Ametik

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

Limitation Of Use

Ametik 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.

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.

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 Ametik by increasing the dosing interval and adjust as needed based upon therapeutic response and tolerability. Monitor renal function.

300 mg trimethobenzamide hydrochloride; the capsule has an opaque purple cap marked “Ametik” and an opaque purple body marked “M079”.

Ametik is contraindicated in patients with known hypersensitivity to trimethobenzamide.

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Acute Dystonic Reactions And Other Extrapyramidal Symptoms (EPS)

Extrapyramidal symptoms (EPS), manifested primarily as acute dystonic reactions, may occur with Ametik. 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 Ametik by increasing the dosing interval or discontinue Ametik.

Avoid Ametik in patients receiving other drugs that are likely to cause EPS (e.g. antipsychotics).

Masking Of Other Serious Disorders

EPS and other CNS symptoms which can occur in patients treated with Ametik 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 Ametik for each patient.

Other CNS Reactions

Other serious CNS adverse reactions such as coma, depression of mood, disorientation, and seizures have been reported with Ametik 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. Consider reducing the daily dosage of Ametik by increasing the dosing interval or discontinuing the drug.

Hepatotoxicity

Ametik is potentially hepatotoxic. Avoid use of Ametik in patients whose signs and symptoms suggest the presence of hepatic impairment. Discontinue Ametik in patients who develop impaired liver function while taking Ametik.

Effects On The Ability To Drive Or Operate Machinery

Ametik 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. 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 Ametik or the other interacting drug should be chosen, depending on the importance of the drug to the patient. Inform patients not to operate motor vehicles or other dangerous machinery until they are reasonably certain that Ametik does not affect them adversely.

Use In Specific Populations

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.

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.

Lactation

Risk Summary

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

Pediatric Use

The safety and effectiveness of Ametik in pediatric patients has not been established.

Ametik 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.

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 Ametik. 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 Ametik by increasing the dosing interval and adjust as needed based upon therapeutic response and tolerability. Monitor renal function.

Renal Impairment

Trimethobenzamide is eliminated by renal excretion. 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.

Hepatic Impairment

Avoid Ametik in patients whose signs and symptoms suggest the presence of hepatic impairment due to the risk of hepatotoxicity. Discontinue Ametik in patients who develop impaired liver function while taking Ametik.

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,
• Psychiatric disorders: disorientation, depression of mood
• Eye disorders: blurred vision
• Hematologic disorders: blood dyscrasias
• Hepatobiliary disorders: jaundice
• Immune system disorders: hypersensitivity, including angioedema and allergic-type skin reactions
• Gastrointestinal disorders: diarrhea
• Musculoskeletal disorders: muscle cramps

No Information Provided

Absorption

The pharmacokinetics of trimethobenzamide in healthy adult subjects were compared when Ametik 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 to 72 hours.