TIGAN Capsule Ref.[10252] Active ingredients: Trimethobenzamide

5.1 Acute Dystonic Reactions and Other Extrapyramidal Symptoms (EPS)

Extrapyramidal symptoms (EPS), manifested primarily as acute dystonic reactions, may occur with Tigan. 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 Tigan by increasing the dosing interval or discontinue Tigan [see Dosage and Administration (2.1)].

Avoid Tigan 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 Tigan 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 Tigan 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 Tigan 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 Tigan by increasing the dosing interval or discontinuing the drug [see Dosage and Administration (2.1), Drug Interactions (7.1, 7.2)].

5.4 Hepatotoxicity

Tigan is potentially hepatotoxic [see Adverse Reactions (6)]. Avoid use of Tigan in patients whose signs and symptoms suggest the presence of hepatic impairment. Discontinue Tigan in patients who develop impaired liver function while taking Tigan.

5.5 Effects on the Ability to Drive or Operate Machinery

Tigan 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 Tigan 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 Tigan does not affect them adversely.

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

7.1 Alcohol

Alcohol may increase the CNS depressant effects of Tigan and may cause drowsiness [see Warnings and Precautions (5.3, 5.5)]. Avoid concomitant use of Tigan with alcohol.

7.2 Other Drugs that Cause CNS Depression or EPS

The concurrent use of Tigan with other drugs that cause CNS depression or EPS (e.g., sedatives, hypnotics, opiates, anxiolytics, antipsychotics, and anticholinergics, may potentiate the effects of Tigan [see Warnings and Precautions (5.1, 5.2, 5.3, 5.5)]. Either Tigan 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.

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.

Risk Summary

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

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

Tigan 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)].

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 Tigan. 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 Tigan 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)].

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)].

Avoid Tigan 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 Tigan in patients who develop impaired liver function while taking Tigan.