Consumer medicine information

Fluconazole Sandoz Capsules

Fluconazole

BRAND INFORMATION

Brand name

Fluconazole Sandoz

Active ingredient

Fluconazole

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Fluconazole Sandoz Capsules.

SUMMARY CMI

Fluconazole Sandoz®

Consumer Medicine Information (CMI) summary

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

1. Why am I using Fluconazole Sandoz?

Fluconazole Sandoz contains the active ingredient fluconazole. Fluconazole Sandoz capsules is used to treat certain fungal and yeast infections.

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

2. What should I know before I use Fluconazole Sandoz?

Do not start treatment if you have ever had an allergic reaction to fluconazole, or any of the ingredients listed at the end of the CMI or any other similar medicines such as miconazole, ketoconazole or clotrimazole.

Tell your doctor if you have had any allergic reaction to any antifungal, or any foods, preservatives or dyes or any other medicines. Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

You must not be given Fluconazole Sandoz if you are taking certain medicines. For more information, see Section 2. What should I know before I use Fluconazole Sandoz? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Fluconazole Sandoz and affect how it works. A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Fluconazole Sandoz?

  • Swallow Fluconazole Sandoz capsules whole with water.
  • Your doctor will decide how much Fluconazole Sandoz will be given to you each day and for how long. It will depend on your condition and other factors. More instructions can be found in Section 4. How do I use Fluconazole Sandoz? in the full CMI.

5. What should I know while using Fluconazole Sandoz?

Things you should do
  • Tell your doctor if you have any medical conditions, are on any medicines, or if you are pregnant, plan to become pregnant or are breastfeeding.
  • For more information on “Things you should do” can be found in Section 6 in the full CMI
Things you should not do
  • Do not start treatment if you ever had an allergic reaction to any medicine containing fluconazole, any of the ingredients listed at the end of this CMI, or any other similar medicines such as miconazole, ketoconazole or clotrimazole.
  • Do not stop taking Fluconazole Sandoz or lower the dosage without checking with your doctor.
  • Do not give your medicine to anyone else, even if they have the same condition as you.
  • Do not use Fluconazole Sandoz to treat any other medical complaints unless your doctor tells you to.
Looking after your medicine
  • Keep your medicine in its original pack until it is time to take it.
  • Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it in the bathroom or near a sink, or in the car or on window sills.
  • Store Fluconazole Sandoz below 25°C.
  • Do not use this medicine after the expiry date.

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

6. Are there any side effects?

Fluconazole Sandoz is generally well tolerated. Side effects may include nausea, vomiting, abdominal pain, diarrhoea, headache, skin rash or redness and easy bruising of the skin, seizures, signs of frequent or worrying infections such as fever, severe chills, sore throat or mouth ulcers, or change in liver function.

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



FULL CMI

Fluconazole Sandoz®

Active ingredient(s): fluconazole (flu-con-a-zole)

Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I using Fluconazole Sandoz?

Fluconazole Sandoz contains the active ingredient fluconazole. Fluconazole Sandoz is used to treat certain fungal and yeast infections.

Fluconazole Sandoz belongs to a group of medicines called azole antibiotics.

It works by preventing the growth of the fungal and yeast organisms causing your infection.

Ask your doctor if you have any questions about why Fluconazole Sandoz has been prescribed for you.

Your doctor may have prescribed it for another reason.

Fluconazole Sandoz is available only with a doctor's prescription.

This medicine is not addictive.

2. What should I know before I use Fluconazole Sandoz?

Warnings

Do not start treatment with Fluconazole Sandoz if:

  • you are allergic to fluconazole, or any of the ingredients listed at the end of this leaflet, or any medicines related to fluconazole such as miconazole, ketoconazole or clotrimazole. Always check the ingredients to make sure you can use this medicine.
  • Symptoms of an allergic reaction include
    - shortness of breath
    - wheezing or difficulty breathing
    - swelling of the face, lips, tongue or other parts of the body
    - skin rash, itching or hives

You must not be given Fluconazole Sandoz if you are taking any of the following medicines:

  • terfinadine or astemizole (a medicine used to treat allergy)
  • cisapride (a medicine used to treat stomach problems)
  • erythromycin (a medicine used to treat infections)
  • pimozide (a medicine used to treat mental illness)
  • quinidine (a medicine used to treat irregular heartbeat).

Check with your doctor if you:

  • have allergies to any foods, preservatives or dyes or any other medicines
  • are taking medicines for any other condition
  • have any other medical conditions
    - have liver problems
    - have heart problems
    - have kidney problems

Your doctor may need to monitor the function of the liver using blood tests. Be sure to follow the doctor's advice if regular checks on your/ your child's liver are recommended.

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

Pregnancy and breastfeeding

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

Fluconazole Sandoz use should be avoided during pregnancy except on doctor's advice for severe or life-threatening infections. Effective contraception should be used in women of childbearing potential and should continue throughout the treatment period and for approximately 1 week after the final dose. Your doctor can discuss with you the risks and benefits involved.

Talk to your doctor about the need for an additional method of contraception while being given Fluconazole Sandoz.

Fluconazole Sandoz may decrease the effectiveness of some birth control pills.

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

Fluconazole Sandoz is not recommended for use whilst breastfeeding however your doctor can discuss with you the risks and benefits involved.

3. What if I am taking other medicines?

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

Some medicines should not be taken with Fluconazole Sandoz.

These are listed under Section 2. What should I know before treatment with Fluconazole Sandoz.

Some medicines and Fluconazole Sandoz may interfere with each other. These medicines and some others may be affected by Fluconazole Sandoz and affect how it works. You may need different amounts of your medicines, or you may need to take different medicines. These include:

  • some medicines for diabetes such as glipizide, tolbutamide or glibenclamide
  • some antibiotics, antiviral and antifungal drugs such as rifampicin, rifabutin, zidovudine, amphotericin B, azithromycin, saquinavir or voriconazole
  • some drugs used for heart problems, such as amiodarone or verapamil
  • some drugs used in problems with the immune system, such as ciclosporin, tacrolimus, sirolimus or tofacitinib
  • some medicines used to lower cholesterol, such as atorvastatin, simvastatin or fluvastatin
  • cyclophosphamide, vincristine, vinblastine, olaparib or ibrutinib (used to treat certain types of cancers)
  • tolvaptan (used to treat low levels of sodium in your blood or for kidney problems)
  • halofantrine (used to treat malaria)
  • warfarin (used to stop blood clots)
  • phenytoin (used to treat epilepsy)
  • prednisone (used to treat inflammation or suppress the immune system)
  • theophylline (used to treat asthma)
  • some benzodiazepines such as midazolam
  • lemborexant (used to treat insomnia or sleeping difficulties)
  • ivacaftor (used to manage cystic fibrosis)
  • lurasidone (used to manage schizophrenia)
  • hydrochlorothiazide (used for treating fluid problems)
  • the contraceptive pill (birth control pill)
  • carbamazepine (used in the treatment of epilepsy and bipolar disorder)
  • NSAIDS such as naproxen, diclofenac and celecoxib
  • Vitamin A
  • opioid pain killers such as alfentanil, fentanyl and methadone
  • losartan (used for treating high blood pressure)
  • antidepressants such as amitriptyline and nortriptyline.

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

4. How do I use Fluconazole Sandoz?

How much to take

Adults

  • The dose will depend on your infection and how you respond to Fluconazole Sandoz. It usually ranges from 50 mg to 400 mg once daily.

Children

  • The dose for a child will depend on body weight and usually ranges from 3 mg to 12 mg per kilogram of body weight.

However, depending on how serious the infection is, and how you react to this medicine, your doctor may ask you to take a different dose.

When to take Fluconazole Sandoz

  • Try to take your medicine at about the same time each day.
    Taking it at the same time each day will have the best effect. It will also help you to remember when to take it.
  • It does not matter if you take this medicine before or after food.

How to take Fluconazole Sandoz

  • Swallow the capsules whole with water.

How to long to take Fluconazole Sandoz

  • Continue taking Fluconazole Sandoz until you finish the pack or until your doctor recommends.
  • The length of time you take Fluconazole Sandoz will depend on the sort of infection you have.
  • Patients with a weakened immune system or those with difficult infections may need long-term treatment to prevent the infection from returning.
  • Do not stop taking your Fluconazole Sandoz because you are feeling better.
  • If you do not complete the full course prescribed by your doctor, the infection may not clear completely or your symptoms may return.

If you forget to use Fluconazole Sandoz

Fluconazole Sandoz should be used as prescribed. If you miss your dose at the usual time, please see the following instructions.

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

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

Otherwise, take it as soon as you remember, then go back to take it as you would normally.

If you use too much Fluconazole Sandoz

If you think that you have used too much Fluconazole Sandoz, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

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

5. What should I know while using Fluconazole Sandoz?

Things you should do

  • If you are a woman of child-bearing age, you should avoid becoming pregnant while taking Fluconazole Sandoz. Talk to your doctor about the need for an additional method of contraception while being given Fluconazole Sandoz. If you do become pregnant while taking Fluconazole Sandoz, tell your doctor immediately.
  • If you suffer from HIV or have a weakened immune system and develop a rash while taking Fluconazole Sandoz, tell your doctor immediately. If this rash worsens, Fluconazole Sandoz may need to be stopped.
  • Be sure to follow your doctor's advice if regular checks on your liver are recommended. In rare cases, Fluconazole Sandoz may affect the liver and may need to be stopped.
  • If the symptoms of your infection do not improve within a few days, or if they become worse, tell your doctor.
  • Remind any doctor, dentist, or pharmacist you visit that you are using Fluconazole Sandoz.

Things you should not do

  • Do not start treatment if you have ever had an allergic reaction to any medicine containing fluconazole, any of the ingredients listed at the end of this CMI
  • Do not stop taking Fluconazole Sandoz or lower the dosage without checking with your doctor.
    If you do not complete the full course prescribed by your doctor, all of the organisms causing your infection may not be killed. These organisms may continue to grow and multiply so that your infection may not clear completely or may return.
  • Do not give your medicine to anyone else, even if they have the same condition as you.
  • Do not use Fluconazole Sandoz to treat any other medical complaints unless your doctor tells you to.

Driving or using machines

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

Drinking alcohol

No information available.

Looking after your medicine

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

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

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

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

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

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

Less serious side effects

Less serious side effectsWhat to do
Gut or Gastrointestinal related
  • nausea or feeling sick, vomiting
  • stomach pain, indigestion, diarrhoea
  • constipation
General
  • headache
Skin changes
  • acne
  • hot flushes
Eye related
  • blurred or abnormal vision
Others
  • low blood potassium which can result in fatigue, muscle cramps and abnormal heart rhythms*
  • changes in liver function*
*These side effects may show up when you have a blood test.		Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Allergy or reaction related
  • swelling of the face, lips or tongue
  • difficulty in swallowing or breathing
  • asthma, wheezing, shortness of breath
Skin changes
  • yellowing of the skin or eyes, also called jaundice
  • sudden or severe itching, skin rash, hives
  • bleeding or bruising more easily than normal
  • reddish or purplish blotches under the skin
  • flaking of the skin
Changes to urine
  • dark urine and light-coloured bowel movements (cholestasis)
Signs of frequent or worrying infections such as:
  • fever, severe chills, sore throat or mouth ulcers
Other:
  • fainting, seizures or fits
  • fast or irregular heartbeat
  • increased sweating
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

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

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

Reporting side effects

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

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

7. Product details

This medicine is only available with a doctor's prescription.

What Fluconazole Sandoz contains

Active ingredient
(main ingredient)		fluconazole
Other ingredients
(inactive ingredients)
  • lactose monohydrate
  • maize starch
  • magnesium stearate
  • colloidal anhydrous silica
  • sodium lauryl sulfate
  • titanium dioxide
  • gelatin
  • indigo carmine
  • brilliant scarlet 4R CI16255 (200 mg capsules only)
  • shellac
  • black monogramming ink (107581 or 2328)
  • propylene glycol.
Potential allergens
  • lactose

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

What Fluconazole Sandoz looks like

Fluconazole Sandoz 50 mg – Hard gelatin capsules with a turquoise cap and white body, marked with FC50
(AUST R 104285).

Fluconazole Sandoz 100 mg – Hard gelatin capsules with a blue cap and white body, marked with FC100
(AUST R 104288).

Fluconazole Sandoz 200 mg – Hard gelatin capsules with a purple cap and white body, marked with FC200
(AUST R 104293).

Available in blister packs of 28 capsules.

Who distributes Fluconazole Sandoz

Sandoz Pty Ltd
ABN 60 075 449 553
54 Waterloo Road
Macquarie Park, NSW 2113
Tel: 1800 726 369

Novartis New Zealand Ltd
PO Box 99102
Newmarket, Auckland 1149
New Zealand
Tel: 0800 354 335

This leaflet was revised in October 2022.

Published by MIMS November 2022

BRAND INFORMATION

Brand name

Fluconazole Sandoz

Active ingredient

Fluconazole

Schedule

S4

 

1 Name of Medicine

Fluconazole.

2 Qualitative and Quantitative Composition

Each Fluconazole Sandoz 50 mg capsules contains 50 mg fluconazole.
Each Fluconazole Sandoz 100 mg capsules contains 100 mg fluconazole.
Each Fluconazole Sandoz 150 mg capsules contains 150 mg fluconazole.
Each Fluconazole Sandoz 200 mg capsules contains 200 mg fluconazole.

Excipients with known effect.

Lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Fluconazole Sandoz 50 mg capsules.

Hard gelatin capsules, turquoise cap, white body with the imprint FC50.

Fluconazole Sandoz 100 mg capsules.

Hard gelatin capsules, blue cap white body with the imprint FC100.

Fluconazole Sandoz 150 mg capsules*.

Hard gelatin capsules, white cap white body with the imprint FC150.

Fluconazole Sandoz 200 mg capsules.

Hard gelatin capsules, purple cap white body with the imprint FC200.

4 Clinical Particulars

4.1 Therapeutic Indications

Orally for treatment of cryptococcal meningitis in patients who are unable to tolerate amphotericin B.

Note.

Data suggest that the clinical efficacy of fluconazole is lower than that of amphotericin B in the treatment of the acute phase of cryptococcal meningitis.
Maintenance therapy to prevent relapse of cryptococcal meningitis in patients with acquired immune deficiency syndrome (AIDS).
Treatment of oropharyngeal and oesophageal candidiasis in AIDS and other immunosuppressed patients.
Secondary prophylaxis of oropharyngeal candidiasis in patients with human immunodeficiency virus (HIV) infection.
Serious and life threatening Candida infections in patients who are unable to tolerate amphotericin B.

Note.

It remains to be shown that fluconazole is as effective as amphotericin B in the treatment of serious and life threatening Candida infections. Until such data are available, amphotericin B remains the drug of choice.
Vaginal candidiasis, when topical therapy has failed.
Treatment of extensive tinea corporis, extensive tinea cruris and extensive tinea pedis infections in immunocompetent patients in whom topical therapy is not a practical treatment option. Usually, topical therapy should be attempted first because oral therapy has a less favourable ratio of benefits to risks. See Section 4.8 Adverse Effects (Undesirable Effects).

4.2 Dose and Method of Administration

Dosage.

Since oral absorption is rapid and almost complete, there is no need to change the daily dosage on transferring from the intravenous to the oral route or vice versa.
The daily dose of Fluconazole Sandoz should be based on the infecting organism and the patient's response to therapy. Treatment should be continued until clinical parameters or laboratory tests indicate that active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal candidiasis often require maintenance therapy to prevent relapse.
Adults.

Cryptococcal meningitis in patients who are unable to take or tolerate amphotericin B.

The usual dose is 400 mg on the first day followed by 200 mg once daily. A dosage of 400 mg once daily may be used, based on medical judgment of the patient's response to therapy. Patients not responding to treatment for up to 60 days would appear unlikely to respond to Fluconazole Sandoz.
Duration of treatment for cryptococcal infections will depend on the clinical and mycological response, but should continue for ten to twelve weeks after cerebrospinal fluid becomes culture negative. Negative serology does not necessarily indicate eradication of the disease; a proportion of such patients relapse in due course.

Prevention of relapse of cryptococcal meningitis in patients with AIDS.

After the patient receives a full course of primary therapy, Fluconazole Sandoz may be administered at a daily dose of 100 to 200 mg.

Treatment of oropharyngeal and oesophageal candidiasis.

The recommended dose for oropharyngeal candidiasis is 100 mg on the first day followed by 50 mg once daily. For the treatment of oesophageal candidiasis, the recommended dose is 200 mg on the first day followed by 100 mg once daily. Clinical evidence of candidiasis usually resolves within several days, but treatment should be continued for at least two to three weeks, especially in patients with severely compromised immune function. Patients with severe oesophageal candidiasis may need treatment to be continued for two weeks following resolution of symptoms. Approximately half of the clinically cured patients remain colonised.

Secondary prophylaxis against oropharyngeal candidiasis in patients with HIV infection.

The recommended dose is 150 mg as a single dose once weekly.

Serious and life threatening candidal infections in patients unable to tolerate amphotericin B.

The usual dose is 400 mg on the first day followed by 200 mg daily. Depending on the clinical response, the dose may be increased to 400 mg daily. Duration of treatment is based on clinical response; patients should be treated for a minimum of four weeks and for at least two weeks following resolution of symptoms.

Vaginal candidiasis when topical therapy has failed.

Fluconazole Sandoz 150 mg should be administered as a single oral dose.
In those patients who responded to treatment, the median time to onset of symptom relief was one day (range: 0.04-9 days) and to complete symptom relief was two days (range: 0.5-20 days).

Extensive tinea infections, severe tinea pedis.

For extensive tinea infections (tinea corporis, tinea cruris), or severe tinea pedis in immunocompetent patients in whom topical therapy is not practical, the recommended dosage is 150 mg once weekly for four weeks.
Children. As with similar infections in adults, the duration of treatment is based on the clinical and mycological response. Fluconazole Sandoz is administered as a single dose each day.

Treatment of mucosal candidiasis.

The recommended dosage is 3 mg/kg daily. A loading dose of 6 mg/kg may be used on the first day to achieve steady-state levels more rapidly.

Treatment of systemic candidiasis and cryptococcal infection.

The recommended dosage is 6 to 12 mg/kg daily, depending on the severity of the disease.
For children with impaired renal function the daily dose should be reduced in accordance with the guidelines given for adults.

Children 4 weeks of age and younger.

Neonates excrete fluconazole slowly. In the first two weeks of life, the same mg/kg dosing as in older children should be used but administered every 72 hours. During weeks 3 and 4 of life the same dose should be given every 48 hours.

Method of administration.

Fluconazole Sandoz is normally administered orally. If oral administration is not possible, it may be administered by intravenous infusion.

Dosage adjustment.

Renal impairment.

Fluconazole is predominantly excreted in the urine as unchanged drug. No adjustments in single dose therapy are necessary. In multiple dose treatment of patients with renal impairment, normal doses should be given on days 1 and 2 of treatment and thereafter the dosage intervals or the daily dose should be modified in accordance with creatinine clearances as in Table 1.
For patients receiving regular dialysis, administer one recommended dose after every dialysis session.
These are suggested dose adjustments based on pharmacokinetics following administration of single doses. Further adjustment may be needed depending on clinical condition.
When serum creatinine is the only measure of renal function available, the Cockcroft-Gault equation should be used to estimate the creatinine clearance in mL/minute.

Elderly.

Dosage should be adjusted for elderly patients with renal impairment (see Renal impairment, above).

4.3 Contraindications

Known sensitivity to fluconazole, related azole compounds or any of the excipients of Fluconazole Sandoz.
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. Co-administration of other drugs known to prolong the QT interval and which are metabolized 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).

4.4 Special Warnings and Precautions for Use

Anaphylaxis has been reported in rare instances.
Fluconazole has been associated with rare cases of serious hepatic toxicity, including fatalities, primarily in patients with serious underlying medical conditions. In cases of fluconazole-associated hepatoxicity, no obvious relationship to total daily dose, duration of therapy, sex or age of the patient has been observed.
Patients who develop abnormal liver function tests during fluconazole therapy should be monitored for the development of more severe liver injury. Fluconazole should be discontinued if clinical signs and symptoms consistent with liver disease develop that may be attributable to fluconazole (see Section 4.8 Adverse Effects (Undesirable Effects)).
Patients have rarely developed exfoliative cutaneous reactions, e.g. Stevens-Johnson syndrome and toxic epidermal necrolysis, during treatment with fluconazole. Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported. AIDS patients are more prone to the development of serious cutaneous reactions to many drugs. If a rash that is attributable to fluconazole develops in a patient treated for a superficial fungal infection, fluconazole should be discontinued. If patients with invasive/ systemic fungal infections develop rashes, they should be monitored closely and fluconazole discontinued if bullous lesions or erythema multiforme develop (see Section 4.8 Adverse Effects (Undesirable Effects)).
Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. Fluconazole causes QT prolongation via the inhibition of Rectifier Potassium Channel current (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 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)).
In rare cases, as with other azoles, anaphylaxis has been reported.
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).
Fluconazole Sandoz 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.
Adrenal insufficiency has been reported in patients receiving other azoles (e.g. ketoconazole). Cases of adrenal insufficiently were reported in patients receiving fluconazole. Adrenal insufficiency relating to concomitant treatment with prednisone is described in Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

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.

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 hepatic injury. Fluconazole should be discontinued 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.

Dosage should be adjusted for elderly patients with renal impairment (see Section 4.2 Dose and Method of Administration).

Paediatric use.

See Section 4.2 Dose and Method of Administration, Dosage, Children; Section 5.2 Pharmacokinetic Properties.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Fluconazole is an inhibitor of the cytochrome P450 system, particularly the CYP2C and to a lesser extent the CYP3A isoforms. Coadministration of fluconazole with some other drugs metabolized primarily by these P450 isoforms may result in altered plasma concentrations of these medications that could change therapeutic effects and/or adverse event profiles. There are possibilities that other drugs may affect the metabolism of fluconazole and that fluconazole may affect the metabolism of other drugs. In vitro studies conducted in human hepatic microsomes demonstrate that the extent of inhibition of CYP3A isoforms is lowest with fluconazole, when compared with ketoconazole and itraconazole.
Clinically or potentially significant drug interactions have been observed between fluconazole and the following agents: short acting benzodiazepines, cisapride, coumarin-type anticoagulants, ciclosporin, hydrochlorothiazide, oral hypoglycaemics, phenytoin, rifampicin, rifabutin, tacrolimus and theophylline. These are described in greater detail below.

Effects of other medicinal products on fluconazole.

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

Hydrochlorothiazide.

Concomitant oral administration of fluconazole 100 mg and hydrochlorothiazide 50 mg for ten days in normal volunteers resulted in an increase of 41% in Cmax and an increase of 43% in area under the concentration vs time 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 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 4-5 days after discontinuation of fluconazole treatment due to the long half-life of fluconazole (see Section 4.3 Contraindications).

Alfentanil.

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

Amitriptyline, nortriptyline.

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

Amphotericin B.

Concurrent administration of fluconazole and amphotericin B in infected normal and immunosuppressed mice showed the following results: a small additive antifungal effect in systemic infection with 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 two studies is unknown.
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. Coadministration of cisapride is contraindicated in patients receiving fluconazole (see Section 4.3 Contraindications).

Terfenadine.

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

Astemizole.

Concomitant administration of fluconazole with astemizole may decrease the clearance of astemizole. Resulting increased plasma concentrations of astemizole can lead to QT prolongation and rare occurrences of torsade de pointes. Co-administration of fluconazole and astemizole is contraindicated (see Section 4.3 Contraindications).

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 QTc prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and pimozide is contraindicated (see Section 4.3 Contraindications).

Quinidine.

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

Erythromycin.

Concomitant use of fluconazole and erythromycin has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsade de pointes) and consequently sudden heart death. Coadministration of fluconazole and erythromycin is contraindicated.
Concomitant use that should be avoided or 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).

Lemborexant.

Concomitant administration of fluconazole increased lemborexant Cmax 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.
Interaction of fluconazole with the following agents may result in increased exposure to these drugs. Careful monitoring and/or dosage adjustment should be considered.

Anticoagulants.

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

Short acting benzodiazepines.

Studies in human subjects have reported changes in midazolam pharmacokinetics and clinical effects that are dependent on dosage and route of administration. Single doses of fluconazole 150 mg resulted in modest increases in midazolam concentrations and psychomotor effects following oral administration of 10 mg that may not be clinically significant. At doses used to treat systemic mycoses, fluconazole resulted in substantial increases in midazolam concentrations and psychomotor effects following oral administration of midazolam 7.5 mg, but only modest increases that are not likely to be clinically significant following intravenous infusion of midazolam 0.05 mg/kg. This effect on midazolam appears to be more pronounced following oral administration of fluconazole than with fluconazole administered intravenously. There have been reports of sleepiness and disturbed consciousness in patients taking fluconazole for systemic mycoses and triazolam. However, in most of these cases, the patients had serious underlying illnesses and/or concomitant therapies that could have contributed to the reported events, and a relationship with a fluconazole-triazolam interaction has not been established. If concomitant benzodiazepine therapy is necessary in patients being treated with fluconazole, consideration should be given to decreasing the benzodiazepine dosage, and monitoring the patient's response. Fluconazole increases the AUC of triazolam (single dose) by approximately 50% Cmax with 20-32% and increases the half life by 25-50% due to the inhibition of metabolism of triazolam. Dosage adjustments of triazolam may be necessary.

Carbamazepine.

Azole antifungals may raise carbamazepine plasma concentrations. Fluconazole inhibits the metabolism of carbamazepine and an increase in serum carbamazepine of 30% has been observed. Since high plasma concentrations of carbamazepine and/or carbamazepine-10,11-epoxy may result in adverse effects (e.g. dizziness, drowsiness, ataxia, diplopia), the dosage of carbamazepine should be adjusted accordingly and/or plasma concentrations monitored when used concomitantly with fluconazole.

Calcium channel blockers.

Certain dihydropyridine calcium channel antagonists (nifedipine, isradipine, amlodipine, 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 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 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 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.

Everolimus.

Although not studied in vivo or in vitro, fluconazole may increase serum concentrations of everolimus through inhibition of CYP3A4.

Halofantrine.

Fluconazole can increase halofantrine plasma concentration due to an inhibitory effect on CYP3A4. Concomitant use of fluconazole and halofantrine has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsades de pointes) and consequently sudden heart death. This combination should be avoided.

HMG-CoA reductase inhibitors.

The risk of myopathy and rhabdomyolysis increases (dose-dependent) when fluconazole is co-administered with HMG-CoA reductase inhibitors metabolized 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 creatine kinase should be monitored. HMG-CoA reductase inhibitors should be discontinued if a marked increase in creatine 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.

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.

Losartan.

Fluconazole inhibits the metabolism of losartan to its active metabolite (E-3174) 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.

Non-steroidal anti-inflammatory drugs.

The Cmax and AUC of flurbiprofen was increased by 23% and 81%, respectively, when coadministered with fluconazole compared to administration of flurbiprofen alone. Similarly, the Cmax and AUC of the pharmacologically active isomer [S-(+)-ibuprofen] was increased by 15% and 82% respectively, when fluconazole was coadministered 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.

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

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.

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.

Saquinavir.

Fluconazole increases the AUC of saquinavir by approximately 50%, increases Cmax by approximately 55% and decreases clearance of saquinavir by approximately 50% 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.

Theophylline.

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

Tofacitinib.

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

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 of CYP3A4.

Vitamin A.

Based on a case report in one patient receiving combination therapy with all-trans-retinoid acid (an acid form of vitamin A) and fluconazole, CNS related undesirable effects have developed in the form of pseudotumour cerebri, which disappeared after discontinuation of fluconazole treatment. This combination may be used but the incidence of CNS related undesirable effects should be borne in mind.

Voriconazole.

(CYP2C9, CYP2C19 and CYP3A4 inhibitor). Concomitant administration of voriconazole and fluconazole at any dose is not recommended.

Warfarin.

A single dose of warfarin 15 mg given to normal volunteers, following 14 days of orally administered fluconazole 200 mg resulted in a 12% increase in the prothrombin time response (area under the prothrombin time, time curve). One in 13 subjects experienced a twofold increase in prothrombin time response. In postmarketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, haematuria and melaena) have been reported in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. Careful monitoring of prothrombin time in patients receiving fluconazole and coumarin type anticoagulants is recommended.

Zidovudine.

Fluconazole increases Cmax and AUC by 85% and 75% of zidovudine, respectively due to decrease in oral zidovudine clearance of approximately 45%. The half-life of zidovudine was likewise prolonged by approximately 128% following combination therapy with fluconazole. Patients receiving this combination should be monitored for the development of zidovudine-related adverse effects. Dosage reduction of zidovudine may be considered.
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 ethinyl estradiol or levonorgestrel AUC after the administration of fluconazole 50 mg. The mean increase in ethinyl estradiol AUC was 6% (range: -47 to 108%) and levonorgestrel AUC increased 17% (range: -33 to 141%).
In a second study, 25 normal females received daily doses of fluconazole 200 mg 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 levonorgestrel and ethinyl estradiol 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 levonorgestrel compared to placebo was 25% (range: -12 to 82%) and the mean percentage increase for ethinyl estradiol 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 ethinyl estradiol 35 microgram and norethindrone 0.5 mg. AUC of ethinyl estradiol 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 cross study in 18 healthy subjects assessed the effect of a single oral dose of azithromycin 1,200 mg on the pharmacokinetics of a single oral dose of fluconazole 800 mg as well as the effects of fluconazole on the pharmacokinetics of azithromycin. The estimated ratio of the mean AUC of fluconazole 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 2.

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)
Use in pregnancy should be avoided except in patients with severe or potentially life-threatening fungal infections in whom fluconazole may be used if the anticipated benefit outweighs the possible risk to the fetus.
Effective contraceptive measures should be considered in women of child-bearing potential and should continue throughout the treatment period and for approximately 1 week (5 to 6 half-lives) after the final dose.
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.
In one large observational cohort study, first trimester exposure to oral fluconazole was associated with a small increased risk of musculoskeletal malformations, corresponding to approximately 1 additional case per 1000 women treated with cumulative doses ≤ 450 mg compared with women treated with topical azoles and to approximately 4 additional cases per 1000 women treated with cumulative doses over 450 mg. The adjusted relative risk was 1.29 (95% CI 1.05 to 1.58) for 150 mg oral fluconazole and 1.98 (95% CI 1.23 to 3.17) for doses over 450 mg fluconazole.
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 uses and these events is unclear. Adverse fetal 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.
Case reports describe a distinctive and a rare pattern of birth defects among infants whose mother received high-dose (400-800 mg/day) fluconazole during most or all of the first trimester of pregnancy. The features seen in these infants include brachycephaly, abnormal facies, abnormal calvarial development, cleft palate, femoral bowing, thin ribs and long bones, arthrogryposis, and congenital heart disease.
 Fluconazole has been found in human breast milk at concentrations similar to those in plasma, hence its use in breastfeeding women is not recommended. The elimination half-life from breast milk approximates the plasma elimination half-life of 30 hours. The estimated daily infant dose of fluconazole from breast milk (assuming mean milk consumption of 150 mL/kg/day) based on the mean peak milk concentration is 0.39 mg/kg/day, which is approximately 40% of the recommended neonatal dose (< 2 weeks of age) or 13% of the recommended infant dose for mucosal candidiasis.
The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for fluconazole and any potential adverse effects on the breastfed child from fluconazole or from the underlying maternal condition.
A pharmacokinetic study in 10 lactating women, who had temporarily or permanently stopped breast-feeding their infants, evaluated fluconazole concentrations in plasma and breast milk for 48 hours following a single 150 mg dose of fluconazole. Fluconazole was detected in breast milk at an average concentration of approximately 98% of those in maternal plasma. The mean peak breast milk concentration was 2.61 mg/L at 5.2 hours post-dose.

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)

Adults.

Summary of safety profile.

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).
The safety profile of fluconazole appears similar in adults and children. The profile established for adults, given different dosage regimens and for different indications is given below.
Multiple daily dosing for treatment of oral and oropharyngeal candidiasis, cryptococcal meningitis or systemic candidiasis. Fluconazole is generally well tolerated. 16% of over 4,000 patients treated in clinical trials of seven days or more experienced adverse events. Treatment was discontinued in 1.5% of patients due to adverse clinical events and in 1.3% due to laboratory abnormalities.
Clinical adverse events were reported more frequently in HIV infected patients (21%) than in non-HIV infected patients (13%); however, the patterns in HIV infected and non-HIV infected patients were similar. The proportions of patients discontinuing therapy due to clinical adverse events were similar in the two groups (1.5%).
In some patients, particularly those with serious underlying diseases such as AIDS and cancer, changes in renal and haematological function test results and hepatic abnormalities have been observed during treatment with fluconazole and comparative agents, but the clinical significance and relationship to treatment is uncertain.

Hepatobiliary.

In combined clinical trials and marketing experience, the spectrum of hepatic reactions has ranged from mild transient elevations in transaminases to clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities. Elevations in plasma levels of hepatic enzymes have been observed both in otherwise healthy patients and in patients with underlying disease (see Section 4.4 Special Warnings and Precautions for Use). There have been rare cases of serious hepatic reactions during treatment with fluconazole (see Section 4.4 Special Warnings and Precautions for Use). Instances of fatal hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly AIDS or malignancy) and often while taking multiple concomitant medications. In addition, transient hepatic reactions, including hepatitis and jaundice, have occurred among patients with no other identifiable risk factors. In each of these cases, liver function returned to baseline on discontinuation of fluconazole.
In two comparative trials evaluating the efficacy of fluconazole for the suppression of relapse of cryptococcal meningitis, a statistically significant increase was observed in median AST (SGOT) levels from a baseline value of 30 IU/L to 41 IU/L in one trial and 34 IU/L to 66 IU/L in the other. The overall rate of serum transaminase elevations of more than eight times the upper limit of normal was approximately 1% in fluconazole treated patients in the premarketing clinical trials which included patients with severe underlying disease (predominantly AIDS or malignancies), most of whom were receiving multiple concomitant medications, including many known to be hepatotoxic. The incidence of abnormally elevated serum transaminases was greater in patients taking fluconazole concomitantly with one or more of the following medications: rifampicin, phenytoin, isoniazid, valproic acid or oral sulfonylurea hypoglycaemic agents.
Other adverse effects observed include the following (see Table 3):
Single 150 mg dose for vaginal candidiasis. See Table 4.
Dermal therapeutic studies in patients treated with 150 mg weekly. See Table 5.

Children.

In clinical studies, 562 children, from birth to 17 years, received doses from 1 to 12 mg/kg/day, for up to 129 days. The majority of patients (n = 522) received 2 to 8 mg/kg/day for up to 97 days. Overall, approximately 10.3% experienced adverse events which were considered treatment related. The incidence of these adverse reactions and laboratory abnormalities do not suggest any marked difference between the paediatric population relative to the adult population. Based on this clinical trial data, the following adverse events were considered treatment related. See Table 6.

Postmarketing experience.

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

Cardiovascular.

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

Nervous system disorders.

Dizziness.

Gastrointestinal.

Dyspepsia, vomiting.

Immunological.

Anaphylaxis (including face oedema, angioedema and pruritus).

Metabolism and nutrition disorders.

Hypercholesterolaemia, hypertriglyceridaemia and hypokalaemia.

Hepatobiliary.

Hepatocellular necrosis.

Skin and subcutaneous tissue disorders.

Fixed drug eruption, urticaria, acute generalized exanthematous pustulosis.
Drug reaction with eosinophilia and systemic symptoms (DRESS).

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

The minimal lethal human dose has not been established. 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. Signs and symptoms are likely to be an extension of those under 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%.
In mice and rats receiving very high doses of fluconazole, clinical effects in both species included decreased motility and respiration, ptosis, lacrimation, salivation, urinary incontinence, loss of righting reflex and cyanosis; death was sometimes preceded by clonic convulsions.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (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. Fluconazole 50 mg daily given for up to 28 days has been shown not to affect corticosteroid levels or adrenocorticotrophic hormone (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.

Microbiology.

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 species. Activity has been demonstrated in vivo in normal and immunocompromised animals against infections with Candida sp., including systemic candidiasis, and in normal animals with Cryptococcus neoformans, including intracranial infections. One case of cross resistance of Candida to fluconazole in a patient (not infected with human immunodeficiency virus (HIV)) previously treated with ketoconazole has been reported. The efficacy of fluconazole in vivo is greater than would be apparent from in vitro testing against the abovementioned fungi.
Concurrent administration of fluconazole and amphotericin B in infected normal and immunocompromised mice showed antagonism of the two drugs in systemic infection with Aspergillus fumigatus. The clinical significance of results obtained in these studies is unknown.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Adults.

The pharmacokinetic properties of fluconazole are similar following administration by the intravenous or oral routes. In normal volunteers, the bioavailability of orally administered fluconazole is over 90% compared with intravenous administration. In fasted normal volunteers, peak plasma concentrations occur between one and five hours after the 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 five to ten days with oral doses of 50 to 400 mg once daily. Steady-state levels are approximately 2.5 times the levels achieved with single doses. Administration of a loading dose (on day 1) of twice the usual daily dose enables plasma levels to approximate to 90% steady-state levels by day 2.
There are differences in the pharmacokinetics of fluconazole between adults and children, with children (after the neonatal period) generally having a faster elimination rate and larger volume of distribution than in adults. These differences result in less accumulation on multiple dosing in children, with steady-state achieved faster than in adults.

Distribution.

The apparent volume of distribution approximates to total body water. Plasma protein binding is low (11 to 12%).
Fluconazole has been found to achieve good penetration into all tissues and body fluids studied. See Table 7.

Metabolism.

No data available.

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 dose of Fluconazole Sandoz may need to be reduced in patients with impaired renal function (see Section 4.2 Dose and Method of Administration). A three 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, once daily and once weekly dosing for all other indications. Neonates have reduced elimination rates relative to adults and even higher volumes of distribution in comparison with older children. During the first two weeks after birth, the clearance of fluconazole increases (and the half-life is decreased) as renal function develops. The half-life obtained in infants was consistent with that found in older children, although the volume of distribution was higher. During the first year of life, the pharmacokinetics of fluconazole is similar to older children. No marked sex related differences in pharmacokinetics are evident in children.
In children, the following mean pharmacokinetic data have been reported (see Table 8).
Clearance corrected for bodyweight was not affected by age in these studies. Mean body clearance in adults is reported to be 0.23 mL/minute/kg.
In premature newborn infants (gestational age of 26 to 29 weeks), the mean clearance within 36 hours of birth was 0.180 mL/minute/kg, which increased with time to a mean of 0.218 mL/minute/kg six days later and 0.333 mL/minute/kg 12 days later. Similarly, the half-life was 73.6 hours, which decreased with time to a mean of 53.2 hours six days later and 46.6 hours 12 days later.

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 two to seven times the recommended human dose). Male rats treated with 5 and 10 mg/kg/day had an increased incidence of hepatocellular adenomas.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate, maize starch, magnesium stearate, colloidal anhydrous silica, sodium lauryl sulfate, titanium dioxide, gelatin, indigo carmine (50 mg, 100 mg and 200 mg capsules only) and brilliant scarlet 4R CI16255 (200 mg capsules only). Printing Ink: shellac, black monogramming ink (107581 or 2328), propylene glycol.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
For information on interactions with other medicines and other forms of interactions, 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

Fluconazole Sandoz 50 mg capsules: Available as blister packs or bottles of 28 capsules.
Fluconazole Sandoz 100 mg capsules: Available as blister packs or bottles of 28 capsules.
Fluconazole Sandoz 150 mg capsules: Available as blister packs or bottles of 28 or 1 capsules.
Fluconazole Sandoz 200 mg capsules: Available as blister packs or bottles of 28 capsules.
Not all presentations may be marketed in Australia.

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.
Molecular formula: C13H12F2N6O.
Molecular weight: 306.3.

CAS number.

86386-73-4.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine (Pack size of 28 capsules).
Schedule 3 - Pharmacist Only Medicine (Pack size of 1 capsule).

Summary Table of Changes