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Trimethobenzamide
Trimethobenzamide
Trimethobenzamide
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Trimethobenzamide
Clinical data
Trade namesTigan, Tebamide
AHFS/Drugs.comMonograph
MedlinePlusa682693
Routes of
administration		Oral, rectal, intramuscular
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability60-100%
Elimination half-life7 to 9 hours (mean)
Excretionurine (30-50%), faeces
Identifiers
  • N-{[4-(2-dimethylaminoethoxy)phenyl]methyl}-
    3,4,5-trimethoxy-benzamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.004.848 Edit this at Wikidata
Chemical and physical data
FormulaC21H28N2O5
Molar mass388.464 g·mol−1
3D model (JSmol)
  • O=C(c1cc(OC)c(OC)c(OC)c1)NCc2ccc(OCCN(C)C)cc2
  • InChI=1S/C21H28N2O5/c1-23(2)10-11-28-17-8-6-15(7-9-17)14-22-21(24)16-12-18(25-3)20(27-5)19(13-16)26-4/h6-9,12-13H,10-11,14H2,1-5H3,(H,22,24) checkY
  • Key:FEZBIKUBAYAZIU-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Trimethobenzamide (trade names Tebamide, Tigan) is an antiemetic used to prevent nausea and vomiting.

Mechanism of action

[edit]

Trimethobenzamide is an antagonist of the D2 receptor.[1] It is believed to affect the chemoreceptor trigger zone (CTZ) of the medulla oblongata to suppress nausea and vomiting.

Side effects

[edit]

Possible side effects include drowsiness, dizziness, headache, muscle cramps, and blurred vision. More serious adverse effects include skin rash, tremors, parkinsonism, and jaundice.

Formulations

[edit]

Trimethobenzamide is marketed under the brand names Tebamide and Tigan, manufactured by GlaxoSmithKline and King Pharmaceuticals, respectively. It is available as oral capsules and injectable formulations.

Trimethobenzamide was also available as a rectal suppository, but such formulations were banned by the U.S. Food and Drug Administration on April 6, 2007, due to unproven efficacy.[2]

Synthesis

[edit]
Trimethobenzamide synthesis: Hoffmann La Roche, U.S. patent 2,879,293 (1959).

Alkylation of the sodium salt of p-hydroxybenzaldehyde (1) with 2-dimethylaminoethyl chloride affords the ether (2). Reductive amination of the aldehyde in the presence of ammonia gives diamine (3). Acylation of that product with 3,4,5-trimethoxybenzoyl chloride affords trimethobenzamide (4).

See also

[edit]

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Trimethobenzamide

View on Grokipedia
from Grokipedia
Trimethobenzamide is a derivative and centrally acting agent indicated for the treatment of and nausea associated with in adults. It primarily exerts its therapeutic effect by directly depressing the (CTZ) in the , thereby inhibiting emetic impulses at the central level without significant peripheral or antihistaminic activity. The drug is administered orally as 300 mg capsules of trimethobenzamide , typically three to four times daily as needed, and was first approved by the U.S. in 1974. Pharmacokinetically, trimethobenzamide is rapidly absorbed following oral dosing, achieving peak plasma concentrations in about 45 minutes, with an elimination of 7 to 9 hours; approximately 30% to 50% of the dose is excreted unchanged in the , primarily via glomerular filtration. Dosage adjustments are recommended for patients with renal impairment ( clearance ≤70 mL/min/1.73 m²) to mitigate the risk of adverse reactions, and the drug is contraindicated in individuals with known to trimethobenzamide and not recommended in pediatric patients due to the potential for serious and effects. Common adverse effects include drowsiness, , , and , while rare but severe reactions encompass convulsions, coma, , and . Although an injectable formulation exists for intramuscular use, the rectal form was withdrawn from the U.S. market in due to insufficient evidence of efficacy. Trimethobenzamide is metabolized hepatically to an N-oxide derivative with minimal drug-drug interactions reported, though caution is advised in patients with hepatic impairment or those taking other depressants. is uncommon but possible, with isolated case reports of acute linked to its use.

Medical uses

Indications

Trimethobenzamide is indicated in adults for the treatment of as well as associated with . These approvals stem from clinical evaluations demonstrating its efficacy in controlling emesis in these settings, with the U.S. (FDA) confirming substantial evidence of effectiveness for these uses following a drug efficacy study implementation in 2002. The drug is commonly employed for the prevention and treatment of as well as associated with . For instance, it helps manage in surgical patients during recovery and in individuals with acute , where symptoms arise from inflammatory or infectious processes in the digestive tract. Its use in these contexts is supported by early clinical trials, though with efficacy generally lower than that of antiemetics. Trimethobenzamide is not indicated for , which involves vestibular mechanisms outside its primary site of action in the , nor for , where more targeted agents like 5-HT3 antagonists are preferred due to limited comparative efficacy data from older studies. While some historical investigations explored its role in chemotherapy-related emesis, current guidelines do not recommend it for this purpose, emphasizing its restricted evidence base beyond FDA-approved indications.

Dosage and administration

Trimethobenzamide is available in oral capsule form at a strength of 300 mg and as an intramuscular () injection at a concentration of 100 mg/mL. For oral administration in adults, the recommended dosage is 300 mg three to four times daily as needed for the control of and , with a maximum daily dose of 1,200 mg. The lowest effective dose should be used, and adjustments can be made based on therapeutic response and tolerability. In patients with renal impairment (creatinine clearance ≤70 mL/min/1.73 m²), including some geriatric patients, the daily dosage should be reduced by increasing the dosing interval, with monitoring of renal function and further adjustments as needed. Use is not recommended in patients with signs or symptoms of hepatic impairment due to the risk of ; therapy should be discontinued if liver dysfunction develops during treatment. For IM administration in adults, the recommended dosage is 200 mg (2 mL) three to four times daily, injected deeply into the upper outer quadrant of the to minimize discomfort such as , stinging, or swelling. The following IM injection occurs within 15 to 35 minutes, with a duration of effect lasting 2 to 3 hours. IM use requires similar dosage adjustments for renal impairment as with the oral route, while hepatic impairment contraindicates use. Intravenous administration is strictly prohibited due to the risk of severe and collapse. Trimethobenzamide is intended for short-term use, typically until symptoms of resolve, and is not recommended for use in pediatric patients (contraindicated for IM administration) due to risks of and other serious effects. Oral capsules may be taken with or without food.

Contraindications and precautions

Contraindications

Trimethobenzamide is contraindicated in patients with known to the drug or any of its components, including those with a history of or other severe allergic reactions. The intramuscular () formulation of trimethobenzamide is strictly contraindicated in pediatric patients due to the high risk of toxicity, including serious (CNS) effects and potential exacerbation of conditions resembling Reye's syndrome.

Precautions

Trimethobenzamide requires caution in elderly patients due to increased susceptibility to adverse effects, including and drowsiness that may impair balance and elevate the of falls; dose reduction by extending the dosing interval is recommended, along with close monitoring of renal function as age-related declines can heighten risks. In patients with renal impairment ( clearance ≤70 mL/min/1.73 m²), dosage adjustment is necessary because the drug is primarily excreted by the kidneys, leading to prolonged and accumulation; regular renal function monitoring is advised. For hepatic impairment, trimethobenzamide should be avoided if signs of liver dysfunction are present, and discontinued if liver function deteriorates during , given the potential for exacerbated effects in compromised liver . Drug interactions with trimethobenzamide include additive (CNS) depression when combined with alcohol, opioids, or other sedatives, which can intensify drowsiness and impair psychomotor skills; concurrent use should be avoided or closely monitored. Trimethobenzamide should not be used in patients with comatose states or severe CNS depression, as administration of antiemetics in these situations can mask symptoms of underlying , such as or disease progression. Reports of other CNS reactions include , depression of mood, disorientation, and seizures; consider dosage reduction or discontinuation if these occur. Monitoring is essential with trimethobenzamide, as its CNS effects may mask symptoms of serious underlying conditions, such as , intestinal obstruction, or , potentially delaying ; thorough of the cause is required before and during use. The drug is intended for short-term management of acute and and should not be used long-term to avoid unnecessary exposure to risks. Regarding pregnancy, the limited available data with trimethobenzamide in pregnant women are not sufficient to inform a drug-associated for major birth defects and ; animal reproduction studies showed no adverse developmental effects at doses up to 1.6 times the recommended human dose. It should be used during only if the potential benefit justifies the potential to the . In lactation, data on trimethobenzamide excretion in human milk are lacking, and its use is not recommended due to potential risks to the ; a decision should be made to discontinue or the , weighing benefits against hazards.

Adverse effects

Common adverse effects

The common adverse effects of trimethobenzamide primarily involve the (CNS) and are typically mild and transient. The most frequently reported CNS effects include drowsiness, which is the predominant side effect, as well as , , and ; these are attributed to the drug's CNS properties. Gastrointestinal (GI) effects are less common but may manifest as mild , cramps, or . Other occasional effects during short-term use include muscle cramps, , or tremors. Trimethobenzamide is generally well-tolerated, with these effects often resolving as the body adjusts or upon discontinuation of therapy.

Serious adverse effects

Trimethobenzamide can cause extrapyramidal symptoms, including acute dystonic reactions such as muscular spasms and opisthotonos, as well as parkinsonian-like symptoms like tremors, rigidity, akathisia, and akinesia. These effects are rare, particularly noted in children, and may be exacerbated by high doses or concurrent use of other medications that induce extrapyramidal symptoms, such as antipsychotics. These effects are a primary reason for contraindication in pediatric patients. Caution is advised in elderly patients due to general increased sensitivity to side effects. Management typically involves dosage reduction or discontinuation of the drug, with acute dystonia treated using anticholinergic agents. Hepatic effects from trimethobenzamide are uncommon but serious, manifesting as , elevated liver enzymes, or rare cases of cholestatic . Symptoms of may include upper , dark urine, pale stools, , , and yellowing of the skin or eyes, necessitating immediate medical evaluation and potential discontinuation. The drug should be avoided in patients with pre-existing hepatic impairment. Allergic reactions to trimethobenzamide include skin rash and urticaria, with very rare instances of severe such as or . These reactions require prompt intervention, and the drug is contraindicated in individuals with known to it. Other serious adverse effects encompass convulsions, which have been reported in cases of overdose or in sensitive patients, often alongside , disorientation, or mood depression. The risk increases with concomitant use of depressants like alcohol or sedatives, and such events are rare.

Pharmacology

Pharmacodynamics

The mechanism of action of trimethobenzamide is not fully understood but is believed to involve direct depression of the (CTZ) in the , thereby inhibiting emetic impulses to the center. This central action blocks the emetic response triggered by agonists, such as , as demonstrated in animal models where pretreatment with trimethobenzamide prevented apomorphine-induced in dogs. The drug does not directly suppress impulses at the center itself but modulates upstream signaling in the CTZ to reduce and centrally mediated by chemotherapeutic agents, postoperative stimuli, or other CTZ activators. This central action provides selectivity, as trimethobenzamide does not significantly affect peripheral emetic pathways, such as those induced by intragastric irritants like in animal studies. Trimethobenzamide exhibits weak antihistaminic properties that may provide minor supportive inhibition of signals, particularly in scenarios involving histaminergic influences on the CTZ, but lacks significant activity. Therapeutically, this profile makes trimethobenzamide particularly effective for and arising from central CTZ , such as postoperative or drug-induced emesis, but it is less efficacious against vestibular or peripheral causes of that do not primarily involve the CTZ.

Pharmacokinetics

Trimethobenzamide exhibits good absorption following oral or intramuscular administration. The oral bioavailability is comparable to intramuscular dosing, with plasma concentration-time profiles being similar between routes. The time to maximum plasma concentration (T_max) is about 45 minutes after a 300 mg oral capsule and 30 minutes after a 200 mg intramuscular injection. Onset of action occurs within 10-40 minutes orally and 15-35 minutes intramuscularly. The drug is widely distributed throughout the body and crosses the blood-brain barrier to reach the in the . The volume of distribution has not been well-characterized in available studies. Trimethobenzamide undergoes hepatic primarily through oxidation to form the trimethobenzamide N-oxide , with limited data on involvement of enzymes; the pharmacologic activity of this metabolite has not been evaluated. No active metabolites have been identified. Elimination of trimethobenzamide occurs with a of 7-9 hours. Approximately 30-50% of a single dose is excreted unchanged in the within 48-72 hours, with the remainder eliminated via through biliary . The is prolonged in patients with renal or hepatic impairment due to substantial renal elimination and hepatic metabolism, respectively.

Chemistry

Physical and chemical properties

Trimethobenzamide is a derivative with the molecular formula C21_{21}H28_{28}N2_{2}O5_{5} for the free base and C21_{21}H29_{29}ClN2_{2}O5_{5} for the salt, the latter having a molecular weight of 424.92 g/mol. The IUPAC name is N-[[4-[2-(dimethylamino)ethoxy]phenyl]methyl]-3,4,5-trimethoxy. The compound appears as a white to off-white crystalline . It has a of 187–191 °C for the hydrochloride salt. Trimethobenzamide hydrochloride is soluble in (≥51 mg/mL), as well as in and , though solubility in is slightly lower. The salt exhibits a pKa of approximately 8.8 for the tertiary amine group (conjugate acid), indicating its basic ionization behavior. It is stable under normal storage conditions, such as inert atmosphere at 2–8 °C, with no significant degradation reported under standard handling. The logP value is 2.29, indicating moderate .

Synthesis

The primary synthesis of trimethobenzamide, as first described in a 1959 patent assigned to Hoffmann-La Roche, involves a three-step process starting from p-hydroxybenzaldehyde. In the initial step, the sodium salt of p-hydroxybenzaldehyde is alkylated with 2-(dimethylamino)ethyl chloride in a solvent such as chlorobenzene under reflux conditions for approximately 15 hours to yield 4-(2-(dimethylamino)ethoxy)benzaldehyde. This intermediate then undergoes reductive amination with ammonia gas in the presence of a Raney nickel catalyst, hydrogen gas at 80°C and 1000 psi pressure, producing 4-(2-(dimethylamino)ethoxy)benzylamine. Finally, this benzylamine is acylated by reaction with 3,4,5-trimethoxybenzoyl chloride in a solvent like acetonitrile or benzene under reflux for 8 hours, followed by treatment with hydrochloric acid to form the hydrochloride salt of trimethobenzamide in high purity. This classical route, developed by inventors Moses Wolf Goldberg and Sidney Teitel at Hoffmann-La Roche, provides the compound as its hydrochloride salt with a reported melting point of 185–186°C and is suitable for large-scale production without involvement of stereocenters, as trimethobenzamide is achiral. Modern variations focus on improving efficiency and safety by avoiding the use of hazardous acid chlorides. One such improved process employs direct amidation of 3,4,5-trimethoxybenzoic acid with 4-(2-(dimethylamino)ethoxy)benzylamine, catalyzed by boric acid in the presence of polyethylene glycol (PEG 600) as a co-solvent in xylene under reflux for 24 hours, with water removal via a Dean-Stark apparatus. The reaction mixture is then basified with aqueous sodium hydroxide, cooled, and extracted to isolate the free base, which is subsequently converted to the hydrochloride salt using ethanolic HCl, yielding trimethobenzamide hydrochloride with 99.5% HPLC purity and an overall yield of approximately 80% from the benzoic acid starting material (melting point 188–190°C). This method enhances scalability, reduces environmental impact, and minimizes impurities compared to the original acid chloride approach.

History and development

Discovery and approval

Trimethobenzamide was developed by in the late as a agent designed to suppress and associated with gastrointestinal disorders, , , and therapeutic interventions. The compound, specifically 4-[2-(diethylamino)ethoxy]-N-(3,4,5-trimethoxybenzoyl) hydrochloride, was patented under U.S. Patent 2,879,293, filed on February 19, 1957, and granted on March 24, 1959, to inventors Moses Wolf Goldberg and Sidney Teitel. This patent detailed its synthesis through the reaction of a substituted with 3,4,5-trimethoxybenzoyl , highlighting its potential as an effective based on initial pharmacological evaluations. Preclinical studies conducted during its early development demonstrated trimethobenzamide's activity on the (CTZ) in the , an area responsible for detecting emetic stimuli, supporting its efficacy in animal models. These findings paved the way for clinical evaluation, with initial marketing occurring in the early under trade names such as Tigan, prior to the 1962 Kefauver-Harris Amendments requiring proof of efficacy for new drugs. As a pre-1962 drug, trimethobenzamide underwent review under the Drug Efficacy Study Implementation () program, leading to FDA approval of its oral capsule and forms in 1974 for the treatment of , as well as nausea associated with . This approval marked its first widespread clinical use in these indications, confirming its safety and effectiveness based on submitted data. Key milestones in its commercialization included licensing for distribution to GlaxoSmithKline under the brand Tebamide and to , which acquired the new drug applications in 1999 and marketed it as Tigan.

Regulatory actions

In 2002, the U.S. (FDA) issued a notice under the Drug Efficacy Study Implementation () program resolving outstanding issues for trimethobenzamide injection and capsules, confirming their efficacy for treating based on substantial evidence from adequate and well-controlled studies. This action also declared that of any unapproved trimethobenzamide capsule formulations was unlawful and subject to regulatory , requiring manufacturers to provide proof of efficacy or cease distribution. No changes were made to the approvals for oral capsules or intramuscular injections, which remained available. A significant regulatory decision occurred in 2007 when the FDA withdrew approval for trimethobenzamide hydrochloride suppositories, effective May 9, following a long-standing review initiated in that found a lack of substantial demonstrating their for and . The agency ordered manufacturers to immediately cease production and distribution of these suppository products, deeming their continued marketing illegal without an approved . This action stemmed from the 1979 DESI evaluation, which had provided an opportunity for hearings but ultimately concluded the suppositories did not meet modern efficacy standards. These U.S. regulatory changes shifted clinical use of trimethobenzamide to oral and intramuscular formulations only, enhancing focus on routes with established efficacy while eliminating the option due to insufficient supporting data. As of 2025, there have been no reported FDA recalls or additional safety-related actions for approved trimethobenzamide products. Internationally, trimethobenzamide remains approved in select countries, including and some Latin American nations, though formulations vary and often exclude suppositories; in the , it has limited status with no centralized approval through the post-2000s.

Society and culture

In the United States, trimethobenzamide is classified as a prescription-only medication and is not subject to control under any DEA schedule, as it has no recognized potential for abuse. The FDA has approved it in oral capsule form (300 mg) and intramuscular injection (100 mg/mL) for the treatment of nausea and vomiting. Internationally, trimethobenzamide requires a prescription for in and select regions, with limited use in and other markets; it is not approved or marketed as an over-the-counter product anywhere. As of 2025, its regulatory status remains unchanged, and formulations continue to be withdrawn in the United States.

Brand names and availability

Trimethobenzamide is primarily marketed under the brand name Tigan, originally developed and manufactured by , which was acquired by in 2010. Historical brand names include Tebamide, associated with earlier formulations of the drug. Generic versions of trimethobenzamide hydrochloride have been widely available in the United States since the expiration of the original patents. Pfizer discontinued the branded Tigan capsules in 2021, leading to a temporary shortage that was resolved with the launch of generic capsules by Chartwell in late 2023; other manufacturers include Lupin and Par Pharmaceuticals (for injection). Current formulations include 300 mg oral capsules and 200 mg/2 mL intramuscular injection vials for single-dose use. Rectal suppositories were discontinued in the U.S. in 2007 due to FDA withdrawal of approval for lack of proven efficacy. The drug is most commonly available in the United States, with limited presence in other regions such as Turkey (marketed as Emedur by Sanofi), and is not widely marketed in Europe or Asia. In Turkey, Emedur is available only by prescription and is offered in forms including 200 mg film-coated tablets, suppositories (such as 100 mg strength combined with 20 mg benzocaine), and 200 mg/2 mL intramuscular injectable solutions. Trimethobenzamide is available only by prescription and is not sold over-the-counter in any country.

References

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  27. https://www.govinfo.gov/content/pkg/FR-2002-12-24/pdf/02-32365.pdf
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  29. https://www.govinfo.gov/content/pkg/FR-2002-12-24/pdf/02-32344.pdf
  30. https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts
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  41. https://www.mayoclinic.org/drugs-supplements/trimethobenzamide-oral-route/description/drg-20066471
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