Promethazine

Promethazine is identified as a standalone signal for torsade de pointes in FDA Adverse Event Reporting System analysis. Concomitant use of other QT-prolonging medications significantly increases the risk of fatal cardiac arrhythmia.

Asthma, COPD, Bronchiectasis

Anticholinergic drying of airway secretions worsens lower respiratory tract diseases including asthma and COPD. May also depress cough reflex.

Promethazine is contraindicated in comatose patients due to risk of further CNS depression, respiratory compromise, and hemodynamic instability.

Phenothiazines may lower seizure threshold. Promethazine should be used with caution in patients with seizure disorders or those receiving medications that lower seizure threshold.

Concurrent use of monoamine oxidase inhibitors increases the risk of severe extrapyramidal symptoms including acute dystonia and akathisia.

Hepatic impairment reduces promethazine clearance, potentially producing toxic accumulation. Given the already-low oral bioavailability (12.3–40%) driven by hepatic metabolism, liver dysfunction may substantially increase systemic exposure.

Contraindicated in patients with known hypersensitivity to promethazine or any other phenothiazine derivative.

FDA black box warning contraindicating promethazine in children under 2 years of age. Review of 125 adverse event reports (1969–2003) documented respiratory depression in 22 children aged 1.5 months to 2 years, 7 of whom died, across a wide dose range (0.45–6.4 mg/kg) and all administration routes.

Listed on the American Geriatrics Society 2023 Beers Criteria as potentially inappropriate in older adults. Anticholinergic burden increases risk of delirium, confusion, falls, constipation, urinary retention, and blurred vision.

Anticholinergic mydriasis from muscarinic blockade increases intraocular pressure in narrow-angle glaucoma, risking acute angle-closure crisis.

FDA black box warning. Promethazine must not be administered by intra-arterial or subcutaneous injection routes. Only deep intramuscular injection is acceptable for parenteral use. IV administration carries risk of severe thrombophlebitis and extravasation injury.

Potent muscarinic blockade exacerbates urinary retention in patients with prostatic hypertrophy or bladder neck obstruction.

History of bone marrow suppression is a relative contraindication for all phenothiazines due to the rare risk of agranulocytosis and thrombocytopenia.