PROMETHAZINE HYDROCHLORIDE AND 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 antagonizes histamine H1 receptors, reducing allergic symptoms; it also has anticholinergic, antiemetic, and sedative effects. Codeine is an opioid agonist at mu-opioid receptors, producing analgesia and antitussive effects by central mechanisms.
| Metabolism | Promethazine is extensively metabolized in the liver via oxidation (including CYP2D6) and glucuronidation. Codeine is metabolized by CYP2D6 to morphine (active), by CYP3A4 to norcodeine, and by glucuronidation. |
| Excretion | Renal: Codeine and metabolites ~90% (free and conjugated), Promethazine and metabolites primarily renal; minor biliary/fecal (<5% for codeine, ~6% for promethazine). |
| Half-life | Promethazine: 10-19 hours (range 5-30h); Codeine: 2.5-4 hours (rapidly metabolized); Clinical context: sustained antitussive effect from codeine despite short half-life. Half-life of promethazine extends with hepatic impairment. |
| Protein binding | Promethazine: 93% bound primarily to albumin; Codeine: 7-25% bound primarily to albumin (low binding). |
| Volume of Distribution | Promethazine: Vd ~14-17 L/kg (high tissue distribution, extensive CNS penetration); Codeine: Vd ~3-6 L/kg (moderate; penetrates CNS). |
| Bioavailability | Oral: Promethazine 25% (extensive first-pass metabolism); Codeine ~50-90% (variable, mean ~60%); Rectal: Promethazine ~80% relative to IM; IM: Promethazine ~100%. |
| Onset of Action | Oral: 30-60 minutes for both antitussive and sedative effects. Rectal: comparable; IM: 20-30 minutes. |
| Duration of Action | Codeine: 4-6 hours antitussive; Promethazine: sedative 6-12 hours, antiemetic 4-6 hours. May be prolonged with hepatic disease. |
Adults: 5 mL (containing promethazine 6.25 mg and codeine 10 mg) orally every 4-6 hours as needed; maximum 30 mL per day.
| Dosage form | SYRUP |
| Renal impairment | GFR < 30 mL/min: Avoid use due to risk of CNS depression and accumulation of codeine metabolites. GFR 30-60 mL/min: Use with caution; consider dose reduction (e.g., 50% of usual dose) and monitor for adverse effects. GFR > 60 mL/min: No adjustment required. |
| Liver impairment | Child-Pugh Class A: No adjustment. Child-Pugh Class B: Reduce dose by 50% and monitor for excessive sedation. Child-Pugh Class C: Avoid use due to risk of encephalopathy and reduced codeine metabolism. |
| Pediatric use | Age ≥ 12 years: 5 mL orally every 4-6 hours as needed; maximum 30 mL per day. Age 6-11 years: 2.5 mL orally every 4-6 hours; maximum 15 mL per day. Age < 6 years: Contraindicated. Weight-based dosing for codeine: 0.5-1 mg/kg/dose every 4-6 hours; promethazine 0.25-0.5 mg/kg/dose; not recommended in children due to respiratory depression risk. |
| Geriatric use | Elderly patients (>65 years): Use lowest effective dose, typically 2.5-5 mL orally every 4-6 hours; maximum 20 mL per day. Avoid in patients with cognitive impairment or respiratory compromise due to increased sensitivity to CNS effects. |
| 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 excreted into breast milk (M/P ratio ~2.5) with risk of neonatal opioid toxicity, especially in CYP2D6 ultra-rapid metabolizers; contraindicated per FDA. Promethazine excretion minimal but may cause neonatal drowsiness, irritability; use not recommended. Alternatives preferred. |
| Teratogenic Risk |
■ FDA Black Box Warning
WARNING: RISK OF RESPIRATORY DEPRESSION IN CHILDREN; CONCOMITANT USE OF OPIOIDS WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS MAY RESULT IN PROFOUND SEDATION, RESPIRATORY DEPRESSION, COMA, AND DEATH. Avoid use in children < 6 years due to risk of fatal respiratory depression.
| Common Effects | nausea/vomiting |
| Serious Effects |
["Hypersensitivity to promethazine, codeine, or any component","Children < 6 years","Postoperative management in children after tonsillectomy/adenoidectomy","Comatose states","Severe respiratory depression","Concurrent MAO inhibitor use (within 14 days)","Acute asthma attack"]
| Precautions | ["Respiratory depression risk, especially in children and elderly","Contraindicated in patients < 6 years","Risk of serotonin syndrome with other serotonergic drugs","Risk of abuse, addiction, and dependence","Head injury or increased intracranial pressure","Severe hepatic or renal impairment","Avoid alcohol and other CNS depressants","Anticholinergic effects may worsen glaucoma, urinary retention, etc."] |
Loading safety data…
| First trimester: Promethazine carries limited human data but no clear teratogenic signal; codeine is associated with increased risk of congenital malformations (e.g., respiratory, cardiovascular) in some studies. Second trimester: Codeine may cause fetal dependence; promethazine poses low risk. Third trimester: Codeine use risks neonatal respiratory depression, withdrawal, and opioid withdrawal syndrome; promethazine may cause maternal hypotension and fetal distress. |
| Fetal Monitoring | Monitor maternal respiratory rate, sedation level, and bowel function. Assess fetal heart rate tracing with prolonged use near term. Monitor neonatal respiratory status after delivery if used in third trimester. Consider umbilical cord blood gas analysis if signs of neonatal depression. |
| Fertility Effects | Codeine may impair fertility via opioid-induced hormonal changes (reduced LH/FSH, hyperprolactinemia). Promethazine may cause mild menstrual irregularities due to anticholinergic effects. Reversible upon discontinuation. |