PROMETHAZINE HYDROCHLORIDE AND DEXTROMETHORPHAN HYDROBROMIDE
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, antiemetic, and sedative. Dextromethorphan is a cough suppressant that acts as an NMDA receptor antagonist and sigma-1 receptor agonist.
| Metabolism | Promethazine is extensively metabolized in the liver via oxidation and conjugation, with CYP2D6 playing a role. Dextromethorphan is metabolized by CYP2D6 to dextrorphan, an active metabolite. |
| Excretion | Promethazine: primarily hepatic metabolism, renal excretion of metabolites (~70%, <1% unchanged); fecal excretion (20-30%). Dextromethorphan: hepatic metabolism, renal excretion of metabolites and <1% unchanged drug. |
| Half-life | Promethazine: 10-19 hours (mean 12 hours). Dextromethorphan: extensive metabolizers (CYP2D6) 3-5 hours; poor metabolizers 20-30 hours. Clinical context: accumulation with repeated dosing, especially in poor metabolizers. |
| Protein binding | Promethazine: ~93% bound to albumin. Dextromethorphan: ~60-70% bound to albumin. |
| Volume of Distribution | Promethazine: 14-18 L/kg (large Vd indicating extensive tissue distribution). Dextromethorphan: 5-10 L/kg (moderate to large Vd). |
| Bioavailability | Oral: Promethazine ~25% (first-pass metabolism). Dextromethorphan: ~11% (extensive first-pass; CYP2D6-dependent variability). |
| Onset of Action | Oral: 20-30 minutes (dextromethorphan antitussive effect within 15-30 min; promethazine sedative effect within 20 min). |
| Duration of Action | Promethazine: 4-12 hours (antihistaminic/sedative). Dextromethorphan: 4-6 hours (antitussive). Note: sedative effects may outlast antitussive effects. |
| Molecular Weight | 284.42 |
| Action Class | Antihistamine / Antiemetic / Antitussive |
For cough and upper respiratory symptoms: 5 mL (containing promethazine hydrochloride 6.25 mg and dextromethorphan hydrobromide 15 mg) orally every 4 to 6 hours, not to exceed 30 mL in 24 hours.
| Dosage form | SYRUP |
| Renal impairment | No specific guidelines; use with caution in renal impairment. Dextromethorphan active metabolite accumulation may occur; consider reducing dose or extending interval when GFR < 30 mL/min. |
| Liver impairment | Contraindicated in severe hepatic impairment (Child-Pugh class C). In moderate impairment (Child-Pugh class B), reduce dose or extend interval; avoid use if possible due to risk of promethazine accumulation and CNS depression. |
| Pediatric use | Children ≥6 years: 2.5 to 5 mL (promethazine 3.125-6.25 mg / dextromethorphan 7.5-15 mg) orally every 4 to 6 hours; not to exceed 20 mL in 24 hours. Not recommended for children <6 years due to risk of respiratory depression and side effects. |
| Geriatric use | Elderly patients are more sensitive to anticholinergic effects, hypotension, and sedation. Use lowest effective dose and monitor closely. Avoid in patients with dementia or cognitive impairment. |
| 1st trimester | Risk cannot be ruled out. Adequate studies in pregnant women are lacking. Use only if potential benefit justifies potential risk to fetus. |
| 2nd trimester | Risk cannot be ruled out. Similar caution as first trimester. Limited data available. |
| 3rd trimester | Risk cannot be ruled out; may cause respiratory depression or withdrawal symptoms in neonates if used near term. Avoid close to delivery. |
Clinical note
CNS depressants may enhance sedative effects Can cause respiratory depression in children and extrapyramidal symptoms.
| FDA category | Animal |
| Placental transfer | Promethazine crosses placenta; dextromethorphan likely crosses placenta but limited human data. |
| Breastfeeding |
■ FDA Black Box Warning
Do not use in children younger than 2 years due to risk of respiratory depression and death. Use in children 2 years and older with caution. Also, promethazine should not be used in patients with known hypersensitivity to phenothiazines.
| Common Effects | nausea/vomiting |
| Serious Effects | Respiratory depression (especially in children and with overdose), Severe CNS depression (drowsiness, sedation, coma), Extrapyramidal symptoms (dystonia, akathisia, tardive dyskinesia), Neuroleptic malignant syndrome (hyperthermia, rigidity, autonomic instability), Seizures, Serotonin syndrome (when combined with serotonergic drugs), Cardiac arrhythmias (QT prolongation, torsades de pointes), Severe hypotension or hypertension, Agranulocytosis, leukopenia, thrombocytopenia, Cholestatic jaundice, hepatitis, Anaphylaxis, angioedema, Photosensitivity, severe skin reactions (Stevens-Johnson syndrome) |
Hypersensitivity to promethazine, dextromethorphan, or any componentComatose statesLower respiratory tract symptoms (e.g., asthma, COPD)Use of MAO inhibitors within 14 daysPatients receiving opioids in large doses or with acute alcoholism
| Precautions |
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| Excreted in breast milk in low levels; potential for sedation or respiratory depression in infant. Use caution, especially in neonates or preterm infants. |
| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | Pregnancy category C. First trimester: Promethazine has been associated with respiratory depression in neonates if used near term; dextromethorphan has shown minimal risk in animal studies, but human data are limited. Third trimester: Use near delivery may cause extrapyramidal symptoms and respiratory depression in the newborn. Avoid during labor. |
| Fetal Monitoring | Monitor maternal CNS depression and respiratory status. Fetal monitoring recommended if used near term due to risk of neonatal respiratory depression. Assess neonatal Apgar scores and observe for extrapyramidal symptoms. |
| Fertility Effects | Promethazine may inhibit ovulation and impair fertility due to anticholinergic effects. Dextromethorphan has no known significant effect on fertility based on animal studies. |
| Respiratory depression (especially in children), CNS depression, anticholinergic effects, extrapyramidal reactions, neuroleptic malignant syndrome (rare), bone marrow suppression (agranulocytosis), photosensitivity, and potential for abuse (dextromethorphan). Avoid alcohol and other CNS depressants. |
| Food/Dietary | Grapefruit juice may increase dextromethorphan levels; avoid concurrent consumption. Alcohol enhances CNS depression and sedation; avoid alcoholic beverages. Tyramine-containing foods (aged cheese, cured meats) may cause hypertensive crisis if used with MAOIs (contraindicated). |
| Clinical Pearls | Promethazine + dextromethorphan combines an antihistamine with antitussive properties. Promethazine is a phenothiazine with strong sedative and anticholinergic effects; monitor for respiratory depression in children under 2 years (black box warning). Dextromethorphan is a NMDA antagonist; doses >30 mg may cause dissociative effects. Avoid use with MAOIs or SSRIs due to serotonin syndrome risk. Promethazine can cause QT prolongation; caution with other QT-prolonging agents. Use lowest effective dose for shortest duration; not for chronic cough. |
| Patient Advice | Drowsiness is very common; avoid driving or operating machinery. · Do not use with alcohol or other CNS depressants. · Do not exceed recommended dose; high doses of dextromethorphan can cause hallucinations or dissociation. · Seek medical attention if cough persists >7 days or is accompanied by fever, rash, or headache. · Use caution in elderly due to increased risk of dizziness, sedation, and anticholinergic effects. · Do not use in children under 6 years of age. |