Tinidazole (Page 3 of 5)
7.2 Potential Effects of Other Drugs on Tinidazole
CYP3A4 Inducers and Inhibitors: Simultaneous administration of tinidazole with drugs that induce liver microsomal enzymes, i.e., CYP3A4 inducers such as phenobarbital , rifampin, phenytoin , and fosphenytoin (a pro-drug of phenytoin), may accelerate the elimination of tinidazole, decreasing the plasma level of tinidazole. Simultaneous administration of drugs that inhibit the activity of liver microsomal enzymes, i.e., CYP3A4 inhibitors such as cimetidine and ketoconazole , may prolong the half-life and decrease the plasma clearance of tinidazole, increasing the plasma concentrations of tinidazole.
Cholestyramine: Cholestyramine was shown to decrease the oral bioavailability of metronidazole by 21%. Thus, it is advisable to separate dosing of cholestyramine and tinidazole to minimize any potential effect on the oral bioavailability of tinidazole.
Oxytetracycline: Oxytetracycline was reported to antagonize the therapeutic effect of metronidazole.
7.3 Laboratory Test Interactions
Tinidazole, like metronidazole, may interfere with certain types of determinations of serum chemistry values, such as aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT), lactate dehydrogenase (LDH), triglycerides, and hexokinase glucose. Values of zero may be observed. All of the assays in which interference has been reported involve enzymatic coupling of the assay to oxidation-reduction of nicotinamide adenine dinucleotide (NAD + ↔ NADH). Potential interference is due to the similarity of absorbance peaks of NADH and tinidazole.
Tinidazole, like metronidazole, may produce transient leukopenia and neutropenia; however, no persistent hematological abnormalities attributable to tinidazole have been observed in clinical studies. Total and differential leukocyte counts are recommended if re-treatment is necessary.
8 USE IN SPECIFIC POPULATIONS
Teratogenic effects: Pregnancy Category C
The use of tinidazole in pregnant patients has not been studied. Since tinidazole crosses the placental barrier and enters fetal circulation it should not be administered to pregnant patients in the first trimester.
Embryo-fetal developmental toxicity studies in pregnant mice indicated no embryo-fetal toxicity or malformations at the highest dose level of 2,500 mg/kg (approximately 6.3-fold the highest human therapeutic dose based upon body surface area conversions). In a study with pregnant rats a slightly higher incidence of fetal mortality was observed at a maternal dose of 500 mg/kg (2.5-fold the highest human therapeutic dose based upon body surface area conversions). No biologically relevant neonatal developmental effects were observed in rat neonates following maternal doses as high as 600 mg/kg (3-fold the highest human therapeutic dose based upon body surface area conversions). Although there is some evidence of mutagenic potential and animal reproduction studies are not always predictive of human response, the use of tinidazole after the first trimester of pregnancy requires that the potential benefits of the drug be weighed against the possible risks to both the mother and the fetus.
8.3 Nursing Mothers
Tinidazole is excreted in breast milk in concentrations similar to those seen in serum. Tinidazole can be detected in breast milk for up to 72 hours following administration. Interruption of breast-feeding is recommended during tinidazole therapy and for 3 days following the last dose.
8.4 Pediatric Use
Other than for use in the treatment of giardiasis and amebiasis in pediatric patients older than three years of age, safety and effectiveness of tinidazole in pediatric patients have not been established.
Pediatric Administration: For those unable to swallow tablets, tinidazole tablets may be crushed in artificial cherry syrup, to be taken with food [see Dosage and Administration ( 2.2)].
8.5 Geriatric Use
Clinical studies of tinidazole did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
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) ].
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.
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:
Tinidazole Tablets pink oral tablets contain 250 mg or 500 mg of tinidazole. Inactive ingredients include pregelatinized starch NF, croscarmellose sodium NF, magnesium stearate NF, microcrystalline cellulose NF, polyvinyl alcohol-part hydrolyzed USP, titanium dioxide USP, polyethylene glycol 3000 NF, talc USP, and FD&C red # 40 aluminum lake.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Tinidazole is an antiprotozoal, antibacterial agent. [See Clinical Pharmacology ( 12.4) ].
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 (Cmax ) of 47.7 (±7.5) µg/mL with a mean time to peak concentration (Tmax ) 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 (T1/2 ) 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 did not affect AUC or T1/2 in 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%. 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 to 14 hours. Tinidazole is excreted by the liver and the kidneys. Tinidazole is excreted in the urine mainly as unchanged drug (approximately 20 to 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)].
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