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. |
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 | 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 is excreted in breast milk, with M/P ratio approximately 2.5; risk of infant opioid toxicity, especially in CYP2D6 ultrarapid metabolizers. Promethazine is present in low levels but may cause infant sedation. Contraindicated in breastfeeding due to potential for respiratory depression. |
| Teratogenic Risk |
■ 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 |
Children <12 years of age; breastfeeding infants; known hypersensitivity to promethazine, codeine, or other phenothiazines; severe respiratory depression; acute or severe bronchial asthma; upper airway obstruction; post-operative pain in children undergoing tonsillectomy/adenoidectomy; concurrent use of MAO inhibitors or within 14 days.
| Precautions | 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. |
Loading safety data…
| 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. |