Consumer medicine information

APO-Fluconazole One

Fluconazole

BRAND INFORMATION

Brand name

APO-Fluconazole One

Active ingredient

Fluconazole

Schedule

S3

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Fluconazole One.

What is in this leaflet

This leaflet answers some common questions about fluconazole. It does not contain all the available information. It does not take the place of talking to your pharmacist.

All medicines have risks and benefits. Your pharmacist has weighed the risks of you using this medicine against the benefits they expect it will have for you.

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

Keep this leaflet with the medicine. You may want to read it again.

What this medicine is used for

Fluconazole is used to treat a fungal infection known as vaginal thrush (vaginal candidiasis). Fluconazole belongs to a group of medicines known as azole antifungals.

Vaginal thrush is an infection caused by a yeast-like fungus called Candida. Candida is one of the many organisms that live in the vagina and its growth is normally balanced by your body's immune system. If this natural balancing is upset, Candida can multiply in the vagina to cause the symptoms of thrush.

How it works

Fluconazole works by preventing the growth of the fungi causing your infection.

Ask your pharmacist if you have any questions about why this medicine has been prescribed for you. Your pharmacist may have prescribed this medicine for another reason

This medicine is available without a doctor's prescription, but your pharmacist's advice is required.

This medicine is not addictive.

This medicine is not recommended for children under 18 years of age, except under doctor advice.

Before you take this medicine

When you must not take it

Do not take this medicine if you have an allergy to:

  • fluconazole
  • any other azole antifungals e.g. clotrimazole
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

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

Do not take this medicine if you are taking any of the following medicines:

  • terfenadine (only in patients receiving fluconazole at multiple doses of 400mg/day)
  • cisapride
  • astemizole
  • erythromycin
  • quinidine
  • pimozide
  • voriconazole

Do not take this medicine if you are pregnant or plan to become pregnant. Fluconazole may affect your developing baby if you take it during pregnancy. Your pharmacist will discuss with you the risks and benefits involved.

Do not use this medicine if you are a female of childbearing age unless you are using adequate contraception. Effective contraception should be taken during treatment and for about 1 week after the final dose.

Do not take this medicine if you are breast-feeding. Fluconazole may pass into breast milk and affect your baby.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

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

Before you start to take it

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

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

  • abnormal or irregular vaginal bleeding or blood-stained discharge
  • vulvar or vaginal sores, ulcers or blisters
  • lower abdominal pain or burning when passing urine
  • liver, kidney or heart problems
  • low potassium levels in the blood
  • adrenal problems
  • lactose, or galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption. This product contains lactose.

Tell your pharmacist if you are planning to have an operation. Some medicines used during anaesthetics may interact with fluconazole.

If you have not told your pharmacist about any of the above, tell them before you start taking this medicine.

Taking other medicines

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

Some medicines may interact with fluconazole. These include:

Medicines not to be taken with fluconazole:

  • astemizole, used for allergies
  • cisapride, used to treat stomach problems
  • quinidine, used to treat heart problems
  • erythromycin, an antibiotic
  • pimozide, used to treat mood disorders
  • voriconazole, an antifungal medicine

Medicines to be taken with care with fluconazole:

  • terfenadine (do not take this medicine if you are receiving fluconazole at multiple doses of 400mg/day)
  • amiodarone, used for heart problems
  • some medicines used to treat diabetes (e.g. glipizide, chlorpropamide, tolbutamide, glibenclamide, glimepiride, gliclazide, pioglitazone, rosiglitazone)
  • some antibiotics and antiviral drugs (e.g. erythromycin, amphotericin B, rifampicin. rifabutin, zidovudine, saquinavir)
  • some medicines used to suppress the immune system (e.g. ciclosporine, tacrolimus, sirolimus, prednisone)
  • some medicines used to treat cancer (e.g. cyclophosphamide, ibrutinib, olaparib, vincristine, vinblastine)
  • vitamin A
  • antidepressants (e.g. amitriptyline, nortriptyline)
  • warfarin or ticlopidine, used to stop blood clots
  • phenytoin and carbamazepine used to treat epilepsy
  • theophylline, used to treat asthma
  • medicines used during anaesthetics (e.g. alfentanyl, midazolam, fentanyl)
  • benzodiazepines (e.g. triazolam)
  • hydrochlorothiazide, used for treating fluid problems
  • medicines used to treat high blood pressure (e.g. losartan, amlodipine, felodipine)
  • medicines used to treat high cholesterol (e.g. simvastatin, fluvastatin, atorvastatin)
  • medicines to treat low levels of sodium in the blood (e.g. tolvaptan)
  • some medicines used for pain relief (e.g. methadone, celecoxib)
  • halofantrine, used to treat malaria
  • the contraceptive pill

Talk to your doctor or pharmacist about the need for an additional method of contraception while taking fluconazole.

If you are taking any of these, you may need a different dose, or you may need to take different medicines.

Other medicines not listed above may also interact with fluconazole.

How to take this medicine

Follow all directions given to you by your pharmacist carefully. They may differ to the information contained in this leaflet.

How much to take

A single dose of one capsule.

How to take it

Swallow the whole capsule with a glass of water.

When to take it

It does not matter whether you take this medicine with or without food.

If you take too much (overdose)

If you think that you or anyone else may have taken too much of this medicine, immediately telephone your doctor or the Poisons Information Centre (Tel: 13 11 26 in Australia) for advice. Alternatively go to the Accident and Emergency Department at your nearest hospital. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking this medicine

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you have taken this medicine.

Tell any other doctors, dentists and pharmacists who are treating you that you have taken this medicine.

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

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

Things you must not do

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

Do not take your medicine to treat any other complaint unless your doctor or pharmacist tells you to.

Things to be careful of

Tell your doctor or pharmacist immediately if you develop a rash soon after taking this medicine. People with AIDS or weak immune system may be more prone to serious side effects of the skin.

What you can do to avoid thrush in the future

  • avoid wearing synthetic underwear
  • wear loose-fitting cotton briefs, stockings
  • wash the area regularly, but do not wash and dry yourself harshly
  • avoid vaginal deodorants, perfumed soaps and bath additives

Ask your doctor or pharmacist for more information for things you can do to avoid thrush in the future.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking fluconazole.

This medicine helps most people with vaginal thrush, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not.

Do not be alarmed by the following lists of 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 or vomiting
  • stomach pain, indigestion, wind
  • diarrhoea
  • muscle or back pain
  • headache

The above list includes the more common side effects. Mostly, these are mild.

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

  • skin reactions or rash
  • 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)
  • yellowing of the skin or eyes (jaundice); dark urine, pale stools; loss of appetite; unusual tiredness (signs of liver disease)

The above list includes serious side effects. You may need medical attention. Most of these side effects are rare.

If you experience any of the following, contact your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin (signs of an allergic reaction)
  • fast, slow or irregular heart beat or palpitations and/or fainting.
  • severe blisters and bleeding of the lips, eyes, mouth, nose and genitals
  • a severe rash with skin peeling, fever, chills and aching muscles.

The above list includes very serious side effects that are usually very rare. You may need 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 occur in some patients.

Storage and disposal

Storage

Keep your medicine in its pack until it is time to take it. If you take your medicine out of its pack it may not keep well.

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

Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep this medicine where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If the medicine has passed its expiry date, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

Hard gelatine capsule of size '1' with sky blue body and cap.

Each pack contains 1 capsule.

AUST R 152959.

Ingredients

Each capsule contains 150 mg of fluconazole as the active ingredient.

It also contains the following:

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

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

This medicine contains sugars (as lactose) and sulfites.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113
Australia
Tel: +61 2 8877 8333
Web: www1.apotex.com/au

The APOTEX and APOHEALTH trademarks are used under licence.

This leaflet was updated in December 2020.

Published by MIMS March 2021

BRAND INFORMATION

Brand name

APO-Fluconazole One

Active ingredient

Fluconazole

Schedule

S3

 

1 Name of Medicine

Fluconazole.

2 Qualitative and Quantitative Composition

Each capsule contains 150 mg fluconazole, as its active ingredient.

Excipients with known effect.

Each capsule contains sugars (as lactose) and sulfites.
For the full list of excipients see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Fluconazole is available as a hard gelatin capsule of size '1' with sky blue body and cap.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of vaginal candidiasis.

4.2 Dose and Method of Administration

Fluconazole is intended for oral administration.

Adults.

One capsule (150 mg fluconazole) should be administered as a single oral dose.

Use in renal impairment.

Fluconazole is predominantly excreted in the urine as unchanged drug. No adjustments in single dose therapy are necessary in patients with minor or moderate renal impairment.

Children.

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

4.3 Contraindications

Known sensitivity to fluconazole; to related azole compounds or to any of the excipients of this product.
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).

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, 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 the Rectifier Potassium Channel current (Ikr). The QT prolongation caused by other medicinal products (such as amiodarone) may be amplified via the inhibition of cytochrome P450 (CYP) 3A4 (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). During postmarketing surveillance, there have been very rare cases of QT prolongation and torsades de pointes in patients taking fluconazole. These reports include 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.
These capsules contain lactose and should not be given to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

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. Fluconazole 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 adjustments in single dose therapy are necessary in elderly patients with minor to moderate renal impairment.

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 fluconazole.
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 other agents. These are described in greater detail below.

Concomitant use of the following agents with fluconazole is contraindicated.

Cisapride.

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

Effects of other medicinal products on fluconazole.

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

Hydrochlorothiazide.

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

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

Rifampicin.

Administration of a single oral dose of fluconazole 200 mg after chronic rifampicin administration resulted in a 25% decrease in AUC and a 20% shorter half-life of fluconazole in normal volunteers. Depending on clinical circumstances, an increase of the dose of fluconazole should be considered when it is administered with rifampicin.

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

Gastrointestinal drugs.

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

Effects of fluconazole on other medicinal products.

Fluconazole is a potent inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and a moderate inhibitor of CYP3A4. In addition to the observed/ documented interactions mentioned below, there is a risk of increased plasma concentration of other compounds metabolized by CYP2C9 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 4-5 days after discontinuation of fluconazole treatment due to the long half-life of fluconazole.

Alfentanil.

A study observed a reduction in clearance and distribution volume as well as prolongation of t1/2 of alfentanil following concomitant treatment with fluconazole. A possible mechanism of action is fluconazole's inhibition of CYP3A4. Dosage adjustment of alfentanil may be necessary.

Amitriptyline, nortriptyline.

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

Amphotericin B.

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

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 concentration and psychomotor effects following oral administration of midazolam 7.5 mg, but only modest increases that are not likely to be clinically significant following intravenous infusion of midazolam 0.05 mg/kg. This effect on midazolam appears to be more pronounced following oral administration of fluconazole than with fluconazole administered intravenously. If concomitant benzodiazepine therapy is necessary in patients being treated with fluconazole, consideration should be given to decreasing the benzodiazepine dosage, and monitoring the patient's response.
Fluconazole increases the AUC of triazolam (single dose) by approximately 50%, Cmax with 20-32% and increases the half-life by 25-50% due to the inhibition of metabolism of triazolam. Dosage adjustments of triazolam may be necessary.

Calcium channel blockers.

Certain 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.

Ciclosporin.

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

Cyclophosphamide.

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

Fentanyl.

One fatal case of possible fentanyl-fluconazole interaction was reported. The author judged that the patient died from fentanyl intoxication. Furthermore, in a 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.

Ibrutinib.

Moderate inhibitors of CYP3A4 such as fluconazole increase plasma ibrutinib concentrations and may increase risk of toxicity. If the combination cannot be avoided, reduce the dose of ibrutinib as instructed in ibrutinib prescribing information and provide close clinical monitoring.

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.

Nonsteroidal 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.

Olaparib.

Moderate inhibitors of CYP3A4 such as fluconazole increase olaparib plasma concentrations; concomitant use is not recommended. If the combination cannot be avoided, reduce the dose of olaparib as instructed in the Lynparza (olaparib) Prescribing Information.

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 of CYP2C8 and CYP2C9, it may also interact with other sulfonylureas (e.g. glimepiride and gliclazide) and the thiazolidinediones (e.g. pioglitazone and rosiglitazone), which are metabolised by these enzymes.
When fluconazole and sulfonylureas or thiazolidinediones are coadministered, blood glucose concentrations should be monitored carefully, and the dose of oral hypoglycaemic agent adjusted accordingly. The possibility of a hypoglycaemic episode should be borne in mind.

Phenytoin.

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

Prednisone.

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

Rifabutin.

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

Saquinavir.

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

Sirolimus.

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

Sulfonylureas.

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

Tacrolimus.

Fluconazole may increase the serum concentrations of orally administered tacrolimus up to 5 times due to inhibition of tacrolimus metabolism through CYP3A4 in the intestines. No significant pharmacokinetic changes have been observed when tacrolimus is given intravenously. Increased tacrolimus levels have been associated with nephrotoxicity. Dosage of orally administered tacrolimus should be decreased depending on tacrolimus concentration. 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 is increased when tofacitinib is coadministered with medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19.

Tolvaptan.

Exposure to tolvaptan is significantly increased (200% in AUC; 80% in Cmax) when tolvaptan, a CYP3A4 substrate, is co-administered with fluconazole, a moderate CYP3A4 inhibitor, with risk of significant increase in adverse effects particularly significant diuresis, dehydration and acute renal failure. In case of concomitant use, the tolvaptan dose should be reduced and the patient managed cautiously.

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.

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 of 13 subjects experienced a twofold increase in prothrombin time response. In postmarketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, haematuria and melaena) have been reported in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. Careful monitoring of prothrombin time in patients receiving fluconazole and coumarin type anticoagulants is recommended.

Zidovudine.

Fluconazole increases Cmax and AUC of zidovudine, respectively, due to decrease in oral zidovudine clearance. The half-life of zidovudine was likewise prolonged following combination therapy with fluconazole. Patients receiving this combination should be monitored for the development of zidovudine related adverse reactions. Dosage reduction of zidovudine may be considered.

Voriconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor).

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

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

Oral contraceptives.

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

Two way interactions.

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

Azithromycin.

An open label, randomised, three way crossover study in 18 healthy subjects assessed the effect of a single oral dose of azithromycin 1,200 mg on the pharmacokinetics of a single oral dose of fluconazole 800 mg as well as the effects of fluconazole on the pharmacokinetics of azithromycin. The estimated ratio of the mean AUC of fluconazole coadministered with azithromycin to fluconazole administered alone was 101%. The estimated ratio of the mean AUC of azithromycin coadministered with fluconazole to azithromycin administered alone was 107%. The estimated ratio of the mean Cmax of fluconazole coadministered with azithromycin to fluconazole administered alone was 104%. The estimated ratio of the mean Cmax of azithromycin coadministered with fluconazole to azithromycin administered alone was 82%. See Table 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.

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 these dose levels. The effects on parturition in rats are consistent with the species specific oestrogen lowering property produced by high doses of fluconazole. Such a hormone change has not been observed in women treated with fluconazole (see Section 5.1 Pharmacodynamic Properties).
(Category D)
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 (400-800 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.
Australian Categorisation 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.

4.7 Effects on Ability to Drive and Use Machines

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

4.8 Adverse Effects (Undesirable Effects)

Fluconazole is generally well tolerated. See Table 2.

Postmarketing experience.

In addition, the following adverse events have occurred during postmarketing.

Cardiac disorders.

Torsades de pointes (see Section 4.4 Special Warnings and Precautions for Use).

Gastrointestinal disorders.

Dyspepsia, vomiting.

Nervous system disorders.

Dizziness, seizures.

Immune system disorders.

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

Metabolism and nutrition disorders.

Hypercholesterolaemia, hypertriglyceridaemia and hypokalaemia.

Hepatobiliary disorders.

Hepatocellular necrosis, hepatic failure, hepatitis, jaundice.

Investigations.

QT prolongation (see Section 4.4 Special Warnings and Precautions for Use).

Skin and subcutaneous tissue disorders.

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

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

Symptoms.

The minimal lethal human dose has not been established. There have been plenty of reports of overdosage with fluconazole, and in one case, a 42-year old patient infected with human immunodeficiency virus 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.
Signs and symptoms are likely to be an extension of those under Section 4.8 (see Section 4.8 Adverse Effects (Undesirable Effects)).

Treatment.

There is no specific antidote. Treatment is symptomatic and supportive, including respiratory and cardiovascular function. Monitor for hypokalaemia and elevated liver enzymes; and obtain a full blood count to monitor for possible thrombocytopenia and agranulocytosis.
Fluconazole is largely excreted in the urine; forced volume diuresis would probably increase the elimination rate. A three hour haemodialysis session decreases plasma levels by approximately 50%.
Contact the Poisons Information Centre on 13 11 26 (Australia) for advice on the management of overdosage.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

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.

Clinical trials.

Fluconazole administered orally or intravenously was active in a variety of animal models of fungal infections using standard laboratory strains of fungi. Fluconazole exhibits in vitro activity against Cryptococcus neoformans and Candida spp. Activity has been demonstrated in vivo in normal and immunocompromised animals against infections with Candida spp., including systemic candidiasis and in normal animals with C. neoformans, including intracranial infections. 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.

5.2 Pharmacokinetic Properties

The pharmacokinetic properties of fluconazole are similar following administration by the intravenous or oral routes.

Absorption.

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 postdose 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 levels achieved with single doses. The apparent volume of distribution approximates to total body water. Plasma protein binding is low (11-12%).

Distribution.

Fluconazole has been found to achieve good penetration into all tissues and body fluids studied. See Table 3.

Metabolism and excretion.

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 single dose therapy for vaginal candidiasis.

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 the mouse lymphoma system. Cytogenetic studies in vivo and in vitro showed no evidence of chromosomal mutations.

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.

6 Pharmaceutical Particulars

6.1 List of Excipients

In addition, each capsule contains the following inactive ingredients: lactose monohydrate, maize starch, colloidal anhydrous silica, purified talc, sodium lauryl sulfate, gelatin, titanium dioxide, patent blue V.

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

Each blister pack contains one capsule. AUST R 152959.

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 is a white to off-white crystalline powder, which is sparingly soluble in water and saline.

Chemical structure.

Chemical Name: 2-(2,4-diflurophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)-2-propanol.
Structural formula:
Molecular Formula: C13H12F2N6O.
Molecular Weight: 306.3.

CAS number.

86386-73-4.

7 Medicine Schedule (Poisons Standard)

S3 - Pharmacist Only Medicine.

Summary Table of Changes