PROMETHAZINE HYDROCHLORIDE
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 histamine H1 receptor antagonist, blocking the effects of histamine at H1 receptors. It also has anticholinergic, antiemetic, sedative, and antidopaminergic properties.
| Metabolism | Primarily hepatic metabolism via CYP2D6 to promethazine sulfoxide and other metabolites; also undergoes S-oxidation and N-demethylation. |
| Excretion | Primarily hepatic metabolism; renal excretion of metabolites accounts for <1% of unchanged drug; biliary/fecal excretion of metabolites ~70-80%. |
| Half-life | Terminal elimination half-life is 10-19 hours in adults; prolonged in hepatic impairment (up to 30+ hours) and in elderly. |
| Protein binding | 93% bound primarily to albumin. |
| Volume of Distribution | 9-16 L/kg; indicates extensive tissue distribution and accumulation in tissues. |
| Bioavailability | Oral: ~25% due to first-pass metabolism; IM: ~70-80%; IV: 100%; rectal: ~25-30%. |
| Onset of Action | Oral: 20-30 minutes; IM: 15-20 minutes; IV: 3-5 minutes; rectal: 30-60 minutes. |
| Duration of Action | 5-6 hours for oral/IM/rectal; 4-6 hours for IV; clinical effects may persist longer due to active metabolites. |
| Molecular Weight | 320.88 |
| Action Class | Antihistamine (first-generation) / Antiemetic / Phenothiazine |
25-50 mg intramuscular or intravenous injection every 4-6 hours as needed; also 12.5-25 mg orally every 4-6 hours.
| Dosage form | TABLET |
| Renal impairment | No specific dose adjustment recommended; use with caution in severe renal impairment (CrCl <10 mL/min) due to risk of accumulation. |
| Liver impairment | Child-Pugh Class A: no adjustment; Class B: reduce dose by 50%; Class C: avoid use or reduce dose by 75%. |
| Pediatric use | 2-6 years: 5-6.25 mg orally every 4-6 hours; 6-12 years: 6.25-12.5 mg orally every 4-6 hours; >12 years: as adult; intramuscular: 0.25-0.5 mg/kg every 4-6 hours. |
| Geriatric use | Start at lowest effective dose (e.g., 12.5 mg orally or 12.5-25 mg IM/IV); increase cautiously due to increased risk of sedation, confusion, and anticholinergic effects. |
| 1st trimester | Limited human data; animal studies not conducted; potential risk of congenital malformations (retrospective studies suggest possible association with limb reduction defects, but data are conflicting). Use only if clearly needed. |
| 2nd trimester | Use with caution; may cause transient neonatal depression if used near term. No specific second trimester concerns beyond general maternal benefit-risk. |
| 3rd trimester | Avoid near term (last 2 weeks) due to potential for respiratory depression, irritability, and paradoxical CNS stimulation in neonates. May prolong labor if used as antiemetic. |
Clinical note
CNS depressants may enhance sedative effects Can cause respiratory depression in children and extrapyramidal symptoms.
| FDA category | Animal |
| Placental transfer | Crosses placenta; fetal blood concentrations approximate maternal levels. Documented placental transfer in humans via umbilical cord blood samples. |
■ FDA Black Box Warning
Promethazine is contraindicated in children less than 2 years of age due to risk of fatal respiratory depression. Use in children 2 years and older should be avoided with other respiratory depressants.
| Common Effects | nausea/vomiting |
| Serious Effects | Respiratory depression (especially in children and with high doses), Severe sedation and impaired cognitive/motor function, Extrapyramidal symptoms (dystonia, akathisia, tardive dyskinesia), Neuroleptic malignant syndrome (rare), Cholestatic jaundice and hepatic injury, Agranulocytosis and leukopenia, Seizures (especially in patients with epilepsy or with high doses), QT prolongation and cardiac arrhythmias (torsades de pointes), Hypotension and orthostatic hypotension, Photosensitivity and skin reactions |
Comatose statesCNS depression from alcohol or other depressantsKnown hypersensitivity to promethazine or phenothiazinesUse in children <2 years of age (risk of respiratory depression, including fatalities)Intra-arterial or subcutaneous administration (risk of severe tissue injury/necrosis)
| Precautions |
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| Breastfeeding | Excreted into breast milk in small amounts; manufacturer recommends caution. Peak milk concentration occurs 2-3 hours after dose. Monitor infant for drowsiness, irritability, or feeding difficulties. Consider alternative agents if prolonged therapy needed. |
| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | First trimester: Limited human data, no increased risk of major malformations from population-based studies. Second and third trimesters: Use associated with transient neonatal extrapyramidal signs, sedation, withdrawal symptoms if used near term. May inhibit neonatal platelet aggregation. |
| Fetal Monitoring | Monitor maternal blood pressure for hypotension, fetal heart rate variability if used in labor, neonatal respiratory depression and extrapyramidal symptoms after delivery. |
| Fertility Effects | No specific studies; animal studies show some anti-fertility effects at high doses, but human relevance unknown. |
| Risk of respiratory depression, especially in children, CNS depression; avoid with alcohol or other sedatives, May cause bone marrow suppression, agranulocytosis, Anticholinergic effects (e.g., urinary retention, blurred vision), Extrapyramidal reactions, tardive dyskinesia, Neuroleptic malignant syndrome (rare), May elevate prolactin levels, Interference with pregnancy test |
| Food/Dietary | Avoid alcohol and CNS depressants. No significant food interactions; may be taken with food if gastric upset occurs. Grapefruit juice may increase systemic exposure? (Not well established; consider monitoring for increased sedation). |
| Clinical Pearls | Promethazine hydrochloride is a phenothiazine derivative with strong antihistaminic, antiemetic, sedative, and anticholinergic properties. It is contraindicated in children under 2 years due to risk of fatal respiratory depression. Avoid intra-arterial or subcutaneous administration due to risk of tissue necrosis. Use with caution in patients with asthma, COPD, sleep apnea, myasthenia gravis, and prostate hypertrophy. May cause QT prolongation; monitor ECG in at-risk patients. For severe extravasation, treat with phentolamine. Can interfere with urine glucose tests and pregnancy tests. |
| Patient Advice | Do not use in children under 2 years old; use with caution in children over 2. · May cause severe drowsiness; do not drive or operate heavy machinery. · Avoid alcohol and other CNS depressants. · Report any muscle stiffness, tremor, or involuntary movements. · If using for motion sickness, take at least 30 minutes before travel. · Do not take with other antihistamines or cold medications. · May cause dry mouth; use sugar-free candy or ice chips. · If you have a history of seizures, asthma, or glaucoma, discuss with your doctor. |