PROMETHAZINE HYDROCHLORIDE,PHENYLEPHRINE HYDROCHLORIDE W/CODEINE PHOSPHATE
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, sedative, and antiemetic via central dopamine D2 and muscarinic M1 receptor blockade. Phenylephrine is a sympathomimetic amine that acts as a selective α1-adrenergic receptor agonist, causing vasoconstriction. Codeine is an opioid agonist at mu-opioid receptors, producing analgesia and antitussive effects, partly after O-demethylation to morphine.
| Metabolism | Promethazine: Hepatic via CYP2D6, glucuronidation, and N-demethylation. Phenylephrine: Primarily hepatic via MAO-A (oxidative deamination) and sulfation (SULT1A3). Codeine: Hepatic via CYP2D6 (O-demethylation to morphine), CYP3A4 (N-demethylation to norcodeine), and glucuronidation. |
| Excretion | Promethazine: ~70% renal as metabolites, minor biliary/fecal. Phenylephrine: ~86-96% renal as metabolites (sulfate and glucuronide conjugates). Codeine: ~90% renal, primarily as morphine and norcodeine conjugates; 5-10% unchanged. Fecal excretion minimal. |
| Half-life | Promethazine: 9-16 h (adults); prolonged in hepatic impairment. Phenylephrine: 2-3 h (oral); 5-10 min (IV due to rapid redistribution). Codeine: 2.5-3.5 h; active metabolites (morphine) 2-3 h. |
| Protein binding | Promethazine: 85-93% bound (albumin). Phenylephrine: 95% bound (albumin). Codeine: 7-25% bound (primarily alpha1-acid glycoprotein). |
| Volume of Distribution | Promethazine: 9-12 L/kg (extensive tissue distribution). Phenylephrine: 0.3-0.6 L/kg (due to polar nature). Codeine: 3.5-6 L/kg (wide distribution). |
| Bioavailability | Promethazine: oral ~25% (high first-pass); IM ~88-100%; rectal ~70%. Phenylephrine: oral ~38% (gut wall and hepatic metabolism); IM/SC ~100%. Codeine: oral ~90% (minimal first-pass); IM ~100%. |
| Onset of Action | Oral: Promethazine 20 min; Phenylephrine 15-30 min; Codeine 30-45 min. IM: Promethazine 10-15 min. Rectal: Promethazine 20 min. IV (codeine not typically IV): immediate. |
| Duration of Action | Promethazine: 4-12 h (dose-dependent; sedation up to 12 h). Phenylephrine: 4-6 h (oral); IM/SC 1-2 h. Codeine: 4-6 h (analgesia); antitussive 4-6 h. |
Each 5 mL of oral solution contains promethazine hydrochloride 6.25 mg, phenylephrine hydrochloride 5 mg, and codeine phosphate 10 mg. Adult dose: 5 mL every 4 to 6 hours as needed. Maximum 30 mL per day.
| Dosage form | SYRUP |
| Renal impairment | GFR 10-50 mL/min: administer every 6 hours. GFR <10 mL/min: administer every 8-12 hours. Codeine accumulation risk: consider alternative. |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B: reduce dose by 50% or extend interval. Child-Pugh C: contraindicated due to risk of codeine toxicity and promethazine accumulation. |
| Pediatric use | Children ≥6 years: 2.5-5 mL every 4-6 hours (based on codeine 0.5-1 mg/kg/dose). Maximum 6 doses per day. Note: codeine contraindicated in children <12 years for post-tonsillectomy/adenoidectomy and in any child <18 years with breathing problems. |
| Geriatric use | Start at 2.5 mL every 6 hours. Increase cautiously. Monitor for anticholinergic effects (confusion, sedation, constipation) and respiratory depression. Consider avoiding in patients with hepatic impairment or prolonged QT interval. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
CNS depressants may enhance sedative effects Can cause respiratory depression in children and extrapyramidal symptoms.
| FDA category | Animal |
| Breastfeeding | Codeine is excreted in breast milk; risk of infant opioid toxicity; promethazine may cause drowsiness; phenylephrine is poorly excreted. M/P ratio not well established. Avoid due to potential CNS depression in infant. |
| Teratogenic Risk | Phenylephrine may cause fetal hypoxia due to vasoconstriction; codeine is associated with neural tube defects and respiratory depression at high doses; promethazine is not teratogenic in animal studies but may cause neonatal respiratory depression if used near term. First trimester: Avoid codeine due to risk of congenital malformations. Second trimester: Use only if benefit outweighs risk; phenylephrine may reduce uteroplacental blood flow. Third trimester: Codeine may cause neonatal respiratory depression and withdrawal; promethazine may cause extrapyramidal signs in neonate. |
■ FDA Black Box Warning
Codeine: Risk of respiratory depression, especially in children; not recommended for use in children under 12 years or post-tonsillectomy/adenoidectomy. Promethazine: Severe respiratory depression, including death, in children <2 years; contraindicated in this age group.
| Common Effects | nausea/vomiting |
| Serious Effects |
Absolute: Hypersensitivity to any component; children <2 years (promethazine); <12 years for codeine (unless risk-benefit considered); post-operative pain in children <18 undergoing tonsillectomy/adenoidectomy; severe hypertension or coronary artery disease (phenylephrine); concurrent MAOI therapy or within 14 days; asthma or respiratory depression (codeine); acute narrow-angle glaucoma (promethazine). Relative: Benign prostatic hyperplasia; urinary retention; pyloroduodenal obstruction; hepatic or renal impairment; breastfeeding (codeine passes into milk); seizure disorders; elderly patients (increased sensitivity).
| Precautions | Respiratory depression: Use caution in patients with COPD, sleep apnea, or other respiratory conditions. CNS depression: Additive effects with alcohol, sedatives, or other CNS depressants. Anticholinergic effects: Risk of urinary retention, blurred vision, constipation. Cardiovascular effects: Phenylephrine may cause hypertension, bradycardia, or arrhythmias; avoid in severe hypertension or coronary artery disease. Serotonin syndrome: Caution with MAOIs or other serotonergic drugs. Hepatotoxicity: Rare but reported with promethazine. Tardive dyskinesia: With prolonged promethazine use. |
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| Fetal Monitoring | Monitor maternal blood pressure, heart rate, and respiratory status; fetal heart rate monitoring for signs of distress; assess neonatal respiratory function and withdrawal symptoms after delivery; watch for extrapyramidal signs in neonate if promethazine used near term. |
| Fertility Effects | No specific studies; codeine may affect ovulation via prolactin elevation; phenylephrine and promethazine unknown; use may impair fertility due to effects on hormonal regulation. |