Tindazole - Tinidazole tablet, Film Coated

Tinidazole Tablet is a nitroimidazole antimicrobial indicated for:

• Trichomoniasis (
  1.1 Trichomoniasis

  Tinidazole is indicated for the treatment of trichomoniasis caused by

  Trichomonas vaginalis.

  The organism should be identified by appropriate diagnostic procedures. Because trichomoniasis is a sexually transmitted disease with potentially serious sequelae, partners of infected patients should be treated simultaneously in order to prevent re-infection

  [see Clinical Studies ].
  )
• Giardiasis: in patients age 3 and older (
  1.2 Giardiasis

  Tinidazole is indicated for the treatment of giardiasis caused by

  Giardia duodenalis

  (also termed

  G. lamblia

  ) in both adults and pediatric patients older than three years of age

  [see Clinical Studies ].
  )
• Amebiasis: in patients age 3 and older (
  1.3 Amebiasis

  Tinidazole is indicated for the treatment of intestinal amebiasis and amebic liver abscess caused by

  Entamoeba histolytica

  in both adults and pediatric patients older than three years of age. It is not indicated in the treatment of asymptomatic cyst passage

  [see Clinical Studies ].
  )
• Bacterial Vaginosis: in  adult women ( 1.4,
  8.1 Pregnancy

  Risk Summary

  
  
  Available published data from a case-control study and case report with Tinidazole Tablets use in pregnant women are insufficient to identify a risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks associated with untreated lower genital tract infections during pregnancy

  (see Clinical Considerations)

  . In animal reproduction studies, oral administration of tinidazole to pregnant mice and rats during organogenesis at 6 and 3 times, respectively, the maximum recommended human dose (based on body surface area comparison) showed a slight increase in fetal mortality in rats at the highest dose, with no other adverse fetal effects noted in either species

  (see Data)

  .
  
  

  The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
  
  

  Data

  
  
  

  Animal Data

  
  
  Embryo-fetal developmental toxicity studies in pregnant mice administered oral tinidazole on gestation days (GD) 7 to 12 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 administered oral tinidazole on GD 9 to 14, 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 surviving rat neonates following maternal doses as high as 600 mg/kg (3-fold the highest human therapeutic dose based upon body surface area conversions).
  )

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Tinidazole Tablets and other antibacterial drugs, Tinidazole Tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria (1.5).

• Trichomoniasis: a single 2 g oral dose taken with food. Treat sexual partners with the same dose and at the same time (
  2.3 Trichomoniasis

  The recommended dose in both females and males is a single 2 g oral dose taken with food. Since trichomoniasis is a sexually transmitted disease, sexual partners should be treated with the same dose and at the same time.
  )
• Giardiasis: Adults: a single 2 g dose taken with food. Pediatric patients older than three years of age: a single dose of 50 mg/kg (up to 2 g) with food (
  2.4 Giardiasis

  The recommended dose in adults is a single 2 g dose taken with food. In pediatric patients older than three years of age, the recommended dose is a single dose of 50 mg/kg (up to 2 g) with food.
  )
• Amebiasis,
  Intestinal:
  Adults: 2 g per day for 3 days with food. Pediatric patients older than three years of age: 50 mg/kg/day (up to 2 g per day) for 3 days with food (
  2.5 Amebiasis

  Intestinal:

  The recommended dose in adults is a 2 g dose per day for 3 days taken with food. In pediatric patients older than three years of age, the recommended dose is 50 mg/kg/day (up to 2 g per day) for 3 days with food.

  Amebic Liver Abscess:

  The recommended dose in adults is a 2 g dose per day for 3-5 days taken with food. In pediatric patients older than three years of age, the recommended dose is 50 mg/kg/day (up to 2 g per day) for 3-5 days with food. There are limited pediatric data on durations of therapy exceeding 3 days, although a small number of children were treated for 5 days without additional reported adverse reactions. Children should be closely monitored when treatment durations exceed 3 days.
  ).
  Amebic liver abscess:
  Adults: 2 g per day for 3-5 days with food. Pediatric patients older than three years of age: 50 mg/kg/day (up to 2 g per day) for 3-5 days with food (
  2.5 Amebiasis

  Intestinal:

  The recommended dose in adults is a 2 g dose per day for 3 days taken with food. In pediatric patients older than three years of age, the recommended dose is 50 mg/kg/day (up to 2 g per day) for 3 days with food.

  Amebic Liver Abscess:

  The recommended dose in adults is a 2 g dose per day for 3-5 days taken with food. In pediatric patients older than three years of age, the recommended dose is 50 mg/kg/day (up to 2 g per day) for 3-5 days with food. There are limited pediatric data on durations of therapy exceeding 3 days, although a small number of children were treated for 5 days without additional reported adverse reactions. Children should be closely monitored when treatment durations exceed 3 days.
  )
• Bacterial vaginosis: Adult women: 2 g once daily for 2 days taken with food, or 1 g once daily for 5 days taken with food (
  2.6 Bacterial Vaginosis

  The recommended dose is a 2 g oral dose once daily for 2 days taken with food or a 1 g oral dose once daily for 5 days taken with food. The use of tinidazole in pregnant patients has not been studied for bacterial vaginosis.
  )

• 250 mg tablets are pink color, circular shaped film coated scored tablets with "250" debossed on one side and " T│P" on the other side
• 500 mg tablets are pink color, capsule shaped film coated scored tablets with "500" debossed on one side and " T│P" on the other side

• Pediatric Use: Data on tinidazole use in children is limited to treatment of giardiasis and amebiasis in patients age 3 and older (
  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 ].
  )
• Hemodialysis patients: If tinidazole is administered the same day and prior to hemodialysis, administer an additional ½ dose after end of hemodialysis (
  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 Pharmacokinetics

  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  following an overnight fast. Oral administration of four 500 mg tablets of Tinidazole 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 Tinidazole 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 Tinidazole Tablets with food did not affect AUC or T

  _1/2

  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%.

  Elimination

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

  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)].
  )
• Lactation: Breastfeeding is not recommended. Discontinue breastfeeding during and for 72 hours after the last dose of Tinidazole Tablet (8.2)