PROMETHAZINE W/ DEXTROMETHORPHAN
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 and antiemetic; dextromethorphan is a non-opioid antitussive that acts as an NMDA receptor antagonist and sigma-1 receptor agonist.
| Metabolism | Promethazine is metabolized in the liver via CYP2D6; dextromethorphan is metabolized via CYP2D6 to active metabolite dextrorphan. |
| Excretion | Renal: promethazine ~6% unchanged, dextromethorphan ~0.5% unchanged; metabolites primarily renal. Biliary/fecal: minor routes for both. |
| Half-life | Promethazine: 9-16 h; dextromethorphan: 3-5 h (extensive metabolizers), 30-50 h (poor metabolizers). Clinical context: dosing interval typically 4-6 h for dextromethorphan; promethazine accumulates with repeated dosing. |
| Protein binding | Promethazine: 88-93% bound to albumin; dextromethorphan: 60-70% bound to albumin and alpha1-acid glycoprotein. |
| Volume of Distribution | Promethazine: Vd 12-18 L/kg (large, extensive tissue distribution); dextromethorphan: Vd 5-7 L/kg (moderate). |
| Bioavailability | Promethazine: oral ~25% (extensive first-pass metabolism), rectal ~25%; dextromethorphan: oral 50-70% (extensive first-pass metabolism). |
| Onset of Action | Oral: promethazine 20-30 min, dextromethorphan 30-60 min. Rectal: promethazine similar. |
| Duration of Action | Promethazine: 6-12 h; dextromethorphan: 5-6 h. Clinical notes: promethazine may cause prolonged sedation; dextromethorphan effects last 5-6 h. |
| Molecular Weight | 284.4 |
| Action Class | Antihistamine / Antiemetic / Antitussive |
5 mL (containing promethazine 6.25 mg and dextromethorphan 15 mg) orally every 4-6 hours as needed, not to exceed 30 mL (promethazine 37.5 mg, dextromethorphan 90 mg) per 24 hours.
| Dosage form | SYRUP |
| Renal impairment | GFR 30-50 mL/min: No adjustment needed. GFR 10-29 mL/min: Use with caution; reduce dose by 50% or extend interval. GFR <10 mL/min: Avoid use due to risk of accumulation of dextromethorphan metabolites. |
| Liver impairment | Child-Pugh Class A (mild): No adjustment. Child-Pugh Class B (moderate): Reduce dose by 50% or extend interval. Child-Pugh Class C (severe): Avoid use due to reduced clearance of both components. |
| Pediatric use | Children 12 years and older: 5 mL (promethazine 6.25 mg/dextromethorphan 15 mg) orally every 4-6 hours, not to exceed 30 mL in 24 hours. Children 6 to under 12 years: 2.5 mL (promethazine 3.125 mg/dextromethorphan 7.5 mg) orally every 4-6 hours, not to exceed 15 mL in 24 hours. Children under 6 years: Not recommended due to risk of respiratory depression. |
| Geriatric use | Use with caution; initiate at the lower end of the dosing range (e.g., 2.5-5 mL every 6 hours) due to increased sensitivity and risk of anticholinergic effects, sedation, and falls. Avoid in patients with significant cognitive impairment or increased fall risk. |
| 1st trimester | Avoid due to possible teratogenic effects; dextromethorphan associated with neural tube defects in animal studies. |
| 2nd trimester | Use only if clearly needed; limited human data but risk cannot be excluded. |
| 3rd trimester | Avoid near term; promethazine may cause respiratory depression and extrapyramidal symptoms in neonate; dextromethorphan may cause withdrawal. |
Clinical note
CNS depressants may enhance sedative effects Can cause respiratory depression in children and extrapyramidal symptoms.
| FDA category | Animal |
| Placental transfer | Both drugs cross placenta; promethazine has documented transfer with fetal levels approximately 50% of maternal; dextromethorphan transfer is likely but not well quantified. |
| Breastfeeding |
■ FDA Black Box Warning
Do not use in children younger than 6 years due to risk of respiratory depression and death; avoid use in children <2 years.
| Common Effects | nausea/vomiting |
| Serious Effects | Respiratory depression (especially in children and with CYP2D6 poor metabolizers), Neuroleptic malignant syndrome, Severe hypotension, Seizures, Extrapyramidal symptoms (dystonia, akathisia, tardive dyskinesia), Agranulocytosis, Cholestatic jaundice, Serotonin syndrome (with concurrent serotonergic drugs) |
Hypersensitivity to promethazine or dextromethorphanComatose statesRespiratory depressionMAOI therapy (current or within 14 days)Children <2 years for promethazine (risk of respiratory depression)
| Precautions | Respiratory depression (especially in children and elderly), CNS depression, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome (rare), photosensitivity, impaired cognitive/motor function. |
Loading safety data…
| Promethazine is excreted into breast milk; may cause drowsiness or irritability in infant. Dextromethorphan is excreted in low amounts; monitor for sedation. Use with caution; alternatives preferred. |
| Lactation Rating | L3 - Moderately Safe |
| Teratogenic Risk | FDA Pregnancy Category C. First trimester: Limited data; animal studies with promethazine show skeletal abnormalities at high doses; dextromethorphan not clearly teratogenic but weak association with neural tube defects in some studies. Second and third trimesters: No known specific malformations; avoid near term due to risk of neonatal respiratory depression and extrapyramidal effects from promethazine. |
| Fetal Monitoring | Monitor maternal blood pressure, heart rate, and respiratory status; assess for excessive sedation or extrapyramidal symptoms. Fetal monitoring: heart rate and movement patterns; ultrasound for growth if used chronically. Near term: monitor newborn for respiratory depression, hypotonia, and poor feeding. |
| Fertility Effects | Promethazine may elevate prolactin levels, potentially causing galactorrhea, menstrual irregularities, and reversible ovulation suppression. Dextromethorphan has no known direct effect on fertility. Limited data on combination; consider potential endocrine disruption. |
| Food/Dietary |
| Grapefruit and grapefruit juice may increase serum levels of dextromethorphan; avoid concurrent consumption. Alcohol potentiates CNS depression and should be avoided. Tyramine-rich foods may theoretically interact with promethazine in susceptible individuals; however, significant interactions are not well documented. |
| Clinical Pearls | Promethazine has strong anticholinergic effects and can cause sedation; use with caution in elderly due to risk of confusion, falls, and anticholinergic toxicity. Dextromethorphan at supratherapeutic doses can produce dissociative effects similar to ketamine; monitor for abuse potential. Do not use in children <2 years due to risk of respiratory depression. Avoid co-administration with MAOIs or within 14 days. Promethazine is contraindicated in patients with known G6PD deficiency due to risk of hemolytic anemia. |
| Patient Advice | This medication may cause drowsiness; avoid driving or operating machinery until you know how it affects you. · Do not exceed recommended dose; taking more can lead to serious side effects including hallucinations and respiratory depression. · Avoid alcohol and other sedatives while taking this medication as they increase sedation and respiratory depressant effects. · Do not use if you are taking or have recently taken monoamine oxidase inhibitors (MAOIs) like phenelzine or selegiline. · If you are pregnant, planning to become pregnant, or breastfeeding, consult your healthcare provider before using. · Do not give to children under 2 years of age due to risk of severe respiratory depression. |