FUNZELA Fluconazole 200mg Tablet 1's

Indications/Uses

For the treatment of the following infections caused by susceptible strains of microorganisms: Crytococcosis including cryptococcal meningitis and infections at other sites.
Systemic candidiasis, including candidemia, disseminated candidiasis and other forms of invasive candidal infection including infections of the peritoneum, endocardium, eye, respiratory and urinary tracts.
Mucosal candidiasis including oropharyngeal, esophageal, non-invasive bronchopulmonary infections, candiduria, mucocutaneous and denture sore mouth.
Genital candidiasis including vaginal candidiasis (acute or reccurrent), candidal balanitis.
Deep endemic mycoses, including coccidiomycosis, paracoccidiomycosis, blastomycosis, sporotrichosis and histoplasmosis in immunocompetent patients.
Superficial fungal infections such as dermatomycosis and onychomycosis including tinea pedis, tinea capitis, tinea corporis, tinea cruris, tinea versicolor, and dermal candida infections.
For the prophylaxis of transplant patients, patients with malignancy who are receiving cytotoxic chemotherapy, immunosuppressive therapy or radiation therapy, and other patients who are at risk of developing candida infections and serious fungal infections such as coccidioidomycosis and cryptococcal infections.
For the prophylaxis of HIV/AIDS patients who are at risk of developing candida infections and serious fungal infections such as coccidioidomycosis and cryptococcal infections.

Dosage/Direction for Use

Since fluconazole has >90% bioavailability, oral and intravenous dosing are the same. The intravenous route should be considered for patients who cannot tolerate or are unable to take fluconazole orally. See Table 2.


Recommended Dosing Regimen for Children: Usual recommended dose: 3 to 12 mg/kg body weight once daily. Do not exceed 600 mg once daily in children. See Table 3.


For children less than 4 weeks, the same fluconazole dose as above should be given. However, the dosage regimen is changed as follows: See Table 4.


The following dose equivalency scheme should generally provide equivalent exposure in paediatric and adult patients. See Table 5.


Dosage in Patients with Impaired Renal Function: No dosage adjustment is necessary for patients with renal impairment who are to receive a single dose of fluconazole. For patients who need multiple doses of fluconazole, an initial loading dose of 50 to 400 mg is required followed by a daily dose based on creatinine clearance as shown in Table 6.


These are suggested dose adjustments based on Fluconazole pharmacokinetics after administration of multiple doses in patients with renal impairment. Further dose adjustment may be needed depending on the patient's clinical condition.
When serum creatinine is the only measure of renal function available, use the following formula to estimate the creatinine clearance.

Overdosage

Death, often following clonic seizures, occurred at 1.5 hours to 3 days after administration of 1 to 2 grams of fluconazole. In one patient with human immunodeficiency virus (HIV) infection, hallucinations and paranoid behaviour were reported after ingestion of 8.2 g of fluconazole.
The patient required hospitalization ad the condition resolved after 48 hours.
If acute overdosage occurs, supportive and symptomatic treatment should be initiated as necessary. The stomach may be emptied by gastric lavage. Fluconazole is also removed by hemodialysis and plasma fluconazole concentration usually decreases to 50% after 3-hours of hemodialysis.

Administration

May be taken with or without food.

Contraindications

Hypersensitivity to fluconazole, other azole antifungals and to any of the excipients of Funzela. Co-administration with cisapride and terfenadine.

Special Precautions

Serious adverse hepatic effects have been reported with fluconazole. Although these are rare, these should be considered when giving fluconazole therapy. If signs and symptoms of liver disease develops, treatment should be discontinued immediately; if abnormal liver function tests occur, the patient should be carefully monitored for the possibility of more severe liver injury.
Overgrowth of nonsusceptible strains of candida have been reported in some patients receiving fluconazole. When this occurs, patients may require an alternative anti-fungal therapy.
Anaphylaxis has occurred rarely in patients taking fluconazole.
Rare but serious exfoliative skin disorders such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported during treatment with fluconazole which rarely resulted in a fatal outcome in patients with serious underlying diseases (predominantly AIDS & malignancy). It is recommended that in patients with superficial fungal infection, fluconazole treatment be discontinued at the first sign of rash. Patients with serious underlying disease who develop rashes should be closely observed and fluconazole treatment should be discontinued when bullous lesions or erythema multiforme progresses.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Evidence of mutagenicity was not seen when fluconazole was used in vitro.
There was no evidence of carcinogenicity in studies done in mice and rats receiving fluconazole dosages of 2.5 to 10 mg/kg daily for 24 months. However, onset of parturition is slightly delayed.
Use in Children: A different dosing regimen is recommended for infants less than 4 weeks (see Dosage & Administration).
Use in Elderly: Since elderly patients are more likely to have impaired renal function, dosage should be modified as necessary. However, dosage adjustments based on age alone is not necessary.

Use In Pregnancy & Lactation

Use in pregnancy: Pregnancy Category C. Teratogenic Effects: Teratogenicity has occurred in animals given high doses of fluconazole. 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 months with high-dose (400-800 mg/day) fluconazole therapy for coccidioidomycosis (an unindicated use). The relationship between fluconazole use and these events are unclear. Use fluconazole in pregnancy only if the potential risk justifies the possible risk to the fetus.
Use in lactation: Fluconazole is secreted in human milk at concentrations similar to plasma. Therefore, fluconazole is not recommended in nursing mothers.

Adverse Reactions

Fluconazole is generally well tolerated. Most common adverse effects are abdominal pain, diarrhea, flatulence, nausea, vomiting and taste disturbance. Other reported adverse effects include headache, dizziness, leukopenia, thrombocytopenia, hyperlipidemia ad raised liver enzyme concentrations.
Since fluconazole is used in patients with serious underlying diseases, there are some instances where causal relationship of the adverse event to the treatment is hard to establish.
Gastrointestinal effects: Gastrointestinal effects are the most common adverse reactions reported with fluconazole use. These reactions are usually mild to moderate in nature and do not usually require discontinuation of therapy. These adverse effects are nausea, vomiting, abdominal pain and diarrhea. Rarely, there have been reports of flatus, bloating, dry mouth, hiccups, heartburn and anorexia.
In patients with vulvovaginal candidiasis receiving single dose of fluconazole, abdominal pain, nausea, diarrhea, dyspepsia and dysgeusia have been reported.
Dermatologic and Hypersensitivity Reactions: Rare reports of anaphylaxis have occurred. Rash (including diffuse rash with eosinophilia) and pruritus were also reported. Stevens-Johnson syndrome has also occurred and may be fatal.
In patients with serious diseases such as autoimmune deficiency syndrome (AIDS) or malignancy, exfoliative skin disorders have occurred.
In patients with vulvovaginal candidiasis receiving single dose of fluconazole, angioedema and anaphylaxis were reported rarely.
Hepatic Effects: Rare but serious hepatoxicity (eg, necrosis, clinical hepatitis, cholestasis, fulminant hepatic failure) have been reported.
Although these events may be reversible, there have been reports of death, especially involving patients with serious underlying conditions.
Nervous System Effects: Dizziness and headache have occurred. Somnolence, delirium/coma, dysesthesia, psychiatric disturbances, malaise, paresthesia of hands and feet, fatigue and seizure have been reported rarely.
Hematologic Effects: Eosinophilia, anemia, leukopenia, neutropenia and thrombocytopenia have been reported. Although thrombocytopenia may be reversible after drug discontinuation, there were reports of severe cases necessitating treatment.
Endocrine Effects: Endocrine effects of fluconazole have not been studied. However, there have been reports of alterations on testosterone and endogenous corticosteroid concentrations, as well as changes in ACTH-stimulated cortisol response.
Other Adverse Effects: There have been rare reports of fever, edema, pleural effusion, oliguria, hypotension, arthralgia/myalgia and finger stiffness. Alopecia was also reported, occurring in both genders after 3 months of therapy. Alopecia may respond to either drug discontinuation or dose reduction. Fluconazole may also cause hair loss on the face, axillary, pubic, leg and chest area.

Drug Interactions

See Table 7.




Drug/Laboratory Interactions: Mild, transient in serum concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase-glutamyltransferase and bilirubin have been reported. The patient's liver function should be closely monitored for signs of severe hepatotoxicity.

Storage

Store at temperatures not exceeding 30°C.
Protect from light.
Do not freeze.

Action

Pharmacology: Pharmacodynamics: Fluconazole, a synthetic broad spectrum bis-triazole antifungal agent, is a highly selective inhibitor of cytochrome P450-dependent enzymes and sterol C-14 alpha-demethylation. These actions result in impairment of ergosterol synthesis in fungal cell membrane, leading to growth inhibition, abnormal cell wall formation, and accumulation of intracellular lipids and membranous vesicles. Depending on the concentration, Fluconazole may be fungicidal or fungistatic.
Antimicrobial Spectrum of Activity: Fluconazole has a relative selectivity for fungal cytochrome P450 system. It exhibits in vitro activity against Cryptococcus neoformans and Candida spp and has demonstrated fungistatic activity in normal and immunocompromised animal models for systemic and intracranial fungal infections due to Cryptococcus neoformans and for systemic infections due to Candida albicans. Development of resistance to fluconazole has not been studied; however, there have been reports of cases of superinfection with Candida spp other than Candida albicans, which are often inherently nonsusceptible to fluconazole.
Like other azole antifungal agents, most fungi show a higher apparent sensitivity to fluconazole in vivo than in vitro. Activity has been demonstrated against fungal infections caused by Aspergillus flavus and Aspergillus fumigatus in mice. Fluconazole is active in animal models of endemic mycoses, including one model of Blastomyces dermatitidis pulmonary infections, one model of Coccidioides immitis intracranial infections and several models of Histoplasma capsulatum pulmonary infection.
Coadministration of fluconazole and amphotericin B in infected normal and immunosuppressed mice showed a small additive antifungal effect in systemic infection with Aspergillus fumigatus.
Pharmacokinetics: The pharmacokinetic properties of fluconazole are similar after intravenous or oral administration. Bioavailability of oral fluconazole is >90% in healthy volunteers.
Peak plasma fluconazole concentrations in fasted healthy volunteers occur between 1 and 2 hours with a terminal plasma elimination half-life of 30 hours after oral administration. A single oral 400 mg dose leads to a mean C_max of 6.72 mcg/mL; after single oral doses of 50 to 400 mg, plasma concentrations and AUC are dose-proportional. A single 150 mg oral dose given to 10 lactating women resulted in a mean C_max of 2.61 mcg/mL.
Steady-state concentrations are reached within 5 to 10 days after oral doses of 50 to 400 mg given once daily. Administration of a loading dose (day 1) of twice the usual daily dose results in plasma concentrations close to steady state by day 2. The apparent volume of distribution either single or multiple oral doses for up to 14 days. See Table 1.




In healthy volunteers, fluconazole is cleared primarily by renal excretion, with 80% of the dose appearing in the urine unchanged, and 11% as metabolites. Fluconazole's pharmacokinetics are markedly affected by reduction in renal function. There is an inverse relationship between elimination half-life and creatinine clearance. Dose may need to be reduced in patients with impaired renal function. A 3 hour hemodialysis session decreases plasma concentrations by 50%.
Doses of 200 to 400 mg once daily for up to 2 weeks in healthy volunteers were associated with small, inconsistent effects on testosterone and endogenous corticosteroid concentrations and the ACTH-stimulated cortisol response.

MedsGo Class

Antifungals