaque body and cap. Each pack contains 1 capsule.
  • APOHEALTH Clotrimazole Cream is a tube with a screwcap containing 10 g of a white cream.

APOHEALTH THRUSH TREATMENT DUO - AUST R 229520

Who distributes this medicine

Arrotex Pharmaceuticals Pty Ltd
15-17 Chapel Street
Cremorne VIC 3121

This leaflet was prepared in September 2024.

Published by MIMS October 2024

BRAND INFORMATION

Brand name

APOHealth Thrush Treatment Duo

Active ingredient

Fluconazole; Clotrimazole

Schedule

S3

 

1 Name of Medicine

Fluconazole, clotrimazole.

2 Qualitative and Quantitative Composition

The capsule contains 150 mg fluconazole and the cream contains clotrimazole 10 mg/g.

Excipients with known effect.

The capsule contains sugars (as lactose) and sulfites.
The cream contains benzyl alcohol as the preservative.
For the full list of excipients see Section 6.1 List of Excipients.

3 Pharmaceutical Form

APOHealth Thrush Treatment Duo.

APOHealth Fluconazole One.

Capsule, fluconazole 150 mg (sky blue gelatin capsule).

APOHealth Clotrimazole cream.

Cream, clotrimazole 10 mg/g (1%).

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of vaginal and vulvovaginal candidiasis.

4.2 Dose and Method of Administration

Capsule.

Adults.

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.

4.3 Contraindications

Known sensitivity to fluconazole, clotrimazole, related azole compounds or to any of its excipients of APOHealth Fluconazole One capsule or APOHealth Clotrimazole cream.
Co-administration of terfenadine is contraindicated in patients receiving fluconazole at multiple doses of 400 mg/day or higher based upon results of a multiple dose interaction study.
Co-administration 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 in patients receiving fluconazole (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

Anaphylaxis has been reported in rare instances.
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. If patients with invasive/systemic fungal infections develop rashes, they should be monitored closely and fluconazole discontinued if bullous lesions or erythema develop (see Section 4.8 Adverse Effects (Undesirable Effects)).
Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. Fluconazole causes QT prolongation via the inhibition of Rectifier Potassium Channel current. The QT prolongation caused by other medicinal products (such as amiodarone) maybe amplified via the inhibition of cytochrome P450 (CYP3A4) (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). 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. Patients with hypokalaemia and advanced cardiac failure are at an increased risk for the occurrence of life-threatening ventricular arrhythmias and torsades de pointes. Fluconazole should be administered with caution to patients with these potentially proarrhythmic conditions (see Section 4.8 Adverse Effects (Undesirable Effects)).
Fluconazole is a potent CYP2C9 and CYP2C19 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole treated patients who are concomitantly treated with drugs with a narrow therapeutic window metabolised through CYP2C9, CYP2C19 and CYP3A4 should be monitored (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Adrenal insufficiency has been reported in patients receiving other azoles (e.g. ketoconazole).
Cases of adrenal insufficiency were reported in patients receiving fluconazole.
The capsules contain lactose and should not be given to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.
If evidence of local intolerance develops when using the cream, consider withdrawal of the medicine and institution of appropriate therapy.
Use of clotrimazole cream may reduce the effectiveness and safety of latex products, e.g. condoms and diaphragms. This effect is temporary and occurs only during treatment. Clotrimazole cream is not intended for ophthalmic use.

Use in hepatic impairment.

Fluconazole should be administered with caution to patients with liver dysfunction.
Fluconazole has been associated with rare cases of serious hepatic toxicity including fatalities, primarily in patients with serious underlying medical conditions. In cases of fluconazole-associated hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, sex or age of 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. Thrush treatment 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)).

Use in renal impairment.

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

Use in the elderly.

No data available.

Paediatric use.

Fluconazole is not recommended for use in children under 18 years of age except under medical advice.

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 APOHealth Fluconazole One.
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. 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.
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. 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.
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.

Azithromycin.

An open-label, randomized, three-way crossover 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. There was no significant pharmacokinetic interaction between fluconazole and azithromycin.

Effects of fluconazole on other medicinal products.

Fluconazole is a potent inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and 2C19 and a moderate inhibitor of CYP3A4. In addition to the observed/ documented interactions mentioned below, there is a risk of increased plasma concentration of other compounds metabolized by CYP2C9, CYP2C19 and CYP3A4 co-administered with fluconazole. Therefore caution should be exercised when using these combinations and the patients should be carefully monitored. The enzyme inhibiting effect of fluconazole persists 4 to 5 days after discontinuation of fluconazole treatment due to the long half-life of fluconazole (see Section 4.3 Contraindications).

Alfentanil.

A study observed a reduction in clearance and distribution volume as well as prolongation of T1/2 of alfentanil following concomitant treatment with fluconazole. A possible mechanism of action is fluconazole's inhibition of CYP3A4. Dosage adjustment of alfentanil may be necessary.

Amitriptyline, nortriptyline.

Fluconazole increases the effect of amitriptyline and nortriptyline. 5-nortriptyline and/or S-amitriptyline may be measured at initiation of the combination therapy and after one week. Dosage of amitriptyline/nortriptyline should be adjusted, if necessary.

Amphotericin B.

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

Concomitant use of the following agents with fluconazole is contraindicated.

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).

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 coadministration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored (see Section 4.3 Contraindications).

Astemizole.

Concomitant administration of fluconazole with astemizole may decrease the clearance of astemizole. Resulting increased plasma concentrations of astemizole can lead to QT prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and astemizole is contraindicated (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

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 4.5 Interactions with Other Medicines and Other Forms of Interactions).

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 torsade de pointes.
Coadministration of fluconazole and quinidine is contraindicated.

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. Coadministration of fluconazole and erythromycin is contraindicated (see Section 4.3 Contraindications).

Concomitant use that should be used with caution.

Amiodarone.

Concomitant administration of fluconazole with amiodarone may increase QT prolongation. Caution must be exercised if the concomitant use of fluconazole and amiodarone is necessary, notably with high-dose fluconazole (800 mg).

Anticoagulants.

Careful monitoring of prothrombin time in patients receiving fluconazole and indanedione anticoagulants is recommended.

Oral contraceptives.

Fluconazole at a dose of 50 mg for ten days decreased the AUC for ethinyloestradiol by 16%, but values for levonorgestrel were unchanged.
Interaction of fluconazole with the following agents may result in increased exposure to these drugs. Careful monitoring and/or dosage adjustment should be considered.

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 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.
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.

Calcium channel blockers.

Certain calcium channel antagonists (nifedipine, isradipine, amlodipine, verapamil and felodipine) are metabolised by CYP3A4. Fluconazole has the potential to increase the systemic exposure of the calcium channel antagonists. Frequent monitoring for adverse events is recommended.

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.

Celecoxib.

During concomitant treatment with fluconazole (200 mg daily) and celecoxib (200 mg) the celecoxib Cmax and AUC increased by 68% and 134%, respectively. Half of the celecoxib dose may be necessary when combined with fluconazole.

Cyclosporin.

A pharmacokinetic 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 monitoring in patients, with or without impaired renal function, receiving fluconazole is recommended.

Cyclophosphamide.

Combination therapy with cyclophosphamide and fluconazole results in an increase in serum bilirubin and serum creatinine. The combination may be used while taking increased consideration to the risk of increased serum bilirubin and serum creatinine.

Fentanyl.

One fatal case of possible fentanyl fluconazole interaction was reported. The author judged that the patient died from fentanyl intoxication. Furthermore, in a randomised 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. HMG-CoA reductase inhibitors should be discontinued if a marked increase in creatinine kinase is observed or myopathy/rhabdomyolysis is diagnosed or suspected.

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.

Non-steroidal anti-inflammatory drugs.

Although not specifically studied, fluconazole has the potential to increase the systemic exposure of other NSAIDs that are metabolized by CYP2C9 (e.g. naproxen, lornoxicam, meloxicam, diclofenac). Frequent monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of dosage of NSAIDs may be needed.

Oral hypoglycaemic agents.

The effects of fluconazole on the pharmacokinetics of the sulfonylurea oral hypoglycaemic agents tolbutamide, glipizide part of this section, 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.

Prednisone.

There was a case report that a liver-transplanted patient treated with prednisone developed acute adrenal cortex insufficiency when a 3 month therapy with fluconazole was discontinued. The discontinuation of fluconazole presumably caused an enhanced CYP3A4 activity which led to increased metabolism of prednisone. Patients on long-term treatment with fluconazole and prednisone should be carefully monitored for adrenal cortex insufficiency when fluconazole is discontinued.

Rifabutin.

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

Saquinavir.

Fluconazole increases the AUC of saquinavir and decreases clearance of saquinavir due to inhibition of saquinavir's hepatic metabolism by CYP3A4 and inhibition of P-glycoprotein. Dosage adjustment of saquinavir may be necessary.

Sirolimus.

Fluconazole increases plasma concentrations of sirolimus presumably by inhibiting the metabolism of sirolimus via CYP3A4 and P-glycoprotein. This combination may be used with a dosage adjustment of sirolimus depending on the effect/concentration measurements.

Sulfonylureas.

Fluconazole has been shown to prolong the serum half-life of concomitantly administered oral sulfonylureas (e.g. chlorpropamide, glibenclamide, glipizide, tolbutamide) in healthy volunteers. Frequent monitoring of blood glucose and appropriate reduction of sulfonylurea dosage is recommended during coadministration.

Tacrolimus.

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.

Tofacitinib.

Exposure of tofacitinib is increased when tofacitinib is coadministered with medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g. fluconazole). Dosage adjustment of tofacitinib may be necessary.

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 all-trans-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).

Concomitant administration of voriconazole and fluconazole at any dose is not recommended.

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.

Guidance on the clinical management of drug interactions.

See Table 1.

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 APOHealth Clotrimazole cream.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category D)
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 (400-800 mg/day) fluconazole therapy for coccidiomycosis. The relationship between fluconazole use and these events is unclear.
Controlled clinical studies for APOHealth Clotrimazole cream in pregnant women do not exist, however, epidemiological investigations give no indication that harmful effects on the mother and child should be anticipated when used during pregnancy.
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.
APOHealth Thrush Treatment Duo 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.
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.
 Fluconazole has been found in human breast milk at concentrations similar to plasma, hence its use in nursing mothers is not recommended. Although systemic absorption of clotrimazole following topical or vaginal administration is low, caution should be exercised when clotrimazole is administered to breastfeeding mothers as there is no information on whether or not clotrimazole is excreted in breast milk. Hence, the use of APOHealth Thrush Treatment Duo in breastfeeding women is not recommended.

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.

4.8 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.

Hepatobiliary disorders.

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

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

Skin and subcutaneous skin disorders.

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

Nervous system.

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

Gastrointestinal.

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

Metabolism and nutrition disorders.

Anorexia.

Psychiatric.

Insomnia, nervousness.

Reproductive.

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

Eye disorders.

Abnormal vision.

Renal and urinary disorders.

Polyuria, renal pain.

Vascular disorders.

Flushing, hot flushes.

General disorders and administration site conditions.

Fatigue, malaise, pain, rigors, thirst, asthenia, fever.

Musculoskeletal and connective tissue disorders.

Back pain, myalgia.

Infections and infestations.

Pharyngitis, herpes simplex.

Hepatobiliary disorders.

Cholestasis, jaundice, bilirubin increased.

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

Hepatobiliary disorders.

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

Cardiac disorders.

Torsade de pointes, QT prolongation.

The following adverse events have occurred during experience with overall fluconazole use.

Blood and lymphatic system.

Leucopenia including neutropenia and agranulocytosis, thrombocytopenia.

Post-marketing experience.

Cardiac disorders.

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

Gastrointestinal disorders.

Dyspepsia, vomiting.

Nervous system disorders.

Seizures, dizziness.

Immune system disorders.

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

Metabolism and nutrition disorders.

Hypercholesterolaemia, hypertriglyceridaemia and hypokalaemia.

Hepatobiliary disorders.

Hepatic failure, hepatitis, hepatocellular necrosis, jaundice.

Skin and subcutaneous tissue disorders.

Alopecia, exfoliative skin disorders including Stevens-Johnson syndrome and toxic epidermal necrolysis, drug reactions with eosinophilia and systemic symptoms (DRESS).
APOHealth Clotrimazole cream is generally well tolerated after local application. The following have been reported infrequently: erythema, stinging, blistering, peeling, oedema, pruritus, urticaria and general irritation.

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 http://www.tga.gov.au/reporting-problems.

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 APOHealth Clotrimazole cream.

Treatment.

In the event of overdosage, symptomatic treatment (with supportive measures and gastric lavage if necessary) 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 Poison Information Centre on 131126 (Australia).

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 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. 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.
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 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.
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.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

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).

Clotrimazole.

Pharmacokinetic investigations after dermal application have shown that only a small amount of clotrimazole (< 2% of the dose) is absorbed.

Distribution.

Fluconazole.

Adults: 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 2.

Clotrimazole.

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.

Metabolism and excretion.

Fluconazole.

Adults: 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.

5.3 Preclinical Safety Data

Genotoxicity.

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. 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).
APOHealth Clotrimazole cream has shown no observed mutagenicity in animal studies.

Carcinogenicity.

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.
APOHealth Clotrimazole cream has shown no observed carcinogenicity in animal studies.

6 Pharmaceutical Particulars

6.1 List of Excipients

The capsule contains the following excipients: lactose monohydrate, maize starch, colloidal anhydrous silica, purified talc, sodium lauryl sulfate, gelatin, titanium dioxide, Patent blue V.
The 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, purified water.

6.2 Incompatibilities

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

APOHealth Fluconazole One.

Blister pack.

APOHealth Clotrimazole cream.

10 g tube.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Fluconazole.

Fluconazole is a bis-triazole antifungal it is a white to off-white crystalline powder, which is sparingly soluble in water and saline.
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.

Chemical structure.


CAS number.

86386-73-4.

Clotrimazole.

Clotrimazole is a white to pale yellow crystalline powder, practically insoluble in water, soluble in chloroform and ethanol.
Chemical name: 1-(0-chloro-α, α-diphenylbenzyl) imidazole. Molecular formula: C22H17ClN2. Molecular weight: 344.84.

Chemical structure.


CAS number.

23593-75-1.

7 Medicine Schedule (Poisons Standard)

S3 - Pharmacist only medicine.

Summary Table of Changes