Consumer medicine information

Dizole One

Fluconazole

BRAND INFORMATION

Brand name

Dizole One

Active ingredient

Fluconazole

Schedule

What is in this leaflet

This leaflet answers some common questions about DIZOLE ONE.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor or pharmacist has weighed the risks of you taking DIZOLE ONE against the benefits expected for you.

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

Keep this leaflet with your medicine. You may need to read it again.

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

What DIZOLE ONE is used for

DIZOLE ONE is used to treat a type of fungal infection called vaginal thrush.

DIZOLE ONE contains the active ingredient fluconazole, which belongs to a group of medicines called azole antifungals. These medicines work by preventing the growth of these fungi causing your infection.

What is vaginal thrush

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

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

Common symptoms of vaginal thrush include:

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

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

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

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

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

There is no evidence that DIZOLE ONE is addictive.

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

DIZOLE ONE is not recommended for children under 18 years of age except under doctor supervision.

Before you take DIZOLE ONE

When you must not take it

Do not take DIZOLE ONE if you have an allergy to:

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

Some of the symptoms of an allergic reaction may include

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

Do not take DIZOLE ONE if you are taking

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

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

Do not take DIZOLE ONE if you are pregnant, suspect you may be pregnant or if you may become pregnant during treatment. It may affect your developing baby if you take it during pregnancy.

Do not take DIZOLE ONE if you are breastfeeding. The active ingredient in DIZOLE ONE passes into breast milk and there is a possibility that your baby may be affected.

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 doctor or pharmacist.

Before you start to take it

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

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

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

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

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

If you have not told your doctor or pharmacist about any of the above, tell him/her before you start taking DIZOLE ONE.

Taking other medicines

Do not take DIZOLE ONE if you are taking

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

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

Some medicines and DIZOLE ONE may interfere with each other. These include:

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

Talk to your doctor about the need for an additional method of contraception while taking DIZOLE ONE. DIZOLE ONE may decrease the effectiveness of some birth control pills.

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

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

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

How to take DIZOLE ONE

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

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

How much to take

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

Do not give DIZOLE ONE to children under 18 years of age except under doctor supervision.

How to take it

Swallow the capsule whole with a glass of water.

DIZOLE ONE can be taken with or without food.

If you take too much (overdose)

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

While you are taking DIZOLE ONE

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking DIZOLE ONE

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

Use effective contraception to prevent pregnancy while taking DIZOLE ONE.

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

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

Things you must not do

Do not take DIZOLE ONE to treat any other complaints unless your doctor or pharmacist tells you to.

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

Things to be careful of

Tell your doctor immediately if you develop a rash while taking DIZOLE ONE.

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

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

Side effects

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

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

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

Do not be alarmed by the following list of possible side effects. You may not experience any of them.

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

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

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

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

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

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

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

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

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

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

After taking DIZOLE ONE

Storage

Keep your capsules in the pack until it is time to take them. If you take the capsules out of the pack they may not keep well.

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

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

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

Disposal

If your doctor or pharmacist tells you to stop taking this medicine or it's the expiry date has passed, ask your pharmacist what to do with it.

Product description

What it looks like

DIZOLE ONE is a hard white gelatin capsule, marked with "G" and "FC 150" in black ink.

Each pack contains 1 capsule.

Ingredients

The active ingredient in DIZOLE ONE is fluconazole 150 mg.

Each capsule also contains the following inactive ingredients:

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

Dizole One contains sulfites, phenylalanine and sugars as lactose.

Supplier

DIZOLE ONE is supplied in Australia by:

Alphapharm Pty Ltd trading as Viatris
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.viatris.com.au
Phone: 1800 274 276

Australian registration number:
DIZOLE ONE - AUST R 162766

This leaflet was prepared in January 2024.

DIZOLE ONE® is a Viatris company trade mark

Published by MIMS March 2024

BRAND INFORMATION

Brand name

Dizole One

Active ingredient

Fluconazole

Schedule

1 Name of Medicine

Fluconazole.

2 Qualitative and Quantitative Composition

Each capsule contains 150 mg of fluconazole as the active ingredient.
Excipients with known effect: Dizole One also contains sulfites, phenylalanine and sugars as lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Dizole One a size 1, white opaque body and white opaque cap, hard gelatin capsule, printed with "FC 150" and "G" on both body and cap in black ink.

4 Clinical Particulars

4.1 Therapeutic Indications

Dizole One, given orally, is indicated for vaginal candidiasis.

4.2 Dose and Method of Administration

Dizole One is administered orally.

Adults.

For vaginal candidiasis when topical therapy has failed, fluconazole 150 mg (Dizole One) should be administered as a single oral dose.

Children.

Single-dose fluconazole is not recommended for use in children under 18 years of age except under doctor supervision.

Renal impairment.

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

4.3 Contraindications

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

4.4 Special Warnings and Precautions for Use

Skin and subcutaneous tissue disorders.

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. Dizole One should not be used again if a rash develops that is attributable to fluconazole.

Anaphylaxis.

Anaphylaxis has been reported in rare instances.

QT interval prolongation.

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 (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 post-marketing surveillance, there have been very rare cases of QT prolongation and torsades de pointes in patients taking fluconazole. These reports included seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities and concomitant medications that may have been contributory. Patients with hypokalemia 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)).

Terfenadine.

The coadministration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored.

CYP2C9, CYP2C19 and CYP3A4 interactions.

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 metabolized through CYP2C9, CYP2C19 and CYP3A4 should be monitored (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Adrenal insufficiency.

Adrenal insufficiency has been reported in patients receiving other azoles (e.g. ketoconazole). Reversible cases of adrenal insufficiency were reported in patients receiving fluconazole.

Lactose.

Dizole One capsules contain lactose monohydrate and should not be given to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

Candidiasis.

Studies have shown an increasing prevalence of infections with Candida species other than C. albicans. These are often resistant (e.g. C. krusei and C. auris) or show reduced susceptibility to fluconazole (C. glabrata). Such infections may require alternative antifungal therapy secondary to treatment failure. Therefore, prescribes are advised to take into account the prevalence of resistance in various Candida species to fluconazole (see Section 5.1 Pharmacodynamic Properties).

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 hepatoxicity, no obvious relationship to total daily dose, duration of therapy, sex or age of the patient has been observed.
Dizole One 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.

Dizole One is not recommended for use in children.

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

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 C_max and an increase of 43% in (AUC) of fluconazole, compared to fluconazole given alone. An effect of this magnitude should not necessitate a change in the fluconazole dose regimen in subjects receiving diuretics, although the prescriber should bear it in mind.

Rifampicin.

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

Alfentanil.

A study observed a reduction in clearance and distribution volume as well as prolongation of t_1/2 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.

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).

Amitriptyline, nortriptyline.

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

Amphotericin B (amphotericin).

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

Anticoagulants.

In an interaction study, fluconazole increased the prothrombin time (12%) after warfarin administration in healthy males. In post-marketing experience as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena) have been reported, in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. Prothrombin time in patients receiving coumarin-type anticoagulants should be carefully monitored. Dose adjustment of warfarin may be necessary.

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. Co-administration of fluconazole and astemizole is contraindicated (see Section 4.3 Contraindications).

Azithromycin.

An open-label, randomised, three-way cross study in 18 healthy subjects assessed the effect of a single 1200 mg oral dose of azithromycin on the pharmacokinetics of a single 800 mg oral dose of fluconazole as well as the effects of fluconazole on the pharmacokinetics of azithromycin. There was no significant pharmacokinetic interaction between fluconazole and azithromycin.

Carbamazepine.

Fluconazole inhibits the metabolism of carbamazepine and an increase in serum carbamazepine of 30% has been observed. There is a risk of developing carbamazepine toxicity. Dosage adjustment of carbamazepine may be necessary depending on concentration measurements/effects.

Calcium channel blockers.

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

Celecoxib.

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

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 20 mg four times a day yielded a significant increase in cisapride plasma levels and prolongation of QTc interval. The co-administration of cisapride is contraindicated in patients receiving fluconazole (see Section 4.3 Contraindications).

Ciclosporin.

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

Cyclophosphamide monohydrate.

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

Erythromycin.

Concomitant use of fluconazole and erythromycin has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsades de pointes) and consequently sudden heart death. Co-administration of fluconazole and erythromycin is contraindicated (see Section 4.3 Contraindications).

Fentanyl.

One fatal case of possible fentanyl fluconazole interaction was reported. The author judged that the patient died from fentanyl intoxication. Furthermore, in a randomized crossover study with twelve healthy volunteers it was shown that fluconazole delayed the elimination of fentanyl significantly. Elevated fentanyl concentration may lead to respiratory depression.

Halofantrine.

Fluconazole can increase halofantrine plasma concentration due to an inhibitory effect on CYP3A4.

HMG-CoA reductase inhibitors.

The risk of myopathy and rhabdomyolysis increases when fluconazole is coadministered with HMG-CoA reductase inhibitors metabolised through CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin. If concomitant therapy is necessary, the patient should be observed for symptoms of myopathy and rhabdomyolysis and creatinine kinase should be monitored. HMG-CoA reductase inhibitors should be discontinued if a marked increase in creatinine kinase is observed or myopathy/rhabdomyolysis is diagnosed or suspected. Lower doses of HMG-CoA reductase inhibitors may be necessary as instructed in the statins prescribing information.

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.

Ivacaftor (alone or combined with drugs in the same therapeutic class).

Coadministration with ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, increased ivacaftor exposure by 3-fold. A reduction of the ivacaftor (alone or combined) dose is necessary as instructed in the ivacaftor (alone or combined) prescribing information.

Lemborexant.

Concomitant administration of fluconazole increased lemborexant C_max and AUC by approximately 1.6- and 4.2-fold, respectively which is expected to increase risk of adverse reactions, such as somnolence. Avoid concomitant use of lemborexant.

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.

Lurasidone.

Moderate inhibitors of CYP3A4 such as fluconazole may increase lurasidone plasma concentrations. If concomitant use cannot be avoided, reduce the dose of lurasidone as instructed in the lurasidone prescribing information.

Methadone.

Fluconazole may enhance the serum concentration of methadone. Dosage adjustment of methadone may be necessary.

Nonsteroidal anti-inflammatory drugs (NSAIDs).

The C_max and AUC of flurbiprofen were increased by 23% and 81%, respectively, when co-administered with fluconazole compared to administration of flurbiprofen alone. Similarly, the C_max and AUC of the pharmacologically active isomer [S-(+)-ibuprofen] were increased by 15% and 82%, respectively, when fluconazole was co-administered with racemic ibuprofen (400 mg) compared to administration of racemic ibuprofen alone. Although not specifically studied, fluconazole has the potential to increase the systemic exposure of other NSAIDs that are 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 contraceptives.

Fluconazole at a dose of 50 mg for 10 days decreased the AUC for ethinylestradiol by 16%, but values for levonorgestrel were unchanged. There were no relevant effects on hormone level in the 50 mg fluconazole. At 200 mg daily, the AUCs of ethinylestradiol and levonorgestrel were increased 40% and 24%, respectively. Multiple dose use of fluconazole at these doses is unlikely to have an effect on the efficacy of the combined oral contraceptive.

Oral hypoglycaemic agents.

The effects of fluconazole on the pharmacokinetics of the sulfonylurea oral hypoglycaemic agents tolbutamide, glipizide and glibenclamide were examined in three placebo controlled crossover studies in normal volunteers. All subjects received the sulfonylurea alone and following treatment with fluconazole 100 mg as a single daily oral dose for 7 days. Fluconazole administration resulted in significant increases in C_max 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 co-administered, blood glucose concentrations should be monitored carefully and the dose of the sulphonylurea adjusted accordingly. The possibility of a hypoglycemic episode should be borne in mind.

Phenytoin.

Concomitant administration of oral fluconazole (200 mg) with phenytoin at steady state resulted in an average increase of 75% of phenytoin AUC values in normal volunteers. Careful monitoring of phenytoin concentrations in patients receiving fluconazole and phenytoin is recommended. Fluconazole inhibits the hepatic metabolism of phenytoin. With coadministration, serum phenytoin concentration levels should be monitored in order to avoid phenytoin toxicity.

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 torsades de pointes. Co-administration of fluconazole and pimozide is contraindicated (see Section 4.3 Contraindications).

Prednisone.

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

Quinidine.

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

Short acting benzodiazepines.

Studies in human subjects have reported changes in midazolam pharmacokinetics and clinical effects that are dependent on dosage and route of administration. Single doses of fluconazole 150 mg resulted in modest increases in midazolam concentrations and psychomotor effects following oral administration of 10 mg that may not be clinically significant. At doses used to treat systemic mycoses, fluconazole resulted in substantial increase in midazolam concentrations and psychomotor effects following oral administration of 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 monitoring the patient's response.

Rifabutin.

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

Rifampicin.

Concomitant administration of fluconazole and rifampicin resulted in a 25% decrease in the area under the concentration versus time curve (AUC) and a 20% shorter half-life of fluconazole in normal volunteers. In patients receiving concomitant rifampicin and depending on clinical circumstances, an increase of the fluconazole dose should be considered.

Saquinavir.

Fluconazole increases the AUC of saquinavir with approximately 50%, C_max with approximately 55% 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.

Terfenadine.

Because of the occurrence of serious cardiac dysrhythmias secondary to prolongation of the QTc interval in patients receiving azole antifungals in conjunction with terfenadine, interaction studies have been performed. One study at a 200 mg daily dose of fluconazole failed to demonstrate a prolongation in QTc interval. Another study at a 400 mg and 800 mg daily dose of fluconazole demonstrated that fluconazole taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. The combined use of fluconazole at doses of 400 mg or greater with terfenadine is contraindicated (see Section 4.3 Contraindications). The co-administration of fluconazole at doses lower than 400 mg per day with terfenadine 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 co-administered 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.

Tolvaptan.

Exposure to tolvaptan is significantly increased (200% in AUC; 80% in C_max) 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.

Triazolam.

Fluconazole increases the AUC of triazolam (single dose) by approximately 50%, C_max with 20-32% and increases t_1/2 by 25-50% due to the inhibition of metabolism of triazolam. Dosage adjustments of triazolam 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).

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

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 two-fold increase in prothrombin time response. In post-marketing 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 C_max 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.

Gastrointestinal drugs.

In fasted normal volunteers, absorption of orally administered fluconazole does not appear to be affected by agents that increase gastric pH. Single dose administration of fluconazole (100 mg) with cimetidine (400 mg) resulted in a 13% reduction in AUC and a 21% reduction in C_max 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.
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 given orally. In an intravenous perinatal study in rats at 5, 20 and 40 mg/kg, dystocia and prolongation of parturition were observed in a few dams at 20 and 40 mg/kg, but not at 5 mg/kg. The disturbances in parturition were reflected by a slight increase in the number of stillborn pups and decrease of neonatal survival at these dose levels. The effects on parturition in rats are consistent with the species specific oestrogen lowering property produced by high doses of fluconazole. Such a hormone change has not been observed in women treated with fluconazole (see Section 5.1 Pharmacodynamic Properties).
(Category D)
Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.
There have been reports of spontaneous abortion and congenital abnormalities in infants whose mothers were treated with 150 mg of fluconazole as a single or repeated dose in the first trimester.
There are no adequate and well controlled studies in pregnant women. There have been reports of multiple congenital abnormalities in infants whose mothers were being treated for three or more months with high dose fluconazole therapy (400 to 800 mg/day) for coccidiomycosis. The relationship between fluconazole use and these events is unclear.
A study found any maternal exposure to fluconazole during pregnancy may increase the risk of spontaneous abortion and that doses higher than 150 mg during the first trimester may increase the risk of cardiac septal closure anomalies.
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.
Fluconazole has been found in human breast milk at concentrations similar to those in plasma, hence, its use in breastfeeding women 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.
Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported in association with fluconazole treatment (see Section 4.4 Special Warnings and Precautions for Use).
In some patients, particularly those with serious underlying diseases such as AIDS and cancer, changes in renal and hematological function test results and hepatic abnormalities (see Section 4.4 Special Warnings and Precautions for Use) have been observed during treatment with fluconazole and comparative agents, but the clinical significance and relationship to treatment is uncertain.
The following undesirable effects have been observed and reported during treatment with fluconazole with the following frequencies: very common ≥ 1/10; common ≥ 1/100 to < 1/10; uncommon ≥ 1/1,000 to < 1/100; rare ≥ 1/10,000 to < 1/1,000; very rare < 1/10,000; not known cannot be estimated from the available data. See Table 1.

Paediatric population.

The pattern and incidence of adverse events and laboratory abnormalities recorded during paediatric clinical trials are comparable to those seen in adults.

Reporting suspected adverse effects.

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

4.9 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.
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 Poisons Information Centre on 13 11 26 (Australia).

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. Interaction studies with antipyrine indicate that single or multiple doses of fluconazole 50 mg do not affect its metabolism.

Clinical trials.

No data available.

Microbiology.

Fluconazole administered orally or intravenously was active in a variety of animal models of fungal infections using standard laboratory strains of fungi.
In vitro, fluconazole displays antifungal activity against clinically common Candida species (including C. albicans, C. parapsilosis, C. tropicalis). C. glabrata shows reduced susceptibility to fluconazole while C. krusei and C. auris are resistant to fluconazole. The minimum inhibitory concentrations (MICs) and epidemiological cut-off value (ECOFF) of fluconazole for C. guilliermondii are higher than for C. albicans.
Fluconazole also exhibits in vitro activity against Cryptococcus neoformans and Cryptococcus gattii as well as the endemic moulds Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum and Paracoccidioides brasiliensis.
Activity has been demonstrated in vivo in normal and immunocompromised animals against infections with Candida spp., including systemic candidiasis, and in normal animals with Cryptococcus neoformans, including intracranial infections. One case of cross-resistance of Candida to fluconazole in a patient [not infected with human immunodeficiency virus (HIV)] previously treated with ketoconazole has been reported. The efficacy of fluconazole in vivo is greater than would be apparent from in vitro testing against the above mentioned fungi.
Concurrent administration of fluconazole and amphotericin B (amphotericin) in infected normal and immunocompromised mice showed antagonism of the two drugs in systemic infection with Aspergillus fumigatus. The clinical significance of results obtained in these studies is unknown.

5.2 Pharmacokinetic Properties

Absorption.

The pharmacokinetic properties of fluconazole are similar following administration by the intravenous or oral routes. In normal volunteers, the bioavailability of orally administered fluconazole is over 90% compared with intravenous administration. Oral administration is not affected by concomitant food intake. 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 to 50 hours). Plasma concentrations are proportional to dose and steady-state levels are reached within 5-10 days with oral doses of 50-400 mg once daily. Steady-state levels are approximately 2.5 times the levels achieved with single doses. Administration of loading dose (on day 1) of twice the usual daily dose enables plasma levels to approximate to 90% steady-state levels by day 2. The apparent volume of distribution approximates to total body water. Plasma protein binding is low (11 to 12%).

Distribution.

Fluconazole has been found to achieve good penetration into all tissues and body fluids studied. The levels of fluconazole in saliva and sputum are similar to plasma levels.

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 are markedly affected by reduction in renal function, however, no adjustments in single-dose therapy are necessary. There is an inverse relationship between the elimination half-life and creatinine clearance. The dose of fluconazole may need to be reduced in patients with impaired renal function (see Section 4.2 Dose and Method of Administration). A 3-hour haemodialysis session reduces plasma concentration by about 50%.
The long plasma elimination half-life provides the basis for single dose therapy for vaginal candidiasis.
There are differences in the pharmacokinetics of fluconazole between adults and children, with children, after the neonatal period, generally having a faster elimination rate and larger volume of distribution than adults.

5.3 Preclinical Safety Data

Genotoxicity.

Fluconazole, with or without metabolic activation, was negative in tests for mutagenicity in four strains of Salmonella typhimurium and in the mouse lymphoma system. Cytogenetic studies in vivo and in vitro showed no evidence of chromosomal mutations.

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 2-7x the 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

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

6.2 Incompatibilities

See Section 4.4 Special Warnings and Precautions for Use; 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

Dizole One 150 mg is packaged in blister pack (PVC/Al or PVC/PVDC/Al) of 1 capsule.

Australian register of therapeutic goods (ARTG).

AUST R 162766 - Dizole One Fluconazole 150 mg capsule blister pack - (new formulation).

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

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-difluorophenyl)-1, 3-bis (1H-1,2,4-triazol-1-yl)-2-propanol.

CAS number.

86386-73-4.
Molecular formula: C₁₃H₁₂F₂N₆O.
Molecular weight: 306.3.

7 Medicine Schedule (Poisons Standard)

S3 (Pharmacist Only Medicine).

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Dizole One

Fluconazole

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Dizole One 150 mg