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Bedside Snapshot
  • Primary Uses: Antiemetic, sedating antihistamine, adjunct for migraine/nausea, allergic reactions
  • Preferred Routes: IM, PO, or rectal; IV use controversial due to severe tissue injury risk
  • Common ED Dose: 12.5-25 mg IM or PO q4-6h PRN; if IV: 6.25-12.5 mg (diluted, large vein, slow push)
  • Duration: 4-6 hours for antiemetic/sedative effects
  • Critical Dangers: Severe tissue injury with IV use (gangrene), respiratory depression (especially children <2 years), heavy sedation, anticholinergic effects
Brand & Generic Names
  • Generic Name: Promethazine hydrochloride
  • Brand Names: Phenergan, generics
Medication Class

First-generation H1 antihistamine (phenothiazine derivative); antiemetic; sedative; anticholinergic with additional antidopaminergic and weak alpha-adrenergic blocking properties

Pharmacology

Mechanism of Action:

  • H1 histamine receptor antagonism: Potent antagonist, reducing histamine-mediated symptoms (pruritus, rhinorrhea, urticaria) and providing central sedative and antiemetic effects
  • Anticholinergic (M1) activity: Significant activity contributing to antiemetic effects but also causing dry mouth, urinary retention, constipation, blurred vision, and delirium in susceptible patients
  • Dopamine D2 receptor antagonism: Weak activity in chemoreceptor trigger zone contributes to antiemetic effects but predisposes to extrapyramidal symptoms
  • Alpha-adrenergic blockade: Mild activity may lead to orthostatic hypotension and reflex tachycardia
  • Blood-brain barrier penetration: Crosses readily; strong central H1 and M1 effects account for sedating properties

Pharmacokinetics:

  • Onset: PO/IM within 20 minutes; IV within 3-5 minutes when given slowly
  • Duration: 4-6 hours for antiemetic and sedative effects, sometimes longer in elderly or hepatic impairment
  • Oral Bioavailability: Moderate; significant first-pass metabolism but adequate systemic levels
  • Distribution: Highly lipophilic; widely distributed with significant CNS penetration; highly protein bound
  • Metabolism: Primarily hepatic (CYP2D6 and others) to several metabolites
  • Elimination: Excreted in urine and bile mainly as metabolites; elimination half-life ~10-19 hours, prolonged in elderly and hepatic dysfunction
Indications
  • Nausea and vomiting: Symptomatic treatment when other agents unavailable, contraindicated, or ineffective
  • Migraine/headache: Adjunctive therapy (often combined with ketorolac, prochlorperazine, or metoclopramide) for added antiemetic and sedative effect
  • Allergic reactions: Short-term management (urticaria, pruritus) as second-line agent after non-sedating antihistamines, especially when sedation desired
  • Pre- or post-operative sedation/antiemetic: Under anesthesia protocols (less common in modern practice)
  • Motion sickness and vertigo: Adjunct therapy
Dosing & Administration

Available Forms:

  • Tablets/capsules: 12.5 mg, 25 mg, 50 mg
  • Oral syrup/solution: 6.25 mg/5 mL or 25 mg/5 mL (varies by product)
  • Rectal suppositories: 12.5 mg, 25 mg, 50 mg
  • Injectable solution: 25 mg/mL and 50 mg/mL for IM/IV use (IM route strongly preferred)

Standard Adult Dosing (Always Follow Local Protocol):

Indication / Route Typical Dose Frequency Notes
Nausea/vomiting – PO 12.5-25 mg PO Every 4-6 hours as needed Use lowest effective dose; consider non-sedating options first
Nausea/vomiting – IM (preferred parenteral) 12.5-25 mg deep IM Every 4-6 hours as needed Deep IM only; avoid subcutaneous injection
Nausea/vomiting – IV (if institution allows) 6.25-12.5 mg IV (diluted) Every 4-6 hours as needed Give in ≥10 mL NS over ≥10-15 minutes via large vein; extreme caution due to tissue injury risk
Allergic reaction – PO/IM 25 mg PO or IM Every 4-6 hours as needed Adjunct to H1/H2 blockers and steroids; sedation may be beneficial or undesirable
Sedation at bedtime 25-50 mg PO Once nightly Avoid in elderly and those at high risk for respiratory depression

Maximum Daily Dose: 100-150 mg/day (all routes combined); use lower maximums in elderly, hepatic impairment, or with CNS depressants

Contraindications

Contraindications:

  • Children <2 years of age (boxed warning – risk of fatal respiratory depression)
  • Known hypersensitivity to promethazine or other phenothiazines
  • Comatose state or severe CNS depression
  • Intra-arterial or subcutaneous injection; IV use via hand/wrist veins or through small-bore catheters contraindicated due to extravasation risk

Major Precautions:

  • Elderly, patients with sleep apnea, COPD, or other respiratory compromise: high risk for respiratory depression, especially with opioids/benzodiazepines
  • History of extrapyramidal symptoms or neuroleptic malignant syndrome with phenothiazines or antipsychotics
  • Seizure disorders: phenothiazines may lower seizure threshold
  • Cardiovascular disease: alpha-blockade and QT-prolonging potential may cause hypotension or arrhythmias
  • Anticholinergic burden: may worsen urinary retention, glaucoma (especially narrow-angle), constipation, and delirium
  • IV administration: if absolutely necessary, use diluted solution, large proximal vein, slow administration, and continuous monitoring; stop immediately with any pain, burning, or swelling
Black Box Warning: Severe tissue injury, including gangrene, can occur with IV promethazine from extravasation, inadvertent intra-arterial injection, or perivascular injection. Many hospitals restrict or prohibit IV use.
Pediatric Warning: Contraindicated in children <2 years due to risk of fatal respiratory depression. Use lowest effective dose and extreme caution in older children, especially with other CNS depressants.
Adverse Effects

Common:

  • Sedation, drowsiness, impaired coordination
  • Dry mouth, blurred vision, constipation, urinary retention (anticholinergic)
  • Hypotension, dizziness, orthostasis
  • Injection-site discomfort with IM administration

Serious:

  • Severe tissue injury with IV use: Burning, pain, erythema, edema, blistering, necrosis, gangrene (sometimes requiring surgical debridement or amputation)
  • Respiratory depression and apnea, particularly in young children or when combined with opioids/other CNS depressants
  • Extrapyramidal symptoms (dystonia, akathisia, parkinsonism) and rare neuroleptic malignant syndrome
  • Seizures in predisposed individuals or at high doses
  • Agranulocytosis, leukopenia (rare)
  • Severe allergic reactions, including anaphylaxis
Special Populations

Pediatric Use:

  • Contraindicated in children <2 years due to risk of fatal respiratory depression
  • For children ≥2 years: 0.25-1 mg/kg/dose (max 25 mg) PO/IM/rectal q4-6h PRN
  • Many institutions avoid promethazine in pediatrics or restrict to second-line after safer agents
  • IV use in pediatrics strongly discouraged due to high risk of severe tissue injury

Geriatric Patients:

  • Start with lowest doses (6.25-12.5 mg)
  • Increased sensitivity to sedation, anticholinergic effects, and respiratory depression
  • Higher risk of falls, confusion, and delirium
  • Prolonged elimination half-life; adjust dosing intervals

Hepatic Impairment:

  • Reduced metabolism and prolonged effects
  • Use lower doses and extend dosing intervals
  • Monitor closely for excessive sedation and anticholinergic toxicity

Pregnancy/Lactation:

  • Category C; use only if benefits outweigh risks
  • May be used near term for labor-related nausea but can cause CNS depression in neonate
  • Excreted in breast milk; use with caution during lactation
Monitoring

Clinical Monitoring:

  • Level of consciousness, respiratory rate, and oxygen saturation, especially when co-administered with opioids or benzodiazepines
  • Hemodynamic status (BP, HR) in patients at risk of hypotension or receiving IV doses
  • Injection/infusion site for pain, burning, swelling, or color change; stop immediately if extravasation suspected
  • For repeated or high-dose use, monitor for anticholinergic toxicity (confusion, urinary retention, ileus) and extrapyramidal symptoms
  • In pediatrics and frail adults, closely monitor for signs of oversedation and respiratory compromise
Clinical Pearls
Route Selection: Given the risk of severe tissue injury, many EDs have moved away from IV promethazine. Consider IM or PO routes or alternative antiemetics (ondansetron, prochlorperazine, metoclopramide, droperidol) when possible.
If IV Use Required: Treat it like a vesicant: dilute, use large vein, slow push, and stop immediately if patient reports burning or you see any swelling.
Age Screening: Always screen for age <2 years, significant respiratory disease, and concurrent sedatives before giving promethazine—these are the patients most likely to get into trouble.
Useful Situations: Promethazine's sedating and anticholinergic profile can be useful (e.g., migraine with nausea, itchy/anxious allergic patient) but is a liability in older or medically fragile patients.
Documentation: Document your indication and route choice clearly, especially if you use IV promethazine, given its medicolegal history and boxed warnings.
References
  • 1. Lexicomp. (2024). Promethazine: Drug information. Wolters Kluwer.
  • 2. U.S. Food and Drug Administration. (2006). Phenergan (promethazine) injection: Boxed warning for severe tissue injury, including gangrene.
  • 3. StatPearls Publishing. (2023). Promethazine. In StatPearls.
  • 4. Tintinalli, J. E., Ma, O., Yealy, D. M., Meckler, G. D., Stapczynski, J. S., Cline, D. M., & Thomas, S. H. (2019). Tintinalli's Emergency Medicine: A Comprehensive Study Guide (9th ed.). McGraw-Hill Education.
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