Consumer medicine information

ASPEN FLUCONAZOLE Injection for Intravenous Infusion

Fluconazole

BRAND INFORMATION

Brand name

Aspen Fluconazole Injection for Intravenous Infusion

Active ingredient

Fluconazole

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using ASPEN FLUCONAZOLE Injection for Intravenous Infusion.

What is in this leaflet

This leaflet answers some common questions about ASPEN FLUCONAZOLE injection. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you being given ASPEN FLUCONAZOLE injection against the benefits they expect it will have for you.

If you have any concerns about being given this medicine, ask your doctor or pharmacist.

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

What ASPEN FLUCONAZOLE injection is used for

ASPEN FLUCONAZOLE contains fluconazole as the active ingredient and is used to treat certain fungal and yeast infections.

It 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 this medicine has been prescribed for you. Your doctor may have prescribed it for another purpose.

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

There is no evidence that it is addictive.

Before you are given it

When you must not be given it

You must not be given ASPEN FLUCONAZOLE injection if you have an allergy to:

  • fluconazole
  • medicines related to fluconazole such as miconazole, ketoconazole or clotrimazole
  • any of the ingredients listed at the end of this leaflet.

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.

You must not be given this medicine if you are taking other medicines called cisapride or terfenadine. Tell your doctor if you are taking cisapride or terfenadine.

You must not be given this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

If you are not sure whether you should be given this medicine, talk to your doctor.

Before you are given it

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

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

  • liver, heart or kidney problems
  • AIDS
  • cancer
  • currently on a sodium or fluid restricted diet.

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding. Your doctor can discuss with you the risks and benefits involved.

If you have not told your doctor about any of the above, tell them before you are given ASPEN FLUCONAZOLE injection.

Taking other medicines

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

Some medicines may be affected by ASPEN FLUCONAZOLE or may affect how well it works. You may need to take different amounts of your medicine or you may need to take different medicines. These include:

  • cisapride
  • terfenadine
  • some medicines used to treat allergies
  • some medicines for diabetes such as glipizide or glibenclamide
  • some antibiotics and antiviral drugs such as rifampicin, rifabutin or zidovudine
  • some drugs used in problems with the immune system, such as cyclosporin or tacrolimus
  • warfarin (used to stop blood clots)
  • phenytoin (used to treat epilepsy)
  • theophylline (used to treat asthma)
  • short acting benzodiazepines such as midazolam
  • hydrochlorothiazide (used for treating fluid problems).

Your doctor has more information on medicines to be careful with or avoid while being given this medicine.

How it is given

How much is given

Your doctor will decide what dose you will receive depending on the type of infection, any pre-existing conditions and your response to the treatment.

If you are elderly or have reduced kidney function, your doctor may prescribe a lower dose.

How it is given

ASPEN FLUCONAZOLE injection will be given to you under the supervision of a doctor.

It is administered intravenously via a ‘drip’ line into a vein.

If you receive too much (overdose)

Because ASPEN FLUCONAZOLE injection is given to you under the supervision of your doctor, it is very unlikely that you will receive too much.

However, if you think you may have been given too much of this medicine, tell your doctor immediately or contact the Poisons Information Centre on 131 126 for advice.

While you are receiving it

Things you must do

Tell any other doctor, dentist or pharmacist that you are being given ASPEN FLUCONAZOLE injection, especially if you are about to be started on any new medicines.

If you are going to have surgery, tell the surgeon or anaesthetist that you are being given this medicine. It may affect other medicines used during surgery.

Tell your doctor immediately if you become pregnant while you are being given this medicine.

Keep all of your doctor’s appointments so that your progress can be checked. Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

Things to be careful of

If you suffer from HIV or have a weakened immune system and develop a rash while being given ASPEN FLUCONAZOLE injection, tell your doctor immediately. If this rash worsens, ASPEN FLUCONAZOLE injection may need to be stopped.

Side effects

Tell your doctor as soon as possible if you do not feel well while you are being treated with ASPEN FLUCONAZOLE injection. This medicine helps most people with fungal and yeast infections, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Ask your doctor to answer any questions you may have.

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

  • nausea, vomiting
  • headache
  • dizziness
  • stomach pain, indigestion, diarrhoea
  • acne
  • rash.

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:

  • 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
  • blisters and bleeding in the lips, eyes, mouth, nose and genitals
  • fainting, seizures or fits
  • jaundice, a yellowing of the skin or eyes
  • bleeding or bruising more easily than normal, reddish or purplish blotches under the skin
  • frequent infections such as fever, severe chills, sore throat or mouth ulcers
  • unusual hair loss or thinning
  • fast or irregular heart beat.

These are serious side effects. You may need urgent medical attention. Serious side effects are rare.

Tell your doctor, nurse or pharmacist anything else that is making you feel unwell, even if you think the problems are not connected with this medicine and are not referred to in this leaflet. Other side effects not listed above may also occur in some people.

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

After using it

Storage

ASPEN FLUCONAZOLE injection will be stored in the pharmacy or on the ward. It is kept in a cool dry place, protected from light, where the temperature stays below 25°C.

Product description

What it looks like

ASPEN FLUCONAZOLE injection is a clear, colourless sterile solution in an infusion bag.

Available in packs of 10 infusion bags.

Ingredients

Active ingredient:
Each 100 mL infusion bag contains 200 mg of fluconazole, equating to a strength of 2 mg/mL fluconazole.

Inactive ingredients:

  • sodium chloride
  • water for injections.

Sponsor

Aspen Pharmacare Australia Pty Ltd
34-36 Chandos St
St Leonards NSW 2065
Australia

Australian Registration Number:
AUST R 128728

This leaflet was prepared in
February 2012.

Published by MIMS September 2013

BRAND INFORMATION

Brand name

Aspen Fluconazole Injection for Intravenous Infusion

Active ingredient

Fluconazole

Schedule

S4

 

Name of the medicine

Fluconazole.

Excipients

Sodium chloride and water for injection.

Description

Chemical name: 2-(2,4-difluorophenyl)-1,3- bis(1H-1,2,4-triazol-1-yl)-propan-2-ol. Molecular formula: C13H12F2N6O. MW: 306.3. CAS: 86386-73-4. Fluconazole is a white to off white crystalline powder which is sparingly soluble in water and saline. Aspen Fluconazole Injection for Intravenous Infusion is a clear, colourless solution. It is formulated in a 0.9% sodium chloride solution, with each 100 mg (50 mL) bag containing 7.5 mmol of Na+ and Cl-, each 200 mg (100 mL bag) containing 15 mmol of Na+ and Cl- and each 400 mg (200 mL) bag containing 30 mmol Na+ and Cl-. This should be considered in patients on a sodium or fluid restricted diet.

Pharmacology

Pharmacodynamic properties.

Fluconazole, a member of the triazole class of antifungal agents, is a potent and selective inhibitor of fungal enzymes necessary for the synthesis of ergosterol.
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.

Pharmacokinetic properties.

Fluconazole's pharmacokinetic properties are similar following its oral or intravenous administration. In fasted normal volunteers, peak plasma concentrations occur between one and two hours after the dose with a terminal plasma elimination half-life of approximately 30 hours (range 20 to 50 hours). Orally administered fluconazole is well absorbed, with plasma levels (and systemic bioavailability) being over 90% of the levels achieved following intravenous administration. Absorption by the oral route is not affected by the joint administration of food. Maximum plasma concentrations when fasting are obtained between 0.5 and 1.5 hours postdose, with a clearance half-life of approximately 30 hours.
Plasma concentrations are proportional to the dose. 90% steady-state levels are reached after 4 or 5 days with multiple once daily doses. The administration of a higher dose on the first day, double that of the normal daily dose, raises plasma levels to 90% of the equilibrium status levels by the second day.
The apparent volume of distribution is close to that of total body water. Fluconazole achieves good penetration in all body fluids studied. The levels of fluconazole in saliva and sputum are similar to plasma levels. In patients with fungal meningitis, fluconazole levels in the CSF are approximately 80% of the corresponding plasma levels. High skin concentrations of fluconazole, above serum concentrations, are achieved in the stratum corneum, epidermis-dermis and eccrine sweat. Fluconazole accumulates in the stratum corneum. Binding to plasma proteins is low (11-12%).
Clearance is mostly renal, with approximately 80% of the unmodified dose appearing in the urine. The clearance of fluconazole is proportional to creatinine clearance. There is no evidence of circulating metabolites.
Fluconazole's long plasma elimination half-life makes it possible to administer a single dose in the treatment of genital candidiasis and a daily dose in the treatment of other indications.

Impaired renal function.

In patients with impaired renal function, the half-life is 98 to 125 hours.

Children.

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. 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 marked sex related difference in pharmacokinetics are evident in children.
In children, the following mean pharmacokinetic data have been reported (see Table 1).
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.

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 species, including systemic candidiasis, and in normal animals with C. neoformans, including intracranial infections. One case of cross resistance of Candida to fluconazole in a patient (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.

Indications

Aspen Fluconazole Injection is indicated for the following conditions but should be used only when fluconazole cannot be administered orally.
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.

Contraindications

Known hypersensitivity to fluconazole, related azole compounds or any of the excipients of Aspen Fluconazole Injection.
Concomitant administration with cisapride is contraindicated.
Coadministration of terfenadine is contraindicated in patients receiving fluconazole injection at multiple doses of 400 mg per day or higher based upon results of a multiple dose interaction study (see Interactions with Other Medicines).

Precautions

Anaphylaxis.

Anaphylaxis has been reported in rare instances.
Risk-benefit should be considered when the following medical problems exist.

Cardiac function impairment.

Some azoles, including fluconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During postmarketing surveillance, there have been very rare cases of QT prolongation and torsades de pointes in patients taking fluconazole. These reports included seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities and concomitant medications that may have been contributory. Fluconazole should be administered with caution to patients with these potentially pro-arrhythmic conditions (see Adverse Effects).

Hepatic function impairment.

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 with hepatotoxicity, 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 Adverse Effects).

Underlying diseases such as AIDS and cancer.

In some patients, particularly those with serious underlying diseases such as AIDS and cancer, abnormalities in haematological, hepatic, renal and other biochemical function test results have been observed during treatment with fluconazole. However, the clinical significance and relationship to treatment is uncertain.

Elderly patients with renal impairment.

Dosage should be adjusted for elderly patients with renal impairment (see Dosage and Administration).

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 severe cutaneous reactions to many drugs.
If a rash develops in a patient treated for a superficial fungal infection, which is considered attributable to fluconazole, further therapy with this agent 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.

Use in pregnancy.

(Category D)
There are no adequate and well controlled studies in pregnant women. There have been reports of multiple congenital abnormalities in infants whose mothers were being treated for 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. Adverse foetal effects have been seen in animals only at high dose levels associated with maternal toxicity. These findings are not considered relevant to fluconazole used at therapeutic doses.
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 foetus.

Use in lactation.

Fluconazole has been found in human breast milk at concentrations similar to those in plasma, hence its use in breastfeeding women is not recommended.

Use in elderly.

Dosage should be adjusted for elderly patients with renal impairment.

Carcinogenicity, mutagenicity, impairment of fertility.

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.
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.
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 of 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.

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 drugs that could change therapeutic effects and/or adverse event profiles.
Clinically or potentially significant drug interactions have been observed between fluconazole and the following agents: short acting benzodiazepines, cisapride, coumarin type anticoagulants, cyclosporin, hydrochlorothiazide, oral hypoglycaemics, phenytoin, rifampicin, rifabutin, tacrolimus and theophylline. These are described in greater detail below.

Effects of fluconazole on other medicines.

Concomitant use of the following agents with fluconazole is contraindicated.

Cisapride.

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

Terfenadine.

Serious dysrhythmias (secondary to prolongation of the ATc interval) have occurred in patients receiving azole antifungals in conjunction with terfenadine. One study of a 200 mg daily dose of fluconazole failed to demonstrate a prolongation in QTc interval. Another study of 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. Patients should be carefully monitored if they are being concurrently prescribed fluconazole at multiple doses lower than 400 mg/day and terfenadine. The combined use of fluconazole at doses of 400 mg or greater with terfenadine is contraindicated (see Contraindications).

Effects of other medicinal products on fluconazole.

Interaction of fluconazole with the following agents may result in increased exposure to these drugs. Careful monitoring and/or dosage adjustment should be considered.
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 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 of fluconazole is significantly decreased by the concomitant administration of the following agent.

Rifampicin.

The concomitant administration of fluconazole and rifampicin gave rise to a 25% reduction in the AUC and a 20% shorter half-life of fluconazole. Thus, an increase in the dose of fluconazole should be considered for patients receiving concomitant rifampicin.
The following drug interactions relate to the use of multiple dose fluconazole; their relevance to single dose fluconazole has not yet been established.

Anticoagulants.

In an interaction study, fluconazole increased the prothrombin time (12%) after warfarin administration in healthy males. 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. Prothrombin time in patients receiving coumarin type anticoagulants should be carefully monitored.

Benzodiazepines (short acting).

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 true interaction between fluconazole and triazolam 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 the patients should be appropriately monitored.

Cyclosporin.

A pharmacokinetic study conducted on kidney transplant patients showed that a daily dose of fluconazole 200 mg slowly increased the concentrations of cyclosporin. However, another multiple dose study using fluconazole 100 mg daily showed that levels of cyclosporin were not affected in patients following bone marrow transplants. Thus, the monitoring of the plasma concentration of cyclosporin is recommended in patients taking fluconazole.

Oral hypoglycaemic agents, tolbutamide, glipizide and glibenclamide (sulfonylurea).

Fluconazole has been shown to prolong the serum half-life of concomitantly administered oral sulfonylureas (glibenclamide, glipizide) in healthy volunteers. Fluconazole and oral sulfonylureas may be given jointly to diabetic patients, although the possibility of a hypoglycaemic episode must be considered. Blood glucose levels must, therefore, be monitored and the dose of sulfonylurea adjusted accordingly.

Phenytoin.

The concomitant administration of fluconazole and phenytoin may increase levels of phenytoin to a clinically significant degree. If both drugs need to be given concomitantly, levels of phenytoin must be monitored and the dose of phenytoin adjusted to maintain therapeutic levels.

Theophylline.

In a placebo controlled interaction study, the administration of fluconazole 200 mg daily for 14 days, led to a reduction of 18% in the mean plasma clearance figure of theophylline. Therefore, patients receiving high doses of theophylline or patients with high risk of theophylline toxicity should be carefully monitored for signs of theophylline toxicity when receiving fluconazole. Treatment should be appropriately modified if signs of toxicity develop.

Warfarin.

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

Zidovudine.

Two pharmacokinetic studies have shown increases in levels of zidovudine, caused very probably by the fall in the conversion of zidovudine to its main metabolite. One study determined the levels of zidovudine in AIDS or ARC patients before and after the daily administration of 200 mg fluconazole for 15 days. A significant increase was observed in the zidovudine AUC (20%). A second randomised two period, two treatment crossover study examined the levels of zidovudine in patients infected with HIV. On two occasions, with an interval of 21 days, patients received zidovudine 200 mg every eight hours, either with or without 400 mg of fluconazole daily for seven days. The AUC of zidovudine increased significantly (74%) during joint administration with fluconazole. Therefore, patients receiving this combination should be monitored for the appearance of adverse reactions related to zidovudine.

Rifabutin.

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

Tacrolimus.

There have been reports that an interaction exists when fluconazole is administered concomitantly with tacrolimus, leading to increased serum levels of tacrolimus. There have also been reports of nephrotoxicity in patients to whom fluconazole and tacrolimus were coadministered. Patients receiving tacrolimus and fluconazole concomitantly should be carefully monitored.
Interaction of fluconazole with the following agents may not require dosage adjustment.

Oral contraceptives.

Two pharmacokinetic studies were conducted with combined oral contraceptives and multiple fluconazole doses. In the study using 50 mg fluconazole, there were no relevant effects on hormone level. However, using 200 mg fluconazole daily, the area under the curve (AUC) for ethinyloestradiol and levonorgestrel increased by 40 and 24%, respectively. Thus, multiple dose use of fluconazole at these levels is unlikely to affect the efficacy of combined oral contraceptives.

Two way interactions.

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

Azithromycin.

An open label, randomized, 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%.
Guidance on the clinical management of drug interactions is provided in Table 2.

Adverse Effects

Adults.

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 - Aspen Fluconazole is generally well tolerated. 16% of over 4000 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 disorders.

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 Precautions). 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 crytococcal meningitis, a statistically significant increase was observed in median AST 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 reactions observed include the following. (Frequencies are categorized as follows. Very common ≥ 10%; 1% ≤ common < 10%; 0.1% ≤ uncommon < 1%; 0.01% ≤ rare < 0.1%.)

Blood and lymphatic system disorders.

Rare: leucopenia (including neutropenia and agranulocytosis), thrombocytopenia.

Gastrointestinal disorders.

Common: nausea, vomiting, abdominal pain, diarrhoea.

Immunological system disorders.

Rare: anaphylaxis.

Metabolism and nutrition disorders.

Rare: hypercholesterolaemia, hypertriglyceridaemia, hypokalaemia.

Nervous system disorders.

Common: headache. Rare: seizures.

Skin and subcutaneous tissue disorders.

Common: rash. Rare: angioedema, exfoliative skin disorders including Stevens-Johnson syndrome and toxic epidermal necrolysis (see Precautions), alopecia.

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.

Cardiac disorders.

Uncommon: cardiomyopathy.

Ear and labyrinth disorders.

Uncommon: deafness.

Gastrointestinal disorders.

Common: vomiting, diarrhoea, abdominal pain. Uncommon: nausea, dyspepsia, ileus, stomatitis, loose stools.

Hepatobiliary disorders.

Uncommon: hepatocellular damage, jaundice.

Metabolism and nutrition disorders.

Uncommon: anorexia.

Nervous system disorders.

Uncommon: headache, taste perversion.

Respiratory, thoracic and mediastinal disorders.

Uncommon: hypoxia, respiratory disorder.

Skin and subcutaneous tissue disorders.

Uncommon: rash (erythematous and maculopapular), pruritus, purpura.

Vascular disorders.

Uncommon: hypertension.

Postmarketing experience.

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

Cardiovascular.

Torsades de pointes (see Precautions).

Gastrointestinal.

Dyspepsia, vomiting.

Hepatobiliary disorders.

Hepatocellular necrosis.

Immune system disorders.

Anaphylaxis (including face oedema, angioedema and pruritus).

Investigations.

QT prolongation (see Precautions).

Metabolism and nutrition disorders.

Hypercholesterolaemia, hypertriglyceridaemia and hypokalaemia.

Nervous system disorders.

Dizziness.

Dosage and Administration

Fluconazole may be administered either orally or by intravenous infusion at a rate not exceeding 200 mg/hour. 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 Aspen Fluconazole 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 Aspen Fluconazole.
Duration of treatment for cryptococcal infections will depend on the clinical and mycological response, but should continue for 10 to 12 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 AIDS patients.

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

Oropharyngeal 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 colonized.

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.

Children.

As with similar infections in adults, the duration of treatment is based on the clinical and mycological response. Aspen Fluconazole is administered as a single dose each day.

Mucosal candidiasis.

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

Systemic candidiasis and cryptococcal infection.

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 older children should be used but administered every 72 hours. During weeks 3 to 4 of life, the same dose should be given every 48 hours.

Elderly.

Dosage should be adjusted for elderly patients with renal impairment.

Impaired renal function.

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 3.
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 following formula (based on sex, weight and age of patient) should be used to estimate the creatinine clearance in mL/minute.

Administration.

If Aspen Fluconazole Injection for Intravenous Infusion is administered to patients requiring sodium or fluid restriction, consideration should be given to the salt content of the infusion fluid (15 mmol/100 mL) and the total volume of fluid administered.
Aspen Fluconazole has been used safely for up to 14 days of intravenous therapy. The intravenous infusion should be administered at a maximum rate of approximately 200 mg/hour, given as a continuous infusion.
Aspen Fluconazole is intended only for intravenous administration using sterile equipment.
Aspen Fluconazole is for single use in one patient only. Discard any residue.
Aspen Fluconazole should be inspected visually for particulate matter and discolouration prior to administration whenever solution and container permit. Do not use if the solution is cloudy or precipitated or if the seal is not intact.
Aspen Fluconazole Injection for Intravenous Infusion is compatible with the following.
Ringers solution.
Normal saline.
Mixing with any other drug prior to infusion is not recommended.

Overdosage

There has been a reported case of overdose with fluconazole. A 42 year old patient infected with human immunodeficiency virus developed hallucinations and exhibited paranoid behaviour after reportedly ingesting fluconazole 8,200 mg, unverified by his doctor. The patient was admitted to hospital and his condition resolved within 48 hours.
In the event of overdose, contact the Poisons Information Centre on 131 126 for advice on management.
As 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%.

Presentation

Solution for infusion (clear, colourless), 100 mg/50 mL, 200 mg/100 mL, 400 mg/200 mL: 10's (infusion bags).

Storage

Store below 25°C. Protect from light.

Poison Schedule

S4.