INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
FLUCORIC

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

FLUCORIC

Flucoric 50 Capsules
Flucoric 100 Capsules
Flucoric 150 Capsules
Flucoric 200 Capsules

COMPOSITION
Sugar free.
Flucoric 50 Capsules
Each capsule contains
Fluconazole         50 mg
Flucoric 100 Capsules
Each capsule contains
Fluconazole         100 mg
Flucoric 150 Capsules
Each capsule contains
Fluconazole         150 mg
Flucoric 200 Capsules
Each capsule contains
Fluconazole         200 mg

PHARMACOLOGICAL CLASSIFICATION
A 20.2.2 Fungicides.

PHARMACOLOGICAL ACTION:
Mechanism of action
Fluconazole is a member of the triazole antifungal agents which, in sensitive fungi, inhibits cytochrome P-450 dependent enzymes resulting in impairment of ergosterol synthesis in fungal cell membranes. It 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 childbearing age.
PHARMACOKINETICS
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%).
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 super infection with Candida species other than C. Albicans, which are inherently not susceptible to fluconazole (e.g., Candida krusei). Such cases may require alternative antifungal therapy.

INDICATIONS:
Once the results of cultures and other laboratory studies become available, anti-infective therapy should be adjusted accordingly.
Flucoric 50, 100 and 200 Capsules are 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

Flucoric 150 Capsules

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 medicine or to related triazole 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)
Co-administration of cisapride is contra-indicated in patients receiving fluconazole.
Multiple-dose therapy should be carefully monitored in patients with renal impairment (see Warnings).
Safety in pregnancy and lactation has not been established.

WARNINGS
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 injury
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 the 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.
Dermatologic
Patients have less frequently developed pruritis, rashes, urticaria, angiooedema, dry skin, abnormal odour, 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 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 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:

Creatinine Clearance (mL/min)	Percent of Recommended Dose
>50	100%
11 –50	50%
Patients receiving regular haemodialysis	100% after each dialysis

These are suggested dose adjustments based on pharmacokinetics following administration of multipledoses. 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

INTERACTIONS
Anticoagulants: Fluconazole has been shown to prolong prothrombin times in subjects receiving warfarin. In post-marketing experience, bleeding events (bruising, epistaxis, gastro-intestinal 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.
Oral hypoglycemics: 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.
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 cyclosprin levels in patients with bone marrow transplants. Cyclosporin plasma concentration monitoring in patients receiving fluconazole is recommended.
Hydrochlorothiazide: Co-administration of multiple doses of hydrochlorothiazide may increase the plasma concentrations of fluconazole.
Phenytoin: Concomitant administration of fluconazole and phenytoin may increase the levels of phenytoin to a clinically significant degree.
Theophylline: Concomitant administration of fluconazole and theophylline may increase the risk of theophyllline toxicity due to a fluconazole induced decrease in plasma theophylline clearance.
Rifampicin: Concomitant administration of fluconazole 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 cardiacdysrhythmias secondary to prolongation of the QTc interval in patients receiving 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 cisapride or terfenadine or astemizole should be carefully monitored.
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 contra-indicated (See Contra-indications). The co-administration 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. Co-administration of cisapride is contra-indicated 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 co-administering fluconazole. Patients should be carefully monitored. (See Warnings)
Other interactions: 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.
PREGNANCY AND LACTATION
See Contra-indications and Warnings.

DOSAGE AND DIRECTIONS FOR USE
Flucoric 50, 100 and 200 Capsules
Adults
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.

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 patient’s 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 1 000 cells per mm³.

Elderly
Where there is no evidence of renal impairment, normal dosage recommendations should be adopted.
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. Fluconazole is administered as a single daily dose.

1.	The recommended dosage for oropharyngeal 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. 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 fluconazole 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, depending on the severity of the disease.

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.

Flucoric 150 Capsules
Adults
For vaginal candidiasis Flucoric 150 Capsules 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, Flucoric 150 Capsules 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.
Children
Insufficient evidence is available to establish safety and efficacy of Flucoric 150 Capsules in the above indications for use in children.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Side-effects
The commonest side-effects associated with fluconazole are symptoms related to the gastro-intestinal tract. These include nausea, vomiting, abdominal pain, diarrhoea and flatulence. After gastro-intestinal symptoms, the second most commonly observed side-effect was rash. 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 (see Warnings), seizures, leucopenia, thrombocytopenia and alopecia have occurred under conditions where a causal association is uncertain.
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).
Gastro-intestinal: Dyspepsia
Haematopoetic and Lymphatic: Leucopenia including neutropenia and agranulocytosis, thrombocytopenia.
Immunologic: Anaphylaxis (including angioedema , face oedema, 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, leukorrhoea and menorrhagia.
Body as a whole: Fatigue, malaise, rigors, flushing.
Other senses: Taste perversion, abnormal vision.

Special Precautions
If a rash develops which is considered attributable to fluconazole, further therapy with this agent should be avoided (See Warnings).
Geriatrics:
No geriatrics-specific problems have been documented with the use of fluconazole.

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 8 200 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 event 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:
Flucoric 50 Capsules
Blue/white hard gelatin, self locked capsules of size '4' imprinted with 'RANBAXY' in black edible ink on both cap and body containing white to off-white powder.
Flucoric 100 Capsules
Blue/white hard gelatin, self locked capsules of size '2' imprinted with 'RANBAXY' in black edible ink on both cap and body containing white to off-white powder.
Flucoric 150 Capsules
Blue/blue hard gelatin, self locked capsules of size '1' imprinted with 'RANBAXY' in black edible ink on both cap and body containing white to off-white powder.
Flucoric 200 Capsules
Purple/white hard gelatin, self locked capsules of size '0' imprinted with 'RANBAXY' in black edible ink on both cap and body containing white to off-white powder.

PRESENTATION
Flucoric 50 Capsules
Cartons containing blister strips consisting of white, opaque PVC (PVdC coated) film with an aluminium foil backing containing 14 capsules each.
Flucoric 100 Capsules
Cartons containing blister strips consisting of white, opaque PVC (PVdC coated) film with an aluminium foil backing containing 14 capsules each.
Flucoric 150 Capsules
Cartons containing blister strips consisting of white, opaque PVC (PVdC coated) film with an aluminium foil backing containing 1 or 4 capsules each.
Flucoric 200 Capsules
Cartons containing blister strips consisting of white, opaque PVC (PVdC coated) film with an aluminium foil backing containing 28 capsules each.

STORAGE INSTRUCTIONS
Store below 25°C protected from moisture
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBERS
Flucoric 50 Capsules:        37/20.2.2/0114
Flucoric 100 Capsules:        37/20.2.2/0115
Flucoric 150 Capsules:        37/20.2.2/0116
Flucoric 200 Capsules:        37/20.2.2/0117

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION
RANBAXY (SA) (PTY) LTD
Third Floor
Outspan House,
1006 Lenchen Avenue North
Centurion

DATE OF PUBLICATION OF THE PACKAGE INSERT
September 2003

New addition to this site: March 2004
Source: Pharmaceutical Industry
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