Tinidazole Tablets

Name: Tinidazole Tablets

Dosage Forms and Strengths

  • 250 mg tablets are yellow, round, tablets, with “207” debossed on left side of the scoring on one side and plain on the other side.
  • 500 mg tablets are yellow, oval, tablets, with “208” debossed on left side of the scoring on one side and plain on the other side.

Warnings and Precautions

Neurological Adverse Reactions

Convulsive seizures and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity, have been reported in patients treated with tinidazole. The appearance of abnormal neurologic signs demands the prompt discontinuation of tinidazole therapy.

Vaginal Candidiasis

The use of tinidazole may result in Candida vaginitis. In a clinical study of 235 women who received tinidazole for bacterial vaginosis, a vaginal fungal infection developed in 11 (4.7%) of all study subjects [see Clinical Studies (14.5)].

Blood Dyscrasia

Tinidazole should be used with caution in patients with evidence of or history of blood dyscrasia [see Drug Interactions (7.3)].

Drug Resistance

Prescribing Tinidazole Tablets in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Tinidazole Tablets 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:

Tinidazole oral tablets are yellow colored tablets that contain 250 mg or 500 mg of tinidazole. Inactive ingredients include colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, pregelatinized corn starch, titanium dioxide, and yellow iron oxide.

Tinidazole Tablets - Clinical Pharmacology

Mechanism of Action

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

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 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 (AUC0 to ∞ ) 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 resulted in a delay in Tmax of approximately 2 hours and a decline in Cmax of approximately 10%, compared to fasted conditions. However, 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)].

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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Metronidazole, a chemically-related nitroimidazole, has been reported to be carcinogenic in mice and rats but not hamsters. In several studies metronidazole showed evidence of pulmonary, hepatic, and lymphatic tumorigenesis in mice and mammary and hepatic tumors in female rats. Tinidazole carcinogenicity studies in rats, mice or hamsters have not been reported.

Tinidazole was mutagenic in the TA 100, S. typhimurium tester strain both with and without the metabolic activation system and was negative for mutagenicity in the TA 98 strain. Mutagenicity results were mixed (positive and negative) in the TA 1535, 1537, and 1538 strains. Tinidazole was also mutagenic in a tester strain of Klebsiella pneumonia. Tinidazole was negative for mutagenicity in a mammalian cell culture system utilizing Chinese hamster lung V79 cells (HGPRT test system) and negative for genotoxicity in the Chinese hamster ovary (CHO) sister chromatid exchange assay. Tinidazole was positive for in vivo genotoxicity in the mouse micronucleus assay.

In a 60-day fertility study, tinidazole reduced fertility and produced testicular histopathology in male rats at a 600 mg/kg/day dose level (approximately 3-fold the highest human therapeutic dose based upon body surface area conversions). Spermatogenic effects resulted from 300 and 600 mg/kg/day dose levels. The no observed adverse reaction level for testicular and sper- matogenic effects was 100 mg/kg/day (approximately 0.5-fold the highest human therapeutic dose based upon body surface area conversions). This effect is characteristic of agents in the 5-nitroimidazole class.

Animal Toxicology and/or Pharmacology

In acute studies with mice and rats, the LD50 for mice was generally > 3,600mg/kg for oral administration and was > 2,300 mg/kg for intraperitoneal administration. In rats, the LD50 was > 2,000 mg/kg for both oral and intraperitoneal administration.

A repeated-dose toxicology study has been performed in beagle dogs using oral dosing of tinidazole at 100 mg/kg/day, 300 mg/kg/day, and 1000 mg/ kg/day for 28-days. On Day 18 of the study, the highest dose was lowered to 600 mg/kg/day due to severe clinical symptoms. The two compound-related effects observed in the dogs treated with tinidazole were increased atrophy of the thymus in both sexes at the middle and high doses, and atrophy of the prostate at all doses in the males. A no-adverse-effect level (NOAEL) of 100 mg/kg/day for females was determined. There was no NOAEL identified for males because of minimal atrophy of the prostate at 100 mg/kg/day (approximately 0.9-fold the highest human dose based upon plasma AUC comparisons).

Patient Counseling Information

Administration of Drug

Patients should be told to take Tinidazole Tablets with food to minimize the incidence of epigastric discomfort and other gastrointestinal side-effects. Food does not affect the oral bioavailability of tinidazole.

Alcohol Avoidance

Patients should be told to avoid alcoholic beverages and preparations containing ethanol or propylene glycol during Tinidazole Tablets therapy and for 3 days afterward because abdominal cramps, nausea, vomiting, headaches, and flushing may occur.

Drug Resistance

Patients should be counseled that antibacterial drugs including Tinidazole Tablets should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Tinidazole Tablets is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Tinidazole Tablets or other antibacterial drugs in the future.

Manufactured by:
Ingenus Pharmaceuticals NJ, LLC
Fairfield, NJ 07004

Rev. 07/2016

TINIDAZOLE 
tinidazole tablet
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:52682-043
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
TINIDAZOLE (TINIDAZOLE) TINIDAZOLE 250 mg
Inactive Ingredients
Ingredient Name Strength
SILICON DIOXIDE  
CROSCARMELLOSE SODIUM  
HYPROMELLOSE, UNSPECIFIED  
MAGNESIUM STEARATE  
MICROCRYSTALLINE CELLULOSE  
POLYETHYLENE GLYCOL, UNSPECIFIED  
POVIDONE K30  
STARCH, CORN  
TITANIUM DIOXIDE  
FERRIC OXIDE YELLOW  
Product Characteristics
Color YELLOW (Yellow) Score 2 pieces
Shape ROUND (Round) Size 10mm
Flavor Imprint Code 207
Contains     
Packaging
# Item Code Package Description
1 NDC:52682-043-08 40 TABLET in 1 BOTTLE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA203808 08/10/2015
TINIDAZOLE 
tinidazole tablet
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:52682-044
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
TINIDAZOLE (TINIDAZOLE) TINIDAZOLE 500 mg
Inactive Ingredients
Ingredient Name Strength
SILICON DIOXIDE  
CROSCARMELLOSE SODIUM  
HYPROMELLOSE, UNSPECIFIED  
MAGNESIUM STEARATE  
MICROCRYSTALLINE CELLULOSE  
POLYETHYLENE GLYCOL, UNSPECIFIED  
POVIDONE K30  
STARCH, CORN  
TITANIUM DIOXIDE  
FERRIC OXIDE YELLOW  
Product Characteristics
Color YELLOW (Yellow) Score 2 pieces
Shape OVAL (Oval) Size 16mm
Flavor Imprint Code 208
Contains     
Packaging
# Item Code Package Description
1 NDC:52682-044-07 20 TABLET in 1 BOTTLE
2 NDC:52682-044-06 60 TABLET in 1 BOTTLE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA203808 08/10/2015
Labeler - Ingenus Pharmaceuticals NJ, LLC (964680206)
Establishment
Name Address ID/FEI Operations
Ingenus Pharmaceuticals NJ, LLC 964680206 manufacture(52682-043, 52682-044)
Revised: 09/2016   Ingenus Pharmaceuticals NJ, LLC
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