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. |
| Molecular Weight | Promethazine: 284.42 Da; Codeine: 299.36 Da; Combination tablet: molecular weight of the active components. |
| Action Class | Antihistamine (H1-receptor antagonist) / Antiemetic / Opioid antitussive |
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 | Promethazine with codeine is not recommended in the first trimester due to potential teratogenic effects from codeine (CNS defects, inguinal hernia) and promethazine (possible association with congenital heart defects). Use only if clearly needed. |
| 2nd trimester | Use with caution in the second trimester; promethazine may cause respiratory depression in the fetus, and codeine may cause neonatal opioid withdrawal syndrome. Avoid if possible. |
| 3rd trimester | Avoid in the third trimester, especially near term, due to risk of neonatal respiratory depression and withdrawal from codeine. Promethazine may cause extrapyramidal symptoms in the neonate. |
Clinical note
CNS depressants may enhance sedative effects Can cause respiratory depression in children and extrapyramidal symptoms.
| FDA category | Animal |
| Placental transfer | Both promethazine and codeine cross the placenta. Promethazine exhibits moderate transfer; codeine is extensively metabolized to morphine which also crosses readily. Fetal concentrations may approach maternal levels. |
■ 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 | Respiratory depression (especially in children, elderly, or with CYP2D6 ultra-rapid metabolizers), Severe hypotension, Neuroleptic malignant syndrome, Seizures, Cholestatic jaundice, Agranulocytosis, Extrapyramidal symptoms (dystonia, akathisia, tardive dyskinesia), QT prolongation / torsades de pointes, Paradoxical CNS stimulation (especially in children), Serotonin syndrome (when combined with other serotonergic drugs) |
Hypersensitivity to promethazine, codeine, or any componentRespiratory depression (especially in pediatric patients)Asthma or COPD exacerbationUpper airway obstructionConcurrent MAO inhibitor use (or within 14 days)Coma or CNS depressionSevere hepatic impairmentBreastfeeding (especially in infants with CYP2D6 ultra-rapid metabolizer phenotype)Children <6 years of age (risk of respiratory depression from codeine)Postoperative use in children undergoing tonsillectomy/adenoidectomy (FDA black box)
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| Breastfeeding | Codeine is excreted into breast milk in low levels, but some infants are ultra-rapid metabolizers of codeine, leading to potentially fatal morphine accumulation. Promethazine is also excreted and may cause drowsiness or respiratory depression in the infant. The combination is generally contraindicated during breastfeeding. Use alternative analgesics/antiemetics. |
| Lactation Rating | L5 (Avoid) |
| Teratogenic Risk | 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. |
| 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. |
| Food/Dietary | Avoid alcohol; may enhance sedative effects. No specific food restrictions, but high-fat meals may delay absorption. |
| Clinical Pearls | Promethazine with codeine is contraindicated in children <6 years due to risk of fatal respiratory depression. Avoid in patients with asthma or COPD. Use with caution with other CNS depressants. Monitor for signs of serotonin syndrome if combined with serotonergic drugs. |
| Patient Advice | May cause drowsiness; avoid driving or operating machinery. · Do not exceed recommended dose; risk of addiction and dependence. · Do not consume alcohol while taking this medication. · Take with food if gastrointestinal upset occurs. · Stop use and seek medical attention if breathing becomes difficult or you experience rash. |