DIFUZIT

INGREDIENTS

Fluconazole…………………..150 mg

Excipients: Dicalcium phosphate, PVP K30, Lactose, Magnesium stearate, Talc………….q.s 1 capsule

DOSAGE FORM: Hard capsule.

PRESENTATION:

Box of 1 blister x 1 capsule.

Box of 1 blister x 10 capsules.

PHARMACODYNAMICS:

Difuzit contains the active ingredient Fluconazole, the first member of the triazole class of antifungal agents. Its primary mode of action is the inhibition of cytochrome P₄₅₀-14-alpha-demethylase. Difuzit prevents the synthesis of ergosterol, the major sterol in the fungal cell membrane. As a result, the permeability of the fungal cell membranes changes, releasing essential substances (amino acids, potassium, etc.) and reducing the uptake of precursor molecules such as purine, pyrimidine into the fungal cell. Difuzit has no similar effect on the synthesis of cholesterol in human.

PHARMACOKINETICS:

Fluconazole is well absorbed by the gastrointestinal tract. Oral absorption is not affected by concomitant food intake. The bioavailability of orally administered fluconazole is over 90% compared with intravenous administration. Peak plasma concentrations (Cmax) occur between 1 and 2 hours and steady-state concentrations are reached within 5-7 days.

Fluconazole is widely distributed into body tissues and fluids. Fluconazole concentrations in breast milk, joint fluid, saliva, sputum, vaginal fluid and peritoneal fluids were equal to plasma concentrations. Fluconazole concentrations in the CSF are 50% to 90% of the corresponding plasma concentrations even if the meninges are not inflamed. Therefore, fluconazole is widely indicated in fungal infections at different organs.

Fluconazole is cleared primarily by renal excretion, with approximately 80% or higher of the administered dose appearing in the urine as unchanged drug. Plasma elimination half-life for fluconazole is approximately 30 hours following a single dose in a day.

INDICATIONS:

Difuzit is indicated for patients who are intolerant of common antifungal agents or these drugs do not work.

Difuzit is indicated for the treatment of:

- Vaginal candidiasis.

- Oropharyngeal and esophageal candidiasis, Candida urinary tract infections, peritonitis, and other systemic Candida infections including candidemia, disseminated candidiasis, and pneumonia.

- Meningitis caused by Cryptococcus neoformans.

- Mycosis caused by Blastomyces, Coccidioides immititis and Histoplasma.

Prophylaxis: Difuzit is also indicated to decrease the incidence of candidiasis in patients undergoing immunodeficiency, cancer, AIDS, and bone marrow transplantation who receive cytotoxic chemotherapy and/or radiation therapy.

CONTRAINDICATIONS

Hypersensitivity to azole antifungal agents (including ketoconazole, miconazole, and clotrimazole) or any ingredients of the drug.

PRECAUTIONS

Difuzit should be administered with caution to patients with liver or kidney failure, arrhythmias, prolongation of the QT interval on the electrocardiogram.

PREGNANCY AND LACTATION

Pregnancy: There are no adequate studies of fluconazole in pregnant women. Therefore, fluconazole should be used during pregnancy if the potential benefit justifies the potential risk to the fetus.

Breastfeeding: Fluconazole is excreted in human milk at concentrations similar to maternal plasma concentrations. Fluconazole is contraindicated in a nursing woman.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

Patients should be warned about the potential for dizziness or headache while taking fluconazole and should be used with caution during driving or operating machines.

INTERACTIONS

Fluconazole has been shown to increase the plasma concentrations of concomitantly administered oral sulfonylureas (e.g., tolbutamide, glyburide, glipizide), phenytoin (epilepsy medication), theophylline (asthma medication), astermizole (anti-histamine), coumarin anticoagulants (warfarin), antiviral agents (zidovudine),  cisapride, tacrolimus and ciclosporin. Fluconazole may may increase the effect and toxicity of these drugs.

Concurrent administration of fluconazole and rifampicin may affect their pharmacokinetics. Rifampicin reduces the absorption and half-life of fluconazole; so dosage of fluconazole should be increased if used concurrently.

There have been reports that an interaction exists when fluconazole is administered concomitantly with rifabutin or zidovudine in HIV-infected patients. Fluconazole increases plasma concentrations and AUC of rifabutin and main metabolites.

DOSAGE

Dosage and duration of treatment with Difuzit depends on the type of pathogenic fungus, kidney function and response of the patient to the drug. Treatment of infections requiring multiple dosing 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.

For patients with HIV infection and Cryptococcal meningitis, a maintenance therapy should be given to prevent relapse.

Term newborn infants:

First 2 weeks after birth: 3-6 mg/kg, given every 72 hours.

2-4 weeks after birth: 3-6 mg/kg, given every 48 hours.

Children:

Prophylaxis: 3 mg/kg/day in surface fungal infections and 6-12 mg/kg/day in systemic fungal infections.

Treatment: 6 mg/kg/day. In persistent infections, the dose can be increased to 12 mg/kg/24 hours, in 2 divided doses. Do not exceed 600 mg daily.

Adults:

Treatment of mucosal candidiasis:

- Vaginal candidiasis: A single dose (150 mg) once in a day.  For prophylaxis of recurrent vaginal candidiasis, one capsule (150 mg) once a month for 4-12 months is recommended.

- Oropharyngeal candidiasis: The recommended dose is 1 capsule (150 mg) once daily for 1 to 2 weeks.

- Oesophageal candidiasis: The recommended dose is 1 capsule (150 mg) once daily for at least 3 uninterrupted weeks and for at least 2 weeks more after the disappearance of symptoms.

- Systemic fungal infections: The loading dose is 3 capsules; the subsequent dose 1 capsule (150 mg) once daily for at least 4 weeks, and at least 2 weeks more after the disappearance of symptoms.

Treatment of Cryptococcal meningitis: The loading dose is 3 capsules. The subsequent dose is 1-3 capsules once daily for at least 6-8 weeks after insertion of cerebrospinal fluid with a negative result. For HIV-infected patients, the dose of Difuzit should be 1 capsule once daily for a long time to avoid recurrence.

Prophylaxis of fungal infections:

Prophylaxis of candidal infections in patients with bone marrow transplant, the recommended dose of Difuzit is 3 capsules (450 mg) once daily. For patients predicted severe agranulocytosis (the neutrophil count less than 500 cells per mm³), fluconazole should start several days before the anticipated onset of neutropenia and continue for 7 days after recovery from neutropenia after the neutrophil count rises above 1000 cells per mm³.

Renal impairment

No adjustments in single dose therapy are necessary. In patients with impaired renal function who will receive multiple doses of fluconazole:

UNDESIRABLE EFFECTS:

Adverse events occur at an incidence of 5-30% in patients receiving fluconazole for 7 or more days. Treatment was discontinued in 1-2.8% of patients due to adverse clinical events. Patients with vaginal candidiasis were treated with fluconazole, a single dose. The overall incidence of side effects possibly related to fluconazole was 26-31%. Clinical adverse events were reported more frequently in HIV infected patients (21%) than in non-HIV infected patients (13%). However, it was difficult to assess and determine the association between fluconazole and its adverse effect as it has been used in many patients with severe underlying diseases who have used multiple drugs simultaneously.

Common, ADR > 1/100

CNS disorders: headache, dizziness (approximately 2% of the patient).

Gastrointestinal disorders: nausea, vomiting, diarrhea, (approximately 1.5-8.5%).

Uncommon, 1/1000 < ADR < 1/100

Hepatic disorders: transient increase in plasma transaminase and bilirubin (1.5 to 3 times upper limit of normal).

Skin disorders: rash, pruritus.

Rare, ADR < 1/1000

Blood disorders: Eosinophilia, anemia, leucopenia, neutropenia, thrombocytopenia.

Hepatic disorders: Elevated serum transaminase level (8 or more times the upper limit of normal) and discontinuation of therapy.

Skin disorders: exfoliative skin (mainly in patients with AIDS and cancer), Stevens - Johnson syndrome.

Others: Fever, oedema, pleural effusion, hypotension, hypokalaemia, anaphylactic shock.

Inform your doctor about any side effects that may occur during the treatment.

OVERDOSE:

If the clinical diagnosis gives overdose symptoms, the patient must be hospitalized and monitored carefully for at least 24 hours. Monitoring of clinical signs, blood potassium levels and liver and kidney tests should be applied.

In case of severe overdose, hemodialysis should be performed.

SHELF-LIFE: 36 months from the manufacturing date.

STORAGE: Store in cool dry places, below 30⁰C, protect from direct light.

SPECIFICATIONS: MANUFACTURER’S

KEEP OUT OF REACH OF CHILDREN.

READ THE DIRECTION CAREFULLY BEFORE USE.

CONSULT YOUR PHYSICIAN FOR MORE INFORMATION