tinidazole 250 MG Oral Tablet [Tindamax]

INDICATIONS & USAGE Tinidazole Tablets is a nitroimidazole antimicrobial indicated for: Trichomoniasis ( 1.1 ) Giardiasis: in patients age 3 and older ( 1.2 ) Amebiasis: in patients age 3 and older ( 1.3 ) Bacterial Vaginosis: in adult women ( 1.4 , 8.1 ) 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 tinidazole tablets are proven or strongly suspected to be caused by bacteria (1.5). 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 ( 14.1 )]. 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 ( 14.2 ) ]. 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 ( 14.3 , 14.4 ) ]. 1.4 Bacterial Vaginosis Tinidazole is indicated for the treatment of bacterial vaginosis (formerly referred to as Haemophilus vaginitis, Gardnerella vaginitis, nonspecific vaginitis, or anaerobic vaginosis) in adult women [ see Use in Specific Populations ( 8.1 ) and Clinical Studies ( 14.5 ) ]. Other pathogens commonly associated with vulvovaginitis such as Trichomonas vaginalis, Chlamydia trachomatis, Neisseria gonorrhoeae, Candida albicans and Herpes simplex virus should be ruled out. 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 susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. 1.5 Usage 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 susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

DOSAGE AND ADMINISTRATION Trichomoniasis: a single 2 g oral dose taken with food. Treat sexual partners with the same dose and at the same time ( 2.3 ) 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 ) 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 ). 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 ) Bacterial vaginosis: Non-pregnant, 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 ) 2.1 Dosing Instructions It is advisable to take tinidazole with food to minimize the incidence of epigastric discomfort and other gastrointestinal side-effects. Food does not affect the oral bioavailability of tinidazole [see Clinical Pharmacology ( 12.3 )]. Alcoholic beverages should be avoided when taking tinidazole and for 3 days afterwards [see Drug Interactions ( 7.1 )]. 2.2 Compounding of the Oral Suspension For those unable to swallow tablets, tinidazole tablets may be crushed in artificial cherry syrup to be taken with food. Procedure for Extemporaneous Pharmacy Compounding of the Oral Suspension: Pulverize four 500 mg oral tablets with a mortar and pestle. Add approximately 10 mL of cherry syrup to the powder and mix until smooth. Transfer the suspension to a graduated amber container. Use several small rinses of cherry syrup to transfer any remaining drug in the mortar to the final suspension for a final volume of 30 mL. The suspension of crushed tablets in artificial cherry syrup is stable for 7 days at room temperature. When this suspension is used, it should be shaken well before each administration. 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. 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. 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. 2.6 Bacterial Vaginosis The recommended dose in non-pregnant females 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.

WARNINGS AND PRECAUTIONS Seizures and neuropathy have been reported. Discontinue tinidazole tablets if abnormal neurologic signs develop ( 5.1 ) Vaginal candidiasis may develop with tinidazole tablets and require treatment with an antifungal agent ( 5.2 ) Use tinidazole tablets with caution in patients with blood dyscrasias. Tinidazole tablets may produce transient leukopenia and neutropenia ( 5.3 , 7.3 ) 5.1 Potential for Genotoxicity and Carcinogenicity Carcinogenicity has been seen in mice and rats treated chronically with nitroimidazole derivatives, which are structurally related to tinidazole [see Nonclinical Toxicology (13.1)]. Although such data have not been reported for tinidazole, the two drugs are structurally related and have similar biologic effects. However, it is unclear if the positive tumor findings in lifetime rodent studies indicate a risk to patients taking a short course or single dose of tinidazole tablets. Use should be limited to approved indications only. Avoid chronic use. 5.2 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. 5.3 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 ) ]. 5.4 Blood Dyscrasia Tinidazole should be used with caution in patients with evidence of or history of blood dyscrasia [ see Drug Interactions ( 7.3 ) ]. 5.5 Development of Drug Resistant Bacteria 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.

CONTRAINDICATIONS 4 CONTRAINDICATIONS The use of tinidazole is contraindicated: In patients with a previous history of hypersensitivity to tinidazole or other nitroimidazole derivatives. Reported reactions have ranged in severity from urticaria to Stevens-Johnson syndrome [see Adverse Reactions (6.1, 6.2)]. In patients with Cockayne syndrome. Severe irreversible hepatotoxicity/acute liver failure with fatal outcomes have been reported after initiation of metronidazole, another nitroimidazole drug, structurally related to tinidazole, in patients with Cockayne syndrome [see Adverse Reactions (6.2)] Prior history of hypersensitivity to tinidazole or other nitroimidazole derivatives (4, 6.1, 6.2) Patients with Cockayne syndrome (4, 6.2)

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 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-∞) 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 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) ]. 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.