INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
DIFLUCAN CAPSULES 50 mg
DIFLUCAN CAPSULES 200 mg
DIFLUCAN IV INFUSION 100 mL
DIFLUCAN 50 mg/5 mL Powder for Oral Suspension
DIFLUCAN 200 mg/5 mL Powder for Oral Suspension

SCHEDULING STATUS:
Schedule 4.

PROPRIETARY NAME
(and dosage form):

DIFLUCAN
Fluconazole        S4
Prescription
Required

DIFLUCAN CAPSULES 50 mg
DIFLUCAN CAPSULES 200 mg
DIFLUCAN IV INFUSION 100 mL
DIFLUCAN 50 mg/5 mL Powder for Oral Suspension
DIFLUCAN 200 mg/5 mL Powder for Oral Suspension

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 50 mg contains 50 mg fluconazole
Each Diflucan Capsule 200 mg contains 200 mg fluconazole
Diflucan Capsules contain the following inactive ingredients: lactose, maize starch, colloidal silicone dioxide, magnesium stearate and sodium lauryl sulphate in a hard gelatin capsule containing titanium dioxide with or without patent blue as colourants.

Each Diflucan IV Infusion 100 mL contains 200 mg fluconazole (2 mg/mL).
Diflucan Intravenous Infusion is a sterile aqueous solution which is made iso-osmotic with sodium chloride.

Diflucan 50 mg/5 mL Powder for Oral Suspension yields on reconstitution with 24 mL water a suspension containing the equivalent of 50 mg fluconazole per 5 mL with 0,24% m/v sodium benzoate as preservative.
Diflucan 200 mg/5 mL Powder for Oral Suspension yields on reconstitution with 24 mL water a suspension containing the equivalent of 200 mg fluconazole per 5 mL with 0,24% m/v sodium benzoate as preservative.
Diflucan Powder for Oral Suspension contains the following inactive ingredients:
Sucrose (2.88 g per 50 mg dose in 50 mg/5 mL or 2.73 g per 200 mg dose in 200 mg/5 mL), colloidal anhydrous silica, titanium dioxide, xanthan gum, sodium citrate dihydrate, citric acid anhydrous, sodium benzoate and natural orange flavour as flavourant.

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 in adults, 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%).
Pharmacokinetic studies performed in children have shown that fluconazole is cleared faster than in adults, with a half life of 23 hours. The volume of distribution of fluconazole in children under 1 year of age (950 mL/kg) is higher than in adults (700 mL/kg). Accumulation on multiple daily dosing is therefore less and steady state plasma levels are achieved faster than in adults.
In neonates, the half lives determined over the first 2 weeks of life are considerably longer than adult values with a mean of 74 hours at Day 1 and 47 hours at Day 13 of life. The volume of distribution is about 1200 mL/kg in neonates.
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 (approximately 30 hours) provides the basis for once daily dosing in the treatment of systemic conditions and single dose therapy for vaginal candidiasis.
There have been reports of cases of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to fluconazole (e.g., Candida krusei). Such cases may require alternative antifungal therapy
Fluconazole is 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 cultures and other laboratory studies become available, anti-infective therapy should be adjusted accordingly.
Fluconazole is indicated for the treatment of the following conditions in adults and children:

1.	Cryptococcal meningitis and maintenance therapy to prevent relapse of cryptococcal disease in patients with AIDS
2.	Systemic candidiasis
3.	Oropharyngeal and oesophageal candidiasis
4.	Prevention of fungal infections in patients with malignancy who are predisposed to such infections as a result of cytotoxic chemotherapy and radiotherapy

CONTRA-INDICATIONS
Fluconazole should not be used in patients with known sensitivity to the medicine or to related azole compounds.
Co-administration of terfenadine is contra-indicated in patients receiving fluconazole at multiple doses of 400 mg per day or higher based upon results of a multiple dose interaction study (See Interactions section)
Coadministration of cisapride is contraindicated in patients receiving fluconazole.
Pregnancy.
Lactation, as fluconazole is found in breast milk at concentrations similar to plasma.

WARNINGS
Use during pregnancy and lactation
There are no adequate and well controlled studies which assessed the safety of fluconazole treatment in pregnant women. There have been reports of congenital abnormalities in infants whose mothers were treated with fluconazole. The relationship between fluconazole use and these events is unclear.
Effects on Ability to Drive and Use Machines
Experience with fluconazole indicates that therapy is unlikely to impair a patient’s ability to drive or use machinery.
Hepatic Function
Fluconazole has been associated with 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.
The co-administration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored. (See Interactions section)
Dosage in Patients with Impaired Renal Function
Fluconazole is cleared primarily by renal excretion as unchanged drug. No adjustments in single dose therapy are necessary. Multiple-dose therapy should be carefully monitored in patients with renal impairment.
In patients (including children) with impaired renal function, an initial dose of 50 to 400 mg should be given. After the loading dose, the daily dose (according to indication) should be based on the following table:
DOSAGE AND ADMINISTRATION
        DIFLUCAN

Creatinine Clearance (mL/min)	Percent of Recommended Dose
>50	100%
<50	50%
Regular haemodialysis	100% after each dialysis

These are suggested dose adjustments based on pharmacokinetics following administration of multiple doses. Further adjustment may be needed depending upon clinical condition. When serum creatinine is the only measure of renal function available, the following formula (based on sex, weight, and age of the patient) should be used to estimate the creatinine clearance:

Males:	Weight (kg) x (140 minus age)
	72 x serum creatinine (mg/dL)

Conversion of serum creatinine units to SI (i.e., micromol/L):

	Weight (kg) x (140 minus age)
	88,4 x 72 x serum creatinine (mg/dL)

Females:        0.85 x above value

DOSAGE AND DIRECTIONS FOR USE
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.
To reconstitute the powder for oral suspension: Tap the bottle to loosen powder. Add 24 mL of water.
Shake well. Shake immediately prior to use.
Use in Adults

1.	For cryptococcal meningitis the usual dose is 400 mg on the first day followed by 200 mg once daily. Depending on the clinical response of the patient this dose may be increased to 400 mg daily. Usually, duration of treatment for cryptococcal meningitis is 6-8 weeks.
	For the prevention of relapse of cryptococcal meningitis in patients with AIDS, after the patient received a full course of primary therapy, fluconazole may be administered at a daily dose of 100 to 200 mg.
2.	For systemic candidiasis 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 upon the clinical response.
3.	For oropharyngeal candidiasis, the usual dose is 50 to 100 mg once daily for 7-14 days.
	If necessary, treatment can be continued for longer periods in patients with severely compromised immune function.
	For the prevention of relapse of oropharyngeal candidiasis in patients with AIDS, after the patient receives a full course of primary therapy, fluconazole may be administered at a 150 mg once weekly dose.
	For oesophageal candidiasis, the recommended dose is 200 mg on the first day, followed by 100 mg to 200 mg once daily. Doses up to 400 mg/day may be used, based on medical judgment of the patient’s response to therapy. Patients with oesophageal candidiasis should be treated for a minimum of three weeks and for at least two weeks following resolution of symptoms.
4.	The recommended fluconazole dosage for the prevention of candidiasis is 50 mg to 400 mg once daily, based on the patients risk for developing fungal infection. For patients at high risk of systemic infection e.g. patients who are anticipated to have profound or prolonged neutropenia, a dose of 400 mg once daily has been used. Fluconazole administration should start several days before the anticipated onset of neutropenia and continue for 7 days after the neutrophil count rises above 1000 cells per mm³.

Use in Elderly
Where there is no evidence of renal impairment, normal dosage recommendations should be adopted.
Use in Children
As with similar infections in adults, the duration of treatment is based on the clinical and mycological response. The maximum adult daily dosage should not be exceeded in children. Diflucan is administered as a single daily dose.

1.	The recommended dosage of Diflucan for oropharyngeal candidiasis in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Treatment should be administered for at least 2 weeks to decrease the likelihood of relapse.
2.	For the treatment of oesophageal candidiasis, the recommended dosage of Diflucan in children is 6 mg/kg on the first day, followed by 3 mg/kg once daily. Doses up to 12 mg/kg/day may be used based on medical judgment of the patient’s response to therapy. Patients with oesophageal candidiasis should be treated for a minimum of three weeks and for at least 2 weeks following the resolution of symptoms.
3.	For the treatment of systemic candidiasis and cryptococcal infection, the recommended dosage is 6-12 mg/kg/day, depending on the severity of the disease.
4.	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.(For children with impaired renal function, see “Dosage in patients with impaired renal function’.)

For children with impaired renal function the daily dose should be reduced in accordance with the guidelines given for adults, dependent on the degree of renal impairment.
Use in 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.
Intravenous Infusion
Fluconazole is formulated in 0.9% sodium chloride solution, each 200 mg (100 mL bottle) containing 15 mmol each of Na+ and Cl-. Because fluconazole is available as a dilute saline solution, in patients requiring sodium or fluid restriction, consideration should be given to the rate of fluid administration.
Fluconazole intravenous infusion is compatible with the following administration fluids:

a)	Dextrose 20%
b)	Ringer's solution
c)	Normal saline
d)	Potassium chloride in dextrose
e)	Sodium bicarbonate 4.2%

Fluconazole may be infused at a maximum rate of approximately 200 mg/hour 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.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
The commonest side-effects associated with fluconazole are:
Central and Peripheral Nervous System: Headache.
Dermatologic: Rash. If a rash develops which is considered attributable to fluconazole, further treatment with this agent should be stopped.
Gastrointestinal: Nausea, vomiting, abdominal pain, diarrhoea and flatulence.
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 (see “Warnings”).
Liver/Biliary: Hepatic toxicity including rare cases of fatalities, elevated alkaline phosphatase, elevated bilirubin, elevated SGOT, elevated SGPT

Other side-effects include:
Central and Peripheral Nervous System: Dizziness, seizures, hyperkinesia, hypertonia, vertigo.
Dermatologic: Alopecia, exfoliative skin disorders including Stevens-Johnson Syndrome and toxic epidermal necrolysis (See “Warnings”).
Gastrointestinal: Dyspepsia
Haematopoetic and Lymphatic: Leucopenia including neutropenia and agranulocytosis, thrombocytopenia.
Immunologic: Anaphylaxis (including angioedema, face edema pruritis)
Liver/Biliary: Hepatic failure, hepatitis, hepatocellular necrosis, jaundice
Metabolic/Nutritional: Hypercholesterolemia, hypertriglyceridemia, hypokalemia, thirst, polyuria.
Psychiatric: Insomnia, nervousness.
Reproductive: Female sexual dysfunction, intermenstrual bleeding, leukorrhea and menorrhagia.
Body as a whole: Fatigue, malaise, rigors, flushing.
Other senses: Taste perversion, abnormal vision.

Interactions
Fluconazole has been shown to prolong prothrombin times in subjects receiving warfarin. In post-marketing experience, 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. In concomitant treatment with fluconazole and coumarin medicines the dose of anticoagulant should be carefully titrated and the prothrombin time should be carefully monitored. Particular attention should be paid to such patients requiring minor oral surgery and dental procedures.
Benzodiazepines (Short Acting): Concurrent oral administration of midazolam and fluconazole resulted in substantial increases in midazolam concentrations and its psychomotor effects. This effect on midazolam appears to be more pronounced following oral administration of fluconazole than with fluconazole administered intravenously. If concomitant benzodiazepine therapy (e.g., midazolam, triazolam) is necessary in patients on treatment with fluconazole, a reduction of the benzodiazepine dosage should be considered and patients should be appropriately monitored.
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, or cimetidine. No adverse effect has been seen on endogenous steroid levels or on ACTH stimulated cortisol response.
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 cyclosprin levels in patients with bone marrow transplants. Cyclosporin plasma concentration monitoring in patients receiving fluconazole is recommended.
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 cardiac dysrhythmias secondary to prolongation of the QTc interval in patients receiving azole antifungals in conjunction with terfenadine, interaction studies have been performed. One study at a 200 mg daily dose of fluconazole failed to demonstrate a prolongation in QTc interval. Another study at a 400 mg and 800 mg daily dose of fluconazole demonstrated that fluconazole taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. The combined use of fluconazole at doses of 400 mg or greater is contraindicated (See contraindications). The coadministration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored.
Cisapride: There have been reports of cardiac events including torsade de pointes in patients to whom fluconazole and cisapride were coadministered. Coadministration of cisapride is contraindicated in patients receiving fluconazole.
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 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 been reports of nephrotoxicity in patients to whom fluconazole and tacrolimus were coadministered. Patients receiving tacrolimus and fluconazole concomitantly should be carefully monitored for changes in plasma concentrations of tacrolimus and/or nephro- and neurotoxicity.
The use of fluconazole in patients concurrently taking astemizole or other medicines metabolised by the cytochrome P-450 system may be associated with elevations in serum levels of these medicines. In the absence of definitive information, caution should be used when coadministering fluconazole. Patients should be carefully monitored. (See warnings)

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
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 8200 mg of fluconazole. The patient was admitted to hospital and his condition resolved within 48 hours.
The following events have been reported with an overdosage with fluconazole: insomnia, irritability, vomiting, diarrhoea, abdominal pain/cramps, anorexia, bulging fontanel, elevation of alkaline phosphatase and gamma glutamyl transpeptidase, increase in serum calcium, renal failure, fatigue, facial rash, skin erythema, generalized urticaria, arthralgia, itching, numbness of the tongue and distressed mood.
As no clear pattern of overdosage adverse events was identified, it is not possible to relate fluconazole overdosage to a specific pattern of adverse events.
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 50 mg:	Hard gelatin capsules with a white opaque body and a turquoise blue cap imprinted with the Pfizer logo and an identity code such as FLU-50
Diflucan Capsules 200 mg:	Hard gelatin capsules with a white opaque body and cap imprinted with the Pfizer logo and the code FLU-200.
Diflucan IV Infusion 100 mL:	Clear glass vials containing a clear, colourless solution.

Diflucan 50 mg/5 mL and 200 mg/5 mL is a dry powder which yields on reconstitution with water an off-white, orange flavoured suspension.
The colour of the powder is white to off-white

PRESENTATION

Diflucan Capsules 50 mg:	Blister packs containing 14 capsules.
Diflucan Capsules 200 mg:	Blister packs containing 28 and 30 capsules
Diflucan IV Infusion 100 mL:	Glass vials each containing 100 mL.
Diflucan 50 mg/5 mL and         200 mg/5 mL:	Translucent HDPE bottles with child-resistant closures containing 35 mL of reconstituted suspension with a 5 mL overage.

STORAGE INSTRUCTIONS
Diflucan Capsules 50 mg and 200 mg: Store below 30°C.
Diflucan IV Infusion: Store below 30°C. Do not freeze. Discard remaining contents after use.
Diflucan 50 mg/5 mL and 200 mg/5 mL:
Before reconstitution: Store below 30°C in a dry place.
After reconstitution : Store suspension between 30°C and 5°C. Protect from freezing.
Discard unused portion after 2 weeks
Keep out of reach of children.

REGISTRATION NUMBERS

Diflucan Capsules 50 mg:	V/20.2.2/339
Diflucan Capsules 200 mg:	28/20.2.2/151
IV Infusion 100 mL:	Z/20.2.2/272
Diflucan 50 mg/5 mL:	30/20.2.2/0150
Diflucan 200 mg/5 mL:	30/20.2.2/0151

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

DATE OF PUBLICATION OF THIS PACKAGE INSERT
25 January 02

ZIMBABWE DETAILS         7.12 Antifungals (Systemic) Diflucan capsules 50 mg: 88/7.12/2179        PP Diflucan capsules 200 mg: 89/7.12/2308        PP Diflucan IV infusion: 89/7.12/2310        PP Diflucan 50 mg/5 mL: 2000/7.12/3806        PP

Updated on this site: February 2005
Source: Pharmaceutical Industry
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