Tinidazole

Tinidazole is a nitroimidazole antimicrobial indicated for: Trichomoniasis Giardiasis: in patients age 3 and older Amebiasis: in patients age 3 and older Bacterial Vaginosis: in non-pregnant, 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 are proven or strongly suspected to be caused by bacteria.

1.1Trichomoniasis 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 .

1.2Giardiasis 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 .

1.3Amebiasis 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 .

1.4Bacterial Vaginosis Tinidazole

is indicated for the treatment of bacterial vaginosis (formerly referred to as Haemophilus vaginitis, Gardnerella vaginitis, nonspecific vaginitis, or anaerobic vaginosis) in non-pregnant women . Other pathogens commonly associated with vulvovaginitis such as Trichomonas vaginalis, Chlamydia trachomatis, Neisseria gonorrhoeae, Candida albicans and Herpes simplex virus should be ruled out.

1.5Usage 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.

Trichomoniasis: a single 2 g oral dose taken with food. Treat sexual partners 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 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. 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 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

2.1Dosing 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 . Alcoholic beverages should be avoided when taking tinidazole and for 3 days afterwards .

2.2Compounding 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.

2.3Trichomoniasis 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.

2.4Giardiasis 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.

2.5Amebiasis 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.

2.6Bacterial 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.

Seizures and neuropathy have been reported. Discontinue tinidazole tablets if abnormal neurologic signs develop Vaginal candidiasis may develop with tinidazole tablets and require treatment with an antifungal agent Use tinidazole tablets with caution in patients with blood dyscrasias. Tinidazole tablets may produce transient leukopenia and neutropenia ( 5.3 , 7.3 )

5.1Potential for

genotoxicity and carcinogenicity Carcinogenicity has been seen in mice and rats treated chronically with nitroimidazole derivatives, which are structurally related to tinidazole . 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.

5.2Neurological 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.

5.3Vaginal 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 .

5.4Blood Dyscrasia Tinidazole

should be used with caution in patients with evidence of or history of blood dyscrasia .

5.5Development of Drug-Resistance 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.

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 . 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 Prior history of hypersensitivity to tinidazole or other nitroimidazole derivatives ( 4 , 6.1 , 6.2 ) Patients with Cockayne syndrome ( 4 , 6.2 )

8.1Pregnancy 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 . 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 . 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).

8.3Females and Males of Reproductive Potential Infertility

Infertility Males Based on findings in rodents, Tinidazole may impair fertility in males of reproductive potential. It is not known whether effects on fertility are reversible .

Most common adverse reactions for a single 2 g dose of tinidazole (incidence >1%) are metallic/bitter taste, nausea, weakness/fatigue/malaise, dyspepsia/cramps/epigastric discomfort, vomiting, anorexia, headache, dizziness and constipation To report SUSPECTED ADVERSE REACTIONS, contact Edenbridge Pharmaceuticals, LLC at 1-877-381-3336 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical Studies Experience Because

clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Among 3669 patients treated with a single 2 g dose of tinidazole, in both controlled and uncontrolled trichomoniasis and giardiasis clinical studies, adverse reactions were reported by 11.0% of patients. For multi-day dosing in controlled and uncontrolled amebiasis studies, adverse reactions were reported by 13.8% of 1765 patients.

Common (≥ 1% incidence) adverse reactions reported by body system are as follows. (Note: Data described in Table 1 below are pooled from studies with variable designs and safety evaluations.) Other adverse reactions reported with tinidazole include: Central Nervous System: Two serious adverse reactions reported include convulsions and transient peripheral neuropathy including numbness and paresthesia . Other CNS reports include vertigo, ataxia, giddiness, insomnia, drowsiness. Gastrointestinal: tongue discoloration, stomatitis, diarrhea Hypersensitivity: urticaria, pruritis, rash, flushing, sweating, dryness of mouth, fever, burning sensation, thirst, salivation, angioedema Renal: darkened urine Cardiovascular: palpitations Hematopoietic: transient neutropenia, transient leukopenia Other: Candida overgrowth, increased vaginal discharge, oral candidiasis, hepatic abnormalities including raised transaminase level, arthralgias, myalgias, and arthritis. Rare reported adverse reactions include bronchospasm, dyspnea, coma, confusion, depression, furry tongue, pharyngitis and reversible thrombocytopenia. table1 Adverse Reactions in Pediatric Patients : In pooled pediatric studies, adverse reactions reported in pediatric patients taking tinidazole were similar in nature and frequency to adult findings including nausea, vomiting, diarrhea, taste change, anorexia, and abdominal pain.

Bacterial vaginosis : The most common adverse reactions in treated patients (incidence >2%), which were not identified in the trichomoniasis, giardiasis and amebiasis studies, are gastrointestinal: decreased appetite, and flatulence; renal: urinary tract infection, painful urination, and urine abnormality; and other reactions including pelvic pain, vulvo-vaginal discomfort, vaginal odor, menorrhagia, and upper respiratory tract infection

6.2Postmarketing Experience The

following adverse reactions have been identified and reported during post-approval use of tinidazole tablets. Because the reports of these reactions are voluntary and the population is of uncertain size, it is not always possible to reliably estimate the frequency of the reaction or establish a causal relationship to drug exposure. Tinidazole Tablets: Severe acute hypersensitivity reactions have been reported on initial or subsequent exposure to tinidazole.

Hypersensitivity reactions may include urticaria, pruritis, angioedema, Stevens-Johnson syndrome and erythema multiforme. Metronidazole, Another Nitroimidazole Product, Structurally Related to Tinidazole: Cases of severe irreversible hepatotoxicity/acute liver failure, including cases with fatal outcomes with very rapid onset after initiation of systemic use of metronidazole, another nitroimidazole agent structurally related to tinidazole, have been reported in patients with Cockayne syndrome (latency from rug start to signs of liver failure as short as 2 days) .