PROMETHAZINE WITH CODEINE
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 at H1 receptors, acting as a sedative and antiemetic. Codeine is an opioid agonist at mu-opioid receptors, producing analgesia and antitussive effects via central nervous system depression.
| Metabolism | Promethazine primarily undergoes hepatic metabolism (CYP2D6-mediated sulfoxidation and N-demethylation). Codeine is metabolized by CYP2D6 to morphine (active), CYP3A4 to norcodeine, and UGT2B7 to codeine-6-glucuronide. |
| Excretion | Promethazine: renal 70% as metabolites and unchanged drug, biliary/fecal 20-30%. Codeine: renal 90% (5-15% unchanged, rest as morphine and conjugates), fecal <10%. |
| Half-life | Promethazine: 9-16 hours (mean 12 hours), clinically significant for sedation duration. Codeine: 2.5-4 hours (mean 3 hours), with active metabolite morphine 2-3 hours. |
| Protein binding | Promethazine: 93% bound to albumin and lipoproteins. Codeine: 7-25% bound primarily to alpha-1-acid glycoprotein and albumin. |
| Volume of Distribution | Promethazine: Vd 6.8 L/kg (extensive tissue distribution, high CNS penetration). Codeine: Vd 3-6 L/kg (distributes into body tissues including breast milk). |
| Bioavailability | Promethazine: oral 25%, IM 100%, rectal 70-80%, IV 100%. Codeine: oral 60-90% (first-pass metabolism), IM 100%, rectal 80-90%. |
| Onset of Action | Oral promethazine: 20 minutes; codeine: 30-60 minutes. IM promethazine: 20 minutes; codeine: 10-30 minutes. IV promethazine: 3-5 minutes; codeine: 5-10 minutes. Rectal: 20-30 minutes. |
| Duration of Action | Promethazine: 4-12 hours (sedation), depending on dose and route. Codeine: 4-6 hours (analgesia). Combination effects last 4-6 hours for antitussive and sedative effects. |
| Molecular Weight | Promethazine: 284.42 Da; Codeine: 299.36 Da |
| Action Class | Antihistamine / Antiemetic / Opioid Antitussive |
10-20 mg promethazine and 10-20 mg codeine (based on phosphate) orally every 4-6 hours as needed for cough; maximum daily codeine dose 120 mg.
| Dosage form | SYRUP |
| Renal impairment | GFR 30-59 mL/min: Administer every 8 hours; GFR 10-29 mL/min: Administer every 12 hours; GFR <10 mL/min: Avoid use. |
| Liver impairment | Child-Pugh Class A: No adjustment; Child-Pugh Class B: Reduce dose by 50% or extend interval; Child-Pugh Class C: Avoid use. |
| Pediatric use | Not recommended for children under 16 years due to risk of respiratory depression and adverse effects. For ages 16-18, adult dosing may be considered cautiously. |
| Geriatric use | Initiate at lowest effective dose, typically 5 mg promethazine/5 mg codeine orally every 6 hours; monitor for sedation, confusion, and constipation. |
| 1st trimester | Avoid; risk of teratogenicity and respiratory depression. |
| 2nd trimester | Avoid; risk of respiratory depression in fetus. |
| 3rd trimester | Avoid; risk of neonatal respiratory depression, withdrawal, and opioid withdrawal syndrome. |
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; codeine is metabolized to morphine, which crosses readily. |
| Breastfeeding | Codeine is excreted into breast milk; risk of infant opioid toxicity. Promethazine may reduce milk production. Use only if benefits outweigh risks; monitor infant for sedation and respiratory depression. |
■ FDA Black Box Warning
Respiratory depression in children; not for use in pediatric patients <12 years of age due to risk of fatal respiratory depression. Concomitant use of codeine with CYP3A4, CYP2D6 inhibitors, or alcohol may cause fatal respiratory depression. Contraindicated in post-operative pain management in children undergoing tonsillectomy/adenoidectomy.
| 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, QT prolongation / Torsades de pointes, Paradoxical CNS stimulation (especially in children), Physical dependence and addiction (codeine component) |
Known hypersensitivity to promethazine, codeine, or other phenothiazinesSevere respiratory depressionAcute or severe bronchial asthmaConcurrent use of MAOIs or within 14 daysComatose patientsChildren younger than 6 years for antitussive usePostoperative management in children undergoing tonsillectomy/adenoidectomy (due to increased risk of respiratory depression)
| Precautions |
Loading safety data…
| Lactation Rating | L4 - Possibly Hazardous |
| Teratogenic Risk | First trimester: Limited data, but codeine is not associated with major malformations; promethazine has insufficient evidence. Second/third trimester: Codeine may cause neonatal respiratory depression and withdrawal if used near term; promethazine may cause maternal hypotension and neonatal irritability. Avoid in pregnancy, especially near delivery. |
| Fetal Monitoring | Monitor maternal respiratory rate, sedation level, and oxygen saturation; fetal heart rate monitoring if used during labor; assess neonatal Apgar scores, respiratory effort, and signs of opioid withdrawal or sedation at delivery. |
| Fertility Effects | Prolactin elevation from promethazine may impair ovulation; codeine may affect gonadotropin secretion. Limited human data, but reversible suppression of fertility is possible with chronic use. |
| Respiratory depression, especially in children; CNS depression additive with alcohol/other CNS depressants; severe hypotension; anticholinergic effects (dry mouth, urinary retention); risk of serotonin syndrome with other serotonergic drugs; tolerance/dependence; caution in asthma, COPD, or decreased respiratory reserve; avoid in pediatric patients after tonsillectomy/adenoidectomy or with obstructive sleep apnea. |
| Food/Dietary | Avoid alcohol. Grapefruit juice may increase codeine absorption; limit intake. Ma Huang (Ephedra) and other stimulants may counteract sedative effects. St. John's Wort may decrease codeine efficacy. Avoid high-fiber meals immediately before or after dosing as they may reduce absorption. |
| Clinical Pearls | Promethazine with codeine is contraindicated in children <6 years due to risk of respiratory depression and death. Use with caution in patients with asthma, COPD, or sleep apnea. Codeine is a prodrug activated by CYP2D6; ultrarapid metabolizers may experience toxicity. Promethazine is anticholinergic; avoid in patients with angle-closure glaucoma, urinary retention, or GI obstruction. Monitor for CNS depression when combined with alcohol or other CNS depressants. Warning: FDA boxed warning for opioid-induced respiratory depression and abuse potential. Administer with food to reduce gastric irritation. |
| Patient Advice | Do not use in children under 12 years; risk of serious breathing problems. · Do not exceed prescribed dose; may cause dependence or overdose. · Avoid alcohol, sedatives, and other CNS depressants. · May cause drowsiness or dizziness; avoid driving or operating machinery. · Discontinue and seek help if you experience slow or shallow breathing, confusion, or severe constipation. · Report signs of serotonin syndrome (agitation, hallucinations, rapid heart rate, fever, muscle stiffness) if taking other serotonergic drugs. · Promethazine may cause dry mouth, blurred vision, and urinary retention; stay hydrated and use caution. · Store out of reach of children; accidental ingestion may be fatal. |