What are the risks associated with using promethazine (Phenergan)?

Risks of Promethazine

Critical Contraindication and Black Box Warning

Promethazine is absolutely contraindicated in children under 2 years of age due to the risk of fatal respiratory depression, and should be used with extreme caution in children 2 years and older. 1

• Fatal respiratory depression and apnea have been reported in pediatric patients, with postmarketing cases documenting deaths even with weight-based dosing 1
• The FDA has issued a black box warning specifically prohibiting use in children under 2 years 1
• Excessively large doses in pediatric patients may cause sudden death 1

Life-Threatening Adverse Effects

Respiratory Depression

• Promethazine may lead to potentially fatal respiratory depression, particularly when combined with other CNS depressants (alcohol, benzodiazepines, opioids, barbiturates, general anesthetics) 2, 3, 1
• Patients with compromised respiratory function (COPD, sleep apnea) should avoid promethazine entirely 1
• The respiratory depressant effect is enhanced when used as an adjuvant with narcotics and benzodiazepines, requiring dose reduction of standard sedation agents 2

Neuroleptic Malignant Syndrome (NMS)

• A potentially fatal syndrome characterized by hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability (irregular pulse/blood pressure, tachycardia, diaphoresis, cardiac dysrhythmias) 2, 3, 1, 4
• Management requires immediate discontinuation of promethazine, intensive symptomatic treatment, and medical monitoring 1
• Reintroduction of promethazine should be carefully considered due to reported recurrences 1

Severe Injection-Related Complications

• Inadvertent perivascular extravasation, unintentional intra-arterial injection, and intraneuronal/perineuronal infiltration can cause burning, pain, thrombophlebitis, tissue necrosis, and gangrene 2, 3, 5
• These limb-threatening adverse effects, though rare, have been documented for decades 5
• The FDA changed product labeling in December 2023 to add dilution and administration recommendations, with a stated preference for intramuscular over intravenous administration 5
• When given intravenously, must be infused slowly (≤25 mg/min) to minimize hypotension risk 2, 6

Neurological and Psychiatric Risks

Extrapyramidal Effects

• Range from restlessness to severe reactions including oculogyric crises, torticollis, tongue protrusion, and dystonic reactions 2, 3, 1, 7
• Pediatric patients who are acutely ill with dehydration have increased susceptibility to dystonias 1
• These symptoms may be confused with CNS signs of undiagnosed primary disease (encephalopathy, Reye's syndrome) 1

CNS Depression and Paradoxical Reactions

• Impairs mental and physical abilities required for driving and operating machinery 1
• Common effects include drowsiness, sedation, somnolence, blurred vision, dizziness, confusion, and disorientation 1
• Paradoxical reactions include hyperexcitability, abnormal movements, nightmares, delirium, agitated behavior, hallucinations, and convulsive seizures 1, 7

Seizure Risk

• Promethazine lowers seizure threshold and should be used with caution in patients with seizure disorders 1
• Particularly concerning when used with concomitant medications that also affect seizure threshold (narcotics, local anesthetics) 1

Cardiovascular Risks

• Hypotension is common, particularly with rapid intravenous administration 2, 3, 6
• Other cardiovascular effects include increased or decreased blood pressure, tachycardia, bradycardia, and faintness 1
• Strong alpha-adrenergic inhibitory effects contribute to hypotensive side effects 3

Hematologic Risks

• Bone marrow depression including leukopenia, agranulocytosis, thrombocytopenia, and thrombocytopenic purpura 1
• Use with caution in patients with bone marrow depression, especially when combined with other known marrow-toxic agents 1

Other Significant Risks

Anticholinergic Effects

• Dry mouth, blurred vision, urinary retention, and epigastric discomfort 2
• Anticholinergic toxicity must be considered in differential diagnosis of adverse reactions 1

Hepatic Effects

• Cholestatic jaundice has been reported 1
• Elevated transaminase levels documented in case reports 4

Dermatologic and Allergic Reactions

• Dermatitis, photosensitivity, urticaria, and angioneurotic edema 1

Abuse Potential

• Increasing levels of misuse/abuse/dependence reported to European Monitoring Agency (2003-2019) 8
• High number of fatalities (55.6%) associated with abuse, mostly as "drug toxicity/drug abuse" cases with opiates/opioids as most commonly reported concomitant drugs 8
• Over-the-counter availability in some countries increases risk of inappropriate use 7, 8

Special Clinical Considerations

Pediatric Population

• Promethazine should be avoided in pediatric patients with signs/symptoms suggesting Reye's syndrome or other hepatic diseases 1
• Antiemetics are not recommended for uncomplicated vomiting in pediatric patients; use should be limited to prolonged vomiting of known etiology 1
• When used in children ≥2 years, the lowest effective dose should be administered, avoiding concomitant respiratory depressants 1

Drug Interactions

• Enhanced sedative effects when combined with CNS depressants require dose reduction of concomitant agents 2, 3
• The usual promethazine dose of 12.5-25 mg may require reduction when used as adjuvant to narcotics and benzodiazepines 2, 6