2.1 Recommended Adult Dosage

2.2 Dosage Adjustment for Geriatric Patients and/or Patients with Renal Impairment

5.1 Acute Dystonic Reactions and Other Extrapyramidal Symptoms (EPS)

EPS may also include akathisia, restlessness, akinesia, and other parkinsonian-like symptoms (e.g., tremor). Depending on the severity of symptoms, reduce the daily dosage of trimethobenzamide hydrochloride capsules by increasing the dosing interval or discontinue trimethobenzamide hydrochloride capsules [see Dosage and Administration (2.1)].

Avoid trimethobenzamide hydrochloride capsules in patients receiving other drugs that are likely to cause EPS (e.g. antipsychotics) [see Drug Interactions (7.2)].

5.2 Masking of Other Serious Disorders

5.3 Other CNS Reactions

5.4 Hepatotoxicity

5.5 Effects on the Ability to Drive or Operate Machinery

7.1 Alcohol

7.2 Other Drugs that Cause CNS Depression or EPS

8.1 Pregnancy

The limited available data with trimethobenzamide in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage. No adverse developmental effect was observed in animal reproduction studies with administration of trimethobenzamide hydrochloride during organogenesis in pregnant rats at doses 0.16 and 0.8 times the recommended human dose (RHD) and in pregnant rabbits at doses 1.6 times the RHD [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

Reproduction studies with trimethobenzamide hydrochloride were conducted in rats and rabbits following administration of trimethobenzamide hydrochloride during organogenesis and no adverse developmental effect was observed in either species. The only effects observed were an increased percentage of embryonic resorptions or stillborn pups in rats administered 20 mg/kg and 100 mg/kg (0.16 and 0.8 times the RHD of 1200 mg/day, based on body surface area) and increased resorptions in rabbits receiving 100 mg/kg (1.6 times the RHD of 1200 mg/day, based on body surface area). In each study, these adverse effects were attributed to one or two dams.

8.2 Lactation

There is no information on the presence of trimethobenzamide in human milk, the effects of trimethobenzamide hydrochloride capsules on the breastfed infant or the effects of trimethobenzamide hydrochloride capsules on milk production. The lack of clinical data during lactation precludes a clear determination of the risk of trimethobenzamide hydrochloride capsules to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for trimethobenzamide hydrochloride capsules and any potential adverse effects on the breastfed infant from trimethobenzamide hydrochloride capsules or from the underlying maternal condition.

8.4 Pediatric Use

Trimethobenzamide hydrochloride capsules is not recommended for use in pediatric patients due to the risk of EPS and other serious CNS effects, and the risk of exacerbation of underlying disease in pediatric patients with Reye's Syndrome, or other hepatic impairment [see Warnings and Precautions (5.1, 5.2, 5.3, 5.4)].

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

12.1 Mechanism of Action

12.3 Pharmacokinetics

The pharmacokinetics of trimethobenzamide in healthy adult subjects were compared when trimethobenzamide hydrochloride capsules was administered as a 300 mg oral capsule or a 200 mg (100 mg/mL) intramuscular injection. The time to reach maximum plasma concentration (Tmax) was about 30 minutes after intramuscular injection compared to about 45 minutes after oral capsule administration. The plasma concentration-time profile of trimethobenzamide was similar between the two formulations.

Elimination

The mean elimination half-life of trimethobenzamide is 7 to 9 hours.

Metabolism

The major pathway of trimethobenzamide metabolism is through oxidation resulting in the formation of trimethobenzamide N-oxide metabolite. The pharmacologic activity of this major metabolite has not been evaluated.

Excretion

Between 30 to 50% of a single dose in humans is excreted unchanged in the urine within 48 to72 hours.

Specific Populations

Sex

Systemic exposure to trimethobenzamide was similar between men (N=40) and women (N=28). Following a single 300 mg capsule oral administration, the respective mean (SD) Cmax of trimethobenzamide were 3.5 (1.1) and 4.2 (1.6) micrograms/mL in male and female subjects. The respective mean (SD) of AUC0-∞ of trimethobenzamide were 10 (2.7) and 10.4 (2.7) micrograms×hour/mL in male and female subjects.

Race

Pharmacokinetics appeared to be similar for Caucasians (N=53) and African Americans (N=12). Following a single 300 mg capsule oral administration, the respective mean (SD) Cmax of trimethobenzamide was 3.8 (1.3) micrograms/mL in Caucasians and 3.9 (1.7) micrograms/mL in African Americans. The respective mean (SD) AUC0-∞ of trimethobenzamide was 10.4 (2.8) micrograms×hour/mL in Caucasians and 9.8 (2.5) micrograms×hour/mL in African Americans.