PHENERGAN VC W/ CODEINE
Clinical safety rating: avoid
CNS depressants including alcohol and benzodiazepines increase sedation risk Life-threatening respiratory depression may occur especially in CYP2D6 ultra-rapid metabolizers.
Phenergan VC w/ Codeine combines codeine (opioid agonist, mu-receptor), promethazine (histamine H1 antagonist, anticholinergic, sedative), and phenylephrine (alpha-1 adrenergic agonist). Codeine is metabolized to morphine for analgesia and antitussive effects; promethazine suppresses cough via central nervous system depression; phenylephrine causes vasoconstriction to relieve congestion.
| Metabolism | Codeine: primarily metabolized by CYP2D6 to morphine (active) and by CYP3A4 to norcodeine; further glucuronidation. Promethazine: metabolized via CYP2D6 and CYP2B6. Phenylephrine: metabolized by monoamine oxidase (MAO) and sulfation. |
| Excretion | Codeine: renal elimination of metabolites (codeine-6-glucuronide, norcodeine, morphine, morphine-3-glucuronide, morphine-6-glucuronide); ~90% excreted in urine, <10% in feces. Promethazine: renal and biliary elimination as metabolites and unchanged drug; ~70-80% in urine, <20% in feces. |
| Half-life | Codeine: terminal half-life ~3 hours (range 2.5-4.5 h) in adults; extended in renal impairment. Promethazine: terminal half-life ~10-14 hours (range 7-20 h) in adults; prolonged in elderly and hepatic impairment. |
| Protein binding | Codeine: ~7-25% bound primarily to albumin. Promethazine: ~93% bound primarily to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Codeine: ~3-6 L/kg (high tissue distribution). Promethazine: ~12-18 L/kg (extensive tissue binding, large Vd). |
| Bioavailability | Codeine: oral bioavailability ~50-70% (first-pass metabolism); IM ~100%. Promethazine: oral bioavailability ~25-40% (extensive first-pass); IM/IV ~100%. |
| Onset of Action | Oral: codeine onset 30-60 minutes; promethazine onset 20-30 minutes; IM/IV promethazine onset within 5-10 minutes; codeine IM onset 10-30 minutes. |
| Duration of Action | Codeine: analgesic duration 4-6 hours; antitussive duration 4-6 hours. Promethazine: antihistamine/sedative duration 6-12 hours; antiemetic duration up to 12 hours. Combination effect persists 4-6 hours. |
| Molecular Weight | Codeine phosphate: 397.4 g/mol; Phenylephrine HCl: 203.7 g/mol; Promethazine HCl: 320.9 g/mol |
1 to 2 teaspoonfuls (5-10 mL) orally every 4 to 6 hours as needed. Maximum 4 doses in 24 hours.
| Dosage form | SYRUP |
| Renal impairment | Not recommended in severe renal impairment (CrCl <30 mL/min). Use with caution in moderate impairment (CrCl 30-60 mL/min) with extended dosing intervals. No specific dose adjustment provided. |
| Liver impairment | No specific Child-Pugh based recommendations. Use with caution in severe hepatic impairment; consider reduced dosing or extended intervals due to risk of accumulation. |
| Pediatric use | Children 6-12 years: 1 teaspoonful (5 mL) orally every 4-6 hours. Maximum 4 doses in 24 hours. Contraindicated in children <6 years due to risk of respiratory depression. |
| Geriatric use | Initiate with lowest effective dose (e.g., 1 teaspoonful) and monitor for CNS depression, falls, and anticholinergic effects. Consider alternative therapies due to increased sensitivity. |
| 1st trimester | Avoid: associated with congenital malformations (codeine) and possible respiratory depression; use only if benefit outweighs risk. |
| 2nd trimester | Caution: avoid prolonged use; maternal respiratory depression and fetal hypoxia risk. |
| 3rd trimester | Avoid: risk of neonatal respiratory depression, withdrawal syndrome, and premature closure of ductus arteriosus (phenylephrine). |
Clinical note
CNS depressants including alcohol and benzodiazepines increase sedation risk Life-threatening respiratory depression may occur especially in CYP2D6 ultra-rapid metabolizers.
| FDA category | Positive |
| Placental transfer | Codeine and phenylephrine cross the placenta; codeine achieves significant fetal concentrations, phenylephrine transfer is limited but present. |
■ FDA Black Box Warning
WARNING: RESPIRATORY DEPRESSION, DEATH, AND ADDICTION. Codeine can cause respiratory depression, especially in children. Contraindicated in children <12 years; not recommended for children 12-18 with obesity, neuromuscular disease, or compromised respiratory function. Risk of opioid addiction, abuse, and misuse. Concomitant use with benzodiazepines or CNS depressants may cause profound sedation, respiratory depression, coma, and death.
| Common Effects | cough |
| Serious Effects |
Hypersensitivity to any componentSevere asthma or COPDRespiratory depressionPremature infants or neonatesConcurrent MAO inhibitors or within 14 daysSevere hypertension or coronary artery disease (phenylephrine)Breastfeeding in CYP2D6 ultra-rapid metabolizers
| Precautions | Risk of respiratory depression, especially with CYP2D6 ultra-rapid metabolizers, Avoid in children due to risk of respiratory depression, Serotonin syndrome risk with serotonergic drugs, Anticholinergic effects (urinary retention, blurred vision, constipation) from promethazine, Cardiovascular effects from phenylephrine (hypertension, arrhythmias), May impair mental/physical abilities; avoid driving, Risk of severe hypotension with phenothiazines, Use caution in hepatic/renal impairment, asthma, COPD, seizures, or increased intracranial pressure |
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| Breastfeeding |
| Codeine is excreted into breast milk; risk of infant opioid toxicity, especially in CYP2D6 ultra-rapid metabolizers. Phenylephrine has minimal excretion. Avoid or use lowest effective dose for shortest duration. Monitor infant for sedation and respiratory depression. |
| Lactation Rating | L4 (Possibly Hazardous) |
| Teratogenic Risk | First trimester: Limited data; codeine has been associated with increased risk of congenital malformations (particularly cardiac defects) in some studies. Phenergan (promethazine) has conflicting data, with some studies suggesting small increased risk of malformations. Second and third trimesters: Codeine use near term may cause neonatal respiratory depression and withdrawal. Promethazine near term may cause CNS depression, extrapyramidal signs, or jaundice. Overall, risks are low but not negligible. |
| Fetal Monitoring | Monitor maternal respiratory status, sedation level, and bowel function. Fetal monitoring for heart rate variability and signs of distress. Neonatal monitoring for respiratory depression, withdrawal symptoms (irritability, poor feeding), and jaundice postpartum. |
| Fertility Effects | No direct studies on fertility effects in humans. Codeine may suppress gonadotropin release via opioid receptors, potentially impacting menstrual cycle and ovulation. Promethazine may cause hyperprolactinemia, but effects on fertility are unknown. Clinical significance is likely low with short-term use. |
| Food/Dietary | Avoid alcohol. Grapefruit juice may increase codeine levels via CYP3A4 inhibition; however, clinical significance is uncertain. No other specific food interactions. |
| Clinical Pearls | PHENERGAN VC W/ CODEINE contains promethazine, phenylephrine, and codeine. Antitussive effect from codeine is due to suppression of cough center; use with caution in patients with asthma or COPD due to potential respiratory depression. Promethazine is a potent antiemetic but can cause extrapyramidal symptoms, especially in children. Phenylephrine is a decongestant; use cautiously in hypertension, hyperthyroidism, and ischemic heart disease. Avoid concurrent use with MAOIs or within 14 days. Codeine is a prodrug metabolized by CYP2D6 to morphine; ultra-rapid metabolizers (e.g., certain ethnicities) are at risk for toxicity. |
| Patient Advice | Do not exceed recommended dose; may cause drowsiness, avoid driving or operating machinery. · Avoid alcohol and other CNS depressants (e.g., benzodiazepines, opioids) as they increase sedative effects. · Take with food or milk if GI upset occurs. · Report severe constipation, difficulty breathing, or signs of allergic reaction (rash, itching, swelling). · Do not use for more than 7 days for cough or 3 days for cold symptoms unless directed by a doctor. · Store at room temperature away from light and moisture. |