What are the uses and precautions of Phenergan (promethazine)?

Phenergan (Promethazine): Clinical Overview

What is Phenergan?

Phenergan (promethazine) is a first-generation phenothiazine antihistamine with H1-receptor blocking, antiemetic, sedative, and anticholinergic properties, approved for treating allergic conditions, nausea/vomiting, sedation, and motion sickness. 1

Mechanism of Action

Promethazine works through multiple receptor systems:

• Histamine H1-receptor antagonism competitively blocks histamine effects, providing antihistamine and antiemetic activity 2
• Dopaminergic blockade at postsynaptic brain receptors contributes to antiemetic properties 3, 2
• Strong alpha-adrenergic inhibition produces sedative effects and potential hypotensive side effects 3, 2
• Anticholinergic effects contribute to both therapeutic and adverse effects 3, 2

Pharmacokinetics

• Onset of action: Within 5 minutes intravenously, 20 minutes orally 2, 4
• Duration: 4-6 hours typically, though effects may persist up to 12 hours 2, 4
• Half-life: 9-16 hours 3, 2, 4

Approved Indications

Promethazine is FDA-approved for: 1

• Allergic rhinitis (perennial and seasonal) and vasomotor rhinitis
• Allergic conjunctivitis and mild allergic skin reactions (urticaria, angioedema)
• Anaphylaxis as adjunctive therapy after acute management
• Preoperative, postoperative, or obstetric sedation
• Prevention and control of nausea/vomiting with anesthesia and surgery
• Adjunctive therapy for postoperative pain control
• Motion sickness (active and prophylactic treatment)
• Antiemetic therapy in postoperative patients

Critical Safety Warnings

Black Box Warning - Pediatric Respiratory Depression

Promethazine is CONTRAINDICATED in children under 2 years of age due to fatal respiratory depression risk. 1

• Postmarketing fatalities have occurred in children <2 years regardless of weight-based dosing 1
• Use extreme caution in children ≥2 years; use lowest effective dose 1
• Avoid concomitant respiratory depressants in pediatric patients 1

Respiratory Depression

• May cause potentially fatal respiratory depression, particularly with compromised respiratory function (COPD, sleep apnea) 1
• Risk increases with concomitant CNS depressants (opioids, benzodiazepines, alcohol) 1

Tissue Damage with IV Administration

• FDA black box warning exists for injectable promethazine due to serious tissue injury risk with incorrect administration 5
• Can cause thrombophlebitis, tissue necrosis, and gangrene 4
• Must infuse slowly (≤25 mg/min) to minimize hypotension 3, 4

Neuroleptic Malignant Syndrome

• Potentially fatal syndrome characterized by hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability 1
• Requires immediate discontinuation and intensive supportive care 1

Extrapyramidal Effects

• Can cause restlessness, dystonic reactions, and oculogyric crises 3, 1
• Makes promethazine inappropriate for chronic use 4

Seizure Threshold Lowering

• Promethazine lowers seizure threshold 1
• Use with caution in seizure disorders or with medications that affect seizure threshold (narcotics, local anesthetics) 1
• Maintain antiepileptic medications when promethazine must be used in patients with known seizure disorders 2

Dosing Recommendations

Standard Adult Dosing

• Typical dose: 12.5-25 mg intravenously, infused slowly (≤25 mg/min) 3, 4
• Total dose range: 25-100 mg may be used as adjuvant to narcotics and benzodiazepines 3
• Promethazine use may require reduction in standard sedation agent dosages 3

Elderly Patients

In elderly patients, start with 6.25 mg IV promethazine, which is as effective as higher doses with significantly fewer adverse drug reactions. 6

• A 2010 study demonstrated no difference in time to relief between 6.25 mg and 12.5 mg doses 6
• The 6.25 mg dose had significantly fewer adverse reactions (P=0.048) 6

Dose Reductions with Concomitant CNS Depressants

When combining with other sedatives: 1

• Reduce barbiturate dose by at least one-half
• Reduce narcotic dose by one-quarter to one-half
• Excessive promethazine relative to narcotics may cause restlessness and motor hyperactivity in pain patients 1

Drug Interactions

CNS Depressants

• Promethazine potentiates effects of alcohol, sedatives/hypnotics, narcotics, general anesthetics, tricyclic antidepressants, and tranquilizers 1
• Enhanced sedation and respiratory depression risk with combined use 1

Epinephrine

Do NOT use epinephrine to treat promethazine-associated hypotension, as promethazine reverses epinephrine's vasopressor effect. 1

MAO Inhibitors

• Increased incidence of extrapyramidal effects when combined with MAOIs 1

Anticholinergics

• Use caution with concomitant anticholinergic agents due to additive effects 1

Contraindications and Precautions

Absolute Contraindications

• Children <2 years of age 1

Use with Caution

• Narrow-angle glaucoma, prostatic hypertrophy, stenosing peptic ulcer, pyloroduodenal obstruction, bladder-neck obstruction 1
• Cardiovascular disease or hepatic impairment 1
• Bone marrow depression (leukopenia and agranulocytosis reported) 1
• Compromised respiratory function 1
• Seizure disorders 1

Common Adverse Effects

• CNS: Marked drowsiness, sedation, impaired mental/physical abilities, dizziness, confusion 3, 1
• Cardiovascular: Hypotension, particularly with rapid IV administration 3, 4
• Anticholinergic: Dry mouth, blurred vision, urinary retention 3
• Other: Epigastric discomfort, wheezing 3

Clinical Considerations

Misuse Potential

• Promethazine has documented misuse/abuse potential, especially in adolescents 7
• European data (2003-2019) showed 557 abuse/misuse/dependence cases with 310 fatalities (55.6%), mostly involving concomitant opioid use 7
• Healthcare professionals should be vigilant, particularly where over-the-counter availability exists 7

Comparison to Ondansetron

Ondansetron is increasingly preferred over promethazine for nausea/vomiting due to superior safety profile. 5

• Ondansetron lacks CNS/autonomic side effects (sedation, extrapyramidal symptoms, hypotension) present with promethazine 5
• Ondansetron carries no FDA black box warning 5
• Multiple safe administration routes available (IV, orally disintegrating tablet) 5

Patient Counseling Points

• May cause marked drowsiness; avoid driving or operating machinery 1
• Avoid alcohol and other CNS depressants 1
• Supervise pediatric patients during potentially hazardous activities 1
• Report any involuntary muscle movements immediately 1
• Avoid prolonged sun exposure 1

Laboratory Test Interference

• May cause false-negative or false-positive pregnancy tests based on HCG immunological reactions 1
• May increase blood glucose levels 1