Fluconazole 75 mg, Tinidazole 1 gm Film Coated Tablets

Fluconazole is a highly selective inhibitor of fungal cytochrome P450 dependent enzyme lanosterol 14-α-demethylase. This enzyme functions to convert lanosterol to ergosterol. The subsequent loss of normal sterols correlates with the accumulation of 14-α-methyl sterols in fungi and may be responsible for the fungistatic activity of fluconazole. Mammalian cell demethylation is much less sensitive to fluconazole inhibition.

Resistance — A potential for development of resistance to fluconazole is well known. Fungal isolates exhibiting reduced susceptibility to other azoles may also show reduced susceptibility to fluconazole. The frequency of drug resistance development for the various fungi for which this drug is indicated is not known.

Fluconazole resistance may arise from a modification in the quality or quantity of the target enzyme (lanosterol 14-α-demethylase), reduced access to the drug target, or some combination of these mechanisms.

Point mutations in the gene (ERG11) encoding for the target enzyme lead to an altered target with decreased affinity for azoles. Overexpression of ERG11 results in the production of high concentrations of the target enzyme, creating the need for higher intracellular drug concentrations to inhibit all of the enzyme molecules in the cell.

The second major mechanism of drug resistance involves active efflux of fluconazole out of the cell through the activation of two types of multidrug efflux transporters; the major facilitators (encoded by MDR genes) and those of the ATP-binding cassette superfamily (encoded by CDR genes). Upregulation of the MDR gene leads to fluconazole resistance, whereas, upregulation of CDR genes may lead to resistance to multiple azoles.

Resistance in Candida glabratausually includes upregulation of CDR genes resulting in resistance to multiple azoles. For an isolate where the minimum inhibitory concentration (MIC) is categorized as Intermediate (16 to 32 mcg/mL), the highest fluconazole dose is recommended.

The pharmacokinetic properties (PK) of fluconazole are similar following administration by the intravenous or oral routes. In normal volunteers, the bioavailability of orally administered fluconazole is over 90% compared with intravenous administration. Bioequivalence was established between the 100 mg tablet and both suspension strengths when administered as a single 200 mg dose.

Peak plasma concentrations (C max) in fasted normal volunteers occur between 1 and 2 hours with a terminal plasma elimination half-life of approximately 30 hours (range: 20 to 50 hours) after oral administration.

In fasted normal volunteers, administration of a single oral 400 mg dose of fluconazole leads to a mean C maxof 6.72 mcg/mL (range: 4.12 to 8.08 mcg/mL) and after single or multiple oral doses of 50 to 400 mg, fluconazole plasma concentrations and area under the plasma concentration-time curve (AUC) are dose proportional (Table 1).

The C maxand AUC data from a food-effect study involving administration of fluconazole tablets to healthy volunteers under fasting conditions and with a high-fat meal indicated that exposure to the drug is not affected by food. Therefore, fluconazole may be taken without regard to meals (See DOSAGE AND ADMINISTRATION).

*AUC o-inf. C max= peak plasma concentrations, AUC – area under the plasma concentration time curve.

Steady-state concentrations are reached within 5 to 10 days following oral doses of 50 to 400 mg given once daily. Administration of a loading dose (on Day 1) of twice the usual daily dose results in plasma concentrations close to steady-state by the second day. The apparent volume of distribution of fluconazole approximates that of total body water. Plasma protein binding is low (11 to 12%). Following either single- or multiple oral doses for up to 14 days, fluconazole penetrates into all body fluids studied (see table below).

In normal volunteers, saliva concentrations of fluconazole were equal to or slightly greater than plasma concentrations regardless of dose, route, or duration of dosing. In patients with bronchiectasis, sputum concentrations of fluconazole following a single 150 mg oral dose were equal to plasma concentrations at both 4 and 24 hours post dose. In patients with fungal meningitis, fluconazole concentrations in the cerebrospinal fluid (CSF) are approximately 80% of the corresponding plasma concentrations.

A single oral 150 mg dose of fluconazole administered to 27 patients penetrated into vaginal tissue, resulting in tissue: plasma ratios ranging from 0.94 to 1.14 over the first 48 hours following dosing.

A single oral 150 mg dose of fluconazole administered to 14 patients penetrated into vaginal fluid, resulting in fluid: plasma ratios ranging from 0.36 to 0.71 over the first 72 hours following dosing.

Mean body clearance in adults is reported to be 0.23 (17%) mL/min/kg. In normal volunteers, fluconazole is cleared primarily by renal excretion, with approximately 80% of the administered dose appearing in the urine as unchanged drug. About 11% of the dose is excreted in the urine as metabolites.

The pharmacokinetics of fluconazole are markedly affected by reduction in renal function. There is an inverse relationship between the elimination half-life and creatinine clearance. The dose of fluconazole may need to be reduced in patients with impaired renal function (See DOSAGE AND ADMINISTRATION).A 3-hour hemodialysis session decreases plasma concentrations by approximately 50%.

In normal volunteers, fluconazole administration (doses ranging from 200 mg to 400 mg once daily for up to 14 days) was associated with small and inconsistent effects on testosterone concentrations, endogenous corticosteroid concentrations, and the adrenocorticotropic hormone (ACTH)-stimulated cortisol response.

Mechanism of Action — Tinidazole is an antiprotozoal,antibacterial agent. The nitro-group of tinidazole is reduced by cell extracts of Trichomonas. The free nitro- radical generated as a result of this reduction may be responsible for the antiprotozoal activity. Chemically reduced tinidazole was shown to release nitrites and cause damage to purified bacterial DNA in vitro. Additionally, the drug caused DNA base changes in bacterial cells and DNA strand breakage in mammalian cells. The mechanism by which tinidazole exhibits activity against Giardiaand Entamoebaspecies is not known.

Absorption — After oral administration, tinidazole is rapidly and completely absorbed. A bioavailability study of tinidazole tablets was conducted in adult healthy volunteers. All subjects received a single oral dose of 2 g (four 500 mg tablets) of tinidazole tablets following an overnight fast. Oral administration of four 500 mg tablets of tinidazole tablets under fasted conditions produced a mean peak plasma concentration (C max) of 47.7 (±7.5) μg/mL with a mean time to peak concentration (T max) of 1.6 (±0.7) hours, and a mean area under the plasma concentration-time curve (AUC 0 to ∞) of 901.6 (± 126.5) μg hr/mL at 72 hours. The elimination half-life (T 1/2) was 13.2 (±1.4) hours. Mean plasma levels decreased to 14.3 μg/mL at 24 hours, 3.8 μg/mL at 48 hours and 0.8 μg/mL at 72 hours following administration. Steady-state conditions are reached in 2½ to 3 days of multi-day dosing.

Administration of tinidazole tablets with food resulted in a delay in T maxof approximately 2 hours and a decline in C maxof approximately 10%, compared to fasted conditions. However, administration of tinidazole tablets with food did not affect AUC or T 1/2in this study.

In healthy volunteers, administration of crushed tinidazole tablets in artificial cherry syrup, [prepared as described in Dosage and Administration (2.2) ] after an overnight fast had no effect on any pharmacokinetic parameter as compared to tablets swallowed whole under fasted conditions.

Distribution — Tinidazole is distributed into virtually all tissues and body fluids and also crosses the blood-brain barrier. The apparent volume of distribution is about 50 liters. Plasma protein binding of tinidazole is 12%.

Elimination — The plasma half-life of tinidazole is approximately 12 to 14 hours.

Metabolism:Tinidazole is significantly metabolized in humans prior to excretion. Tinidazole is partly metabolized by oxidation, hydroxylation, and conjugation. Tinidazole is the major drug-related constituent in plasma after human treatment, along with a small amount of the 2-hydroxymethyl metabolite. Tinidazole is biotransformed mainly by CYP3A4. In an in vitrometabolic drug interaction study, tinidazole concentrations of up to 75 μg/mL did not inhibit the enzyme activities of CYP1A2, CYP2B6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4. The potential of tinidazole to induce the metabolism of other drugs has not been evaluated.

Excretion:Tinidazole is excreted by the liver and the kidneys. Tinidazole is excreted in the urine mainly as unchanged drug (approximately 20-25% of the administered dose). Approximately 12% of the drug is excreted in the feces.

Specific Populations — Patients with impaired renal function:The pharmacokinetics of tinidazole in patients with severe renal impairment (CrCL < 22 mL/min) are not significantly different from the pharmacokinetics seen in healthy subjects. However, during hemodialysis, clearance of tinidazole is significantly increased; the half-life is reduced from 12.0 hours to 4.9 hours. Approximately 43% of the amount present in the body is eliminated during a 6-hour hemodialysis session [See Use in Specific Populations (8.6)] . The pharmacokinetics of tinidazole in patients undergoing routine continuous peritoneal dialysis have not been investigated.

Patients with impaired hepatic function:There are no data on tinidazole pharmacokinetics in patients with impaired hepatic function. Reduction of metabolic elimination of metronidazole, a chemically-related nitroimidazole, in patients with hepatic dysfunction has been reported in several studies [See Use in Specific Populations (8.7)] .