PROMETHAZINE W/ CODEINE
Clinical safety rating: safe
CNS depressants may enhance sedative effects Can cause respiratory depression in children and extrapyramidal symptoms.
Codeine is a prodrug converted to morphine, a mu-opioid receptor agonist, which inhibits nociceptive transmission; promethazine is a phenothiazine derivative with H1-receptor antagonism, anticholinergic, and antiemetic effects.
| Metabolism | Codeine: Hepatic via CYP2D6 (to morphine), CYP3A4 (to norcodeine); Promethazine: Hepatic via CYP2B6, CYP2D6, and glucuronidation. |
| Excretion | Promethazine: renal (70% as metabolites, <1% unchanged), fecal (20-30%). Codeine: renal (90%, of which 5-10% unchanged, rest as metabolites), fecal (minor). |
| Half-life | Promethazine: 10-19 hours (terminal). Codeine: 2.5-3.5 hours (terminal); prolonged in renal impairment. |
| Protein binding | Promethazine: 93% (primarily to albumin). Codeine: 7-25% (to albumin). |
| Volume of Distribution | Promethazine: 5-14 L/kg (extensive tissue distribution). Codeine: 3-6 L/kg (widely distributed). |
| Bioavailability | Promethazine: oral 25% (due to first-pass metabolism), IM ~88%. Codeine: oral 50-70% (converted to morphine via CYP2D6), IM ~80%. |
| Onset of Action | Oral: 30-60 minutes (both components). IM: 20-30 minutes. IV: 5-10 minutes (antiemetic effect). |
| Duration of Action | Promethazine: 4-12 hours (antihistaminic/sedative). Codeine: 4-6 hours (analgesic). Effects may last longer with hepatic/renal impairment. |
10 mL (1 mg codeine, 6.25 mg promethazine per 5 mL) orally every 4-6 hours as needed for cough. Maximum: 60 mL per day. Do not exceed 5 days.
| Dosage form | SYRUP |
| Renal impairment | eGFR 30-59 mL/min: Administer every 6 hours; eGFR 15-29 mL/min: Administer every 8 hours; eGFR <15 mL/min: Avoid use or consider extended interval due to accumulation of codeine metabolites. |
| Liver impairment | Child-Pugh A: No adjustment; Child-Pugh B: Reduce dose by 50% or extend interval; Child-Pugh C: Avoid use due to risk of hepatic encephalopathy and impaired codeine metabolism. |
| Pediatric use | Use not recommended in children <12 years due to risk of respiratory depression. For ages 12-18: 10-15 mL (with caution) every 4-6 hours as needed. Weight-based dosing: 0.5-1 mg/kg/dose of codeine (max 60 mg/day) with promethazine 0.25-0.5 mg/kg/dose (max 25 mg/dose). |
| Geriatric use | Initiate with 5 mL orally every 6-8 hours; titrate cautiously due to increased sensitivity, risk of sedation, and anticholinergic effects. Maximum daily dose: 40 mL. Avoid in patients with significant cognitive impairment. |
| 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 | Breastfeeding not recommended. Codeine is excreted into breast milk with a milk-to-plasma (M/P) ratio of approximately 2.5-3.0 (for morphine, codeine active metabolite). In mothers who are CYP2D6 ultra-rapid metabolizers, codeine can lead to life-threatening respiratory depression in infants. Promethazine is excreted in low amounts but may cause sedation and apnea in neonates. |
| Teratogenic Risk |
■ FDA Black Box Warning
Warning: Risk of respiratory depression, especially in children; fatal respiratory depression can occur. Codeine is contraindicated in children <12 years and should not be used in children <18 years after tonsillectomy/adenoidectomy. Also, risk of opioid addiction, abuse, and misuse.
| Common Effects | nausea/vomiting |
| Serious Effects |
Hypersensitivity to codeine, promethazine, or any phenothiazine; children <12 years; postoperative management in children <18 years following tonsillectomy/adenoidectomy; significant respiratory depression; acute or severe bronchial asthma; GI obstruction; concurrent use of MAOIs or within 14 days.
| Precautions | Respiratory depression, risk of opioid-induced hyperalgesia, severe hypotension, seizures in patients with porphyria, sedation and impaired motor skills, risk of serotonin syndrome when combined with serotonergic drugs, avoid abrupt discontinuation, use caution in elderly, hepatic/renal impairment, and respiratory disorders. |
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| PROMETHAZINE W/ CODEINE is contraindicated during all trimesters. First trimester: codeine is associated with increased risk of congenital malformations (cardiac, cleft palate) due to opioid receptor activation. Promethazine may cause mild neural tube defects. Second/third trimesters: codeine can cause fetal opioid dependence and neonatal abstinence syndrome; promethazine may cause respiratory depression and thrombocytopenia in neonates. Chronic use may lead to preterm birth and low birth weight. Do not use during labor and delivery due to risk of respiratory depression in the neonate. |
| Fetal Monitoring | If inadvertently used during pregnancy, monitor maternal respiratory status, sedation, and fetal heart rate. In neonates, monitor for respiratory depression, sedation, poor feeding, and opioid withdrawal symptoms (e.g., tremors, irritability) for at least 48 hours after birth. Ultrasound to assess for structural anomalies if used in first trimester. |
| Fertility Effects | Codeine may impair fertility in females via disruption of hypothalamic-pituitary-ovarian axis (reduced gonadotropin secretion) and in males via decreased libido and erectile dysfunction. Promethazine may cause menstrual irregularities due to anticholinergic and antihistamine effects. Reversible upon discontinuation. |