What are the adverse effects of domperidone?

Domperidone Adverse Effects

Domperidone carries significant cardiac and neurological risks that require careful monitoring, particularly QTc prolongation and extrapyramidal symptoms, with regulatory agencies restricting its use due to concerns about sudden cardiac death.

Cardiac Adverse Effects

QTc Prolongation and Arrhythmias

• Domperidone prolongs the QTc interval, necessitating mandatory QTc monitoring with long-term use 1
• National Patient Safety Agency (NPSA) alerts specifically highlight problems with prolonged QTc 1
• Meta-analysis demonstrates that current domperidone use increases the risk of ventricular arrhythmia and sudden cardiac death by 70% (pooled adjusted odds ratio = 1.70; 95% CI 1.47-1.97) 2
• QTc prolongation occurs in approximately 5% of patients treated with domperidone (95% CI: 3.32-8.62) 3
• The most common drugs that prolong QTc when used with domperidone are other QT-prolonging medications 4
• Drug-drug interactions significantly increase risk, with erythromycin and ketoconazole causing multi-fold increases in domperidone exposure through CYP3A4 inhibition 5

Clinical Monitoring Requirements

• Baseline ECG should be obtained before initiating therapy 4
• Electrolyte abnormalities (particularly hypokalemia and hypomagnesemia) must be corrected prior to starting treatment 4
• Long-term use requires ongoing QTc monitoring 1
• In one community-based study, 69.7% of patients were coprescribed QT-interacting drugs with domperidone, yet only 38.1% underwent baseline ECG 6

Neurological Adverse Effects

Extrapyramidal Symptoms

While domperidone is a selective antagonist of peripheral D2 dopamine receptors and does not have the acetylcholine-like effects of metoclopramide, neurological adverse effects can still occur 1:

• Extrapyramidal side effects are less common with domperidone than metoclopramide but remain a concern 1
• Acute dystonia can present as involuntary motor tics or spasms involving the face, extraocular muscles (oculogyric crisis), neck, back, and limb muscles 7
• Akathisia (subjective feeling of restlessness) may occur, often misinterpreted as psychotic agitation or anxiety 8
• Drug-induced Parkinsonism syndrome can develop 7
• Tardive dyskinesia, though more associated with metoclopramide, remains a theoretical risk with dopamine antagonists 1

Neuropsychiatric Effects

• A case report documented infanticide ideation following 3 months of domperidone exposure, representing a potential neuropsychiatric adverse event 9
• Akathisia and depression have been previously described as neuropsychiatric adverse effects 9

Common Side Effects

In a large single-center cohort of 115 gastroparesis patients 10:

• Side effects were reported by 44 patients (38%)
• Most common adverse effects included:
  • Headache
  • Tachycardia/palpitations
  • Diarrhea
• 14 patients (12%) discontinued treatment due to side effects

Endocrine and Reproductive Effects

• Systemic exposure to domperidone may affect reproductive hormones 5
• Pregnant and lactating women should use caution when handling domperidone 5
• The safety of domperidone in lactating women and their nursing children has not been evaluated 5
• Domperidone may cause premature birth, low birth weight foals, or foal morbidity when used inappropriately in veterinary contexts (extrapolated concern for human pregnancy) 5

Gastrointestinal Contraindications

• Do not use in patients with suspected or confirmed gastrointestinal blockage, as domperidone is a prokinetic drug that stimulates gut motility 5
• This contraindication is particularly important given its mechanism of action 1

Regulatory Restrictions and Clinical Context

European Medicines Agency Restrictions

The European Medicines Agency's Committee recommended that metoclopramide not be used long-term due to extrapyramidal side effects and potentially irreversible tardive dyskinesia, leading to increased domperidone use 1. However, domperidone itself now faces restrictions:

• EMA imposed usage restrictions in 2014 limiting age (≤60 years), daily dose (≤30 mg/day), and duration (≤7 days) 11
• Despite these restrictions, a French study found 95% of Parkinson's disease patients receiving domperidone were using it outside EMA guidelines, primarily due to age >60 years (79%) and treatment duration >7 days (84%) 11

FDA Status

• Domperidone is not approved for any indication in humans in the United States 5
• It is available outside the U.S. for gastroparesis treatment 12

Risk-Benefit Considerations

Evidence Quality Concerns

• Two thorough QT studies (TQT) showed conflicting results: the first was negative while the second was marginally positive 13
• At oral doses of 20 mg QID in healthy volunteers, domperidone does not appear strongly associated with QT prolongation based on regulatory gold standard assessments 13
• However, there remains an ill-defined risk at higher systemic concentrations, especially in patients with higher baseline risk of QT prolongation 13

Clinical Practice Patterns

• Domperidone is commonly prescribed with QT-interacting drugs (69.7% in one study), placing patients at increased risk 6
• Inconsistent ECG monitoring occurs in clinical practice despite known cardiac risks 6
• In the FDA Adverse Event Reporting System, 73.3% of 221 nonfatal cardiac events occurred in patients receiving QT-interacting medications 6

Special Populations

Elderly Patients

• Evidence suggests domperidone usage in older populations should be discouraged due to increased risk of cardiac arrhythmia and sudden cardiac death 2
• EMA restrictions limit use to patients ≤60 years 11

Pediatric Patients

• Currently, use is restricted to relief of nausea and vomiting in children older than 12 years for short periods 14
• Among pediatric gastroenterologists, domperidone is used off-label for gastroesophageal reflux disease, dyspepsia, and gastroparesis 14
• Little is known about efficacy in treating GI motility disorders in children, with controversial data in pediatric literature 14