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. |
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 | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
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 |
| Breastfeeding | Codeine and promethazine are excreted into breast milk. Codeine M/P ratio approximately 2.5; risk of infant opioid toxicity, especially in CYP2D6 ultra-rapid metabolizers. Promethazine may cause drowsiness or irritability in infants. Phenylephrine is minimally excreted; M/P ratio unknown. Use contraindicated during breastfeeding due to risks of respiratory depression and sedation. |
■ 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 promethazine, codeine, or any component; pediatric patients <6 years; concurrent use of MAOIs or within 14 days; severe CNS depression; respiratory depression; acute asthma; obstructive airway disease; lower respiratory tract infections; coma; jaundice; pregnancy (opioid withdrawal in neonate).
| 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. |
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| 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. |