TIGAN- trimethobenzamide hydrochloride capsule
Monarch Pharmaceuticals, Inc.
TIGAN - trimethobenzamide hydrochloride injection, solution
Single-Dose Vials: Each 2-mL single-dose vial contains 200 mg trimethobenzamide hydrochloride compounded with 1 mg sodium
citrate 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, 0.5
mg sodium citrate and 0.2 mg citric acid as buffers and pH adjusted to approximately 5.0 with sodium hydroxide.
DESCRIPTION
Chemically, trimethobenzamide HCl is N-[p -[2-(dimethylamino)ethoxy]benzyl]-3,4,5-trimethoxybenzamide monohydrochloride. It has a molecular weight of 424.93
Capsules: Each 300-mg Tigan capsule for oral use contains trimethobenzamide hydrochloride equivalent to 300 mg. The capsule has an opaque purple cap marked "Tigan" and an opaque purple body marked "M079". Inactive Ingredients: D&C Red No. 28, FD&C Blue No. 1, lactose, magnesium stearate, starch and titanium dioxide.
CLINICAL PHARMACOLOGY
Mechanism of Action
The mechanism of action of Tigan 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.
Pharmacokinetics
The 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 15 minutes longer for Tigan 300 mg oral capsule than an I.M. injection. A single dose of Tigan 300 mg oral capsule provided a plasma concentration profile of trimethobenzamide similar to Tigan 200 mg I.M. The relative bioavailability of the capsule formulation compared to the solution is 100%. The mean elimination half-life of trimethobenzamide is 7 to 9 hours. Between 30 � 50% of a single dose in humans is excreted unchanged in the urine within 48-72 hours. 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.
Special Populations
Age
The clearance of trimethobenzamide is not known in patients with renal impairment. However, it may be advisable to consider reduction in the dosing of trimethobenzamide in elderly patients with renal impairment considering that a substantial amount of excretion and elimination of trimethobenzamide occurs via the kidney and that elderly patients may have various degrees of renal impairment. (See PRECAUTIONS: General and DOSAGE AND ADMINISTRATION).
Gender
Systemic exposure to trimethobenzamide was similar between men (N=40) and women (N=28).
Race
Pharmacokinetics appeared to be similar for Caucasians (N=53) and African Americans (N=12).
Renal Impairment
The clearance of trimethobenzamide is not known in patients with renal impairment. However, it may be advisable to consider reduction in the dosing of trimethobenzamide in patients with renal impairment considering that a substantial amount of excretion and elimination of trimethobenzamide occurs via the kidney. (See PRECAUTIONS: General and DOSAGE AND ADMINISTRATION).
INDICATIONS AND USAGE
Tigan is indicated for the treatment of postoperative nausea and vomiting and for nausea associated with gastroenteritis.
CONTRAINDICATIONS
Use of any dosage form in patients with known hypersensitivity to trimethobenzamide is contraindicated.
WARNINGS
Caution should be exercised when administering Tigan to children for the treatment of vomiting. Antiemetics are not recommended for treatment of uncomplicated vomiting in children and their use should be limited to prolonged vomiting of known etiology. There are two principal reasons for caution:
1. The extrapyramidal symptoms which can occur secondary to Tigan may be confused with the central nervous system signs of an undiagnosed primary disease responsible for the vomiting, e.g., Reye's syndrome or other encephalopathy.
2. It has been suspected that drugs with hepatotoxic potential, such as Tigan , may unfavorably alter the course of Reye's syndrome. Such drugs should therefore be avoided in children whose signs and symptoms (vomiting) could represent Reye's syndrome.
Tigan may produce drowsiness. Patients should not operate motor vehicles or other dangerous machinery until their individual responses have been determined.
Usage in Pregnancy: Trimethobenzamide 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 and 100 mg/kg and increased resorptions in rabbits receiving 100 mg/kg. In each study these adverse effects were attributed to one or two dams. The relevance to humans is not known. Since there is no adequate experience in pregnant or lactating women who have received this drug, safety in pregnancy or in nursing mothers has not been established.
Usage with Alcohol: Concomitant use of alcohol with Tigan may result in an adverse drug interaction.
PRECAUTIONS
During the course of acute febrile illness, encephalitides, gastroenteritis, dehydration and electrolyte imbalance, especially in children and the elderly or debilitated, CNS reactions such as opisthotonos, convulsions, coma and extrapyramidal symptoms have been reported with and without use of Tigan (trimethobenzamide hydrochloride) or other antiemetic agents. In such disorders caution should be exercised in administering Tigan , 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 and electrolyte balance, the relief of fever and relief of the causative disease process. Overhydration should be avoided since it may result in cerebral edema. The antiemetic effects of Tigan may render diagnosis more difficult in such conditions as appendicitis and obscure signs of toxicity due to overdosage of other drugs.
General
Adjustment of Dose in Renal Failure
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 Patients
Dose adjustment such as reducing the total dose administered at each dosing or increasing the dosing interval should be considered in elderly patients with renal impairment (creatinine clearance ≤ 70 mL/min/1.73m2). Final dose adjustment should be based upon integration of clinical efficacy and safety considerations