PROMETHAZINE
Clinical safety rating: safe
CNS depressants may enhance sedative effects Can cause respiratory depression in children and extrapyramidal symptoms.
Promethazine is a phenothiazine derivative that acts as a potent histamine H1 receptor antagonist, thereby blocking the effects of histamine. It also has central anticholinergic, antiemetic, and sedative properties, likely mediated through antagonism at muscarinic, dopamine D2, and serotonin receptors in the brain.
| Metabolism | Primarily hepatic metabolism via CYP2D6 and other pathways; undergoes S-oxidation and N-demethylation. Excreted in urine and bile as inactive metabolites. |
| Excretion | Renal (70-80% as metabolites, <1% unchanged); biliary/fecal minor. |
| Half-life | Terminal elimination half-life 9-16 hours; may be prolonged in hepatic impairment. |
| Protein binding | 93% bound primarily to albumin. |
| Volume of Distribution | Vd approximately 9.5-25 L/kg, indicating extensive tissue distribution. |
| Bioavailability | Oral: ~25% (first-pass metabolism); IM: ~70-85%; Rectal: comparable to oral. |
| Onset of Action | IV: 3-5 minutes; IM: 20 minutes; Oral: 20-60 minutes; Rectal: 20-30 minutes. |
| Duration of Action | 4-6 hours (up to 12 hours for antiemetic effect); duration varies with route and indication. |
| Molecular Weight | 284.42 |
| Action Class | First-generation antihistamine (H1 receptor antagonist) with antiemetic and sedative properties |
12.5-25 mg IM or IV every 4-6 hours; also 25 mg PO or PR every 6-8 hours. Maximum 100 mg/day.
| Dosage form | SYRUP |
| Renal impairment | No dose adjustment required for mild-moderate renal impairment (eCrCl >10 mL/min). For severe impairment (eCrCl <10 mL/min), use with caution and reduce dose by 50% as needed. |
| Liver impairment | Child-Pugh Class A: no adjustment. Child-Pugh Class B: reduce dose by 50%. Child-Pugh Class C: avoid use due to risk of hepatic encephalopathy. |
| Pediatric use | Children ≥2 years: 0.5-1 mg/kg IM or IV every 6-8 hours (max 25 mg/dose); or 0.5-1 mg/kg PO every 6-8 hours (max 25 mg/dose). For sedation: 0.5-1 mg/kg PO/IM/IV (max 25 mg). For motion sickness: 0.5 mg/kg PO 1 hour before travel, repeat in 12 hours. |
| Geriatric use | Avoid use in elderly patients ≥65 years due to increased risk of sedation, confusion, falls, and anticholinergic effects (Beers Criteria). If necessary, use lowest effective dose, e.g., 6.25-12.5 mg PO/IM/IV every 6 hours. |
| 1st trimester | Limited data; no evidence of major malformations; avoid in near term due to possible association with respiratory depression in neonates. |
| 2nd trimester | Use only if clearly needed; no specific safety data. |
| 3rd trimester | Avoid in late pregnancy (last 2 weeks) due to risk of respiratory depression, sedation, and withdrawal symptoms in the neonate. |
Clinical note
CNS depressants may enhance sedative effects Can cause respiratory depression in children and extrapyramidal symptoms.
| FDA category | Animal |
| Placental transfer | Promethazine crosses the placenta; fetal serum levels approximate maternal levels within 1-2 hours of administration. |
| Breastfeeding |
■ FDA Black Box Warning
Promethazine is contraindicated for use in pediatric patients younger than 2 years because of the risk of respiratory depression, which may be fatal. Use in children 2 years and older should be with caution and at the lowest effective dose. Promethazine should not be administered via intra-arterial injection due to risk of severe arteriospasm and gangrene.
| Common Effects | nausea/vomiting |
| Serious Effects | Respiratory depression (especially in children and with high doses), Severe tissue injury (including gangrene) with intravenous administration due to perivascular extravasation, Neuroleptic malignant syndrome (rare), Cholestatic jaundice, Agranulocytosis, Seizures, Extrapyramidal symptoms (dystonia, akathisia, parkinsonism), QT prolongation and torsades de pointes (rare) |
Comatose statesSevere CNS depressionUse in children <2 years (risk of respiratory depression)Concurrent use of MAOIsKnown hypersensitivity to phenothiazines
| Precautions | Respiratory depression: Use with caution in patients with respiratory impairment (e.g., COPD, sleep apnea) and avoid in children <2 years., CNS depression: May impair mental/physical abilities; avoid concurrent use with alcohol or other CNS depressants., Extrapyramidal symptoms: Rare but possible, especially with high doses or prolonged use., Neuroleptic malignant syndrome: Potentially fatal reaction characterized by hyperthermia, muscle rigidity, altered mental status., Photosensitivity: Avoid excessive sun exposure., Lowered seizure threshold: Use caution in patients with epilepsy or seizure disorders. |
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| Promethazine is excreted into breast milk in small amounts; may cause drowsiness, irritability, or poor feeding in the infant. The American Academy of Pediatrics considers it compatible with breastfeeding but caution is advised, especially in high doses or prolonged use. |
| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | FDA Pregnancy Category C. First trimester: Limited data; potential risk of congenital malformations (e.g., limb defects) based on animal studies and rare case reports. Second and third trimesters: No evidence of increased major malformations; may cause respiratory depression or extrapyramidal symptoms in neonates if used near term. Avoid during labor due to potential maternal hypotension and fetal distress. |
| Fetal Monitoring | Maternal: Blood pressure, heart rate, and sedation level; monitor for hypotension and anticholinergic effects (dry mouth, blurred vision). Fetal: Heart rate monitoring during labor if used; assess for signs of respiratory depression or extrapyramidal reactions in neonate after delivery. |
| Fertility Effects | No direct evidence of impaired fertility in humans. Animal studies show no adverse effects on fertility at therapeutic doses. Theoretical risk due to prolactin elevation (antidopaminergic effect), which may disrupt ovulation and menstrual cycles; clinical significance unclear. |
| Food/Dietary | Avoid grapefruit juice as it may increase promethazine absorption and risk of side effects. Food does not significantly affect absorption, but taking with food can reduce gastrointestinal upset. |
| Clinical Pearls | Promethazine is a phenothiazine derivative with strong antihistamine (H1) and antiemetic properties, but its use is limited by anticholinergic side effects and sedation. It is not recommended for children under 2 years due to risk of respiratory depression. Administer deep intramuscular injection to avoid tissue necrosis; intravenous administration is contraindicated due to risk of severe tissue damage. May cause QT prolongation; use with caution in patients with cardiac disease or electrolyte abnormalities. Extrapyramidal symptoms, including tardive dyskinesia, can occur with prolonged use. Avoid in patients with narrow-angle glaucoma, prostatic hypertrophy, or urinary retention. |
| Patient Advice | Avoid alcohol and other CNS depressants as they increase sedation and dizziness. · Do not drive or operate heavy machinery until you know how this medication affects you. · Take with food or milk if gastrointestinal upset occurs. · Notify your doctor if you experience vision changes, difficulty urinating, or muscle stiffness. · This medication may cause photosensitivity; use sunscreen and avoid prolonged sun exposure. · Do not exceed recommended dose; overdose can cause serious side effects. · Store at room temperature away from light and moisture. · If you miss a dose, take it as soon as you remember unless it is almost time for your next dose; do not double the dose. |