What prokinetic agents are available in the United States (US) for treating gastrointestinal motility disorders?

Prokinetic Agents Available in the United States

Metoclopramide and erythromycin are the only prokinetic agents currently available in the United States for treating gastrointestinal motility disorders. 1

FDA-Approved Prokinetic Agent

Metoclopramide is the only FDA-approved medication for gastroparesis in the United States. 2, 3, 4

• Dosing: 10 mg three times daily, taken 30 minutes before meals 2, 3
• Duration: Treatment should be limited to less than 12 weeks due to the risk of tardive dyskinesia, which carries a black box warning 1, 3, 4
• Mechanism: Combined dopamine D2 receptor antagonist and cholinergic agonist that increases lower esophageal sphincter pressure, enhances gastric contractility, and accelerates gastric emptying 5, 6
• Efficacy timeline: Requires at least 4 weeks to determine effectiveness in diabetic gastroparesis 2, 3

Critical Safety Concerns with Metoclopramide

The FDA has issued a black box warning for tardive dyskinesia (TD), a potentially irreversible movement disorder. 4

• Risk factors: Duration of treatment beyond 12 weeks, total cumulative dose, elderly patients, women, and diabetics 4
• Acute reactions: Dystonic reactions occur in approximately 1 in 500 patients, more frequently in those under 30 years of age and within the first 24-48 hours of treatment 4
• Other adverse effects: Parkinsonian-like symptoms (bradykinesia, tremor, rigidity), depression with suicidal ideation, and neuroleptic malignant syndrome (rare but potentially fatal) 4
• Monitoring: Reassess at 12 weeks before continuing therapy; discontinue immediately if signs of TD develop 2, 4

Off-Label Prokinetic Agent

Erythromycin can be administered orally or intravenously as an off-label prokinetic agent. 1

• Mechanism: Acts as a motilin receptor agonist, mimicking the effect of the endogenous hormone motilin 5, 7
• Major limitation: Tachyphylaxis develops rapidly, limiting its use to short-term therapy 3, 8
• Clinical application: Most effective for acute exacerbations rather than chronic management 3

Agents NOT Available in the United States

Domperidone, a dopamine D2 receptor antagonist, is not FDA-approved in the United States but is available in Canada, Mexico, and Europe. 1

• Limited access: Can only be obtained through the FDA's Expanded Access to Investigational Drugs program 7
• Advantage over metoclopramide: Does not cross the blood-brain barrier, resulting in fewer central nervous system side effects 8, 5

Cisapride was withdrawn from the US market due to cardiac arrhythmias, despite being previously considered the most effective prokinetic agent. 8, 9

Tegaserod, a partial 5-HT4 receptor agonist, enhances gastric emptying but has no confirmed efficacy in reducing gastroparesis symptoms and is not approved for this indication. 1

Investigational and Emerging Agents

Newer agents are in development targeting diverse gastric motor functions, including novel serotonergic 5-HT4 agonists, dopaminergic D2/3 antagonists, neurokinin NK1 antagonists (such as aprepitant), and ghrelin agonists. 7

Common Clinical Pitfalls

Avoid continuing metoclopramide beyond 12 weeks without careful reassessment due to the cumulative risk of irreversible tardive dyskinesia. 2, 3, 4

Withdraw opioids and GLP-1 agonists in patients with gastroparesis, as these medications directly impair gastrointestinal motility and worsen symptoms. 2, 3

Do not use prokinetics as first-line therapy without implementing dietary modifications first, including 5-6 small, low-fat, low-fiber meals daily. 2, 3

Recognize that the evidence for prokinetic efficacy is limited: Guidelines state there is insufficient evidence to support routine use of any prokinetic agent in infants or children with GERD. 1