Tinidazole (Page 2 of 5)

5.3 Blood Dyscrasia

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

5.4 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.

6 ADVERSE REACTIONS

6.1 Clinical 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 [see Warnings and Precautions ( 5.1)]. 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.

Table 1. Adverse Reactions Summary of Published Reports

	2 g single dose	Multi-day dose
GI: Metallic/bitter taste	3.7%	6.3%
Nausea	3.2%	4.5%
Anorexia	1.5%	2.5%
Dyspepsia/cramps/epigastric discomfort	1.8%	1.4%
Vomiting	1.5%	0.9%
Constipation	0.4%	1.4%
CNS: Weakness/fatigue/malaise	2.1%	1.1%
Dizziness	1.1%	0.5%
Other: Headache	1.3%	0.7%
Total patients with adverse reactions	11.0%(403/3669)	13.8%(244/1765)

Rare reported adverse reactions include bronchospasm, dyspnea, coma, confusion, depression, furry tongue, pharyngitis and reversible thrombocytopenia.

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 [See Clinical Studies ( 14.5) ].

6.2 Postmarketing 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.

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.

7 DRUG INTERACTIONS

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Although not specifically identified in studies with tinidazole, the following drug interactions were reported for metronidazole, a chemically-related nitroimidazole. Therefore, these drug interactions may occur with tinidazole.

7.1 Potential Effects of Tinidazole on Other Drugs

Warfarin and Other Oral Coumarin Anticoagulants: As with metronidazole, tinidazole may enhance the effect of warfarin and other coumarin anticoagulants, resulting in a prolongation of prothrombin time. The dosage of oral anticoagulants may need to be adjusted during tinidazole co-administration and up to 8 days after discontinuation.

Alcohols, Disulfiram: Alcoholic beverages and preparations containing ethanol or propylene glycol should be avoided during tinidazole therapy and for 3 days afterward because abdominal cramps, nausea, vomiting, headaches, and flushing may occur. Psychotic reactions have been reported in alcoholic patients using metronidazole and disulfiram concurrently. Though no similar reactions have been reported with tinidazole, tinidazole should not be given to patients who have taken disulfiram within the last two weeks.

Lithium: Metronidazole has been reported to elevate serum lithium levels. It is not known if tinidazole shares this property with metronidazole, but consideration should be given to measuring serum lithium and creatinine levels after several days of simultaneous lithium and tinidazole treatment to detect potential lithium intoxication.

Phenytoin, Fosphenytoin: Concomitant administration of oral metronidazole and intravenous phenytoin was reported to result in prolongation of the half-life and reduction in the clearance of phenytoin. Metronidazole did not significantly affect the pharmacokinetics of orally-administered phenytoin.

Cyclosporine, Tacrolimus: There are several case reports suggesting that metronidazole has the potential to increase the levels of cyclosporine and tacrolimus. During tinidazole co-administration with either of these drugs, the patient should be monitored for signs of calcineurin-inhibitor associated toxicities.

Fluorouracil: Metronidazole was shown to decrease the clearance of fluorouracil, resulting in an increase in side-effects without an increase in therapeutic benefits. If the concomitant use of tinidazole and fluorouracil cannot be avoided, the patient should be monitored for fluorouracil-associated toxicities.