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. |
| Molecular Weight | Codeine phosphate: 406.36 Da; Promethazine hydrochloride: 320.88 Da. (Combination product: individual components). |
| Action Class | Antihistamine / Antiemetic (Promethazine); Opioid Agonist / Antitussive (Codeine) |
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 | Avoid; limited human data, potential teratogenicity (codeine associated with respiratory depression in neonates from CYP2D6 ultrarapid metabolizers). Promethazine may cause maternal sedation. |
| 2nd trimester | Use only if benefit outweighs risk; codeine can cause fetal dependence and neonatal withdrawal syndrome. Avoid prolonged use or high doses. |
| 3rd trimester | Avoid; codeine may cause neonatal respiratory depression and withdrawal. Promethazine may contribute to maternal sedation and neonatal CNS depression. |
Clinical note
CNS depressants may enhance sedative effects Can cause respiratory depression in children and extrapyramidal symptoms.
| FDA category | Animal |
| Placental transfer | Both codeine and promethazine cross the placenta. Codeine is metabolized to morphine, which readily crosses; fetal/neonatal morphine concentrations can be high. Promethazine crosses to a lesser extent. Evidence from animal studies and human case reports. |
■ 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 | Respiratory depression (especially in children, elderly, or with CYP2D6 ultra-rapid metabolizers), Severe hypotension, Neuroleptic malignant syndrome, Seizures, QT prolongation / Torsades de pointes, Serotonin syndrome (when combined with other serotonergic drugs), Paradoxical CNS stimulation (especially in children), Extrapyramidal symptoms (dystonia, akathisia, tardive dyskinesia), Agranulocytosis, Cholestatic jaundice, Anaphylaxis, Angioedema |
Hypersensitivity to codeine, promethazine, or any excipientsAcute or severe bronchial asthma or respiratory depressionConcomitant use of MAOIs or within 14 daysProlonged QT syndrome (promethazine may prolong QT interval)Children < 6 years of age (risk of fatal respiratory depression, and in some regions contraindicated in < 12 years)
| Precautions |
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| Breastfeeding | Codeine is excreted into breast milk; risk of infant opioid toxicity, especially in CYP2D6 ultra-rapid metabolizers. Promethazine is excreted in small amounts, but may cause infant drowsiness or irritability. Use alternative analgesics and antiemetics if possible. Monitor infant for sedation, respiratory depression, or poor feeding. |
| Lactation Rating | L4 (Possibly Hazardous) – codeine component; promethazine L2 (Safer). Combination rating: Use caution, prefer alternatives. |
| Teratogenic Risk | 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. |
| 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. |
| Food/Dietary | Avoid alcohol and CNS depressants. Grapefruit juice may alter codeine metabolism; avoid concurrent consumption. No significant food interactions with promethazine. Take with food to reduce gastrointestinal discomfort. |
| Clinical Pearls | Combination product: promethazine (antihistamine/antiemetic) + codeine (opioid antitussive). Use only for cough unresponsive to non-opioid antitussives. Anticholinergic effects may worsen glaucoma, urinary retention, or asthma. Codeine is a prodrug via CYP2D6; poor metabolizers have reduced efficacy, ultrarapid metabolizers risk toxicity. Contraindicated in children <18 years after labeling change (FDA black box). Avoid in breastfeeding; codeine may cause infant respiratory depression. Monitor for respiratory depression, especially when combined with other CNS depressants. |
| Patient Advice | This medication contains codeine, an opioid, and promethazine, an antihistamine. Use only as prescribed. · Do not drink alcohol or take other sedatives, including benzodiazepines, sleeping pills, or muscle relaxants, as this can cause severe drowsiness, slowed breathing, coma, or death. · Serious side effects include shallow breathing, confusion, severe dizziness, or fainting. Seek emergency help if these occur. · Do not use this medicine in children younger than 18 years. It can cause life-threatening breathing problems. · Avoid driving or operating machinery until you know how this medication affects you. It may cause drowsiness and impair judgment. · Do not take for longer than prescribed. Tolerance and dependence can develop. Stopping suddenly may cause withdrawal symptoms. · Take with food if stomach upset occurs. Avoid grapefruit juice as it may affect codeine metabolism. |