ADVERSE REACTIONS SECTION.

Adverse Reactions. There have been reports of hypersensitivity reactions and Parkinson-like symptoms. There have been instances of hypotensionreported following parenteral administration to surgical patients. There have been reports of blood dyscrasias, blurring of vision,coma, convulsions, depression of mood, diarrhea, disorientation, dizziness, drowsiness, headache, jaundice, muscle crampsand opisthotonos. If these occur, the administration of the drug should be discontinued. Allergic-type skin reactions have beenobserved; therefore, the drug should be discontinued at the first sign of sensitization. While these symptoms will usually disappearspontaneously, symptomatic treatment may be indicated in some cases.For medical advice about adverse reactions contact your medical professional. To report SUSPECTED ADVERSE REACTIONS,contact JHP at 1-866-923-2547 or MEDWATCH at 1-800-FDA-1088 (1-800-332-1088) or http://www.fda.gov/medwatch/.

CLINICAL PHARMACOLOGY SECTION.

Clinical Pharmacology. Mechanism of ActionThe mechanism of action of Tigan(R) as determined in animals is obscure, but may involve the chemoreceptor trigger zone (CTZ), anarea in the medulla oblongata through which emetic impulses are conveyed to the vomiting center; direct impulses to the vomitingcenter apparently are not similarly inhibited. In dogs pretreated with trimethobenzamide HCl, the emetic response to apomorphine isinhibited, while little or no protection is afforded against emesis induced by intragastric copper sulfate.PharmacokineticsThe pharmacokinetics of trimethobenzamide have been studied in healthy adult subjects. Following administration of 200 mg(100 mg/mL) Tigan I.M. injection, the time to reach maximum plasma concentration (Tmax) was about half an hour, about 15minutes longer for Tigan 300 mg oral capsule than an I.M. injection. single dose of Tigan 300 mg oral capsule provided plasmaconcentration profile of trimethobenzamide similar to Tigan 200 mg I.M. The relative bioavailability of the capsule formulationcompared to the solution is 100%. The mean elimination half-life of trimethobenzamide is to hours. Between 30 50% of singledose in humans is excreted unchanged in the urine within 48 72 hours. The metabolic disposition of trimethobenzamide in humans isnot known. Specifically, it is not known if active metabolites are generated in humans.Special PopulationsAgeThe clearance of trimethobenzamide is not known in patients with renal impairment. However, it may be advisable to considerreduction in the dosing of trimethobenzamide in elderly patients with renal impairment considering that substantial amount ofexcretion and elimination of trimethobenzamide occurs via the kidney and that elderly patients may have various degrees of renalimpairment. (See PRECAUTIONS: General and DOSAGE AND ADMINISTRATION).GenderSystemic exposure to trimethobenzamide was similar between men (N=40) and women (N=28).RacePharmacokinetics appeared to be similar for Caucasians (N=53) and African Americans (N=12).Renal ImpairmentThe clearance of trimethobenzamide is not known in patients with renal impairment. However, it may be advisable to considerreduction in the dosing of trimethobenzamide in patients with renal impairment considering that substantial amount ofexcretion and elimination of trimethobenzamide occurs via the kidney. (See PRECAUTIONS: General and DOSAGE ANDADMINISTRATION).

DESCRIPTION SECTION.

Description. Chemically, trimethobenzamide HCl is N-[p-[2-(dimethylamino)ethoxy]benzyl]-3,4,5-trimethoxybenzamide monohydrochloride. Ithas molecular weight of 424.93 and the following structural formula:Single-Dose Vials: Each 2-mL single-dose vial contains 200 mg trimethobenzamide hydrochloride compounded with mg sodiumcitrate and 0.4 mg citric acid as buffers and pH adjusted to approximately 5.0 with sodium hydroxide.Multi-Dose Vials: Each mL contains 100 mg trimethobenzamide hydrochloride compounded with 0.45% phenol as preservative, 0.5mg sodium citrate and 0.2 mg citric acid as buffers and pH adjusted to approximately 5.0 with sodium hydroxide.. Formula1.jpg.

DOSAGE & ADMINISTRATION SECTION.

Dosage and Administration. (See WARNINGS and PRECAUTIONS.)Dosage should be adjusted according to the indication for therapy, severity of symptoms and the response of the patient.Geriatric PatientsDose adjustment such as reducing the total dose administered at each dosing or increasing the dosing interval should be consideredin elderly patients with renal impairment (creatinine clearance GBP 70 mL/min/1.73m2). Final dose adjustment should be based uponintegration of clinical efficacy and safety considerations. (See CLINICAL PHARMACOLOGY and PRECAUTIONS).Patients with Renal ImpairmentIn subjects with renal impairment (creatinine clearance GBP 70 mL/min/1.73m2), dose adjustment such as reducing the total doseadministered at each dosing or increasing the dosing interval should be considered. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).INJECTABLE, 100 mg/mL (Not for use in pediatric patients) Usual Adult Dosage mL (200 mg) t.i.d. or q.i.d. intramuscularly. NOTE: The injectable form is intended for intramuscular administration only; it is not recommended for intravenous use.Intramuscular administration may cause pain, stinging, burning, redness and swelling at the site of injection. Such effects may beminimized by deep injection into the upper outer quadrant of the gluteal region, and by avoiding the escape of solution along the route.

PRECAUTIONS SECTION.

Precautions. During the course of acute febrile illness, encephalitides, gastroenteritis, dehydration and electrolyte imbalance, especially inchildren and the elderly or debilitated, CNS reactions such as opisthotonos, convulsions, coma and extrapyramidal symptoms havebeen reported with and without use of Tigan(R) (trimethobenzamide hydrochloride) or other antiemetic agents. In such disorderscaution should be exercised in administering Tigan(R), particularly to patients who have recently received other CNS-acting agents(phenothiazines, barbiturates, belladonna derivatives). Primary emphasis should be directed toward the restoration of body fluids andelectrolyte balance, the relief of fever and relief of the causative disease process. Overhydration should be avoided since it may resultin cerebral edema.The antiemetic effects of Tigan(R) may render diagnosis more difficult in such conditions as appendicitis and obscure signs of toxicitydue to overdosage of other drugs.GeneralAdjustment of Dose in Renal FailureA substantial route of elimination of unchanged trimethobenzamide is via the kidney. Dosage adjustment should be considered inpatients with reduced renal function including some elderly patients. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).Geriatric UseClinical studies of trimethobenzamide hydrochloride did not include sufficient numbers of patients aged 65 and over to determinewhether they respond differently from younger patients. Although there are studies reported in the literature that included elderlypatients greater than 65 years old with younger patients, it is not known if there are differences in efficacy or safety parameters for elderly andnon-elderly patients treated with trimethobenzamide. In general, dose selection for an elderly patient should be cautious, usuallystarting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and ofconcomitant disease or other drug therapy.This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patientswith impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken indose selection, and it may be useful to monitor renal function. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

WARNINGS SECTION.

Warnings. Tigan(R) may produce drowsiness. Patients should not operate motor vehicles or other dangerous machinery until their individualresponses have been determined.Usage in PregnancyTrimethobenzamide hydrochloride was studied in reproduction experiments in rats and rabbits and no teratogenicity was suggested.The only effects observed were an increased percentage of embryonic resorptions or stillborn pups in rats administered 20 mg and100 mg/kg and increased resorptions in rabbits receiving 100 mg/kg. In each study these adverse effects were attributed to one ortwo dams. The relevance to humans is not known. Since there is no adequate experience in pregnant or lactating women who havereceived this drug, safety in pregnancy or in nursing mothers has not been established.Usage with AlcoholConcomitant use of alcohol with Tigan(R) may result in an adverse drug interaction.