Fluconazole Medisorb (Capsules) Instructions for Use

Marketing Authorization Holder

Medisorb, JSC (Russia)

ATC Code

J02AC01 (Fluconazole)

Active Substance

Fluconazole (Rec.INN registered by WHO)

Dosage Form

Fluconazole Medisorb

Capsules 150 mg: 1, 2, 3, 4, 7, 8, 10, 12, 14, 16, 20, 21, 28, 30, 40, 42, or 56 pcs.

Dosage Form, Packaging, and Composition

Capsules hard gelatin, size No.2, with a white body and a green cap; contents of capsules: granules and powder white or white with a slight yellowish tint.

Auxiliary substances : lactose monohydrate – 73.8 mg, povidone K-30 (polyvinylpyrrolidone medium molecular) – 1.8 mg, potato starch – 7.2 mg, colloidal silicon dioxide (aerosil) – 4.8 mg, magnesium stearate – 2.4 mg.

Composition of capsulescapsule body titanium dioxide, gelatin;
capsule cap: indigo carmine, titanium dioxide, dye iron oxide yellow, gelatin.

1 pc. – contour cell packaging (1) – carton packs.
1 pc. – contour cell packaging (2) – carton packs.
1 pc. – contour cell packaging (3) – carton packs.
1 pc. – contour cell packaging (4) – carton packs.
2 pcs. – contour cell packaging (1) – carton packs.
2 pcs. – contour cell packaging (2) – carton packs.
2 pcs. – contour cell packaging (3) – carton packs.
2 pcs. – contour cell packaging (4) – carton packs.
4 pcs. – contour cell packaging (1) – carton packs.
4 pcs. – contour cell packaging (2) – carton packs.
4 pcs. – contour cell packaging (3) – carton packs.
4 pcs. – contour cell packaging (4) – carton packs.
7 pcs. – contour cell packaging (1) – carton packs.
7 pcs. – contour cell packaging (2) – carton packs.
7 pcs. – contour cell packaging (3) – carton packs.
7 pcs. – contour cell packaging (4) – carton packs.
10 pcs. – contour cell packaging (1) – carton packs.
10 pcs. – contour cell packaging (2) – carton packs.
10 pcs. – contour cell packaging (3) – carton packs.
10 pcs. – contour cell packaging (4) – carton packs.
14 pcs. – contour cell packaging (1) – carton packs.
14 pcs. – contour cell packaging (2) – carton packs.
14 pcs. – contour cell packaging (3) – carton packs.
14 pcs. – contour cell packaging (4) – carton packs.

Indications

• Cryptococcosis, including cryptococcal meningitis and infections of other localization (e.g., lungs, skin). Fluconazole can be used for the treatment of cryptococcal meningitis in patients with AIDS, for the prevention of relapses of cryptococcal meningitis in patients with AIDS, and as a consolidation therapy after a course of primary treatment.
• Systemic candidiasis, including candidemia, disseminated candidiasis, pneumonia, peritonitis, endocarditis, and infections of other organs. It is indicated for both the treatment and prevention of candidiasis in patients undergoing cytotoxic chemotherapy or radiation therapy, and in those who are undergoing bone marrow transplantation.
• Mucosal candidiasis, including oropharyngeal, esophageal, and vaginal candidiasis. It is effective for both the treatment of acute episodes and the prevention of recurrences in patients with predisposing conditions, such as immunocompromised states.
• Genital candidiasis; a single 150 mg oral dose is typically sufficient for the treatment of acute vaginal candidiasis (vaginal thrush). It can also be used for balanitis caused by Candida species.
• Prevention of fungal infections in patients with malignant neoplasms who are predisposed to such infections as a result of cytotoxic chemotherapy or radiotherapy, particularly in patients with prolonged neutropenia (e.g., during induction chemotherapy for acute leukemia).
• Mycoses of the skin, including tinea pedis (athlete’s foot), tinea corporis (ringworm), tinea cruris (jock itch), tinea versicolor (pityriasis versicolor), and onychomycosis (fungal nail infections) when the causative organism is confirmed to be susceptible to fluconazole.

Contraindications

• Hypersensitivity to fluconazole, other azole antifungal agents, or to any of the excipients listed in the composition of the capsules. Cross-reactivity with other azole derivatives should be considered.
• Concomitant administration with drugs that are known to prolong the QTc interval and are metabolized via the cytochrome P450 3A4 (CYP3A4) enzyme system, such as terfenadine, astemizole, cisapride, pimozide, or quinidine, due to the increased risk of serious, potentially fatal cardiac arrhythmias, including torsades de pointes.
• Concomitant use with erythromycin due to the potential additive effect on QTc prolongation and increased risk of cardiotoxicity.
• Severe hepatic impairment or a history of drug-induced liver injury associated with fluconazole use. The drug is contraindicated in patients with clinical or laboratory evidence of significant hepatic dysfunction, as it may exacerbate the condition.
• Pregnancy, especially during the first trimester, unless the potential benefit to the mother outweighs the potential risk to the fetus. Animal studies have shown fetal toxicity and embryolethality at high doses. Adequate and well-controlled studies in pregnant women are lacking.
• Breastfeeding is generally contraindicated, as fluconazole is excreted in human milk at concentrations similar to plasma, posing a potential risk to the nursing infant.

Dosage Regimen

The dosage of Fluconazole Medisorb should be individualized based on the infecting organism, the patient’s clinical response, and underlying medical conditions, particularly renal function. The capsules can be taken with or without food.

For adults, the dosage is as follows: For vaginal candidiasis, a single oral dose of 150 mg is typically sufficient. For oropharyngeal candidiasis, the recommended dose is 100-200 mg once daily, with treatment continued for at least 2 weeks to prevent relapse. For esophageal candidiasis, the recommended dose is 100-200 mg once daily, with treatment continued for a minimum of 3 weeks and for at least 2 weeks following resolution of symptoms.

For systemic candidiasis (candidemia, disseminated candidiasis), a dose of 400 mg on the first day, followed by 200-400 mg once daily is recommended. Duration of therapy is based on clinical response but is often continued for at least 4 weeks. For cryptococcal meningitis, the recommended dose for initial treatment is 400 mg on the first day, followed by 200-400 mg once daily. The duration for primary therapy is typically 10-12 weeks after the cerebrospinal fluid becomes culture-negative. For prevention of relapse in AIDS patients, the dose is 200 mg once daily.

For dermatomycoses like tinea corporis, cruris, and pedis, a dose of 150 mg once weekly or 50 mg once daily for 2-6 weeks is used. For tinea versicolor, a single 300-400 mg dose or 150 mg once weekly for 2-4 weeks may be effective. For onychomycosis, a dose of 150 mg once weekly is recommended until the infected nail is replaced (which typically takes 6-12 months for fingernails and 12-18 months for toenails).

In elderly patients with no signs of renal impairment, the standard recommended dosage can be used. In patients with renal impairment, dosage adjustment is necessary. If the creatinine clearance (CrCl) is greater than 50 mL/min, the standard dose can be given. If CrCl is ≤50 mL/min (and the patient is not receiving regular dialysis), the dosing interval should be extended. For example, for a CrCl of 21-50 mL/min, the dose should be reduced by 50% or the dosing interval doubled. For patients on hemodialysis, one full recommended dose is given after each dialysis session.

Adverse Reactions

The adverse reaction profile of fluconazole is generally mild and infrequent. The most commonly reported adverse reactions involve the gastrointestinal tract and the nervous system.

Gastrointestinal disorders are frequent and may include abdominal pain, diarrhea, flatulence, dyspepsia, nausea, and vomiting. These symptoms are usually transient and resolve without the need to discontinue therapy. In some cases, particularly with higher doses or prolonged therapy, elevations in liver enzymes (ALT, AST, alkaline phosphatase) and, rarely, clinically apparent hepatotoxicity including hepatitis, cholestasis, and fulminant hepatic failure, have been reported. Patients who develop abnormal liver function tests should be monitored closely and the drug discontinued if symptoms of liver disease develop.

Nervous system disorders commonly include headache and dizziness. Seizures have been reported rarely, primarily in patients with serious underlying disease or those taking other medications that may lower the seizure threshold. Skin and subcutaneous tissue disorders can occur, with rash being the most frequently reported. Severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported rarely but can be life-threatening. Fluconazole should be discontinued if a rash develops that is considered attributable to the drug.

Other adverse reactions include alterations in taste ( dysgeusia), reversible alopecia, and, in some cases, hypercholesterolemia and hypertriglyceridemia. Hematological abnormalities such as leukopenia, thrombocytopenia, and agranulocytosis have been reported very rarely. Allergic and anaphylactic reactions, including angioedema, have also been reported. Prolonged use may lead to the development of resistance or superinfection with non-susceptible fungi or bacteria.

Drug Interactions

Fluconazole is a potent inhibitor of the cytochrome P450 isoenzyme CYP2C9 and a moderate inhibitor of CYP3A4. This inhibition is the primary mechanism for many of its clinically significant drug interactions, which can lead to increased plasma concentrations and an enhanced risk of toxicity of the co-administered drug.

Contraindicated combinations include terfenadine, astemizole, cisapride, pimozide, and quinidine, as fluconazole can significantly increase their plasma levels, leading to QTc interval prolongation and serious cardiac arrhythmias. Concomitant use with erythromycin is also contraindicated due to additive effects on QTc prolongation.

Fluconazole significantly increases the plasma concentrations of warfarin. Prothrombin time should be monitored closely in patients receiving this combination, and the warfarin dose should be adjusted accordingly. It also increases the levels of phenytoin, cyclosporine, tacrolimus, and theophylline, necessitating therapeutic drug monitoring and potential dose reduction of these agents.

Concomitant use with sulfonylurea oral hypoglycemic agents (e.g., glipizide, glyburide) can potentiate their hypoglycemic effect. Blood glucose should be carefully monitored. Fluconazole can increase the systemic exposure to statins (e.g., atorvastatin, simvastatin) metabolized by CYP3A4, increasing the risk of myopathy and rhabdomyolysis. Consider using a statin less dependent on CYP3A4 or suspending statin therapy during fluconazole treatment.

Fluconazole may increase the concentrations of benzodiazepines metabolized by oxidation (e.g., midazolam, triazolam), potentially prolonging their sedative and psychomotor effects. Dose reduction of the benzodiazepine may be necessary. Rifampin, a potent CYP450 inducer, can increase the metabolism of fluconazole, leading to significantly lower fluconazole levels. An increase in the fluconazole dose may be required when co-administered with rifampin.

Concomitant use with hydrochlorothiazide may increase fluconazole plasma levels by reducing its renal clearance. Fluconazole can also alter the metabolism of zidovudine and ritonavir, and monitoring for increased toxicity or altered efficacy is recommended. A comprehensive review of the patient’s medication list is essential before initiating fluconazole therapy.

Overdose

In the event of an overdose, symptomatic and supportive measures should be undertaken. There is no specific antidote for fluconazole. Gastric lavage may be considered if performed soon after ingestion. Clinical monitoring of vital signs and observation for signs of central nervous system effects and gastrointestinal irritation are recommended.

Fluconazole is largely excreted in the urine; therefore, forced diuresis might increase the elimination rate. Hemodialysis for 3 hours can reduce plasma levels by approximately 50% and is an effective method for enhancing the elimination of fluconazole from the body in cases of severe overdose, particularly in patients with impaired renal function. In cases of suspected overdose, it is critical to monitor hepatic and renal function, as well as perform an electrocardiogram to check for QTc interval prolongation, which could predispose to arrhythmias.

Clinical-Pharmacological Group

Antifungal drug

Pharmacotherapeutic Group

Systemic antifungal agents; triazole and tetrazole derivatives

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.