FLUCOZAL 200MG CAPSULES

Indications

• Invasive candidal infections (including candidaemia and disseminated candidiasis)
• Cryptococcal infections (including meningitis)
• Candidal balanitis
• Vulvovaginal candidiasis
• Mucosal candidiasis (except genital)
• Prevention of fungal infections in immunocompromised patients

Dosage

Adults: For most indications, the adult oral dose is 50 mg daily for 2–4

Mechanism of action

Fluconazole selectively inhibits the fungal cytochrome P450 enzyme lanosterol 14-α-demethylase, which is crucial for converting lanosterol to ergosterol, necessary for fungal cell wall synthesis. By binding to the iron in the heme group of this enzyme, fluconazole prevents the demethylation of lanosterol, leading to the accumulation of methylated sterols in the fungal membrane, disrupting its structure and function and halting fungal growth.

Pharmacodynamics

Fluconazole exhibits fungistatic activity against a wide range of fungi, including Candida albicans, Candida glabrata, Candida parapsilosis, Candida tropicalis, and Cryptococcus neoformans. Its action involves interference with cell wall synthesis and growth, as well as cell adhesion, making it effective in treating fungal infections. Resistance can develop due to mutations in the target enzyme or other mechanisms, highlighting the importance of susceptibility testing.

Pharmacokinetics

Fluconazole is well-absorbed after oral administration, with bioavailability exceeding 90%. It has a long half-life, allowing for once-daily dosing. The drug is primarily excreted unchanged in the urine, which necessitates dose adjustments in patients with renal impairment. Fluconazole penetrates well into various body fluids, including cerebrospinal fluid, making it particularly useful for treating central nervous system infections.

Contra-indications

• Acute porphyrias

Adverse effects

• Nausea
• Abdominal pain
• Diarrhea
• Headache
• Dizziness
• Skin rash
• Elevated liver enzymes
• QT interval prolongation

Interactions

• Fluconazole + endothelin receptor antagonists: Severe (increases exposure)
• Fluconazole + bosentan: Severe (increases exposure)
• Fluconazole + antiepileptics: Moderate (increases concentration)
• Fluconazole + fosphenytoin: Moderate (increases concentration)
• Fluconazole + phenytoin: Moderate (increases concentration)
• Fluconazole + coumarins: Moderate (increases anticoagulant effect)
• Fluconazole + rifamycins: Moderate (increases risk of uveitis)
• Fluconazole + rifabutin: Moderate (increases risk of uveitis)
• Fluconazole + ruxolitinib: Moderate (increases exposure)
• Fluconazole + statins: Moderate (increases exposure)

Precautions

• Monitor liver function tests during therapy
• Use with caution in patients with a history of QT interval prolongation
• Assess for potential drug interactions, especially with other medications that prolong QT interval

Pregnancy

Fluconazole is categorized as a pregnancy category D drug, indicating evidence of risk to the fetus. It should be used only if the potential benefit justifies the potential risk.

Breast-feeding

Fluconazole is excreted in breast milk. Caution should be exercised when administering fluconazole to a nursing mother.

Storage

Store at room temperature, protected from light and moisture. Reconstituted solutions should be used promptly or stored at controlled temperatures as specified by product guidelines.

Formulations

• Oral tablets (50 mg, 150 mg, 200 mg)
• Oral suspension (10 mg/mL, 40 mg/mL)
• Intravenous infusion (2 mg/mL)

Mechanism of action

Fluconazole is a very selective inhibitor of fungal cytochrome P450 dependent enzyme _lanosterol 14-α-demethylase_. This enzyme normally works to convert _lanosterol_ to _ergosterol_, which is necessary for fungal cell wall synthesis. The free nitrogen atom located on the azole ring of fluconazole binds with a single iron atom located in the heme group of lanosterol 14-α-demethylase. This prevents oxygen activation and, as a result, inhibits the demethylation of lanosterol, halting the process of ergosterol biosynthesis. Methylated sterols are then found to accumulate in the fungal cellular membrane, leading to an arrest of fungal growth. These accumulated sterols negatively affect the structure and function of the fungal cell plasma membrane. Fluconazole resistance may arise from an alteration in the amount or function of the target enzyme (lanosterol 14-α-demethylase), altered access to this enzyme, or a combination of the above. Other mechanisms may also be implicated, and studies are ongoing. Fluconazole usually is fungistatic in action. Fluconazole and other triazole-derivative antifungal agents (e.g., itraconazole, terconazole) appear to have a mechanism of action similar to that of the imidazole-derivative antifungal agents (e.g., butoconazole, clotrimazole, econazole, ketoconazole, miconazole, oxiconazole). Like imidazoles, fluconazole presumably exerts its antifungal activity by altering cellular membranes resulting in increased membrane permeability, leakage of essential elements (eg, amino acids, potassium), and impaired uptake of precursor molecules (eg, purine and pyrimidine precursors to DNA). Although the exact mechanism of action of fluconazole and other triazoles has not been fully determined, the drugs inhibit cytochrome P-450 14-a-desmethylase in susceptible fungi, which leads to accumulation of C-14 methylated sterols (e.g., lanosterol) and decreased concentrations of ergosterol. It appears that this may occur because a nitrogen atom (N-4) in the triazole molecule binds to the heme iron of cytochrome P-450 14-a-desmethylase in susceptible fungi. Unlike some imidazoles (eg, clotrimazole, econazole, miconazole, oxiconazole) that suppress ATP concentrations in intact cells and spheroplasts of C. albicans, fluconazole does not appear to have an appreciable effect on ATP concentrations in the organism. It is unclear whether this effect is related to the in vivo antifungal effects of the drugs. Fluconazole generally is fungistatic against Candida albicans when the organism is in either the stationary or early logarithmic phase of growth. Fungistatic; may be fungicidal, depending on the concentration; azole antifungals interfere with cytochrome P450 enzyme activity, which is necessary for the demethylation of 14-alpha-methylsterols to ergosterol. Ergosterol, the principal sterol in the fungal cell membrane, becomes depleted. This damages the cell membrane, producing alterations in membrane functions and permeability. In Candida albicans, azole antifungals inhibit transformation of blastospores into invasive mycelial form.

Pharmacodynamics

Fluconazole has been demonstrated to show fungistatic activity against the majority of strains of the following microorganisms, curing fungal infections: _Candida albicans, Candida glabrata (Many strains are intermediately susceptible), Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans_ This is achieved through steroidal inhibition in fungal cells, interfering with cell wall synthesis and growth as well as cell adhesion, thereby treating fungal infections and their symptoms. The fungistatic activity of fluconazole has also been shown in normal and immunocompromised animal models with both systemic and intracranial fungal infections caused by _Cryptococcus neoformans_ and for systemic infections caused by Candida albicans. It is important to note that resistant organisms have been found against various strains of organisms treated with fluconazole. This further substantiates the need to perform susceptibility testing when fluconazole is considered as an antifungal therapy. **A note on steroidal effects of fluconazole** There has been some concern that fluconazole may interfere with and inactivate human steroids/hormones due to the inhibition of hepatic cytochrome enzymes. Fluconazole has demonstrated to be more selective for _fungal_ cytochrome P-450 enzymes than for a variety of mammalian cytochrome P-450 enzymes. Fluconazole 50 mg administered daily for up to 28 days in individuals of reproductive age has been show to have no effect on testosterone plasma concentrations of males and plasma concentrations of steroids in females. A 200-400 mg dose of fluconazole showed no clinically relevant effect on steroid levels or on ACTH-stimulated steroid response in healthy males, in one clinical study mentioned on the European Medicines Agency label. Other studies have shown no significant effects of fluconazole on steroid levels, further confirming these data.