PROMETHAZINE VC 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, which acts as a mu-opioid receptor agonist inhibiting ascending pain pathways and altering pain perception. Promethazine is a phenothiazine derivative that antagonizes histamine H1 receptors, suppresses cough reflex via central action, and has anticholinergic, sedative, and antiemetic effects. Phenylephrine is a selective alpha-1 adrenergic receptor agonist causing vasoconstriction of nasal blood vessels, reducing congestion.
| Metabolism | Codeine is metabolized primarily by CYP2D6 to morphine (active) and by CYP3A4 to norcodeine. Promethazine is metabolized by oxidation in the liver via CYP2D6 and other pathways, with sulfoxidation and N-demethylation. Phenylephrine is metabolized mainly by monoamine oxidase (MAO) in the liver and intestinal wall. |
| Excretion | Renal: 70-80% as unchanged promethazine and metabolites (including codeine and its glucuronides); biliary/fecal: 10-20%. |
| Half-life | Promethazine: 9-16 hours (range 7-20 hours) in adults; codeine: 2.5-3.5 hours (terminal) with clinical considerations for prolonged effects in hepatic impairment and CYP2D6 poor metabolizers. |
| Protein binding | Promethazine: 93% bound primarily to albumin; codeine: 7-25% bound to albumin. |
| Volume of Distribution | Promethazine: Vd ~14 L/kg (large distribution into tissues, CNS penetration); codeine: Vd ~3-6 L/kg. |
| Bioavailability | Oral: 25-30% for promethazine (extensive first-pass metabolism); codeine: 50-70% oral (variable due to CYP2D6 metabolism). |
| Onset of Action | Oral: 20-30 minutes for antitussive effect; IM: 10-20 minutes; IV: 3-5 minutes. |
| Duration of Action | Oral: 4-6 hours (antitussive and sedative); IM/IV: 4-6 hours; clinical note: respiratory depression may persist longer than analgesic effect of codeine. |
1-2 tablets orally every 4-6 hours as needed for cough and congestion. Maximum 12 tablets in 24 hours.
| Dosage form | SYRUP |
| Renal impairment | Avoid use in severe renal impairment (eGFR <30 mL/min). For moderate impairment (eGFR 30-59 mL/min), reduce dose by 50% and monitor for CNS depression. |
| Liver impairment | Contraindicated in severe hepatic impairment (Child-Pugh class C). For moderate impairment (Child-Pugh class B), reduce dose by 50% and extend dosing interval. |
| Pediatric use | Not recommended for children under 6 years. For children 6-11 years: 1/2 to 1 tablet orally every 4-6 hours, maximum 6 tablets in 24 hours. For children ≥12 years: same as adult dose. |
| Geriatric use | Start with lowest effective dose (1 tablet) every 4-6 hours. Monitor for CNS depression, confusion, and constipation. Avoid in patients with significant renal or hepatic impairment. |
| 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 | PROMETHAZINE: Excreted in breast milk (M/P ratio not established); use caution, may cause drowsiness or apnea in infants. CODEINE: Excreted in breast milk (M/P ratio 1:2.5); risk of infant opioid toxicity due to CYP2D6 variability. Contraindicated in breastfeeding unless urgent. |
| Teratogenic Risk |
■ FDA Black Box Warning
Codeine is contraindicated for post-operative pain management in children who have undergone tonsillectomy and/or adenoidectomy. It is contraindicated in children younger than 12 years of age for cough and pain. Use in children under 18 years with risk factors for respiratory depression is not recommended. Concomitant use with CYP3A4 inhibitors may result in fatal respiratory depression.
| Common Effects | nausea/vomiting |
| Serious Effects |
["Children younger than 12 years of age","Post-operative tonsillectomy and/or adenoidectomy in children","Children under 18 years with risk factors for respiratory depression (e.g., obesity, obstructive sleep apnea)","Patients with severe respiratory insufficiency","Concurrent use of MAO inhibitors or within 14 days of such therapy","Patients with known hypersensitivity to any component","Acute or severe bronchial asthma","Severe hypertension or coronary artery disease (due to phenylephrine)","Narrow-angle glaucoma","Urinary retention (due to promethazine anticholinergic effects)","Breastfeeding (due to codeine risk in infants)"]
| Precautions |
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| PROMETHAZINE: First trimester - limited data, avoid; second/third trimester - associated with maternal respiratory depression and neonatal withdrawal. CODEINE: First trimester - crosses placenta, risk of neural tube defects?; second/third trimester - neonatal opioid withdrawal syndrome, respiratory depression. Combination: Avoid in all trimesters unless benefit outweighs risk. |
| Fetal Monitoring | Maternal: Respiratory rate, sedation level, blood pressure, fetal movements. Neonatal: Observe for signs of opioid withdrawal (e.g., high-pitched cry, tremors, poor feeding) and respiratory depression. |
| Fertility Effects | No well-controlled studies. May cause menstrual irregularities (both drugs), but effects on fertility are not established. Codeine may impair spermatogenesis in animal studies. |
| ["Risk of respiratory depression, especially in children and with CYP2D6 ultra-rapid metabolizers","Concomitant use with CNS depressants (e.g., alcohol, benzodiazepines) increases risk of sedation and respiratory depression","Avoid use in patients with severe hypertension, hyperthyroidism, or narrow-angle glaucoma due to phenylephrine","May cause drowsiness, impair mental and physical abilities; avoid driving or operating machinery","Prolonged use may lead to tolerance, dependence, and addiction","Use caution in patients with asthma, COPD, sleep apnea, or other respiratory conditions","May cause neuroleptic malignant syndrome (NMS) with promethazine","Avoid in patients with known hypersensitivity to codeine, promethazine, or phenylephrine"] |