Tindamax (Page 4 of 6)

8.6 Renal Impairment

Because the pharmacokinetics of tinidazole in patients with severe renal impairment (CrCL < 22 mL/min) are not significantly different from those in healthy subjects, no dose adjustments are necessary in these patients.

Patients undergoing hemodialysis: If tinidazole is administered on the same day as and prior to hemodialysis, it is recommended that an additional dose of tinidazole equivalent to one-half of the recommended dose be administered after the end of the hemodialysis [see Clinical Pharmacology ( 12.3)].

8.7 Hepatic Impairment

There are no data on tinidazole pharmacokinetics in patients with impaired hepatic function. Reduced elimination of metronidazole, a chemically-related nitroimidazole, has been reported in this population. Usual recommended doses of tinidazole should be administered cautiously in patients with hepatic dysfunction [see Clinical Pharmacology ( 12.3)].

10 OVERDOSAGE

There are no reported overdoses with tinidazole in humans.

Treatment of Overdosage: There is no specific antidote for the treatment of overdosage with tinidazole; therefore, treatment should be symptomatic and supportive. Gastric lavage may be helpful. Hemodialysis can be considered because approximately 43% of the amount present in the body is eliminated during a 6-hour hemodialysis session.

11 DESCRIPTION

Tinidazole is a synthetic antiprotozoal and antibacterial agent. It is 1-[2-(ethylsulfonyl)ethyl]-2-methyl-5-nitroimidazole, a second-generation 2-methyl-5-nitroimidazole, which has the following chemical structure:

struct-tinidazole

Tindamax pink oral tablets contain 250 mg or 500 mg of tinidazole. Inactive ingredients include croscarmellose sodium, FD&C Red 40 lake, FD&C Yellow 6 lake, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, pregelatinized corn starch, titanium dioxide, and triacetin.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Tinidazole is an antiprotozoal, antibacterial agent. [See Clinical Pharmacology ( 12.4)].

12.3 Pharmacokinetics

Absorption: After oral administration, tinidazole is rapidly and completely absorbed. A bioavailability study of Tindamax tablets was conducted in adult healthy volunteers. All subjects received a single oral dose of 2 g (four 500 mg tablets) of Tindamax following an overnight fast. Oral administration of four 500 mg tablets of Tindamax 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-∞) 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 — 3 days of multi-day dosing.

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

In healthy volunteers, administration of crushed Tindamax 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%. Tinidazole crosses the placental barrier and is secreted in breast milk.

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 vitro metabolic 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.

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

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)].

12.4 Microbiology

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 Giardia and Entamoeba species is not known.

Antibacterial: Culture and sensitivity testing of bacteria are not routinely performed to establish the diagnosis of bacterial vaginosis [see Indications and Usage ( 1.4)]; standard methodology for the susceptibility testing of potential bacterial pathogens, Gardnerella vaginalis, Mobiluncus spp. or Mycoplasma hominis, has not been defined. The following in vitro data are available, but their clinical significance is unknown. Tinidazole is active in vitro against most strains of the following organisms that have been reported to be associated with bacterial vaginosis:

  • Bacteroides spp.
  • Gardnerella vaginalis
  • Prevotella spp.

Tinidazole does not appear to have activity against most strains of vaginal lactobacilli.

Antiprotozoal: Tinidazole demonstrates activity both in vitro and in clinical infections against the following protozoa: Trichomonas vaginalis; Giardia duodenalis (also termed G. lamblia); and Entamoeba histolytica.

For protozoal parasites, standardized susceptibility tests do not exist for use in clinical microbiology laboratories.

Drug Resistance: The development of resistance to tinidazole by G. duodenalis, E. histolytica, or bacteria associated with bacterial vaginosis has not been examined.

Cross-resistance: Approximately 38% of T. vaginalis isolates exhibiting reduced susceptibility to metronidazole also show reduced susceptibility to tinidazole in vitro. The clinical significance of such an effect is not known.

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