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Logo FLUZOL™ 50 mg CAPSULES
FLUZOL™ 150 mg CAPSULES
FLUZOL™ 200 mg CAPSULES
FLUZOL™ IV INFUSION 100 mL

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

FLUZOL™ 50 mg CAPSULES
FLUZOL
150 mg CAPSULES
FLUZOL™ 200 mg CAPSULES
FLUZOL™ IV INFUSION 100 mL

COMPOSITION
Each Fluzol 50 mg capsule contains 50 mg
fluconazole.
Each Fluzol 150 mg capsule contains 150 mg fluconazole.
Each Fluzol 200 mg capsule contains 200 mg fluconazole.
Each Fluzol IV Infusion contains 2 mg fluconazole per 1 mL of solution.

PHARMACOLOGICAL CLASSIFICATION
A.20.2.2 Fungicides.

PHARMACOLOGICAL ACTION
Fluconazole is a triazole antifungal drug which in sensitive fungi inhibits cytochrome P-450 dependent enzymes resulting in impairment of ergosterol synthesis in fungal cell membranes.
Fluconazole is well absorbed following oral administration, bioavailability from the oral route being 90% or more of that from the intravenous route. Peak plasma concentrations are reached within 1 to 2 hours of oral administration. Plasma concentrations are proportional to the dose over a range of 50 mg to 400 mg. Multiple dosing leads to increases in peak plasma concentrations; steady-state concentrations are reached in 6 to 10 days but may be attained on day 2 if a loading dose is given.
The elimination half life of fluconazole is about 30 hours and is increased in patients with impaired renal function. Plasma protein binding is only about 12%.
It has been shown in pharmacokinetic studies performed in children that fluconazole is cleared faster in children than in adults, with a half life of 23 hours.
In children under the age of 1, the volume of distribution of fluconazole (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.
The half lives of fluconazole, in neonates, 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.
Eighty percent or more of fluconazole is excreted unchanged in the urine; about 11% is excreted as metabolites. 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, single dose therapy for vaginal candidiasis and once weekly dosing for other indications.
Cases of super-infection with Candida species other than C. albicans, which are often inherently not susceptible to fluconazole (e.g., Candida krusei), have been reported. Such cases may require alternative antifungal therapy.
Fluconazole has been shown not to affect testosterone plasma concentrations in males or steroid concentrations in females of child-bearing age.

INDICATIONS
Anti-infective therapy should be adjusted according to the results of cultures and laboratory studies. Fluconazole is administered by mouth or by intravenous infusion in similar doses.
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.
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 cruris, tinea corporis, tinea pedis, tinea unguium (onychomycosis), and dermal candida infection.
Insufficient evidence is available to establish safety and efficacy of fluconazole in the above indications for use in children “see Warnings”

CONTRA-INDICATIONS
Hypersensitivity to fluconazole or any of the ingredients of the preparation.
Concomitant administration of cisapride is contraindicated in patients receiving fluconazole.
Concomitant 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)
Multiple dose therapy is contra-indicated in patients with renal impairment.
Pregnancy.
Fluconazole should not be given to breast-feeding women, as fluconazole is found in breast milk at concentrations similar to plasma.

WARNINGS
Use during pregnancy and lactation
Safety in pregnancy and lactation has not been established.
There are no adequate and well controlled studies which assessed the safety of fluconazole treatment in pregnant women. Congenital abnormalities in infants whose mothers were treated with fluconazole have been reported. The relationship between fluconazole use and these events are unclear.
Use in children
Insufficient evidence is available to establish safety and efficacy of fluconazole in children in the following conditions:
1 Vaginal candidiasis.
2 Candidial balanitis.
3 Dermatomycosis.
Effects on Ability to Drive and Use Machines
Experience indicates that fluconazole therapy is unlikely to impair a patient’s ability to drive or use machinery.
Hepatic Function
Cases of serious hepatic toxicity including fatalities, have been associated with fluconazole therapy, primarily in patients with serious underlying medical conditions. In cases of fluconazole-associated hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, age or sex 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.
If clinical signs or symptoms consistent with liver disease develop that may be attributable to fluconazole, fluconazole therapy should be discontinued. Less frequently, patients have developed rashes, pruritis, urticaria, dry skin, angioedema, abnormal odour, exfoliative cutaneous reactions, such as Steven-Johnson Syndrome and toxic epidermal necrolysis during fluconazole therapy. AIDS patients are more susceptible to the development of severe cutaneous reaction to many drugs. If patients with systemic fungal infections develop rashes, they should be closely monitored and if bullous lesions or erythema multiforme develop fluconazole therapy should be discontinued.
Concomitant 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 should be used with caution in patients with impaired renal function.
Eighty percent or more of fluconazole is excreted unchanged in the urine.
No adjustments in single dose therapy are necessary. In patients with renal impairment, multiple-dose therapy should be carefully monitored.
An initial dose of 50 to 400 mg should be administered to patients (including children) with impaired renal function. After the loading dose, the daily dose (according to indication) should be based on the following table:

DOSAGE AND ADMINISTRATION
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. Depending on clinical condition, further adjustment may be required.
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 infections requiring multiple dose treatment should be continued until laboratory tests and clinical parameters indicate that active fungal infection has subsided. An insufficient duration of fluconazole therapy may lead to the recurrence of active infection.
Maintenance therapy in patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal candidiasis is usually necessary to prevent relapse.
Use in Adults
1 Cryptococcal meningitis may be treated with an initial dose of fluconazole 400 mg on the first day followed by 200 mg once daily.
This dose may be increased to 400 mg daily, depending on the clinical response of the patient.
The duration of therapy for cryptococcal meningitis is based on clinical and mycological response, but is usually 6-8 weeks.
Fluconazole may also be used in daily doses of 100 to 200 mg to prevent relapse following a primary course of antifungal therapy for acute cryptococcal meningitis in patients with AIDS.
2 Systemic candidiasis may be treated with an initial dose of fluconazole 400 mg on the first day followed by 200 mg daily. The dose may be increased to 400 mg daily, depending on the clinical response of the patient. Duration of therapy for systemic candidiasis treatment is based on the clinical response of the patient.
3 For oropharyngeal candidiasis, the usual dose is 50 to 100 mg once daily for 7-14 days. In patients with severely compromised immune function, treatment can be continued for longer periods if necessary.
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 in order to prevent a relapse of oropharyngeal candidiasis.
For oesophageal candidiasis, the recommended dose is 200 mg on the first day, followed by 100 mg to 200 mg once daily.
Doses of up to 400 mg daily may be used based on medical judgement 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 For the prevention of candidiasis, a fluconazole dosage of 50 mg to 400 mg once daily is recommended based on the patients risk for developing fungal infection.
A dose of 400 mg once daily has been used in patients who are at high risk of systemic infection e.g. patients who are anticipated to have profound or prolonged neutropenia.
Fluconazole administration should commence several days before the anticipated onset of neutropenia and continue for 7 days after the neutrophil count rises above 1000 cells per mm³.
5 Fluconazole 150 mg should be administered as a single oral dose for vaginal candidiasis.
A 150 mg once monthly dose may be used to reduce the incidence of recurrent vaginal candidiasis. Individualisation of the duration of therapy is necessary but ranges from 4-12 months. Some patients may require more frequent dosing.
6 Fluconazole 150 mg should be administered as a single oral dose, for the treatment of candida balanitis.
7 For dermal infections including tinea cruris, pedis, corporis, and candida infections the recommended dosage is 150 mg once weekly. The recommended duration of therapy is normally 2 to 4 weeks. Tinea pedis may require treatment for up to 6 weeks.
The recommended dosage for tinea unguium is 150 mg once weekly. Treatment should be continued until infected nail is replaced (uninfected nails grow in). Re-growth of fingernails and toenails normally require 3 to 6 months and up to 6 to 12 months, respectively. However, growth rates may vary widely in individuals and by age. Nails occasionally remain disfigured after successful treatment of long term chronic infections.
Use in Elderly
Normal dosage recommendations should be adopted where there is no evidence of renal impairment.
Use in Children
As with similar infections in adults, the duration of fluconazole therapy 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 For the treatment of oropharyngeal candidiasis in children, the recommended fluconazole dosage is 6 mg/kg on the first day, followed by 3 mg/kg once daily. To lower the likelihood of relapse, treatment should be administered for at least 2 weeks.
2 For the treatment of oesophageal candidiasis in children, the recommended fluconazole dosage is 6 mg/kg on the first day, followed by 3 mg/kg once daily.
Based on medical judgment of the patient’s response, doses up to 12 mg/kg/day may be used.
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
Fluconazole is excreted slowly in neonates. In the first two weeks of life the same mg/kg dosing as in older children should be used but administered every 72 hours. The same dose should be given every 48 hours, during weeks 3 and 4 of life.
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:
1 Glucose 20%
2 Ringer’s solution
3 Ringer lactate solution
4 Isotonic sodium chloride solution
5 Sodium hydrogen carbonate 4,2%
6 Potassium chloride in glucose
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 most common side-effects associated with fluconazole are:
Gastrointestinal:
Abdominal pain, diarrhoea, nausea, vomiting, and flatulence.
Abnormalities of hepatic, renal and haematological function have been observed during fluconazole therapy in some patients, particularly those with serious underlying diseases such as AIDS and cancer (see “Warnings”).
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.
Liver/Biliary:
Serious hepatic toxicity has been reported in patients with severe underlying disease. Rare cases of fatalities, elevated alkaline phosphatase, elevated bilirubin, elevated SGOT, elevated SGPT have been observed.

Other side-effects include:
Gastrointestinal:
Dyspepsia
Central and Peripheral Nervous System:
Dizziness, vertigo, seizures, hyperkinesia, hypertonia
Dermatologic:
Skin reactions are rare but exfoliative cutaneous reactions such as toxic epidermal necrolysis and Stevens-Johnson syndrome has been reported, more commonly in patients with AIDS (see warnings).
Alopecia has been reported.
Haematopoetic and Lymphatic:
Leucopenia including agranulocytosis and neutropenia, thrombocytopenia
Liver/Biliary:
Hepatic failure, hepatitis, hepatocellular necrosis, jaundice
Immunologic:
Rare cases of anaphylaxis, angioedema and face oedema pruritis have been reported.
Metabolic/Nutritional:
Hypertriglyceridaemia, hypercholesterolaemia, hypokalaemia, polyuria, thirst
Psychiatric:
Nervousness, insomnia
Reproductive:
Intermenstrual bleeding, leukorrhoea, menorrhagia, female sexual dysfunction
Body as a whole:
Flushing, malaise, fatigue, rigors
Other senses:
Abnormal vision, taste perversion

Interactions
In subjects receiving warfarin, fluconazole has been shown to prolong prothrombin times. In patients receiving concomitant fluconazole and warfarin therapy, bleeding events (haematuria, bruising, epistaxis, gastrointestinal bleeding, and malaena), in association with increases in prothrombin time have been reported.
The dose of anticoagulant should be carefully titrated and the prothrombin time carefully monitored in patients who are being treated concomitantly with fluconazole and coumarin medicines.
Such patients requiring minor oral surgery and dental procedures should be carefully monitored.
Fluconazole has been shown to prolong the serum half life of concomitantly administered oral sulphonylureas.
Clinically significant interactions have not been observed with concomitant administration of fluconazole and oral contraceptives.
Clinically significant interactions have not been observed with concomitant administration of fluconazole and cimetidine.
Benzodiazepines (Short Acting): There is a potentially relevant interaction between midazolam and fluconazole. Data clearly indicates that fluconazole influences the pharmacokinetics of midazolam which results 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 is necessary in patients receiving fluconazole therapy, a reduction of the benzodiazepine dosage should be considered and patients should be appropriately monitored.
No adverse effect has been seen on endogenous steroid levels or on ACTH stimulated cortisol response.
It is recommended that the cyclosporin plasma concentration levels be monitored in patients receiving fluconazole therapy.
In a kinetic study in renal transplant patients cyclosporin concentrations were found to slowly increase following a 200 mg fluconazole dose.
However, in another multiple dose study with 100 mg daily, fluconazole did not affect cyclosporin levels in patients with bone marrow transplants. Administration of multiple doses of hydrochlorothiazide and fluconazole has resulted in clinically significant increases in plasma-fluconazole concentrations.
Administration of phenytoin and fluconazole has resulted in clinically significant increases in phenytoin concentrations.
Fluconazole may reduce the clearance of theophylline. Thus, the concomitant administration of fluconazole and theophylline may increase the risk of theophylline toxicity due to the fluconazole induced decrease in plasma theophylline clearance.
Concomitant administration of rifampicin and fluconazole results in reduced plasma concentration of fluconazole.
Zidovudine: Increased plasma concentrations of zidovudine have been reported.
An increase in zidovudine levels, probably caused by the decreased conversion of zidovudine to its major metabolite was observed during two kinetic studies.
During one of the studies in AIDS or ARC patients, zidovudine levels were determined before and following a dosage of fluconazole 200 mg, daily for 15 days. A significant increase in zidovudine AUC (20%) was observed.
During the second study, a two-period, two-treatment, cross-over study in HIV patients, zidovudine levels were examined.
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. A significant increase in zidovudine AUC (74%) during concomitant administration of zidovudine and fluconazole was observed.
It is recommended that patients receiving concomitant administration of zidovudine and fluconazole be monitored for the development of zidovudine-related adverse reactions.
Terfenadine: The concomittant administration of fluconazole and terfenadine should be avoided because of the risk of cardiac arrhythmias. Increases in terfenadine concentrations following high doses of fluconazole have been associated with ECG abnormalities.
Interaction studies have been performed, because of the occurrence of serious cardiac dysrhythmias secondary to prolongation of the QTc interval in patients receiving azole antifungals in conjunction with terfenadine.
In one of the studies, a prolongation of the QTc interval was not observed, following a 200 mg daily dose of fluconazole.
In a second study, significant increases in terfenadine plasma levels were observed following a 400 mg and 800 mg daily dose of fluconazole.
The concomitant administration of terfenadine and fluconazole at doses of 400 mg or greater is contra-indicated (see contra-indications).
Patients receiving concomitant administration of fluconazole at doses lower than 400 mg per day with terfenadine should be carefully monitored.
Rifabutin: Increases in plasma concentrations of rifabutin has been reported.
Uveitis in patients receiving concomitant administration of fluconazole and rifabutin has been reported.
Patients receiving concomitant administration of rifabutin and fluconazole should be carefully monitored.
Cisapride: The concomitant use of fluconazole with cisapride should be avoided because of the risk of cardiac arrhythmias. Concurrent administration of fluconazole and cisapride could result in increased cisapride concentration and associated toxicity. In patients receiving concomitant fluconazole and cisapride therapy, cardiac events including torsade de pointes has been reported. The concomitant administration of cisapride is contra-indicated in patients receiving fluconazole.
Tacrolimus: There have been reports that an interaction exists when fluconazole is administered concomitantly with tacrolimus, resulting in increased plasma concentrations of tacrolimus. Nephrotoxicity has been reported in patients receiving concomitant administration of fluconazole and tacrolimus.
Patients receiving tacrolimus and fluconazole concomitantly should be carefully monitored for changes in plasma concentrations of tacrolimus and/or nephro- and neurotoxicity.
Fluconazole may interfere with the metabolism of astemizole or other medicines metabolised by the cytochrome P-450 system, presumably through inhibition of cytochrome P-450 (CYP3A4). This may account for the reported increases in plasma concentrations of these medicines. In the absence of definitive information, caution should be used when co-administering fluconazole. Patients should be carefully monitored. (See “Warnings”).

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Overdosage with fluconazole has been reported.
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, generalised 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
FLUZOL 50 mg CAPSULES Hard gelatin capsules, snap-fit closure, turquoise cap/white body with the imprint FC50, containing a white odourless powder.
FLUZOL 150 mg CAPSULES Hard gelatin capsules, snap-fit closure, white cap/white body with the imprint FC150, containing a white odourless powder.
FLUZOL 200 mg CAPSULES Hard gelatin capsules, snap-fit closure, purple cap/white body with the imprint FC200, containing a white odourless powder.
FLUZOL IV INFUSION 100 mL Clear glass vials containing a clear, colourless solution, free from visible particles.

PRESENTATION
FLUZOL 50 mg CAPSULES White, opaque PVC/Aluminium blisters strips containing 14 capsules
FLUZOL 150 mg CAPSULES White, opaque PVC/Aluminium blisters strips containing 1 or 4 capsules
FLUZOL 200 mg CAPSULES White, opaque PVC/Aluminium blisters strips containing 28 or 30 capsules
FLUZOL IV INFUSION 100 mL 100 mL clear glass vials containing clear, colourless solution, free from visible particles

STORAGE INSTRUCTIONS
FLUZOL 50 mg, 150 and 200 CAPSULES Store below 25°C.
Do not remove the blisters from the outer container until required for use.
Keep out of reach of children.
FLUZOL IV INFUSION Store below 25°C.
Do not freeze. Discard remaining contents after use.
Keep out of reach of children.

REGISTRATION NUMBERS
FLUZOL 50 mg CAPSULES         36/20.2.2/0261
FLUZOL 150 mg CAPSULES         36/20.2.2/0262
FLUZOL 200 mg CAPSULES         36/20.2.2/0263
FLUZOL IV INFUSION 100 mL         37/20.2.2/0033

NAME AND BUSINESS ADDRESS OF APPLICANT
Hexal Pharma (SA) (Pty) Ltd
46 Mahogany Road,
Mahogany Ridge,
Westmead
3610

DATE OF PUBLICATION OF THIS PACKAGE INSERT
06/2003

FLUP5
Pro-Print

New addition to this site: May 2005
Source: Community Pharmacy

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