Trimethobenzamide Hydrochloride

6 ADVERSE REACTIONS The following adverse reactions from voluntary reports or clinical studies have been reported with trimethobenzamide. Because many of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Nervous system disorders: Parkinson-like symptoms, coma, convulsions, opisthotonos, dizziness, drowsiness, headache, [see Warnings and Precautions ( 5.1 , 5.2 , 5.3 )] Psychiatric disorders: disorientation, depression of mood Eye disorders: blurred vision Hematologic disorders: blood dyscrasias Hepatobiliary disorders: jaundice [see Warnings and Precautions (5.4) ] Immune system disorders: hypersensitivity, including angioedema and allergic-type skin reactions Gastrointestinal disorders: diarrhea Musculoskeletal disorders: muscle cramps Adverse reactions include hypersensitivity reactions and Parkinson-like symptoms; blood dyscrasias, blurring of vision, coma, convulsions, depression of mood, diarrhea, disorientation, dizziness, drowsiness, headache, jaundice, muscle cramps, and opisthotonos. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Chartwell RX, LLC. at 1-845-232-1683 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

4 CONTRAINDICATIONS Trimethobenzamide hydrochloride capsules are contraindicated in patients with known hypersensitivity to trimethobenzamide [see Adverse Reactions (6) ] . Known hypersensitivity to trimethobenzamide ( 4 )

11 DESCRIPTION Chemically, trimethobenzamide hydrochloride is N-[ p -[2-(dimethylamino)ethoxy]benzyl]-3,4,5-trimethoxybenzamide monohydrochloride. It has a molecular weight of 424.93 and the following structural formula: Capsules: Each capsule for oral use contains trimethobenzamide hydrochloride USP equivalent to 300 mg. The capsule has an opaque purple cap marked “HP” and an opaque purple body marked “180”. The inactive ingredients are lactose monohydrate, magnesium stearate, and corn starch. The capsule shell contains the following ingredients: gelatin, titanium dioxide, D&C Red No. 28, and FD&C Blue No. 1, and sodium lauryl sulfate. White ink contains the following ingredients: Shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, ammonium hydroxide, potassium hydroxide and titanium dioxide. image description

2 DOSAGE AND ADMINISTRATION The recommended adult dosage is 300 mg orally three or four times daily. ( 2.1 ) Geriatric patients and/or patients with renal impairment (creatinine clearance 70 mL/min/1.73m 2 or less): Reduce the daily dosage by increasing the dosing interval; monitor renal function. ( 2.2 , 8.5 , 8.6 ) Select the lowest effective daily dosage and adjust as needed based upon therapeutic response and tolerability. ( 2.1 , 2.2 ) 2.1 Recommended Adult Dosage The recommended adult dosage is 300 mg orally three or four times daily. Select the lowest effective daily dosage and adjust as needed based upon therapeutic response and tolerability. 2.2 Dosage Adjustment for Geriatric Patients and/or Patients with Renal Impairment In geriatric patients and/or in patients with renal impairment (creatinine clearance 70 mL/min/1.73m 2 or less), reduce the daily dosage of trimethobenzamide hydrochloride capsules by increasing the dosing interval and adjust as needed based upon therapeutic response and tolerability. Monitor renal function [see Use in Specific Populations ( 8.5 , 8.6 )] .

1 INDICATIONS AND USAGE Trimethobenzamide hydrochloride capsules are indicated in adults for the treatment of postoperative nausea and vomiting and for nausea associated with gastroenteritis. Limitation of Use: Trimethobenzamide hydrochloride capsules are not recommended for use in pediatric patients due to the risk of extrapyramidal signs and symptoms and other serious central nervous system (CNS) effects, and the risk of exacerbation of the underlying disease in pediatric patients with Reye’s syndrome or other hepatic impairment. Trimethobenzamide hydrochloride capsules are an antiemetic indicated in adults for the treatment of postoperative nausea and vomiting and for nausea associated with gastroenteritis. ( 1 ) Limitation of Use: Trimethobenzamide hydrochloride capsule is not recommended for use in pediatric patients due to the risk of extrapyramidal signs and symptoms and other serious central nervous system (CNS) effects and the risk of exacerbation of the underlying disease in pediatric patients with Reye’s syndrome or other hepatic impairment. ( 1 , 8.4 )

7 DRUG INTERACTIONS Alcohol: May cause drowsiness; avoid concomitant use. ( 7.1 ) Other Drugs that Cause CNS Depression or EPS: Either trimethobenzamide hydrochloride capsules or the other interacting drug should be chosen, depending on the importance of the drug to the patient. If CNS-acting drugs cannot be avoided, monitor patients for CNS adverse reactions. ( 7.2 ) 7.1 Alcohol Alcohol may increase the CNS depressant effects of trimethobenzamide hydrochloride capsules and may cause drowsiness [see Warnings and Precautions ( 5.3 , 5.5 )] . Avoid concomitant use of trimethobenzamide hydrochloride capsules with alcohol. 7.2 Other Drugs that Cause CNS Depression or EPS The concurrent use of trimethobenzamide hydrochloride capsules with other drugs that cause CNS depression or EPS (e.g., sedatives, hypnotics, opiates, anxiolytics, antipsychotics, and anticholinergics, may potentiate the effects of trimethobenzamide hydrochloride capsules [see Warnings and Precautions ( 5.1 , 5.2 , 5.3 , 5.5 )] . Either trimethobenzamide hydrochloride capsules or the other interacting drug should be chosen, depending on the importance of the drug to the patient. If CNS-acting drugs cannot be avoided, monitor patients for CNS adverse reactions.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of trimethobenzamide as determined in animals is obscure, but may involve the chemoreceptor trigger zone (CTZ), an area in the medulla oblongata through which emetic impulses are conveyed to the vomiting center; direct impulses to the vomiting center apparently are not similarly inhibited. In dogs pretreated with trimethobenzamide HCl, the emetic response to apomorphine is inhibited, while little or no protection is afforded against emesis induced by intragastric copper sulfate. 12.3 Pharmacokinetics Absorption The pharmacokinetics of trimethobenzamide in healthy adult subjects were compared when trimethobenzamide hydrochloride capsule was administered as a 300 mg oral capsule or a 200 mg (100 mg/mL) intramuscular injection. The time to reach maximum plasma concentration (T max ) 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 to 72 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) C max of trimethobenzamide were 3.5 (1.1) and 4.2 (1.6) micrograms/mL in male and female subjects. The respective mean (SD) of AUC 0-∞ 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) C max 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) AUC 0-∞ of trimethobenzamide was 10.4 (2.8) micrograms×hour/mL in Caucasians and 9.8 (2.5) micrograms×hour/mL in African Americans.

12.1 Mechanism of Action The mechanism of action of trimethobenzamide as determined in animals is obscure, but may involve the chemoreceptor trigger zone (CTZ), an area in the medulla oblongata through which emetic impulses are conveyed to the vomiting center; direct impulses to the vomiting center apparently are not similarly inhibited. In dogs pretreated with trimethobenzamide HCl, the emetic response to apomorphine is inhibited, while little or no protection is afforded against emesis induced by intragastric copper sulfate.

12.3 Pharmacokinetics Absorption The pharmacokinetics of trimethobenzamide in healthy adult subjects were compared when trimethobenzamide hydrochloride capsule was administered as a 300 mg oral capsule or a 200 mg (100 mg/mL) intramuscular injection. The time to reach maximum plasma concentration (T max ) 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 to 72 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) C max of trimethobenzamide were 3.5 (1.1) and 4.2 (1.6) micrograms/mL in male and female subjects. The respective mean (SD) of AUC 0-∞ 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) C max 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) AUC 0-∞ of trimethobenzamide was 10.4 (2.8) micrograms×hour/mL in Caucasians and 9.8 (2.5) micrograms×hour/mL in African Americans.

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3 DOSAGE FORMS AND STRENGTHS Capsules: 300 mg trimethobenzamide hydrochloride; size ‘1’, two-piece purple opaque cap and purple opaque body, hard gelatin capsules, printed in white with “HP” on cap and in white with “180” on body, filled with white to off-white granular powder. Capsules: 300 mg of trimethobenzamide hydrochloride ( 3 )

Trimethobenzamide Hydrochloride Trimethobenzamide Hydrochloride ISOPROPYL ALCOHOL LACTOSE MONOHYDRATE MAGNESIUM STEARATE STARCH, CORN GELATIN, UNSPECIFIED TITANIUM DIOXIDE D&C RED NO. 28 FD&C BLUE NO. 1 SODIUM LAURYL SULFATE SHELLAC DEHYDRATED ALCOHOL PROPYLENE GLYCOL AMMONIA POTASSIUM HYDROXIDE TRIMETHOBENZAMIDE HYDROCHLORIDE TRIMETHOBENZAMIDE BUTYL ALCOHOL Purple Opaque Cap and Body HP;180

ANDA205950

Trimethobenzamide Hydrochloride

Trimethobenzamide Hydrochloride

62135-773

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Trimethobenzamide Hydrochloride Capsules, USP 300 mg - NDC - 62135-773-30 - 30's - Bottle Label Trimethobenzamide Hydrochloride Capsules, USP 300 mg - NDC - 62135-773-90 - 90's - Bottle Label image description image description

17 PATIENT COUNSELING INFORMATION Inform patients that trimethobenzamide hydrochloride capsules can cause serious adverse reactions. Instruct patients to discontinue trimethobenzamide hydrochloride capsules and contact a healthcare provider immediately if the following serious reactions occur: Acute Dystonic Reactions and Other Extrapyramidal Symptoms [see Warnings and Precautions (5.1) ] Other CNS Reactions [see Warnings and Precautions ( 5.2 , 5.3 )] Hepatotoxicity [see Warnings and Precautions (5.4) ] Effects on the Ability to Drive or Operate Machinery Advise patients that trimethobenzamide hydrochloride capsules can cause drowsiness and may impair their judgment, thinking, or motor skills required for tasks such as driving a motor vehicle or operating machinery. Inform patients not to operate motor vehicles or other dangerous machinery until they are reasonably certain that trimethobenzamide hydrochloride capsules do not affect them adversely [see Warnings and Precautions (5.5) ] . Drug Interactions Inform patients that use of alcohol or concomitant treatment with other CNS-acting drugs can precipitate or worsen CNS depression and/or EPS [see Drug Interactions ( 7.1 , 7.2 )] . Instruct patients avoid alcohol and to tell their health care providers when they start taking any concomitant medication. Manufactured for: Chartwell RX, LLC. Congers, NY 10920 L71695 Revised 10/2023

8.5 Geriatric Use Clinical studies of trimethobenzamide did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. Although there are studies reported in the literature that included geriatric patients 65 years and older with younger patients, it is not known if there are differences in efficacy or safety parameters for geriatric and non-geriatric patients treated with trimethobenzamide hydrochloride capsules. Trimethobenzamide is excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because geriatric patients are more likely to have decreased renal function, reduce the daily dosage of trimethobenzamide hydrochloride capsules by increasing the dosing interval and adjust as needed based upon therapeutic response and tolerability. Monitor renal function [see Dosage and Administration (2.2) , Use in Specific Populations (8.6) ] .

8.4 Pediatric Use The safety and effectiveness of trimethobenzamide hydrochloride capsules in pediatric patients has not been established. Trimethobenzamide hydrochloride capsules are 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 )] .

8.1 Pregnancy Risk Summary 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 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary 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 Risk Summary There is no information on the presence of trimethobenzamide in human milk, the effects of trimethobenzamide hydrochloride capsule on the breastfed infant or the effects of trimethobenzamide hydrochloride capsule 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 The safety and effectiveness of trimethobenzamide hydrochloride capsules in pediatric patients has not been established. Trimethobenzamide hydrochloride capsules are 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 Clinical studies of trimethobenzamide did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. Although there are studies reported in the literature that included geriatric patients 65 years and older with younger patients, it is not known if there are differences in efficacy or safety parameters for geriatric and non-geriatric patients treated with trimethobenzamide hydrochloride capsules. Trimethobenzamide is excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because geriatric patients are more likely to have decreased renal function, reduce the daily dosage of trimethobenzamide hydrochloride capsules by increasing the dosing interval and adjust as needed based upon therapeutic response and tolerability. Monitor renal function [see Dosage and Administration (2.2) , Use in Specific Populations (8.6) ] . 8.6 Renal Impairment Trimethobenzamide is eliminated by renal excretion [see Clinical Pharmacology (12.3) ] . In patients with renal impairment (creatinine clearance 70 mL/min/1.73m 2 or less), reduce the daily dosage by increasing the dosing interval and adjust as needed based upon therapeutic response and tolerability. Monitor renal function [see Dosage and Administration (2.2) ] . 8.7 Hepatic Impairment Avoid trimethobenzamide hydrochloride capsules in patients whose signs and symptoms suggest the presence of hepatic impairment due to the risk of hepatotoxicity [see Warnings and Precautions (5.4) ] . Discontinue trimethobenzamide hydrochloride capsules in patients who develop impaired liver function while taking trimethobenzamide hydrochloride capsules.

16 HOW SUPPLIED/STORAGE AND HANDLING Trimethobenzamide Hydrochloride Capsules, USP are available as a capsule for oral use with an size ‘1’, two-piece purple opaque cap and purple opaque body, hard gelatin capsules, printed in white with “HP” on cap and in white with “180” on body, filled with white to off-white granular powder. Each capsule contains 300 mg of trimethobenzamide hydrochloride. NDC Number Strength Package 62135-773-30 300 mg capsules bottles of 30 62135-773-90 300 mg capsules bottles of 90 Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].