Dermicon Capsule

Fluconazole

Indications

Dermicon a member of the triazole class of antifungal agents, is a potent and selective inhibitor of fungal enzymes necessary for the synthesis of ergosterol. Dermicon is indicated for:

• Vaginal candidiasis (acute or recurrent) Candidal balanitis: The treatment of partners who present with symptomatic genital candidiasis should be considered.
• Mucosal candidiasis: These include oropharyngeal, oesophegeal, noninvasive bronchopulmonary infections, candiduria, mucocutaneous and chronic oral atrophic candidiasis (denture sore mouth). Normal hosts and patients with compromised immune function may be treated.
• Tinea pedis, tinea cruris, tinea versicolor and dermal Candidial Infections: Dermicon is also indicated for nail fungal infections.
• Systemic candidiasis including candidaemia, disseminated candidiasis and other forms of invasive candidal infections of the peritoneum, endocardium and pulmonary and urinary tracts. Candidal infections in patients with malignancy, in intensive care units or those receiving cytotoxic or immunosuppressive therapy, may be treated.
• Cryptococcosis, including cryptococcal meninigitis and infections of other sites (e.g. pulmonary cutaneous) normal hots and patients with acquired immune defciency syndrome (AIDS), organ transplants or other causes of immunosuppression may be treated. Dermicon can be used as maintainance therapy to prevent relapse of cryptococcal disease in patients with AIDS.
• For the prevention of fungal infections in immunocompromised patients considered at risk as a consequence of neutropenia following cytotoxic chemotherapy or radiotherapy, including bone marrow transplant patients.

Other uses:

• Fungal urinary tract infections
• Disseminated candidiasis
• Prophylaxis for fungal infection in neutropenic cancer patients.
• Acute treatment of other systemic fungal infections such as coccidioidomycosis and histoplasmosis.

Pharmacology

Fluconazole is a triazole antifungal agent. It is a potent inhibitor of fungal cytochrome P-450 dependent enzymes. Cytochrome P-450 enzyme system is essential component of fungal cell membrane which is responsible for the synthesis of ergosterol.

Dosage & Administration

Adults:
Candidal balanitis or vaginitis: 150 mg single oral dose.
Mucosal Candidiasis:

• Oropharyngeal candidiasis: the recommamended dose is 50 mg once daily for 7 to 14 days. Treatment should not normally exceed 14 days except in severily immunocompromised patients.
• Atrophic oral candidiasis associated with dentures: the recommended dose is 50 mg once daily for 14 days, administared concurrently with local anti septic measures to the denture.
• For other candidal infections of the mucosa, (except genital candidiasis see above), e.g. oesophagitis, non-invasive bronchopulmonary infections, candiduria, mucocutaneous candidiasis etc. the recommended dose is 50 mg daily, given for 14 to 30 days. In unusually difcult cases of mucosal candidal infections the dose may be increased to 100mg daily.

For tinea pedis, corporis, cruris, versicolor and dermal Candidal infections: the recommended dose is 50 mg once daily. Duration of treatment is normally 2 to 4 weeks but tinea pedis may require treatment for up to 6 weeks. Duration of treatment should not exceed 6 weeks.

For candidaemia, disseminated candidaemia and other invasive candidal infections: the recommended dose is 400 mg on the frst day followed by 200 mg-400 mg once daily. Depending on the clinical response the dose may be increased to 400 mg once daily. Duration of treatment is based upon the clinical response.

For cryptococcal meningitis and cryptococcal infections at other sites: the recommanded dose is 400 mg on frst day follwed by 200 mg once daily. Duration of treatment for cryptoccoal infections will depend on the clinical and mycological response, but is usually at least 6 to 8 weeks for cryptococcal meningitis. For the prevention of relapse of cryptococcal meningitis in patients with AIDS, after the patient recives a full course of primary therapy, Fluconazole may be administerd indefnitely at a daily dose of 100-200 mg.

For the prevention of fungal infections in immunocompromised patients considered at a risk as a consequence of neutropenia following cytotoxic chemotherapy of radiotherapy, the dose should be 50-400 mg daily based on the patients risk for developing fungal infection. For patients at high risk of systemic infections. e.g patients who are anticipated to have profound or prolonged neutropenia such as during bone marrow transplantation, the recommended dose is 400 mg daily. Start dosage several days before anticipated onset of neutropenia and continue for seven days after the neutrophil count rises above 100 cells per mm.

Children over four weeks of age:

• Mucosal candidiasis: The recommended does of fuconazole is 3 mg/kg daily. A loading does of 6mg/kg may be used on the frst day to achieve steady state leaves more repidly.
• Systemic candidiasis and cryptococcal infection: The recommended dosage of fuconazole is 6-12 mg/kg daily, 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 rediotherapy, the dose should be 3-12 mg/kg daily depending on the extent and duration of the induced neutropenia.
• Children below four weeks of age: Neonates excrete fuconazole showly. In the frst two weeks of life the same mg/kg dosing as in older children should be used but administered every 72 hours. During weeks 2-4 of line the same does should be given 48 hours.
• For children with impaired renal function: the daily dose should be reduced in accordance with the guidelines give for adults, dependent on the degree of renal impairment. To facilitate accurate measurement of dose less then 10mg, fuconazole should only be administered to children In hospital using the 50 mg/5 ml
• suspension orally or the Intravenous Infusion, depending on the clinical condition of the child. A suitable measuring device should be used for administration of the suspension. Once reconstituted, the suspension should not be further diluted.

Intravenous-

• Adult: Invasive candidal infections including candidaemia and disseminated candidiasis and cryptococcal infections including meningitis, by IV, 400 mg initially then 200 mg daily, increased if necessary to 400 mg daily, treatment continued according to response (at least 6-8 weeks for cryptococcal meningitis)
• Child: 6-12 mg/kg daily (every 72 hours in neonate up to 2 weeks old, every 48 hours in neonate 2-4 weeks old); maximum 400 mg daily. Prevention of relapse of cryptococcal meningitis, by IV, 100-200 mg daily.

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Interaction

In an interaction study, fuconazole increased the prothombin time after warfarin administration in healthy males. Though the magnitude of change was small (12%) careful monitoring of prothombin time in patients receiving coumarin type anticoagulants is recommended.

Dermicon has been shown to prolong the serum half-life of concomitantly administed oral sulphonyl ureas (chlorpropamide, gilbenclamide, glipizide and tolbutamide) in healthy volunteers. Dermicon and oral sulphonylureas may be co-administered to diabetic patients, but the possibility of a hypoglycemic episode should be borne in mind.

In a kinetic interaction study, co-administration of multiple-dose hydrochlorothiazide to healthy volunteers receiving fuconazole increased plasma concentrations of fuconazole by 40%. An efect of this magnitude should not necessitate a change in the fuconazole dose regimen in subjects recieving concomitant diureties, although the prescribers should bear it in mind.

Concomitant administration of fuconazole and phenytoin may increase the level of phenytoin to a clinically signifcant degree. Administration of fuconazole and rifampicin has resulted in a 25% decrease in the AUC and 20% shorter half-life of fuconazole. Patients recieving concomitant rifampicin, an increase in the fuconazole dose should be considered.

Two kinetic studies with combined oral contraceptive have been performed using muitiple dose of fuconazole. There were no relevant efects on either hormone level in the 50 mg fuconazole study, while at 200 mg daily the AUCs of ethinyl estradiol and levonorgestrel were increased 40% and 4% respectively. Thus multipule dose use of fuconazole at these dose is unlikely to have an efect on the efcacy of the combined oral contraceptives. Dermicon 50 mg daily does not afect endogenous steroid levels in females. 200-400 mg daily has no clinically singnifcant efect on endogenous steroid levels or on ACTH stimulated response in healthy male volunteers.

A kinetic study in renal transplant patients found fuconazole 200 mg daily to slowly increase cyclosporin concentrations. However, in another multiple dose study with 100 mg daily, fuconazole did not afect cyclosporin levels in patients with bone marrow transplants. Cyclosporin plasma concentration monitoring in patients receiving fuconazole is recommended.

Interaction studies have shown that when oral fuconazole is co-administered with food. cemetidine, antacids or following total body irradiation for bone marrow transplantation, no clinically signifcant impairment of fuconazole absorption occurs.

In placebo-controlled interaction study, the administration of fuconazole 200mg for 14 days resulted in an 18% decrease, in the mean plasma clearance of theophyline, Patients who are receiving dose of theophyline or who are otherwise at increased risk for theophyline toxicity should be observed for sign of toxicity while receiving fuconazole, and the therapy modifed appropriately if sign of toxicity while receiving fuconazole, and the therapy modifed appropriately if sign of toxicity develop.

Physicians should be aware that drug-drug interaction studies with other medications have not been conducted, but that such interactions may occur.

Contraindications

Fluconazole should not be used in patients with known hypersensitivity to Fluconazole or to related triazole compounds.

Side Effects

Dermicon is generally well tolerated. The commonest side-efects associated Dermicon are symptoms associated with the gastrointestinal tract; these include nausea, abdominal discomfort, diarrhoea and fatulence. Other adverse events such as rash are rarely encountered (Incidence less than 1%). In rare cases, as with other azoles, anaphylaxis has been reported.

Pregnancy & Lactation

Fluconazole adverse fetal efects have been seen in animals only at dose levels associated with maternal toxicity. These levels are many times in excess of those recommended for therapeutic use. There has been little use during human pregnancy. Accordingly, fuconazole should not be used in pregnancy or in women of child bearing potential unless adequate contraception is employed.

Precautions & Warnings

in some patients, particularly those with serious underlying diseases such as AIDS and cancer, abnormalities of hepatic, renal, haematological and other biochemical function tests have been observed during treatment with fuconazole, but the clinical signifcance and relationship to treatment is uncertain.

Very rarely. patients who died with severe underlying disease and who had received multiple dose fuconazole, had post-mortem fndings which included hapatic necrosis. These patients were receiving multiple concomitant medications, some known to be potentially hepatotoxic, and/or had underlying diseases, which could have caused the hepatic necrosis. Consequently, because a causal relationship with fuconazole cannot be excluded, the risk-beneft ratio of continued fuconazole treatment should be assessed in those patients in whom a signifcant rise of liver enzymes occurs.

Patients have rarely developed exfoliative cutaneous reactions, such pa Stevens Johnson Syndrome and toxic epidermal necrolysis, during treatment with fuconazole. AIDS patients are more prone to the development of severe cutaneous reactions to many drugs.

If a rash develops in a patients treated for a superfaclal fungal infection which is considered attributable to fuconazole further therapy with this agent should be discontinued. In patients with invasive/ systemic fungal infections who develop rashes, they should be monitored closely and fuconazole should be discontinued if bolbous lesions or erythema multiform develop.

Use during lactation: Dermicon is found in human breast milk at concentrations similar to plasma. hence its use in nursing mothers is not recommended.

Driving/Use of machinery: Experience with fuconazole indicates that therapy a unlikely to impair a patient’s ability to drive or use machinery.

Use in Special Populations

Use in the elderly: The normal dose should be used if there is no evidence of renal impairment. In patients with renal impairment, (creatinine clearance less than 40 ml/min) the dosage intervales or orally dosage should be adjusted as described below.

Use in renal impairment: Dermicon is excreted predominantly in the urine as unchanged drug. No adjustments in single dose therapy are required. In multiple dose therapy of patients with renal impairment, normal dose should be given on days 1 and 2 of treatment and thereafter the dosage intervals or daily dosage should be modifed in accordance with creatinine clearance as follows.

• CrCl >40: Dosage interval 24 hours (normal dosage regimen)
• CrCl 21-40: Dosage interval 48 hours or half normal daily dose
• CrCl 10-20: Dosage interval 72 hours or one-third normal daily dose
• Patients receiving regular haemodialysis: One dose after every dialysis session

Overdose Effects

In the event of overdosage, supportive measures and symptomatic treatment with gastric lavage if necessary may be adequate. As fuconazole is excreted largely in the urine, forced volume diuresis would probably increase the elimination rate. A three hour session of haemodialysis decreases plasma levels by approximately 50%

Therapeutic Class

Drugs for subcutaneous and mycoses

Storage Conditions

Keep in a dry place away from light and heat. Keep out of the reach of children.