Upper Gastrointestinal Motility Modifier
Action And Clinical Pharmacology: Domperidone is a peripheral dopamine antagonist structurally related to the butyrophenones with antiemetic and gastroprokinetic properties.
Domperidone effectively increases esophageal peristalsis and lower esophageal sphincter pressure (LESP), increases gastric motility and peristalsis, enhances gastroduodenal coordination and consequently facilitates gastric emptying and decreases small bowel transit time.
The mechanism of action of domperidone is related to its peripheral dopamine receptor blocking properties. Emesis induced by apomorphine, hydergine, morphine or levodopa through stimulation of the chemoreceptor trigger zone (situated outside the blood-brain barrier) can be blocked by domperidone. There is indirect evidence that emesis is also inhibited at the gastric level, since domperidone also inhibits emesis induced by oral levodopa, and local gastric wall concentrations following oral domperidone are much greater than those of the plasma and other organs. Domperidone does not readily cross the blood-brain barrier and therefore is not expected to have central effects.
Domperidone elevates serum prolactin levels but has no effect on circulating aldosterone levels.
Pharmacokinetics: In man, peak plasma levels of domperidone occur within 10 to 30 minutes following i.m. injection and 30 minutes after oral (fasted) administration. Plasma concentrations 2 hours after oral administration are lower than following i.m. injection, and this is likely the result of hepatic first-pass and gut wall metabolism. Peak plasma concentrations are 40 ng/mL following an i.m. injection of 10 mg, 20 ng/mL after a single 10 mg tablet, and 70 to 100 ng/mL after oral doses of 60 mg (tablets or oral drops). The half-life was calculated as approximately 7.0 hours in each case. The degree of human plasma protein binding was calculated from tritiated domperidone concentrations of 10 and 100 ng/mL as 91.7 and 93.0%, respectively.
The major metabolic pathways for domperidone in man are hydroxylation and oxidative N-dealkylation, the products of which are hydroxydomperidone and 2,3-dihydro-2-oxo-1-H-benzimidazol-1-propionic acid, respectively. After oral administration of 40 mg 4-domperidone to healthy volunteers, 31% of the radioactivity is excreted in the urine and 66% in the feces over a period of 4 days.
Indications And Clinical Uses: In the symptomatic management of upper gastrointestinal motility disorders associated with chronic and subacute gastritis and diabetic gastroparesis. Domperidone may also be used to prevent gastrointestinal symptoms associated with the use of dopamine agonist antiparkinsonian agents.
Contra-Indications: In patients with known sensitivity or intolerance to the drug.
Domperidone should not be used whenever gastrointestinal stimulation might be dangerous, i.e., gastrointestinal hemorrhage, mechanical obstruction or perforation.
Also contraindicated in patients with a prolactin-releasing pituitary tumor (prolactinoma).
Manufacturers’ Warnings In Clinical States: Dopamine receptor blocking agents elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of dopamine receptor blocking agents. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis. The available evidence is considered too limited to be conclusive at this time.
Pregnancy: While animal studies have not shown drug-related teratogenic or primary embryotoxic effect on animal fetuses, comparable studies have not been performed in pregnant women. For this reason, domperidone should not be used in pregnant women unless the benefit outweighs the potential hazard.
Lactation: Domperidone is excreted in breast milk in very low concentrations. Therefore, nursing is not recommended for mothers taking domperidone unless the expected benefits outweigh any potential risk.
Children: Safety and efficacy in children have not been established, therefore, domperidone should not be used in children.
Precautions: In the event that the patient develops galactorrhea and/or gynecomastia, withdrawal of the drug will result in alleviation of these symptoms.
Drug Interactions: The concomitant administration of anticholinergic drugs may compromise the beneficial effects of domperidone.
Since domperidone enhances gastric and small intestinal motility, it may accelerate absorption of drugs from the small bowel while slowing absorption of drugs taken up from the stomach, particularly those with sustained-release or enteric-coated formulations.
Care should be exercised when domperidone is administered in combination with MAO inhibitors.
The concomitant administration of domperidone maleate with antacids or H2-receptor blockers does not decrease the absorption of domperidone.
Hepatic Impairment: Since domperidone is highly metabolized in the liver, it should be used with caution in patients with hepatic impairment.
Adverse Reactions: In clinical studies with oral domperidone the overall incidence of side effects with domperidone was:
- CNS (4.6%): dry mouth (1.9%), headache/migraine (1.2%), insomnia, nervousness, dizziness, thirst, lethargy, irritability;
- Gastrointestinal (2.4%): abdominal cramps, diarrhea, regurgitation, changes in appetite, nausea, heartburn, constipation;
- Endocrinological (1.3%): hot flushes, mastalgia, galactorrhea, gynecomastia, menstrual irregularities.
- Mucocutaneous (1.1%): rash, pruritus, urticaria, stomatitis, conjunctivitis.
- Urinary (0.8%): urinary frequency, dysuria.
- Cardiovascular (0.5%): edema, palpitations.
- Musculoskeletal (0.1%): leg cramps, asthenia.
- Miscellaneous (0.1%): drug intolerance.
- Laboratory parameters: elevated serum prolactin, elevation of AST, ALT and cholesterol.
Extrapyramidal phenomena are rare in adults; they reverse spontaneously as soon as treatment is stopped. When the blood-brain barrier is immature (as in infants) or impaired, the possible occurrence of neurological side effects cannot be excluded.
Symptoms And Treatment Of Overdose: Symptoms: Based on the pharmacological properties of domperidone, symptoms of overdosage may include CNS effects (such as drowsiness, disorientation and extrapyramidal reactions, especially in children) and cardiovascular effects (arrhythmia, hypotension) might possibly occur.
Treatment: REG>Anticholinergic, anti-parkinsonian drugs or antihistamines with anticholinergic properties may be helpful in controlling the extrapyramidal reactions. There is no specific antidote to domperidone but in the event of overdosage, gastric lavage as well as the administration of activated charcoal may be useful. Close observation and supportive therapy are recommended. Symptoms are self-limiting and usually disappear within 24 hours.
Dosage And Administration: Upper Gastrointestinal Motility Disorders: The usual dosage in adults is 10 mg orally 3 to 4 times a day, 15 to 30 minutes before meals and at bedtime if required. In severe or resistant cases the dose may be increased to a maximum of 20 mg 3 to 4 times a day.
Nausea and Vomiting Associated with Dopamine Agonist Antiparkinsonian Agents: The usual dosage in adults is 20 mg orally 3 to 4 times a day. Higher doses may be required to achieve symptom control while titration of the antiparkinsonian medication is occurring.
Availability And Storage: Each white to faintly cream, film-coated tablet contains: domperidone maleate 12.72 mg (equivalent to domperidone 10 mg). Nonmedicinal ingredients: cornstarch, hydroxypropyl methylcellulose, lactose, magnesium stearate, microcrystalline cellulose, polysorbate, povidone, pregelatinized starch, propylene glycol and silicone dioxide. Bisulfite-, gluten- and tartrazine-free. HDPE bottles of 500. Store at room temperature between 15 and 30°C, protected from light and moisture.
MOTILIUM® Janssen-Ortho Domperidone Maleate Upper Gastrointestinal Motility Modifier