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. |
| Molecular Weight | 448.02 |
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 | Avoid; risk of congenital malformations (cleft palate, cardiac defects) and first-trimester abortion. |
| 2nd trimester | Avoid; not recommended due to potential fetal respiratory depression and other adverse effects. |
| 3rd trimester | Avoid; risk of neonatal respiratory depression, withdrawal syndrome, and bleeding in mother or newborn. |
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 |
| Placental transfer | Both promethazine and codeine cross the placenta. Codeine is metabolized to morphine, which readily crosses the placental barrier. Promethazine has been detected in fetal tissues. |
■ 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 ingredientBreastfeeding (due to risk of infant opioid toxicity)Children < 6 years old (risk of respiratory depression, especially with codeine)Respiratory depression (especially in settings of acute asthma, COPD, or in patients with or pulmonale)Severe CNS depression or comaAcute or severe bronchial asthmaParalytic ileusKnown CYP2D6 ultra-rapid metabolizer (risk of life-threatening opioid toxicity)Postoperative management of tonsillectomy and/or adenoidectomy in children (risk of death)Concomitant use with MAO inhibitors or within 14 days of discontinuation
| 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…
| Breastfeeding |
| The combination of promethazine and codeine is contraindicated during breastfeeding. Codeine is metabolized to morphine, and there is a risk of infant opioid toxicity, especially in CYP2D6 ultra-rapid metabolizers. Promethazine may cause drowsiness and respiratory depression in infants. Use alternative agents. |
| Lactation Rating | L5 (Contraindicated) |
| Teratogenic Risk | 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. |
| Food/Dietary | Avoid alcohol. Grapefruit juice may increase codeine levels via CYP3A4 inhibition, but interaction is not clinically significant for short-term use. High-fat meals may delay absorption of codeine but do not require dietary restriction. |
| Clinical Pearls | Promethazine is a phenothiazine antiemetic with strong sedative properties; codeine is a prodrug metabolized by CYP2D6 to morphine, so poor metabolizers may have reduced analgesia. Avoid in children <6 years due to risk of fatal respiratory depression. Use with caution in patients with G6PD deficiency as promethazine may cause hemolysis. Monitor for extrapyramidal symptoms with promethazine. |
| Patient Advice | This medication contains codeine, which can be habit-forming; take only as prescribed. · Do not drive or operate machinery until you know how this medicine affects you, as it causes drowsiness and dizziness. · Avoid alcohol and other CNS depressants (e.g., benzodiazepines, opioids) as they increase risk of respiratory depression. · Stop taking and seek medical help if you experience slow/shallow breathing, severe sedation, or symptoms of serotonin syndrome (agitation, hallucination, fever). · Store in a safe place out of reach of children; accidental overdose is dangerous and can be fatal. |