INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
DIFLUCAN CAPSULES 150 mg

DIFLUCAN
Fluconazole
        S4
        Prescription
        Required

SCHEDULING STATUS
Schedule 4.

PROPRIETARY NAME
(and dosage form):

DIFLUCAN CAPSULES 150 mg

COMPOSITION
Diflucan (fluconazole) is a bis-triazole: 2-(2,4-Difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)-2-propanol. Fluconazole is a white to off-white crystalline powder which is sparingly soluble in water and saline. It has a molecular weight of 306,3.
Each Diflucan Capsule 150 mg contains 150 mg fluconazole.
Diflucan Capsules 150 mg contain the following inactive ingredients: lactose, maize starch, colloidal silicone dioxide, magnesium stearate and sodium lauryl sulphate in a hard gelatin capsule with titanium dioxide and patent blue as colourants.

PHARMACOLOGICAL CLASSIFICATION
A.20.2.2 Fungicides.

PHARMACOLOGICAL ACTION
Fluconazole, a member of the triazole antifungal agents, is an inhibitor of fungal sterol synthesis.
After oral administration fluconazole is well absorbed with systemic bioavailability being over 90%. 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 protein binding is low (12%).
The major route of excretion is renal with approximately 80% of the administered dose appearing in the urine as unchanged drug. Fluconazole clearance is proportional to creatinine clearance. There is no evidence of circulating metabolites, but accumulation is significant over 15 days and concentrations may rise 2-3 fold. The long plasma elimination half-life provides the basis for once daily dosing in the treatment of systemic conditions, single dose therapy for vaginal candidiasis and once weekly dosing for other indications.
Fluconazole is highly specific for fungal cytochrome P-450 dependant enzymes. Fluconazole has been shown not to affect testosterone plasma concentrations in males or steroid concentrations in females of child-bearing age.

INDICATIONS
Once the results of the cultures and other laboratory studies become available, anti-infective therapy should be adjusted.
When systemic treatment is indicated and appropriate, Fluconazole is used in the following conditions:

1.	Vaginal candidiasis, acute or recurrent and prophylaxis to reduce the incidence of recurrent vaginal candidiasis.
2.	Candidial balanitis
3.	Dermatomycosis including tinea pedis, tinea corporis, tinea cruris, tinea unguium (onychomycosis), and dermal candida infections.

CONTRA INDICATIONS
Fluconazole should not be used in patients with known sensitivity to the drug or to related triazole compounds.
Multiple dose therapy is contra-indicated in patients with renal impairment.

WARNINGS
Use during pregnancy and lactation
Safety in pregnancy and lactation has not been established.
Use in Children
Insufficient evidence is available to establish safety and efficacy of Diflucan in the above indications for use in children.
Hepatic Function
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. Hepatotoxicity may be reversible on discontinuation of therapy. Patients who develop abnormal liver function tests during fluconazole therapy should be monitored for the development of more serious hepatic injury. Fluconazole should be discontinued if clinical signs or symptoms consistent with liver disease develop that may be attributable to fluconazole.
Patients have less frequently developed pruritis, rashes, urticaria, angiooedema, dry skin, abnormal odour, exfoliative cutaneous reactions, such as Steven-Johnson Syndrome and toxic epidermal necrolysis during treatment with fluconazole. AIDS patients are more prone to the development of severe cutaneous reaction to many drugs. If patients with invasive/systemic fungal infections develop rashes, they should be monitored closely and fluconazole discontinued if bullous lesions or erythema multiforme develop.

DOSAGE AND DIRECTIONS FOR USE
For vaginal candidiasis Diflucan 150 mg should be administered as a single oral dose.
To reduce the incidence of recurrent vaginal candidiasis, a 150 mg once monthly dose may be used. The duration of therapy should be individualised, but ranges from 4-12 months. Some patients may require more frequent dosing.
For Candida balanitis, Diflucan 150 mg should be administered as a single oral dose.
For dermal infections including tinea pedis, corporis, cruris and candida infections the recommended dosage is 150 mg once weekly. Duration of treatment is normally 2 to 4 weeks but tinea pedis may require treatment for up to 6 weeks.
For tinea unguium, the recommended dosage is 150 mg once weekly. Treatment should be continued until infected nail is replaced (uninfected nail grows in). Regrowth of fingernails and toenails normally require 3 to 6 months and 6 to 12 months, respectively. However, growth rates may vary widely in individuals and by age. After successful treatment of long term chronic infections, nails occasionally remain disfigured.
Use in Elderly
Where there is no evidence of renal impairment, normal dosage recommendations should be adopted.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
The commonest side effects associated with fluconazole are symptoms related to the gastrointestinal tract. These include nausea, vomiting, abdominal pain, diarrhoea and flatulence. After gastrointestinal symptoms, the second most commonly observed side effect was rash. If a rash develops which is considered attributable to fluconazole, further therapy with this agent should be avoided. See “Warnings”. Headache has been associated with fluconazole.
In some patients, particularly those with serious underlying diseases such as AIDS and cancer, abnormalities of hepatic, renal and haematological function have been observed during treatment with fluconazole.
Exfoliative skin disorders, seizures, leucopenia, thrombocytopenia, and alopecia have occurred under conditions where a causal association is uncertain.
The following side effects have occasionally been reported with fluconazole therapy: Headache, taste perversion, abnormal vision, insomnia, nervousness, rigors, fatigue, flushing, dizziness, vertigo, hyperkinesia, hypertonia, malaise, thirst, polyuria, hypokalaemia, hypercholestrolaemia, hypertriglyceridaemia, female sexual dysfunction, intermenstrual bleeding, leukorrhoea, menorrhagia and anaphylaxis.
Interactions
Fluconazole has been shown to prolong prothrombin times in subjects receiving warfarin. In concomitant treatment with fluconazole and coumarin drugs the dose of anticoagulant should be carefully titrated.
Fluconazole has been shown to prolong the serum half life of concomitantly administered oral sulphonylureas.
No clinically significant interactions have been seen with coadministration of oral contraceptives, cyclosporin A, or cimetidine. No adverse effect has been seen on endogenous steroid levels or on ACTH stimulated cortisol response.
Co-administration of multiple doses of hydrochlorothiazide may increase the plasma concentrations of fluconazole.
Concomitant administration of Diflucan and phenytoin may increase the levels of phenytoin to a clinical significant degree.
Concomitant administration of fluconazole and theophylline may increase the risk of theophyllline toxicity due to a fluconazole induced decrease in plasma theophylline clearance.
Concomitant administration of Diflucan and rifampicin has resulted in a 25% decrease in the AUC and 20% shorter half-life of fluconazole.
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, cross-over study examined zidovudine levels in HIV 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.
Terfenadine: Because of the occurrence of serious dysrhythmias in patients receiving other azole antifungals in conjunction with terfenadine, interaction studies have been performed and demonstrated that no clinically significant drug interaction was present. Although these events have not been observed in patients receiving fluconazole, the co-administration of fluconazole and terfenadine should be carefully monitored.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
There has been a reported case of overdosage with fluconazole. A 42 year-old patient infected with HIV developed hallucinations and exhibited paranoid behaviour after reportedly ingesting 8200 mg of fluconazole. The patient was admitted to hospital and his condition resolved within 48 hours.
In the advent of overdosage, symptomatic treatment (with supportive measures and gastric lavage if necessary) may be adequate.
Fluconazole is largely excreted in the urine; forced diuresis would probably increase the elimination rate. A three hour haemodialysis session decreases plasma levels by approximately 50%.

IDENTIFICATION

Diflucan Capsules 150 mg:

Hard gelatin capsules with a turquoise blue body and cap, imprinted with the Pfizer logo and an identity code FLU-150.

PRESENTATION
Diflucan Capsules 150 mg: Blister packs containing 1 or 4 capsules.

STORAGE INSTRUCTIONS
Store below 30°C in a dry place. Keep out of reach of children.

REGISTRATION NUMBERS
Diflucan Capsules 150 mg: V/20.2.2/340

NAME AND BUSINESS ADDRESS OF APPLICANT
Pfizer Laboratories (Pty) Ltd
102 Rivonia Road
SANDTON
2196

DATE OF PUBLICATION OF THIS PACKAGE INSERT
25 July 1997

Updated on this site: February 2005
Source: Pharmaceutical Industry
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