Stabilanol

/ Trima

Adults: For the treatment of cryptococcal meningitis and cryptococcal infections of other areas of the body the usual dose is 400 mg on the first day followed by 200 mg – 400 mg daily in a single daily dose. The duration of treatment for cryptococcal meningitis depends on the clinical and mycological response, but is usually at least 6-8 weeks for cryptococcal meningitis, or 10-12 weeks following the negative results of a CNS culture.
For the prevention of a recurrence of cryptococcal meningitis: in patients with AIDS who have been given a full treatment with the full dose, fluconazole may be administered for an indefinite time at a dose of 100-200 mg daily.
For the treatment of deep systemic candidiases: the usual dose is 200-400 mg daily for a duration of approximately 2 years. The duration of the treatment should be individualized.
For the treatment of oropharyngeal candidiasis: The usual dose is 50 mg per day, for 7 to 14 days; in some cases, a dosage of 100 mg/day may be necessary. If necessary, treatment may be continued for a longer period in patients with a severely reduced immune response. For the treatment of atrophic oral candidiasis associated with dentures the usual dose is 50 mg once daily for 14 days, administered concurrently with the topical antiseptic measures on the dentures. For the treatment of other candidal infections of the mucosa (apart from vaginal candidiasis) e.g. oesophageal, non-invasive bronchopneumonal infections, candiduria, chronic mucosal candidiasis etc., the normal effective dose is 50-100 mg daily administered for 14-30 days.
For the treatment of vaginal candidiasis and candidal balanitis: 150 mg fluconazole as a single oral dose should be administered.
For infections caused by dermatophyte: including tinea pedis, tinea corporis, tinea cruris and Candida infections, the recommended dosage is 150 mg once weekly or an oral dosage of 50 mg once daily for 2 to 4 weeks. In case of tinea pedis, further therapy may be required for 6 weeks. The recommended dosage for the treatment of tinea versicolor is 50 mg once daily for 2 to 4 weeks.
For the prevention of fungal infections: in patients with a high risk of developing generalized infection, e.g. in patients who are expected to have severe or prolonged neutropenia such as patients undergoing bone marrow transplant, the recommended dosage is 400 mg once daily. For the prevention of fungal infections in patients with neutropenia and malignant disease who are predisposed to the development of such infections as a result of chemotherapy with cytostatic drugs or radiotherapy, the dose ranges from 50-400 mg daily. Treatment with fluconazole should be started several days prior to onset of anticipated neutropenia and should be continued for 7 days after the neutrophil count has risen above 1000 cells per mm3.
Children older than 4 weeks: As in the treatment of similar infections in adults. Duration of treatment depends on the patient’s clinical and mycological response. The maximum daily dose for adults should not be exceeded in children. Fluconazole should be administered once daily only in the following cases: The recommended dosage for oropharyngeal candidiases is 3 mg/kg/day. An initial dose of 6 mg/kg can be administered on the first day in order to reach the steady state sooner. For the treatment of generalized candidiasis and cryptococcal infections, the recommended dosage is 6 to 12 mg/kg/day depending on the severity of the disease. For prophylactic treatment of fungal infections in patients whose immune response is depressed due to neutropenia following cytotoxic chemotherapy or radiotherapy, the dosage should be 3 to 12 mg/kg/day depending on the severity and duration of neutropenia. In children with impaired renal function, the daily dose should be reduced depending on the severity of the impairment, according to the corresponding dose recommendations for adults.
Neonates: Neonates excrete fluconazole slowly. During the first two weeks of life, the same dose in mg/kg must be administered as for older children, but administered every 72 hours. In weeks 2 to 4, the same dose is administered, but every 48 hours.
Elderly: No dosage adjustment is necessary if there is no evidence of renal impairment. In patients with renal impairment (creatinine clearance less than 50 ml/min) the dosage schedule should be adjusted.
For full details see prescribing information.

Cryptococcal infections: including cryptococcal meningitis. Normal hosts and patients with AIDS, as well as patients with organ transplants or other causes of immunosuppression may also be treated. Fluconazole may be used for the prevention of relapse of cryptococcal infections in patients with AIDS.
Systemic candidiasis:including candidemia, disseminated candidiasis and other forms of invasive candidal infection. These include infections of the peritoneum, endocardium, pulmonary and urinary tracts. Patients with malignancy, in intensive care units, receiving cytotoxic or immunosuppressive therapy, or with other factors predisposing to candidal infections 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. For indications 1 and 2, prior to the commencement of treatment, cultures or appropriate laboratory examinations must be performed (microscope, biopsy examinations) in order to isolate and identify the causative microorganism.

Hypersensitivity to product or azoles. Not to co-administrate with drugs known to prolong QT interval and which are metabolised by CYP3A4, such as cisapride, astemizole, terfenadine, pimozide, quinidine.

Fluconazole is rarely associated with cases of severe hepatotoxicity, including cases of fatality, mainly in patients with a severe underlying medical disorder. In cases of fluconazoleassociated hepatotoxicity, no relationship with the total daily dosage, the period of treatment, nor sex or age of the patient has been observed. Hepatotoxicity in connection with fluconazole use is generally reversible following discontinuation of the treatment. Patients who develop an abnormal hepatic function during fluconazole treatment should be checked for the possible development of severe liver damage. Fluconazole must be withdrawn if clinical signs or symptoms that may indicate liver disease are observed which may be linked with fluconazole use. Very rarely, patients have developed exfoliative cutaneous reactions, such as StevensJohnson syndrome and toxic epidermal necrolysis, during treatment with fluconazole. AIDS patients are more prone to developing severe cutaneous reactions to several drugs. In the event that a rash develops in a patient treated for a superficial fungal infection, which may be attributed to fluconazole, further treatment with fluconazole should be discontinued. If patients with invasive or systemic fungal infections develop rashes, they should be closely monitored and fluconazole discontinued if bullous lesions of erythema multiforme develop. In rare cases, as with other azoles, anaphylaxis has been reported.

Fluconazole is usually well tolerated. In 4000 patients who took fluconazole for various reasons for 7 days or more the frequency of side effects was 16%. The frequency was higher in HIV(+) patients and reached 21%, while in HIV(-) patients this was 13%. Fluconazole is usually well tolerated. The most common side effects are gastrointestinal and include nausea, abdominal discomfort, diarrhoea and flatulence. Other adverse events such as rash are rarely encountered (incidence below 1%). Headache has been associated with fluconazole. Rarely exfoliative dermatitis such as Stevens-Johnson syndrome and toxic epidermal necrolysis, especially in patients with AIDS who are taking other medicines. In certain patients and specifically in patients with severe diseases, such as AIDS and cancer, during treatment with fluconazole and similar drugs disturbances in renal function, immune system function and liver function have been observed, seizures, leucopenia including neutropenia and agranulocytosis, 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.
For full details see prescribing information.

Anticoagulants: Fluconazole has been shown to increase prothrombin time following warfarin administration in healthy males. Though the change was small (12%), careful monitoring of prothrombin time in patients receiving coumarin-type anticoagulants is recommended. Sulphonylureas: Fluconazole has been shown to prolong the serum half life of concomitantly administered oral sulphonylureas (chlorpropamide, glibenclamide, glipizide and tolbutamide) in healthy volunteers. Fluconazole and oral sulphonylureas may be coadministered to diabetic patients, but the possibility of a hypoglycaemic episode should be borne in mind.
Hydrochlorothiazide: In a kinetic interaction study, co-administration of multiple-dose hydrochlorothiazide to healthy volunteers receiving fluconazole increased plasma concentrations of fluconazole by 40%. Such an effect does not necessitate a change in the fluconazole dosage regimen in subjects receiving concomitant diuretics, but it 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 pharmacokinetic studies have been performed on multiple dose fluconazole in combination with orally administered oral contraceptives. No causal effect was observed on hormone levels during the study using 50 mg fluconazole, while with doses of 200 mg fluconazole daily the area under the curve values (AUC) of ethinyl estradiol and of levonorgestrel were increased by 40% and 24% respectively. Consequently it is unlikely that multiple dose use of fluconazole at these levels is unlikely to have an effect on the efficacy of the combined oral contraceptive.
Rifampicin: Concomitant administration of fluconazole and rifampicin resulted in a 25% decrease in the AUC and 20% shorter half-life of fluconazole. In patients receiving concomitant rifampicin, an increase in the fluconazole dose should be considered.
Cyclosporine: In a pharmacokinetic study in patients who had undergone a renal transplant, it was found that the administration of fluconazole at a dose of 200 mg daily caused an increase in cyclosporine concentration. In another study during which multiple doses of fluconazole were administered equivalent to approximately 100 mg daily, no effect was observed on cyclosporine concentration in patients who had undergone a bone marrow transplant. Caution! When fluconazole and cyclosporine are co-administered for more than 10 days, or when fluconazole is administered at a daily dose larger than 200 mg, monitoring of cyclosporine levels in the blood is required, as these may increase with consequent toxic effects.
Theophylline: Patients who are receiving high doses of theophylline or who are otherwise at increased risk for theophylline toxicity should be observed for signs of theophylline toxicity while receiving fluconazole, and therapy modified if signs of toxicity develop.
Zidovudine: Two pharmacokinetic studies showed increased levels of zidovudine, probably due to the reduced rate of conversion to its main metabolite. One study determined the levels of zidovudine in patients with AIDS or AIDS related syndrome before and after the administration of 200 mg fluconazole daily for 15 days. A significant increase in the area under the curve (AUC) was observed, equivalent to approximately 20%. The levels of zidovudine in HIV patients were observed in a second, randomized, cross-over twoperiod study on two products. In both cases, 21 patients received 200 mg zidovudine every 8 hours with or without 400 mg fluconazole daily for 7 days. The AUC of zidovudine increased significantly (74%) with the concurrent administration of fluconazole. Patients to whom zidovudine and fluconazole are co-administered should be monitored for the development of zidovudine-related adverse reactions.
Terfenadine: Cases of serious dysrhythmias secondary to prolongation of the QTc interval in patients receiving other azole antifungals in conjunction with terfenadine, interaction studies have been reported. One study at a daily dose of 200 mg of fluconazole failed to demonstrate a prolonged QTc interval. Another study at a 400 mg and 800 mg daily dose of fluconazole demonstrated that fluconazole taken in multiple doses of 400 mg per day or more did significantly increase plasma levels of terfenadine when taken concomitantly. Because of the potential seriousness of such an interaction, it is recommended that terfenadine should not be taken in combination with fluconazole in doses of 400 mg or more per day.
Astemizole: The use of fluconazole in patients who are concurrently taking astemizole, cisapride or other drugs which are metabolized by the cytochrome P450 enzyme complex may be associated with an increase in the concentrations of these medicines in the blood. Due to the lack of information, caution is required during co-administration of fluconazole and astemizole. Patients should be carefully monitored.
Cisapride: Cardiac episodes including torsade de pointes have been observed in those concurrently taking fluconazole and cisapride. Cisapride is metabolized in the liver by the CYP 3A4 enzyme. As all azoles inhibit this enzyme, the concurrent administration of cisapride with these substances may increase the risk of appearance of cardiac rhythm disturbances (prolongation of QT intervals, ventricular arrhythmias, torsade de pointes). For this reason cisapride should not be administered concurrently with azoles.
Fluconazole/Benzodiazepines (Short Acting): Following oral administration of midazolam, fluconazole resulted in substantial increases in midazolam concentrations and 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 being treated with fluconazole, consideration should be given to decreasing the benzodiazepine dosage, and the patients should be appropriately monitored.
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.
Fluconazole/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. 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. Physicians should be aware that drug-drug interaction studies with other medications have not been conducted, but that such interactions may occur.

Pregnancy: There is little experience of fluconazole use in human pregnancy. Adverse effects on the embryo have been observed on laboratory animals only at high doses, which are associated with toxic effects on pregnant laboratory animals. These findings are not thought to be correlated to fluconazole use at therapeutic doses. However, the use of fluconazole during pregnancy should be avoided, apart from in patients with severe and life-threatening fungal infections, in which fluconazole may be used if the expected benefits from treatment exceed the potential risk of toxic effects on the embryo.
Lactation: Fluconazole is present in human breast milk at concentrations similar to plasma, hence its use in nursing mothers is not recommended.

There has been a reported case of overdose with fluconazole. A 42 year old patient infected with HIV developed hallucinations and exhibited paranoid behaviour after reportedly ingesting 8200 mg of fluconazole, unverified by his physician. The patient was hospitalized and his condition resolved within 48 hours. In the event of overdose, supportive measures and symptomatic treatment, with gastric lavage if necessary, may be adequate. As fluconazole is largely excreted unchanged in the urine, forced volume diuresis would probably increase the elimination rate. A three hour haemodialysis session decreases plasma levels by approximately 50%.