PROMETH 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.
Promethazine is a phenothiazine derivative with antihistaminic, sedative, antiemetic, and anticholinergic effects. Codeine is an opioid agonist; its analgesic and antitussive effects are mediated via mu-opioid receptors.
| Metabolism | Promethazine: Hepatic metabolism via oxidation and conjugation; codeine: Hepatic metabolism via CYP2D6 to morphine, CYP3A4 to norcodeine, and glucuronidation. |
| Excretion | Codeine and its metabolites are primarily excreted renally. Approximately 90% of a dose is excreted in the urine within 24 hours, with 10-15% as unchanged codeine, 40-60% as codeine-6-glucuronide, 5-15% as morphine, and 5-10% as norcodeine. Promethazine is extensively metabolized in the liver and excreted in urine and feces; about 70-80% appears in urine as metabolites and unchanged drug (less than 1% unchanged), with 20-30% in feces via biliary elimination. |
| Half-life | Codeine: terminal elimination half-life is 2.5-4 hours in adults. Promethazine: terminal elimination half-life is 9-16 hours, with a mean of 12 hours. |
| Protein binding | Codeine: approximately 7-25% bound to plasma proteins, mainly albumin. Promethazine: approximately 88-93% bound to plasma proteins, primarily albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Codeine: apparent volume of distribution is 3-6 L/kg, indicating extensive tissue distribution. Promethazine: apparent volume of distribution is 10-20 L/kg, reflecting wide distribution and high tissue affinity. |
| Bioavailability | Codeine: oral bioavailability is 40-70% due to first-pass metabolism. Promethazine: oral bioavailability is approximately 25% due to extensive first-pass metabolism. The combination product is administered orally. |
| Onset of Action | Oral codeine: onset of analgesia within 30-45 minutes. Oral promethazine: onset of antiemetic effect within 20 minutes. For combination product PROMETH VC W/ CODEINE administered orally, clinical effects begin within 30-60 minutes. |
| Duration of Action | Codeine: duration of analgesia is 4-6 hours. Promethazine: duration of antiemetic and sedative effects is 4-12 hours, typically 6-8 hours. |
| Molecular Weight | Codeine: 299.36 Da; Promethazine: 284.42 Da |
10 mL (5 mg codeine, 6.25 mg promethazine) orally every 4-6 hours as needed, not to exceed 60 mg codeine per day.
| Dosage form | SYRUP |
| Renal impairment | eGFR 30-59 mL/min: Use with caution, consider reducing dose by 25-50%; eGFR < 30 mL/min: Use not recommended due to risk of codeine accumulation. |
| Liver impairment | Child-Pugh class A: No adjustment; Child-Pugh class B: Reduce dose by 50%; Child-Pugh class C: Use contraindicated. |
| Pediatric use | Children 6-11 years: 2.5-5 mL (2.5 mg codeine, 3.125 mg promethazine) orally every 4-6 hours; Children 12-17 years: same as adult; Use not recommended in children < 6 years due to respiratory depression risk. |
| Geriatric use | Initiate at lower doses (e.g., 5 mL every 6 hours) due to increased sensitivity to CNS effects and renal impairment; monitor for respiratory depression and constipation. |
| 1st trimester | Contraindicated; risk of fetal malformations (codeine metabolized to morphine crosses placenta; promethazine associated with respiratory depression and potential teratogenic effects). |
| 2nd trimester | Contraindicated; prolonged use may cause neonatal respiratory depression and withdrawal symptoms. Avoid unless absolutely necessary. |
| 3rd trimester | Contraindicated; high risk of neonatal respiratory depression, withdrawal, and prolonged QT interval from promethazine. |
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 | Both components cross placenta: codeine (morphine) and promethazine; codeine metabolism produces morphine which crosses readily; promethazine detected in fetal tissues. |
■ FDA Black Box Warning
Risk of respiratory depression in children; contraindicated in pediatric patients <6 years. Risk of medication errors due to confusion between promethazine-containing products. Not approved for pediatric patients <2 years.
| Common Effects | cough |
| Serious Effects |
Hypersensitivity to codeine, promethazine, or any componentRespiratory depressionAcute or severe bronchial asthmaParalytic ileusConcurrent MAO inhibitors or within 14 daysAcute alcoholismCNS depressionHead injuryElevated intracranial pressureComaPregnancy (particularly third trimester and prolonged use)Breastfeeding
| Precautions | Respiratory depression, particularly in children; CNS depression; impaired cognitive/motor function; risk of abuse and dependence; severe hypotension; increased intraocular pressure; anticholinergic effects; decreased GI motility; masking of toxicity in overdose. |
| Food/Dietary |
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| Breastfeeding | Codeine is excreted into breast milk; risk of infant opioid toxicity, especially in CYP2D6 ultra-rapid metabolizers. Promethazine may impair lactation and cause drowsiness in infant. Contraindicated by FDA due to serious adverse reactions. |
| Lactation Rating | L5 (Contraindicated) |
| Teratogenic Risk | Promethazine VC with Codeine (promethazine, phenylephrine, codeine) carries risks. Codeine is pregnancy category C; first trimester: possible neural tube defects; third trimester: risk of neonatal respiratory depression, opioid withdrawal, and premature labor. Promethazine is category C; first trimester: limited data, possible association with cleft palate; third trimester: risk of respiratory depression and extrapyramidal effects in neonate. Phenylephrine is category C; first trimester: possible risk of gastroschisis; third trimester: may reduce uterine blood flow and cause fetal hypoxia. |
| Fetal Monitoring | Monitor maternal respiratory rate, blood pressure, and sedation level. Fetal monitoring for heart rate variability and signs of distress, especially in third trimester. Neonatal monitoring for respiratory depression, withdrawal symptoms, and extrapyramidal effects post-delivery. |
| Fertility Effects | Codeine: may impair fertility via opioid-induced hormonal changes (reduced LH, FSH, testosterone). Promethazine: possible effects on ovulation due to prolactin elevation. Phenylephrine: no known significant fertility effects. Reversible upon discontinuation. |
| Avoid alcohol entirely; alcohol potentiates CNS depression from both codeine and promethazine. Grapefruit juice may inhibit CYP3A4 metabolism of codeine, increasing toxicity; avoid concurrent use. Take with food if gastrointestinal upset occurs, but avoid high-fat meals as they may delay absorption of codeine. |
| Clinical Pearls | Promethazine VC w/ Codeine contains codeine, a prodrug requiring CYP2D6 metabolism to morphine. Ultra-rapid metabolizers (CYP2D6*2xN genotype) risk severe opioid toxicity; avoid in children <12 years and post-tonsillectomy/adenoidectomy in children <18. Promethazine has anticholinergic properties and can cause respiratory depression additive with codeine; avoid in patients with respiratory compromise. IV promethazine is contraindicated due to risk of severe tissue injury; use deep IM with careful technique. Monitor for serotonin syndrome when combined with other serotonergic drugs. |
| Patient Advice | This medication contains codeine, an opioid that can cause respiratory depression, especially in children; follow dosing exactly as prescribed and do not exceed recommended dose. · Do not consume alcohol or other CNS depressants (benzodiazepines, other opioids) while taking this medication as it increases risk of severe sedation and breathing problems. · Be aware that genetic variations can affect codeine metabolism; seek immediate medical attention for symptoms of opioid toxicity such as extreme sleepiness, confusion, or slow/shallow breathing. · Promethazine may cause drowsiness and impair cognitive or motor skills; avoid driving or operating heavy machinery until you know how you react. · Do not crush, chew, or break tablets; swallow whole with water. Shake the syrup well before measuring dose with the provided measuring device. · Report any signs of serotonin syndrome (agitation, hallucinations, fast heart rate, fever, muscle stiffness) if taken with other medications that affect serotonin. · Store securely out of reach of children and dispose of unused medication via a drug take-back program. |