DIFLUCAN*

fluconazole

50 mg capsule, 150 mg capsule, 200 mg capsule, 50 mg/5 mL powder for oral suspension, 2 mg/mL intravenous infusion

Presentation

Diflucan is available for oral administration as a size 4 hard gelatin capsule with an opaque light turquoise blue cap and white opaque body containing 50 mg fluconazole, as a size 1 hard gelatin capsule with a light turquoise opaque body and cap containing 150 mg fluconazole and as a size 0 hard gelatin capsule with a purple opaque cap and white opaque body containing 200 mg fluconazole. The shells are printed with the standard Pfizer logo and coded FLU-50, FLU-150 and FLU-200, respectively.

The ingredients present in the 50 mg, 150 mg or 200 mg fluconazole capsules include - gelatin, lactose, maize starch, colloidal anhydrous silica, magnesium stearate, sodium lauryl sulfate, titanium dioxide (E171), (50 mg and 150 mg capsules only), patent blue V (E131), (50 mg, and 150 mg capsules only), erythrosine (200 mg capsules only) and indigo carmine (200 mg capsules only).

Diflucan is available as a powder for oral suspension containing fluconazole 50 mg/5 mL. Other ingredients - sucrose, colloidal anhydrous silica, xanthan gum, sodium citrate, citric acid anhydrous, sodium benzoate, titanium dioxide (E171) and natural orange flavour.

Diflucan is also available as an intravenous infusion containing fluconazole 2 mg/mL in a clear, colourless, 0.9% saline solution. The pH of the solution is 4.0 - 8.0. Each 50 mL vial contains 7.5 mmol each of sodium and chloride.

Uses

Actions

Diflucan, a member of a new class of triazole antifungal agents, is a potent and specific inhibitor of fungal sterol synthesis.

Diflucan, both orally and intravenously administered, is active in a variety of animal fungal infection models. Activity has been demonstrated against opportunistic mycoses, such as infections with Candida spp, including systemic candidiasis and in immunocompromised animals; with Cryptococcus neoformans, including intracranial infections, with Microsporum spp; and with Trichophyton spp. Diflucan has also been shown to be active in animal models of endemic mycoses, including infections with Blastomyces dermatitidis; with Coccidioides immitis, including intracranial infection; and with Histoplasma capsulatum in normal and immunosuppressed animals.

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.

Fluconazole is a highly selective inhibitor of fungal cytochrome P-450 sterol C-14 alpha demethylation. Mammalian cell demethylation is much less sensitive to fluconazole inhibition. The subsequent loss of normal sterols correlates with the accumulation of 14 alpha-methyl sterols in fungi and may be responsible for the fungistatic activity of fluconazole. Fluconazole 50 mg daily given up to 28 days has been shown not to affect corticosteroid levels or ACTH stimulated response in healthy female volunteers. Plasma oestradiol levels and urinary free cortisol levels were decreased with little effect on plasma testosterone levels. Interaction studies with antipyrine indicate that single or multiple doses of fluconazole 50 mg do not affect its metabolism.

Pharmacokinetics

The pharmacokinetic properties of Diflucan are similar following administration by the intravenous or oral route.

After oral administration Diflucan is well absorbed, and plasma levels (and systemic bioavailability) are over 90% of the levels achieved after intravenous administration. Oral absorption is not affected by concomitant food intake. Peak plasma concentrations in the fasting state occur between 0.5 and 1.5 hours post dose with a plasma elimination half-life of approximately 30 hours. Plasma concentrations are proportional to dose. Ninety percent steady state levels are reached by day 4-5 with multiple once daily dosing.

Administration of a loading dose (on day 1) of twice the usual daily dose enables plasma levels to approximate to 90% steady state level by day 2. The apparent volume of distribution approximates to total body water. Plasma protein binding is low (11-12%).

Diflucan achieves good penetration into all body fluids studied. See table below.

* Relative to concurrent concentrations in plasma in subjects with normal renal function

+ Independent of degree of meningeal inflammation

The major route of excretion is renal with approximately 80% of the administered dose appearing in the urine as unchanged drug. Diflucan clearance is proportional to creatinine clearance.

There is no evidence of circulating metabolites. The pharmacokinetics of fluconazole are markedly affected by reduction in renal function. There is an inverse relationship between the elimination half-life and creatinine clearance. The dose of Diflucan may need to be reduced in patients with impaired renal function (see DOSAGE AND ADMINISTRATION). A 3-hour haemodialysis session reduces plasma concentration by about 50%.

The long plasma elimination half-life provides the basis for single dose therapy for vaginal candidiasis, once daily and once weekly dosing in the treatment of all other indicated fungal infections.

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 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 2 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 are 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:

Clearance corrected for body weight was not affected by age in these studies. Mean body clearance in adults is reported to be 0.23 mL/min/kg.

In premature newborns (gestational age 26 to 29 weeks), the mean clearance within 36 hours of birth was 0.180 mL/min/kg, which increased with time to a mean of 0.218 mL/min/kg 6 days later and 0.333 mL/min/kg 12 days later. Similarly, the half-life was 73.6 hours, which decreased with time to a mean of 53.2 hours 6 days later and 46.6 hours 12 days later.

Indications

Diflucan is indicated for the treatment of the following conditions:

1. Cryptococcosis, including cryptococcal meningitis and infections of other sites (e.g. pulmonary, cutaneous). Normal hosts, and patients with AIDS, organ transplants or other causes of immunosuppression may be treated. Diflucan can be used as maintenance therapy to prevent relapse of cryptococcal disease in patients with AIDS.
2. Systemic candidiasis including candidaemia, disseminated candidiasis and other forms of invasive candidal infection including infections of the peritoneum, endocardium and pulmonary and urinary tracts. Patients with malignancy, in intensive care units, receiving cytotoxic or immunosuppressive therapy, or with other factors predisposing to candidal infection may be treated.
3. Mucosal candidiasis. These include oropharyngeal, oesophageal, non-invasive bronchopulmonary infections, candiduria, mucocutaneous and chronic oral atrophic candidiasis (denture sore mouth). Normal hosts and patients with compromised immune function may be treated.
4. Vaginal candidiasis, acute or recurrent.
5. Prevention of fungal infection in immunocompromised patients considered at risk as a consequence of HIV infections or neutropenia following cytotoxic chemotherapy, radiotherapy or bone marrow transplant
6. Diflucan 50 mg & 150 mg capsules are also indicated for the treatment of dermatomycoses including tinea pedis, tinea corporis, tinea cruris, pityriasis versicolor & candidiasis.

Diflucan IV is indicated for the same conditions in patients, but should be used only when Diflucan cannot be administered orally.

Dosage and Administration

The daily dose of Diflucan should be based on the nature and severity of the fungal infection. Most cases of vaginal candidiasis respond to single dose therapy. Therapy for those types of infections requiring multiple dose 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 usually require maintenance therapy to prevent relapse.

Use in Adults

1. For cryptococcal meningitis and cryptococcal infections at other sites, the usual dose is 400 mg on the first day followed by 200 to 400 mg once daily. Duration of treatment for cryptococcal infections will depend on the clinical and mycological response, but is usually at least 6-8 weeks for cryptococcal meningitis.
   For the prevention of relapse of cryptococcal meningitis in patients with AIDS, after the patient receives a full course of primary therapy, Diflucan may be administered indefinitely at a single daily dose of 200 mg.
2. For candidaemia, disseminated candidiasis and other invasive candidal infections the usual dose is 400 mg on the first day followed by 200 mg once daily. Depending on the clinical response, the dose may be increased to 400 mg once daily. Duration of treatment is based upon the clinical response.
3. For oropharyngeal candidiasis the usual dose is 50 mg once daily for 7-14 days. If necessary, treatment can be continued for longer periods in patients with severely compromised immune function. For atrophic oral candidiasis associated with dentures the usual dose is 50 mg once daily for 14 days administered concurrently with local antiseptic measures to the denture.
   For other candidal infections of mucosa (except vaginal candidiasis, see below), e.g. oesophagitis, candiduria, mucocutaneous candidiasis etc., the usual effective dose is 50 mg daily, given for 14-30 days.
   In unusually difficult cases of mucosal candidal infections the dose may be increased to 100 mg daily.
4. For vaginal candidiasis Diflucan 150 mg should be administered as a single oral dose.
5. For the prevention of fungal infections in immunocompromised patients the dose should be 50 mg once daily while the patient is at risk as a consequence of receiving cytotoxic chemotherapy, radiotherapy or bone marrow transplant. A higher dose of 100 mg/day may be used in patients at risk of severe recurrent infections.
6. For treatment of dermatomycoses, the usual dosage is 50 mg once daily or 150mg once weekly for two to four weeks. Tinea pedis may require treatment for up to six weeks.

Use in Children

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

1. The recommended dosage of fluconazole for mucosal candidiasis 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.
2. For the treatment of systemic candidiasis and cryptococcal infection, the recommended dosage is 6-12 mg/kg daily, depending on the severity of the disease.
3. For the prevention of fungal infections in immunocompromised patients considered at risk as a consequence of neutropenia following cytotoxic chemotherapy or radiotherapy, the dose should be 3 - 12 mg/kg daily, depending on the extent and duration of the induced neutropenia (see adult dosing).

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.

Use in Elderly

Where there is no evidence of renal impairment, normal dosage recommendations should be adopted. For patients with renal impairment (creatinine clearance < 50 mL/min) the dosage the schedule should be adjusted as described below.

Use in Patients with Renal Impairment

Fluconazole is predominantly excreted in the urine as unchanged drug. No adjustments in single dose therapy are necessary.

In patients with impaired renal function who will receive multiple doses of fluconazole, an initial loading dose of 50 mg to 400 mg should be given. After the loading dose, the daily dose (according to indication) should be based on the following table:

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:

Intravenous Administration

The dose recommendations for oral and intravenous Diflucan are identical.

Diflucan is normally administered orally. If oral administration is not possible, it may be administered by intravenous infusion at a rate not exceeding 200 mg/hour, given as a constant infusion. Diflucan infusion has been used safely for up to fourteen days of intravenous therapy. 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 Diflucan 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.

If Diflucan infusion is administered to patients requiring sodium or fluid restriction, consideration should be given to the salt content of the infusion fluid (7.5 mmol/50 mL) and the total volume of fluid administered.

Diflucan infusions are intended only for intravenous administration using sterile equipment.

Diflucan intravenous infusion is compatible with the following:

1. Ringer's solution
2. Normal saline
3. Dextrose 20%
4. Hartmann's solution
5. Potassium chloride in dextrose
6. Sodium bicarbonate 4.2%
7. Aminofusin

Diflucan may be infused through an existing line with one of the above listed fluids. Although no specific incompatibilities have been noted, mixing with any other drug prior to infusion is not recommended.

Parenteral drug products 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.

Contraindications

Diflucan should not be used in patients with known sensitivity to fluconazole; to related azole compounds; or to any of its excipients.

Concomitant administration of Diflucan with cisapride is contraindicated. (See INTERACTIONS).

Coadministration of terfenadine is contraindicated in patients receiving Diflucan at multiple doses of 400 mg per day or higher based upon results of a multiple dose interaction study. (See INTERACTIONS.)

Warnings and Precautions

The coadministration of Diflucan at doses lower than 400 mg per day with terfenadine should be carefully monitored. (See INTERACTIONS.)

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 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 Diflucan therapy should be monitored for the development of more severe hepatic injury. Diflucan should be discontinued if clinical signs and symptoms consistent with liver disease develop that may be attributable to fluconazole (see ADVERSE EFFECTS).

Patients have rarely developed exfoliative cutaneous reactions, such as Stevens-Johnson Syndrome and toxic epidermal necrolysis, during treatment with Diflucan. AIDS patients are more prone to the development of serious cutaneous reactions to many drugs. If rash which is attributable to fluconazole develops in a patient treated for a superficial fungal infection, Diflucan should be discontinued. If patients with invasive/systemic fungal infections develop rashes, they should be monitored closely and Diflucan discontinued if bullous lesions or erythema multiforme develop (see ADVERSE EFFECTS).

Use During Pregnancy and Lactation

There are no adequate and well controlled studies in pregnant women. There have been reports of multiple congenital abnormalities in infants whose mothers were being treated for 3 or more months with high dose (400-800 mg/day) fluconazole therapy for coccidioidomycosis. 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.

Diflucan is found in human breast milk at concentrations similar to plasma, hence its use in nursing mothers is not recommended.

Driving/Use of Machinery

Experience with Diflucan indicates that therapy is unlikely to impair a patient's ability to drive or use machinery.

Adverse Effects

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.

1. Multiple daily dosing for treatment of oral and for oral and oropharyngeal candidiasis; cryptococcal meningitis; or systemic candidiasis.

Diflucan is generally well tolerated. Sixteen percent 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

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 WARNINGS AND PRECAUTIONS. There have been rare cases of serious hepatic reactions during treatment with Diflucan (see WARNINGS AND 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 Diflucan.

In two comparative trials evaluating the efficacy of Diflucan 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 8 times the upper limit of normal was approximately 1% in fluconazole-treated patients in the pre-marketing 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 Diflucan concomitantly with one or more of the following medications; rifampicin, phenytoin, isoniazid, valproic acid, or oral sulphonylurea hypoglycaemic agents.

Immunological

Rare: anaphylaxis.

Dermatological

Common: rash.

Rare: angioedema, exfoliative skin disorders including Stevens Johnson Syndrome and toxic epidermal necrolysis (see WARNINGS AND PRECAUTIONS), alopecia.

Haemopoietic and lymphatic

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

Metabolic

Rare: hypercholesterolaemia, hypertriglyceridaemia, hypokalaemia.

Gastrointestinal

Common: nausea, vomiting, abdominal pain, diarrhoea.

Central Nervous System

Common: headache.

Rare: seizures.

2. Single 150 mg dose for vaginal candidiasis

Dermatological

Uncommon: pruritus, genital pruritus, rash, erythematous rash, dry skin, abnormal skin odour, urticaria.

Autonomic nervous system

Uncommon: flushing, dry mouth.

Central and peripheral nervous system

Common: headache.

Uncommon: dizziness, vertigo, hyperkinesia, hypertonia.

Gastrointestinal

Common: Nausea, abdominal pain, diarrhoea, dyspepsia.

Uncommon: constipation, anorexia, flatulence, vomiting, loose stools.

Metabolic

Uncommon: thirst.

Psychiatric

Uncommon: insomnia, nervousness, female sexual dysfunction.

Reproductive

Uncommon: intermenstrual bleeding, dysmenorrhoea, leukorrhoea, menorrhagia, uterine spasm, vaginal disorder.

Respiratory

Uncommon: pharyngitis.

Special senses

Uncommon: taste perversion, abnormal vision, visual field defect.

Urinary

Uncommon: polyuria, renal pain.

General

Uncommon: fatigue, hot flushes, malaise, back pain, fatigue, herpes simplex, pain, rigors.

3. Patients treated with 150 mg weekly in dermal therapeutic studies

Dermatological

Common: acne.

Uncommon: pruritus, urticaria.

Central Nervous System

Common: headache.

Uncommon: insomnia, paraesthesia, somnolence.

Gastro-intestinal

Common: abdominal pain, dyspepsia.

Hepatobiliary

Uncommon: elevation of transaminase >2-3 × upper limit of normal.

Adverse reactions in children

In clinical studies, 562 children, from birth to 17 years, received doses from 1 to 12 mg/kg per day, for up to 129 days. The majority of patients (n=522) received 2 to 8 mg/kg per 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:

Post-Marketing experience

In addition, the following adverse events have occurred during post-marketing:

• Central Nervous System: Dizziness
• Gastrointestinal: Dyspepsia, vomiting
• Immunological: Anaphylaxis (including face oedema, angioedema and pruritus)
• Metabolic: Hypercholesterolaemia, hypertriglyceridemia and hypokalemia
• Liver/Biliary: Hepatocellular necrosis

Interactions

Fluconazole is an inhibitor of the cytochrome P450 system, particularly the CYP 2C and to a lesser extent the CYP 3A isoforms. There are possibilities that other drugs may affect the metabolism of fluconazole and that fluconazole may affect the metabolism of other drugs. In vitro studies conducted in human hepatic microsomes, demonstrate that the extent of inhibition of CYP 3A isoforms is lowest with fluconazole, when compared with ketoconazole and itraconazole. The clinically or potential significant drug interactions between fluconazole and the following agents/drug classes which have been observed are described below. The drug-drug interactions described below include both interactions mediated through affects on P450 metabolism and interactions mediated through other mechanisms.

Other drugs that affect the target drug

Hydrochlorothiazide

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

Rifampicin

Administration of a single oral 200 mg dose of fluconalzole 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 Diflucan should be considered when it is administered with rifampicin.

Effects of the target drug on other drugs

Cisapride & astemizole

There have been reports of cardiac events including torsade de pointes in patients to whom fluconazole and cisapride were coadministered. In most of these cases, the patients appear to have been predisposed to arrythmias or had serious underlying illness, and the relationship of the reported events to a possible fluconazole-cisapride drug interaction is uncertain.

Fluconazole may increase the serum levels of cisapride, astemizole or other drugs metabolised by the cytochrome P450 system. Coadministration of cisapride is contraindicated in patients receiving fluconazole (see CONTRAINDICATIONS). Caution should be used when coadministering Diflucan with astemizole, and patients should be carefully monitored.

Cyclosporin

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

Oral Contraceptives

Fluconazole at a dose of 50 mg for 10 days decreased the AUC for ethinyloestradiol by 16%, but values for levonorgestrel were unchanged.

Oral Hypoglycaemic Agents

The effects of fluconazole on the pharmacokinetics of the sulphonylurea oral hypoglycaemic agents tolbutamide, glipizide and glibenclamide were examined in three placebo-controlled crossover studies in normal volunteers. All subjects received the sulphonylurea alone and following treatment with 100 mg of fluconazole as a single daily oral dose for 7 days. Fluconazole administration resulted in significant increases in C_max and AUC of the sulphonylurea. Several subjects in these three studies experienced symptoms consistent with hypoglycaemia. In the glibenclamide study, several volunteers required oral glucose treatment. When Diflucan and sulphonylureas are coadministered, blood glucose concentrations should be monitored carefully and the dose of the sulphonylurea adjusted accordingly.

Phenytoin

Concomitant administration of oral fluconazole (200 mg) with phenytoin at steady state resulted in an average increase of 75% of phenytoin AUC values in normal volunteers. Careful monitoring of phenytoin concentrations in patients receiving Diflucan and phenytoin 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 to a fluconazole-triazolam interaction is uncertain. If concomitant benzodiazepine therapy is necessary in patients being treated with Diflucan, consideration should be given to decreasing the benzodiazepine dosage, and the patients should be appropriately monitored.

Rifabutin

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

Terfenadine

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

Theophylline

In a placebo controlled interaction study, the administration of fluconazole 200 mg for 14 days resulted in an 18% decrease in the mean plasma clearance of theophylline. Patients who are receiving high dose theophylline or who are otherwise at increased risk of theophylline toxicity should be observed for signs of theophylline toxicity while receiving Diflucan, and therapy modified appropriately 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 of 13 subjects experienced a 2-fold increase in his prothrombin time response. In post-marketing experience, as with other azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria and melena) have been reported in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. Careful monitoring of prothrombin time in patients receiving Diflucan and coumarin-type anticoagulants is recommended.

Zidovudine

Two kinetic studies resulted in increased levels of zidovudine most likely caused by the decreased conversion of zidovudine to its major metabolite. One study determined zidovudine levels in AIDS or ARC patients before and following fluconazole 200 mg daily for 15 days. There was a significant increase in zidovudine AUC (20%). A second randomised, two-period, two-treatment crossover study examined zidovudine levels in HIV infected patients. On two occasions, 21 days apart, patients received zidovudine 200 mg every eight hours either with or without fluconazole 400 mg daily for seven days. The AUC of zidovudine significantly increased (74%) during co-administration with fluconazole. Patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions.

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 C_max of fluconazole. Administration of an antacid containing aluminium and magnesium hydroxides immediately prior to a single dose of fluconazole (100 mg) had no effect on the absorption or elimination of fluconazole.

Other

Physicians should be alert to the potential for drug-drug interactions, with other drugs for which pharmacokinetic drug-drug interaction studies have not been conducted.

Fluconazole has been shown to inhibit CYP 2C and to a lesser extent the CYP 3A isoforms. Coadministration of Diflucan with some other drugs metabolised primarily by these P450 isoforms may result in increased plasma concentrations of these drugs that could increase or prolong therapeutic and adverse effects.

Overdosage

There have been case reports of overdosage with Diflucan and in one case, a 42-year-old patient infected with human immunodeficiency virus developed hallucinations and exhibited paranoid behaviour after reportedly ingesting 8,200 mg of Diflucan. The patient was admitted to hospital, and his condition resolved within 48 hours.

In the event of overdosage, symptomatic treatment (with supportive measures and gastric lavage if necessary) may be adequate.

Diflucan 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.

Pharmaceutical Precautions

Store below 30°C (86°F).

Package Quantities

Capsules

50 mg × 28

150 mg × 28

200 mg × 28

Powder for Oral Suspension

50 mg/5mL × 1

Intravenous solution

2 mg/mL × 50 mL

Further Information

Diflucan is a bis-triazole: 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)-2-propanol. Diflucan is a white to off-white crystalline powder which is sparingly soluble in water and saline. It has a molecular weight of 306.3.

   Inhouse Pharmacy (UK)