(Oral Antifungal Capsules and Powder for Oral Suspension)
Fluconazole is chemically identified as 2-(2,4-diffuorophenyl)-1, 3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol. The molecular formula is C13H12F2N6O6 and the molecular weight is 306.3.
Flucamed® contains fluconazole, a member of a new class of triazole agents, a potent and specific inhibitor of fungal sterolsynthesis. Acitivity of fluconazole has been demonstrated against opportunistic mycoses, such as infections with Candida spp, including intracranial infections; with Microsporium spp; and with Trichophton spp.
Fluconazole has also been shown to be active in animal models of endermic mycoses, including infection with Blastomyces dermatitidis, with Coccidioides immitis, including intracranial infection and with Histoplasma capsulatum in normal and immunosuppressed animals.
Fluconazole is highly specific for fungal cytochrome P-450 dependent enzymes.
Fluconazole 50mg daily given up to 28 days has been shown not to affect testosterone plasma concentrations in males or steroid concentration in females of child-bearing age.
Fluconazole 200mg-400mg daily has no clinically significant effect on endogenous steroid levels or on ACTH stimulated response in healthy male volunteers. After oral administration, fluconazole is well absorbed and plasma levels (and systemic bioavailability) are over 90% of the levels achieved after intravenous administration. Oral absorption is not affected by concomitant food intake. Plasma concentrations are proportional to dose. 90% steady-state levels are reached by day 4-5 with once daily dosing.
Administration of loading dose (on day 1) of twice the usual daily dose enables plasma levels to approximate to 90% steady-state levels by day 2. The apparent volume of distribution approximates to total body water. Plasma protein binding is low (11.12%).
Fluconazole achieves good penetration into all body fluid studied. The levels of fluconazole in saliva and sputum are similar to plasma levels. In patients with fungal meningitis, fluconazole levels in the CSF are approximately 80% the corresponding plasma levels.
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.
The long plasma elimination half-life provides the basis for single dose therapy for vaginal candidiasis, once daily and once weekly dosing for other indications.
Treatment with Flucamed® may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly.
Cryptococcosis: Including cryptococcal meningitis and infections of other sites (e.g. pulmonary, cutaneous). Normal hosts and patients with AIDS, organ transplant or other causes of immunosuppression may be treated. Flucamed® can be used as maintenance therapy to prevent relapse of cryptococcal disease in patients with AIDS.
Systemic candidiasis: Including candidemia, disseminated candidiasis and other forms of invasive candidal infections. These include infections of the peritoneum, endocardium, eye, pulmonary and urinary tracts. Patients with malignancy, in intensive care units, receiving cytotoxic or immunosuppressive therapy, or with other factors predisposing to candidal infection may be treated.
Mucosal candidiasis: These include oropharyngeal, esophageal, non-invasive bronchopulmonary infections, candiduria, mucocutaneous and chronic oral atrophic candidiasis (denture sore mouth). Normal hosts and patients with compromised immune function may be treated. Prevention of relapse of oropharyngeal candidiasis in patients with AIDS.
Genital candidiasis: Vaginal candidiasis, acute or recurrent; and prophylaxis to reduce the incidence of recurrent vaginal candidiasis (3 or more episodes a year). Candidal balanitis.
Prevention of fungal infection: In patients with malignancy who are predisposed to such infections as a result of cytotoxic chemotherapy or radiotherapy.
Dermatomycosis: Including Tinea pedis, Tinea corporis, Tinea versicolor, Tinea unguium (onychomycosis), and dermal candida infections.
Deep endermic mycoses: Including coccidiodomycosis, paracoccidioidomycosis, sporotrichosis and histoplasmosis in immunocompetent patients.
Flucamed® should not be used in patients with known sensitivity to fluconazole or related azole compounds.
During Pregnancy and Lactation:
In pregnancy: Use in pregnancy should be avoided in the first trimester except in patients with severe or potentially life threatening fungal infections in whom Flucamed® may be used if the anticipated benefit out weights the possible risk to the foetus.
During Lactation: Fluconazole is found in human breast milk at concentrations similar to plasma, hence its use in nursing mothers is not recommended.
Anticoagulants: In an interaction study, fluconazole increased the prothrombin time after warfarin administration in healthy males. Though the magnitude of change was small (12%), careful monitoring of prothrombin time in patients receiving coumarin-type anticoagulants is recommended.
Sulfonylureas: Fluconazole has been shown to prolong the serum half-life of concomitantly administered oral sulfonylureas (chlopropamide, glibenclamide, glipizide and tolbutamide) in healthy volunteers. Fluconazole and oral sulfonylureas may be co-administered to diabetic patients, but the possibility of a hypoglycemic episode should be borne in mind.
Phenytoin: Concomitant administration of fluconazole and phenytoin may increase the levels of phenytoin to a clinically significant degree. If it is necessary to administer both drugs concomitantly, phenytoin levels should be monitored and the phenytoin dose adjusted to maintain therapeutic levels.
Oral Contraceptives: Two kinetic studies with a combined oral contraceptive have been performed using multiple doses of fluconazole, there were no relevant effects on either hormone level in the 50mg fluconazole study, while at 200mg daily, the AUCs of ethinyl estradiol and levonorgestrel were increased, 40% and 24% respectively. Thus, multiple dose use of fluconazole at these doses is unlikely to have an effect on the efficacy of the combined oral contraceptive.
Rifampicin: Concomitant administration of fluconazole and rifampicin resulted in 25% decrease in the AUC and 20% shorter half-life of fluconazole. In patients receiving concomitant rifampicin, an increase of the fluconazole dose should be considered.
Terfanadine: Because of the occurrence of serious dysrhythmias in patients receiving other azole antifungals in conjunction with terfenadine, interaction studies has been performed, and demonstrated, no clinically significant drug interaction was present. Although, these events have not been observed in patients receiving fluconazole, the co-administration of fluconazole and terfenadine should be carefully monitored.
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 200mg daily for 15days. There was a significant increase in zidovudine AUC (20%). A second randomized, two-period, two-treatment cross-over study examined zidovudine levels in HIV infected patients. On two occasions, 21 days apart, patients received zidovudine 200mg every eight hours either with or without fluconazole 400mg 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.
Interaction studies have shown that when oral fluconazole is co-administered with food, cimetidine, antacids or following total body irradiation for bone marrow transplantation, no clinically significant impairment of fluconazole absorption occurs.
KEEP OUT OF THE REACH OF CHILDREN!
DOSAGE AND ADMINISTRATION
The daily dose of Flucamed® should be based on the nature and severity of the fungal infection. Most cases of vaginal candidiasis respond to single dose therapy. 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 and cryptococcal infections at other sites, the usual does is 400mg on the first day followed by 200mg-400mg once daily. Duration of treatment for cryptococcal infections will depend on the clinical and mycological response, but is usually at least 6-8 weeks for cryptococcal meningitis. For the prevention of relapses of cryptococcal meningitis in patients with AIDS, after the patient receives a full course of primary therapy, fluconazole may be administered indefinitely at a daily dose of 200mg. For candidemia, disseminated candidiasis and other invasive candidal infections, the usual dose is 400mg on the first day followed by 200mg daily. Depending on the clinical response, the dose may be increased to 400mg daily.
Duration of treatment is based upon the clinical response.
2a. For oropharyngeal candidiasis, the usual dose is 50mg once daily by mouth for 7-14days, although 100mg daily may be given if necessary.
2b. For other candidal infections of mucosa e.g. esophagitis, non-invasive bronchopulmonary infections, candidurea, mucocutaneous candidiasis, etc, the usual effective dose is 50mg to 100mg daily, given for 14-30 days. 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 150mg once weekly dose.
3. For the treatment of vaginal candidiasis, fluconazole 150mg should be administered as a single oral dose. To reduce the incidence of recurrent vaginal candidiasis, a 150mg once monthly dose may be used. The duration of therapy should be individualized, but ranges from 4-12 months. Some patients may require more frequent dosing. For Candida balanitis, fluconazole 150mg should be administered as a single oral dose. For the prevention of candidiasis, the recommended fluconazole dosage is 50 to 400mg 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, the recommended daily dose is 400mg once daily. 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.
4. For dermal infections including Tinea pedis, corporis, cruris and candida infections, the recommended dosage is 150mg once weekly or 50mg once daily. Duration of treatment is normally 2 to 4 weeks but Tinea pedis may require treatment for up to 6 weeks. For Tinea vesicolor, the recommended dose is 50mg once daily for 2 to 4 weeks. For Tinea unguium, the recommended dosage is 150mg 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, nail occasionally remain disfigured.
5. For deep endemic mycoses, doses of 200-400mg daily for up 2 years may be required. The duration of therapy should be individualized but ranges from 11-24 months with coccidiodomycosis, 2-17 months with paracoccidiodomycosis, 1-16 months with sporotrichosis and 3-17 months for histoplasmosis.
6. In immunocompromised patients at risk of fungal infections, fluconazole may be given prophylactically in a dose of 50mg to 400mg daily by mouth or by intravenous infusion, although long-term prophylaxis has been associated with the emergence of resistant organisms.
1. Oropharyngeal candidiasis: The recommended dosage of Flucamed® for oropharyngeal candidiasis in children is 6mg/kg body weight on the first day, followed by 3mg/kg once daily. Treatment should be administered for at least 2 weeks to decrease the likelihood of relapse.
2. Esophageal candidiasis: For the treatment of esophageal candidiasis, the recommended dosage of Flucamed® in children is 6mg/kg on the first day, followed by 3mg/kg once daily. Dosage up to 12mg/kg/day may be used based on medical judgment of the patient’s response to therapy. Patients with esophageal candidiasis should be treated for a minimum of three weeks and for at least 2 weeks following the resolution of symptoms.
3. Systemic Cadida infections: For the treatment of candidemia and disseminated Candida infections, daily doses of
6-12mg/kg/day have been used in an open, noncomparative study of a small number of children.
4. Cryptococcal meningitis: For the treatment of acute cryptococcal meningitis, the recommended dosage is 2mg/kg on the first day followed by 6mg/kg once daily. A dosage of 12mg/kg once daily may be used, based on medical judgment of the patient’s response to therapy. The recommended duration of treatment for initial therapy of cryptococcal meningitis is 10-12 weeks after the cerebrospinal fluid becomes culture negative. For suppression of relapse of cryptococcal meningitis in children with AIDS, the recommended dose of FLUCAMED® is 6mg/kg once daily.
The maximum adult daily dosage should not be exceeded in children. Fluconazole is administered as
a single dose each day. For the prevention of fungal infections in immunocompromised patients
considered at risk as a consequence of neutropenia following cytotoxic chemotheraphy, the dose
should be 3-12mg/kg body weight daily, depending on the extent and duration of the induced
neutropenia (see adult dosing).
Flucamed® is generally well tolerated, common side effects are symptoms related to gastro-intestinal tracts.
Mild to moderate nausea, vomiting, abdominal pain and diarrhoea have been reported in about 1.5-8.5% of patients receiving Fluconazole.
Rash and headache have been reported in some patients.
In rare cases as with other azoles, anaphylaxis has been reported.
Store below 300C. Protect from light and moisture. Store capsules in blisters in the provided carton.
Flucamed® is available as:
(1) 50mg Fluconazole capsules in blister pack of 3’s, 10’s and 10 x 10’s
(2) 100mg Fluconazole capsules in blister pack of 10’s and 10 x 10’s
(3) 200mg Fluconazole capsules in blister pack of 10’s and 10 x 10’s (4) 35ml oral suspension (after reconstitution) containing 10mg Fluconazole in 1ml of suspension