Medoflucon

Fluconazole.

Each "Medoflucon" capsule 50mg, contains 50mg of fluconazole.
Each "Medoflucon" capsule 150mg, contains 150mg of fluconazole.

Pharmacology: Pharmacodynamics: Fluconazole is a selective inhibitor of fungal enzymes needed for the synthesis of ergosterol.
It is an orally active bistriazole antifungal agent. Mode of action, in sensitive fungi, is by inhibition of fungal cytochrome P-450 dependent enzymes, which results in impairment of ergosterol synthesis in the fungal cell membrane, resulting in disruption of membrane associated functions. It is active against Blastomyces dermatitidis, Candida sp., Coccidioides immitis, Cryptococcus neoformans, Histoplasma capsulatum, Microsporum sp., and Trichophyton sp. Resistance has developed in some Candida sp.
Pharmacokinetics: Fluconazole is well absorbed following oral administration. The bioavailability orally is 90% or more of that from intravenous administration. Mean peak plasma levels of 6.27µg/ml have been reported in healthy volunteers following a 400mg oral dose. Peak plasma concentrations are reached in one to two hours following oral administration, and the plasma levels are proportional to the dose over the range 50mg to 400mg. Multiple dosing leads to an increase in peak plasma levels, steady state concentrations are achieved in six to ten days. Use of a loading dose means that steady state plasma concentrations can be achieved in two days. Fluconazole is widely distributed, with the apparent volume of distribution being close to that of total body water. The concentrations of fluconazole reached in joint fluid, breast milk, saliva, sputum, peritoneal fluid and vaginal fluids are similar to those in plasma. Cerebro-spinal fluid concentrations range from 50% to 90% of the plasma concentration, even in the absence of inflammation of the meninges.
Protein binding is about 12%.
Fluconazole is eliminated mainly in the urine, with 80% or more being excreted unchanged. About 11% is excreted as metabolites. The elimination half life is about thirty hours, and this is increased with impaired renal function. Fluconazole is removed by dialysis.
Fluconazole renal clearance for the elderly is generally lower than for the younger people.
Toxicology: Preclinical Safety Data: No further relevant information.

Acute or recurrent vaginal candidiasis.
Mucosal candidiasis, including oropharyngeal, oesophageal, non invasive bronchopulmonary infection, candiduria, mucocutaneous and chronic oral atrophic candidiasis.
Tinea pedis, tinea cruris, tinea corporis, tinea versicolor and dermal Candida infection.
Systemic candidiasis, such as candidaemia, disseminated candidiasis and invasive candidal infection of the peritoneum, endocardium and urinary and pulmonary tracts.
Cryptococcosis, including pulmonary and cutaneous infections and cryptococcal meningitis. In AIDS patients, as a maintenance therapy to prevent relapse of cryptococcal disease.
Prevention of fungal infection in immunocompromised patients at risk as a result of neutropenia following cytotoxic chemotherapy or radiotherapy.

"Medoflucon" capsules are for oral administration.
Daily dose of fluconazole should be based on the severity and nature of the fungal infection. For infections requiring multiple doses, treatment should continue until clinical and laboratory tests indicate the subsidence of active fungal infection. An inadequate period of treatment may lead to active infection reoccurring. In patients with cryptococcal meningitis and AIDS, maintenance therapy is usually required to prevent reoccurrence of infection.
Adults: Vaginal candidiasis, a single 150mg dose.
Oropharyngeal candidiasis, 50mg once a day for seven to fourteen days. Treatment should not normally exceed fourteen days except in severely immunocompromised patients.
Atrophic oral candidiasis, 50mg once a day for fourteen days.
Oesophagitis, non invasive bronchopulmonary infection, mucocutaneous candidiasis and candiduria, 50mg once daily for fourteen to thirty days.
The daily dose may be increased to 100mg for unusually difficult mucosal candidal infections.
Tinea pedis, tinea cruris, tinea corporis, tinea versicolor and dermal Candida infection, 50mg once a day for two to four weeks. Tinea pedis may require treatment for up to six weeks. Six week treatment duration should not normally be exceeded.
Candidaemia, disseminated candidiasis and invasive candidal infections, an initial dose of 400mg on the first day followed by 200mg once a day. If required by the clinical response, the dose may be increased to 400mg once a day. The length of treatment is dictated by clinical response.
Cryptococcal meningitis and other cryptococcal infections, an initial dose of 400mg on the first day followed by 200mg - 400mg once a day. The length of treatment depends on mycological and clinical response, for cryptococcal meningitis it is usually six to eight weeks. For prevention of relapse following primary therapy in patients with AIDS, indefinite administration of 100mg - 200mg once a day.
To prevent fungal infection in immunocompromised patients at risk due to neutropenia consequent upon cytotoxic chemotherapy or radiotherapy, 50mg to 400mg once a day. High risk patients, such as bone marrow transplants, should receive 400mg once a day. Dosage should be initiated several days before the anticipated onset of neutropenia and should be continued for seven days after neutrophil count has exceeded 1000 cells/mm³.
Children: Due to the dosage form, use in very young children is not recommended. Duration of therapy is based on clinical and mycological response.
Children over four weeks old: Mucosal candidiasis, 3mg/kg body weight once a day. A loading dose of 6mg/kg bodyweight may be given on the first day to rapidly achieve steady state.
Systemic candidiasis and cryptococcal infections, 6mg - 12mg/kg body weight once a day, depending upon the severity of the infection.
Prevention of fungal infection in immunocompromised patients at risk as a consequence of induced neutropenia, 3mg - 12mg/kg body weight depending upon the extent and duration of the neutropenia.
Children less than four weeks old: A capsule dosage form is not suitable for this age group.
Elderly: No dosage adjustment is necessary unless there is renal impairment (creatinine clearance <40ml/min).
Renal Impairment: No dosage adjustment is necessary for single dose therapy.
In multiple dose therapy, normal dose should be administered on day 1 and day 2. If creatinine clearance is between 21ml - 40ml/min, either subsequently give half the normal dose once a day or prolong the dosing interval to every two days. If creatinine clearance is 10ml - 20ml/min, either give one third the normal dose once a day or prolong the dosing interval to every three days.
Haemodialysis Patients: One dose after every haemodialysis session.

Treatment of overdosage is essentially supportive and symptomatic. Gastric lavage may be useful. Fluconazole is eliminated mainly in the urine, thus forced volume diuresis should increase elimination rate. Haemodialysis will also eliminate some fluconazole.

Patients with known hypersensitivity to fluconazole or related azole compounds. Co-administration of fluconazole with terfenadine and cisapride is also contraindicated.

Some patients, especially those with serious underlying disease, such as AIDS or cancer, treated with fluconazole have been observed to have abnormalities of renal, hepatic, haematological and other biochemical function tests. Clinical significance and causality is uncertain.
In very rare cases, patients with severe underlying disease and treated with fluconazole, who died were found to have hepatic necrosis. All were on concomitant multiple medications, some of which were known to be hepatoxic, or had underlying disease that could have caused hepatic necrosis. As a causal relationship with fluconazole cannot be excluded, in patients with a significant rise in liver enzymes the risk benefit of continued fluconazole therapy should be evaluated.
Patients have, in rare cases, developed exfoliative cutaneous reactions, including Stevens-Johnson Syndrome and toxic epidermal necrolysis, during fluconazole therapy. Development of such severe cutaneous reactions is more likely in AIDS patients.
If rash develops during superficial fungal infection therapy that is attributable to fluconazole, therapy should be discontinued. If it develops in patients being treated for invasive/systemic infection, they should be monitored closely and therapy discontinued if bullous lesions or erythema multiforme develops.
In rare cases, as with other azole, anaphylaxis has been reported. Some azoles, including fluconazole, have been associated with QT prolongation and Torsades de Pointes. Use fluconazole preparation with caution in patients with these potentially pro-arrhythmic conditions.
There have been reports of spontaneous abortion and congenital abnormalities in infants whose mothers were treated with 150 mg of fluconazole as a single or repeated dose in the first trimester.
Effects on Ability to Drive and Use Machines: "Medoflucon" is unlikely to have any effect on the ability to drive or use machinery.

There is little experience of use in human pregnancy. "Medoflucon" should not be used in pregnancy. It should not be used in women of child bearing potential unless adequate contraception is used.
Fluconazole is excreted in milk at levels similar to plasma levels. Use in nursing mothers is not recommended.

"Medoflucon" is generally well tolerated. The most common side effects are those associated with the gastro-intestinal tract. These include the following hepatobiliary disorders, abdominal discomfort, flatulence, nausea and diarrhoea. Rash has been rarely reported. As with other azole compounds, anaphylaxis has been rarely reported.
Nervous system - Headache.
Post marketing observations - Leukopenia, neutropenia, agranulocytosis, thrombocytopenia, angioedema, urticaria, hypokalemia, hypercholesterolemia, dizziness, seizures, taste perversion, dyspepsia, jaundice, alopecia, Steven-Johnson syndrome, toxic epidermal necrolysis have been occasionally reported. See under Precautions for severe skin reactions in AIDS patients.

Fluconazole increased the prothrombin time after warfarin administration by about 12%. Careful monitoring of prothrombin time in patients concomitantly receiving coumarin type anti-coagulants is recommended.
The serum half life of concomitantly administered oral sulphonylureas is prolonged by fluconazole. Concomitant administration to diabetics is recommended, but the possibility of hypoglycaemic episodes should be remembered.
Concomitant administration of multiple dose hydrochlorothiazides with fluconazole led to an increase of 40% in fluconazole plasma concentration. This should not necessitate dosage adjustment, but should be noted.
Concomitant administration with phenytoin may result in a significant increase in phenytoin levels. In such cases phenytoin levels should be monitored and the dosage of phenytoin adjusted to maintain therapeutic levels.
Concomitant administration of fluconazole and rifampicin leads to a 25% decrease in AUC and 20% decrease in half life of fluconazole. In such cases, an increase in fluconazole dose should be considered. High doses of fluconazole with combination oral contraceptives give increases in the AUC for levonorgestrel and ethinyl estradiol, but efficacy of the contraceptives is unlikely to be affected.
Fluconazole 200mg per day was found to slowly increase cyclosporin concentrations. Separately, fluconazole 100mg per day had no effect on cyclosporin levels. It is recommended that patients on concomitant fluconazole and cyclosporin have cyclosporin plasma levels monitored.
It is reported that concomitant administration of fluconazole with food, antacids or cimetidine, and following whole body irradiation does not give any clinically significant alteration to fluconazole absorption.
Concomitant administration of fluconazole and theophylline resulted in a decrease in theophylline plasma clearance. High dose theophylline patients, or those at risk from theophylline toxicity, should be closely observed for toxicity signs and therapy modified if toxicity is seen.
Concomitant administration with rifabutin can lead to elevated plasma levels of rifabutin, with the risk of uveitis, and consideration should be given to reducing rifabutin dosage to 300mg per day. Concomitant administration with terfenadine can lead to accumulation of terfenadine with the risk of cardiac arrhythmia, the two should not be used together.
Short acting benzodiazepines, eg. midazolam, when given together with fluconazole resulted in substantial increases of midazolam concentrations and psychomotor effects.
There have been reports of cardiac events, including Torsades de Pointes in patients to whom fluconazole and cisapride were given together.
Interactions exist when fluconazole is co-administered with tacrolimus, leading to increased serum levels of tacrolimus and nephrotoxicity.
The AUC of zidovudine increased significantly during coadministration with fluconazole and patients should be closely monitored for development of zidovudine related adverse reactions. The use of fluconazole in patients concurrently taking astemizole or other drugs metabolized by the cytochrome P-450 system may be associated with elevations in serum levels of these drugs.
Other specific drug interaction studies have not been reported, but the possibility of other drug-drug interactions cannot be excluded.

Instruction for Use/Handling: For oral administration.
Incompatibilities: None known.

Store in a dry place protected from light at a temperature not exceeding 25°C.
Shelf-Life: 48 months.

Antifungals

J02AC01 - fluconazole ; Belongs to the class of triazole and tetrazole derivatives. Used in the systemic treatment of mycotic infections.

POM