PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

30count-label

100count-label

500count-label

1 INDICATIONS AND USAGE

Trimethobenzamide hydrochloride capsules is indicated in adults for the treatment of postoperative nausea and vomiting and for nausea associated with gastroenteritis.

Limitation of Use:

Trimethobenzamide hydrochloride capsules 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.

4 CONTRAINDICATIONS

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

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

7 DRUG INTERACTIONS

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.

3 DOSAGE FORMS AND STRENGTHS

Capsules: 300 mg trimethobenzamide hydrochloride; the capsule has an opaque lavender cap and opaque lavender body with a white imprint "Novel 660" on cap and "300 mg on body.

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 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

The safety and effectiveness of trimethobenzamide hydrochloride capsules in pediatric patients has not been established.

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

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/1.73m2 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 filled gelatin capsules size 1 lavender opaque cap/lavender opaque body with a white imprint "Novel 660" on cap and "300 mg" on body. Each capsule contains 300 mg of trimethobenzamide hydrochloride.

Store at 20°C to 25°C (68° to 77°F).

[See USP Controlled Room Temperature]

2 DOSAGE AND ADMINISTRATION

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/1.73m2 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)].

11 DESCRIPTION

Chemically, trimethobenzamide hydrochloride is N-[p-[2-(dimethylamino)ethoxy]benzyl]-3,4,5-trimethoxybenzamide monohydrochloride. It has a molecular weight of 424.92 and the following structural formula:

Each capsule for oral use contains trimethobenzamide hydrochloride equivalent to 300 mg. The inactive ingredients are lactose monohydrate, magnesium stearate and pregelatinized starch. The capsule shell contains the following ingredients: D&C Red # 28, FD&C Blue # 1, FD&C Red # 40, gelatin and titanium dioxide. White ink contains the following ingredients: 2-ethoxyethanol, industrial methylated spirit, lecithin, purified water, shellac glaze, simethicone emulsion and titanium dioxide.

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 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.

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 does 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 by:

Novel Laboratories, Inc.

Somerset, NJ 08873

Manufactured for:

Lupin Pharmaceuticals, Inc.

Baltimore, MD 21202

PI6600000206

Rev. 01/2019