PROMETH W/ DEXTROMETHORPHAN
Clinical safety rating: caution
Comprehensive clinical and safety monograph for PROMETH W/ DEXTROMETHORPHAN (PROMETH W/ DEXTROMETHORPHAN).
Promethazine is a phenothiazine derivative that acts as a central H1 receptor antagonist with anticholinergic, antiemetic, and sedative properties. Dextromethorphan is a non-competitive NMDA receptor antagonist and sigma-1 receptor agonist that suppresses cough by acting on the cough center in the medulla oblongata.
| Metabolism | Promethazine is extensively metabolized in the liver via sulfation (primary) and CYP2D6-mediated N-demethylation. Dextromethorphan is metabolized by CYP2D6 to dextrorphan, an active metabolite. |
| Excretion | Promethazine is primarily excreted via renal elimination (70-80% as metabolites, <1% unchanged) and fecal/biliary elimination (20-30%). Dextromethorphan is extensively metabolized; renal excretion accounts for ~45% as dextrorphan and other metabolites, with minimal unchanged drug (<1%). |
| Half-life | Promethazine: terminal elimination half-life 10-14 hours (range 5-30 hours). Clinical context: prolonged half-life in elderly or hepatic impairment; requires dose adjustment in severe liver disease. Dextromethorphan: 3-6 hours for extensive CYP2D6 metabolizers; 24-48 hours in poor metabolizers. |
| Protein binding | Promethazine: 93% bound primarily to albumin. Dextromethorphan: 60-70% bound to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Promethazine: 7-9 L/kg, indicating extensive tissue distribution. Dextromethorphan: 5-7 L/kg, with high tissue binding. Clinical meaning: large Vd suggests poor dialyzability and prolonged washout. |
| Bioavailability | Promethazine: oral 25% (extensive first-pass metabolism), intramuscular 100%, rectal 70-80%. Dextromethorphan: oral 11-60% (dependent on CYP2D6 metabolism), intramuscular not available. |
| Onset of Action | Oral: promethazine 20 minutes, dextromethorphan 15-30 minutes. Intramuscular: 20 minutes. Rectal: 30-60 minutes. |
| Duration of Action | Promethazine: 4-12 hours (antihistamine effects up to 24 hours). Dextromethorphan: 4-6 hours for antitussive effect. Clinical note: sedative effects may last longer than antitussive effects. |
| Molecular Weight | 284.41 |
Adults: 10 mL (containing promethazine 6.25 mg and dextromethorphan 15 mg) orally every 4-6 hours, not to exceed 4 doses (40 mL) in 24 hours.
| Dosage form | SYRUP |
| Renal impairment | GFR ≥ 30 mL/min: no adjustment. GFR < 30 mL/min: avoid use due to risk of CNS depression and accumulation of metabolites. |
| Liver impairment | Child-Pugh A (mild): no adjustment. Child-Pugh B (moderate): reduce dose by 50% or prolong dosing interval. Child-Pugh C (severe): avoid use. |
| Pediatric use | Children 6-11 years: 5 mL (half the adult dose) every 4-6 hours, max 4 doses/24h. Children 2-5 years: 2.5 mL every 4-6 hours, max 4 doses/24h. Not recommended under 2 years due to risk of respiratory depression. |
| Geriatric use | Initiate at lowest effective dose (e.g., 5 mL every 6-8 hours). Monitor for sedation, confusion, and anticholinergic effects. Avoid in elderly with dementia or high fall risk. |
| 1st trimester | Avoid use in first trimester; dextromethorphan has been associated with malformations in animal studies, and promethazine may cause fetal harm. Use only if clearly needed. |
| 2nd trimester | Use with caution; dextromethorphan and promethazine cross placenta. No adequate studies in humans; weigh benefits vs risks. |
| 3rd trimester | Avoid near term; promethazine may cause extrapyramidal effects or respiratory depression in neonates. Dextromethorphan may cause neonatal withdrawal. |
Clinical note
Comprehensive clinical and safety monograph for PROMETH W/ DEXTROMETHORPHAN (PROMETH W/ DEXTROMETHORPHAN).
| Placental transfer | Both drugs cross the placenta; promethazine reaches fetal concentrations similar to maternal, and dextromethorphan is transferred but with limited data. |
| Breastfeeding | Both promethazine and dextromethorphan are excreted in breast milk. Promethazine may cause drowsiness or irritability in infants; dextromethorphan is generally considered compatible, but monitor for sedation. Avoid in breastfeeding mothers of premature or jaundiced infants. |
■ FDA Black Box Warning
Promethazine should not be used in children younger than 2 years of age due to the risk of respiratory depression that can be fatal. Use with caution in children older than 2 years.
| Serious Effects |
Hypersensitivity to promethazine or dextromethorphanComatose statesSevere CNS depressionConcurrent MAOI therapy or within 14 daysChildren less than 2 years of age (due to risk of respiratory depression)Asthma attack or lower respiratory tract symptoms
| Precautions | Respiratory depression, especially in children and elderly, CNS depression and impaired alertness, Anticholinergic effects (e.g., dry mouth, urinary retention), Extrapyramidal symptoms with high doses, Neuroleptic malignant syndrome (rare), Photo-sensitivity, Seizure threshold lowering, Increased risk of hypotension, Hepatic impairment may require dose adjustment |
| Food/Dietary | Avoid grapefruit juice as it may increase dextromethorphan levels. No significant food interactions with promethazine. |
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| Lactation Rating | L3 (Moderately Safe) for dextromethorphan component; promethazine is L4 (Possibly Hazardous) due to potential CNS effects. |
| Teratogenic Risk | First trimester: Limited human data; animal studies with promethazine show no consistent teratogenicity. Dextromethorphan is not teratogenic in animal studies. Second/third trimester: Use of promethazine near term may cause respiratory depression or extrapyramidal symptoms in neonates. Dextromethorphan has minimal fetal risk. Overall, FDA Pregnancy Category C for promethazine; dextromethorphan is Category A (no evidence of risk). |
| Fetal Monitoring | Monitor maternal blood pressure, heart rate, and respiratory status. Assess fetal heart rate and movement if used near term. Observe neonate for signs of respiratory depression, sedation, or extrapyramidal effects if used during labor. |
| Fertility Effects | No specific studies on fertility in humans. Animal studies with promethazine have shown no impairment of fertility. Dextromethorphan has no known effects on fertility. |
| Clinical Pearls | Promethazine (a phenothiazine antiemetic/antihistamine) combined with dextromethorphan (an NMDA receptor antagonist/antitussive) is used for cough and cold symptoms. Promethazine can cause respiratory depression, especially in children, and is contraindicated under age 2. Dextromethorphan at high doses can cause dissociative effects; avoid concurrent use with MAOIs or serotonergic drugs. This combination has significant anticholinergic effects (dry mouth, urinary retention, constipation). Use cautiously in patients with asthma, COPD, or sleep apnea due to respiratory depression risk. |
| Patient Advice | Do not use in children younger than 2 years due to risk of serious breathing problems. · May cause drowsiness or dizziness; avoid driving or operating heavy machinery until you know how you react. · Avoid alcohol and other CNS depressants (e.g., benzodiazepines, opioids) as they increase sedation and respiratory depression risk. · Do not take with MAO inhibitors or within 14 days of stopping them. · Increase fluid intake to help loosen mucus. · Stop use and seek medical attention if cough persists > 1 week, is accompanied by fever or rash, or if excessive sedation occurs. |