PHENERGAN W/ CODEINE
Clinical safety rating: avoid
CNS depressants including alcohol and benzodiazepines increase sedation risk Life-threatening respiratory depression may occur especially in CYP2D6 ultra-rapid metabolizers.
Promethazine is a phenothiazine derivative with H1 receptor antagonist activity, antiemetic, and sedative properties. Codeine is an opioid agonist that binds to mu-opioid receptors in the CNS, inhibiting pain transmission and causing cough suppression.
| Metabolism | Promethazine is metabolized primarily in the liver by CYP2D6 and to a lesser extent by other CYP enzymes. Codeine is metabolized by CYP2D6 to morphine (active) and by CYP3A4 to norcodeine. |
| Excretion | Renal: 70% (codeine as unchanged and metabolites, ~10% as morphine-3-glucuronide, <10% as morphine); biliary/fecal: 30% (promethazine as sulfoxides and glucuronides). |
| Half-life | Promethazine: 9-16 h; codeine: 3.5 h (terminal), prolonged in renal impairment (up to 18 h). |
| Protein binding | Promethazine: 93% bound (primarily albumin); codeine: 7-25% bound (plasma proteins, mainly albumin). |
| Volume of Distribution | Promethazine: 9-22 L/kg (extensive tissue distribution); codeine: 3-6 L/kg (high tissue affinity). |
| Bioavailability | Oral: promethazine 25-30% (due to first-pass metabolism); codeine 50-90% (mean ~60%). |
| Onset of Action | Oral: 30-60 min (antitussive); IM/IV: 5-15 min (antihistaminic effect). |
| Duration of Action | Promethazine: 4-12 h; codeine: 4-6 h. With extended release: up to 12 h. |
10 mL (containing promethazine 6.25 mg and codeine 10 mg) orally every 4 to 6 hours, not to exceed 60 mL (codeine 60 mg) per day.
| Dosage form | SYRUP |
| Renal impairment | GFR 30-60 mL/min: Administer 75% of normal dose. GFR 10-29 mL/min: Administer 50% of normal dose. GFR <10 mL/min: Administer 25% of normal dose. Monitor for respiratory depression and sedation. |
| Liver impairment | Child-Pugh Class A: No adjustment necessary. Child-Pugh Class B: Reduce dose by 50% and monitor. Child-Pugh Class C: Avoid use; consider alternative therapy. |
| Pediatric use | Children ≥6 years: 5 mL (promethazine 3.125 mg and codeine 5 mg) orally every 4-6 hours as needed. Maximum daily dose: 30 mL (codeine 30 mg). Not recommended for children <6 years due to risk of respiratory depression. |
| Geriatric use | Initiate at 5 mL (promethazine 3.125 mg and codeine 5 mg) orally every 6 hours. Avoid doses >30 mL/day due to increased risk of respiratory depression, sedation, and falls. Consider alternative therapies. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
CNS depressants including alcohol and benzodiazepines increase sedation risk Life-threatening respiratory depression may occur especially in CYP2D6 ultra-rapid metabolizers.
| FDA category | Positive |
| Breastfeeding | Codeine excreted into breast milk; M/P ratio approximately 1.25 (morphine, active metabolite). Avoid in breastfeeding mothers with CYP2D6 ultra-rapid metabolism due to risk of neonatal CNS depression. Promethazine may reduce milk production. Use caution; monitor infant for sedation, poor feeding, respiratory depression. |
| Teratogenic Risk |
■ FDA Black Box Warning
Respiratory depression in children; contraindicated in children <6 years. Risk of death in children <12 years. Concomitant use with CYP3A4 inducers/inhibitors may alter opioid metabolism. Post-operative respiratory depression in children following tonsillectomy/adenoidectomy.
| Common Effects | cough |
| Serious Effects |
Hypersensitivity to promethazine, codeine, or any component; children <6 years; significant respiratory depression; acute or severe bronchial asthma; GI obstruction; concurrent MAO inhibitors; known CYP2D6 ultra-rapid metabolizers; post-operative pain in children after tonsillectomy/adenoidectomy.
| Precautions | Respiratory depression; CNS depression; abuse potential; risk of oversedation; serotonin syndrome with serotonergic drugs; severe hypotension; QT prolongation; increased risk of seizures; avoid in patients with compromised respiratory function; not recommended in breastfeeding; avoid abrupt discontinuation. |
Loading safety data…
| First trimester: Avoid unless benefit outweighs risk. Codeine associated with congenital malformations (cleft palate, neural tube defects) at high doses; promethazine associated with limb defects in some studies. Second/third trimester: Chronic use may cause neonatal opioid withdrawal syndrome, respiratory depression. Avoid near term due to risk of maternal respiratory depression and neonatal apnea. |
| Fetal Monitoring | Monitor maternal respiratory rate, sedation level, bowel function. Fetal monitoring for growth restriction if chronic use. Neonatal monitoring for withdrawal symptoms (irritability, poor feeding, respiratory depression) if used near term. Assess CYP2D6 genotype before prescribing if possible. |
| Fertility Effects | No direct evidence of fertility impairment. Promethazine may increase prolactin levels, potentially affecting ovulation. Codeine may affect gonadotropin secretion in high doses. Use with caution in patients planning pregnancy. |