Trimethobenzamide Hydrochloride

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. 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 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. ( 1 , 8.4 )

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/1.73m2 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/1.73m2 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 )] .

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

5 WARNINGS AND PRECAUTIONS Acute Dystonic Reactions and Other Extrapyramidal Symptoms (EPS) : Depending on the severity of symptoms, reduce the dosage or discontinue the drug. Treat acute dystonic reactions with anticholinergics. Avoid trimethobenzamide hydrochloride capsules in patients receiving other drugs that are likely to cause EPS. ( 5.1 , 7.2 ) Masking of Other Serious Disorders : EPS and other CNS symptoms in patients treated with trimethobenzamide hydrochloride capsules may be confused with CNS signs of undiagnosed primary disease (e.g., encephalopathy, metabolic imbalance, Reye's Syndrome). If CNS symptoms occur, evaluate the risks and benefits of continuing trimethobenzamide hydrochloride capsules. ( 5.2 , 7.2 ) Other CNS Reactions : Coma, depression of mood, disorientation, and seizures have been reported. The recent use of other drugs that cause CNS depression or EPS symptoms may also increase the risk; consider reducing the dosage or discontinuing the drug. ( 5.3 , 7.1 , 7.2 ) Hepatotoxicity : Avoid use in patients whose signs and symptoms suggest the presence of hepatic impairment. Discontinue trimethobenzamide hydrochloride capsules in patients who develop impaired liver function while on treatment. ( 5.4 , 8.7 ) Effects on the Ability to Drive or Operate Machinery : Mental and/or physical abilities may be impaired. Concomitant use of other drugs that cause CNS depression or EPS symptoms may increase this effect; either trimethobenzamide hydrochloride capsules or the other interacting drug should be chosen, depending on the importance of the drug to the patient. ( 5.5 , 7.1 , 7.2 ) 5.1 Acute Dystonic Reactions and Other Extrapyramidal Symptoms (EPS) Extrapyramidal symptoms (EPS), manifested primarily as acute dystonic reactions, may occur with trimethobenzamide hydrochloride capsules. Dystonic reactions may include sudden onset of muscular spasms, especially in the head and neck or opisthotonos. Other EPS include laryngospasm, dysphagia, and oculogyric crisis. Involuntary spasms of the tongue and mouth may lead to difficulty in speaking and swallowing. Anticholinergic drugs can be used to treat acute dystonic reactions. 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 EPS and other CNS symptoms which can occur in patients treated with trimethobenzamide hydrochloride capsules may be confused with CNS signs of undiagnosed primary disease (e.g., encephalopathy, metabolic imbalance, Reye's syndrome)) [see Warnings and Precautions ( 5.1 , 5.3 )]. If CNS symptoms occur, evaluate the risks and benefits of continuing trimethobenzamide hydrochloride capsules for each patient. 5.3 Other CNS Reactions Other serious CNS adverse reactions such as coma, depression of mood, disorientation, and seizures have been reported with trimethobenzamide hydrochloride capsules administration. The recent use of other drugs that cause CNS depression or EPS symptoms (e.g., alcohol, sedatives, hypnotics, opiates, anxiolytics, antipsychotics, and anticholinergics) may also increase the risk for these serious CNS reactions [see Warnings and Precautions (5.1 , 5.5 )]. Consider reducing the daily dosage of trimethobenzamide hydrochloride capsules by increasing the dosing interval or discontinuing the drug [see Dosage and Administration (2.1) , Drug Interactions (7.1 , 7.2 )] . 5.4 Hepatotoxicity Trimethobenzamide hydrochloride capsules is potentially hepatotoxic [see Adverse Reactions (6) ] . Avoid use of trimethobenzamide hydrochloride capsules in patients whose signs and symptoms suggest the presence of hepatic impairment . Discontinue trimethobenzamide hydrochloride capsules in patients who develop impaired liver function while taking trimethobenzamide hydrochloride capsules. 5.5 Effects on the Ability to Drive or Operate Machinery Trimethobenzamide hydrochloride capsules can cause drowsiness and may impair the mental and/or physical abilities required for the performance of hazardous tasks such as driving a motor vehicle or operating machinery [see Warnings and Precautions (5.1 , 5.3 )] . Concomitant use of other drugs that cause CNS depression or EPS symptoms (e.g., alcohol, sedatives, hypnotics, opiates, anxiolytics, antipsychotics, and anticholinergics) may increase this effect. Either trimethobenzamide hydrochloride capsules or the other interacting drug should be chosen, depending on the importance of the drug to the patient [ Drug Interactions (7.1 , 7.2 )]. 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.

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.

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 Lupin Pharmaceuticals, Inc. at 1-866-403-7592 or FDA at 1-800-FDA-1088 or WWW.FDA.GOV/MEDWATCH .

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.