PHERAZINE 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.
Codeine: Opioid receptor agonist (mu-receptor), suppresses cough reflex. Phenylephrine: Alpha-1 adrenergic receptor agonist, vasoconstrictor. Promethazine: Histamine H1 receptor antagonist, anticholinergic, antiemetic.
| Metabolism | Codeine: CYP2D6 (to morphine), CYP3A4 (to norcodeine); Promethazine: CYP2D6, glucuronidation; Phenylephrine: Monoamine oxidase (MAO) and sulfation. |
| Excretion | Renal: codeine (40-70% as free and conjugated metabolites, including morphine, norcodeine, and hydromorphone); phenylephrine (80-90% as conjugated metabolites, 10% unchanged); promethazine (primarily as sulfoxides and glucuronides, renal elimination about 70%). Fecal/biliary: minor. |
| Half-life | Codeine: 2.5-3.5 hours (terminal); phenylephrine: 2-3 hours; promethazine: 10-19 hours (clinical context: prolonged in renal impairment, accumulation with chronic use). |
| Protein binding | Codeine: ~7-25% (albumin); phenylephrine: ~95% (albumin); promethazine: ~86-93% (albumin, alpha-1-acid glycoprotein). |
| Volume of Distribution | Codeine: 3-6 L/kg (extensive tissue distribution, crosses blood-brain barrier); phenylephrine: 4-5 L/kg (poor CNS penetration due to hydrophilic nature); promethazine: 9-20 L/kg (large Vd, extensive tissue binding). |
| Bioavailability | Oral: codeine 40-70% (first-pass metabolism to morphine and others); phenylephrine: <40% (significant presystemic metabolism in gut wall and liver); promethazine: ~25% (extensive first-pass metabolism). |
| Onset of Action | Oral: codeine (30-60 minutes); phenylephrine (15-30 minutes); promethazine (20-30 minutes). |
| Duration of Action | Codeine: 4-6 hours (analgesia); phenylephrine: 3-6 hours (decongestant); promethazine: 4-12 hours (antiemetic, sedative). Duration of antitussive effect for codeine up to 6 hours. |
Adults: 5 mL (one teaspoonful) orally every 4 to 6 hours as needed; each 5 mL contains promethazine hydrochloride 5 mg, phenylephrine hydrochloride 5 mg, and codeine phosphate 10 mg. Maximum daily dose: codeine 120 mg (6 doses).
| Dosage form | SYRUP |
| Renal impairment | GFR 10-50 mL/min: administer every 6-8 hours. GFR <10 mL/min: administer every 8-12 hours. Avoid use if GFR <30 mL/min for regular dosing due to risk of codeine accumulation. |
| Liver impairment | Child-Pugh Class B: reduce dose by 50% and extend interval to every 8-12 hours. Class C: avoid use due to risk of codeine-induced encephalopathy. |
| Pediatric use | Children 6-12 years: 5 mL (one teaspoonful) orally every 4-6 hours as needed; maximum 6 doses per day. Children 2-5 years: 2.5 mL every 4-6 hours as needed; maximum 4 doses per day. Not recommended in children <2 years due to risk of respiratory depression. |
| Geriatric use | Initial dose: 2.5 mL every 6-8 hours as needed; titrate cautiously. Maximum 4 doses per day. Monitor for hypotension, sedation, and constipation. Avoid in patients with impaired renal or hepatic function. |
| 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 is excreted in breast milk (M/P ratio ~2.5); risk of infant opioid toxicity, especially in CYP2D6 ultra-rapid metabolizers (potentially fatal). Promethazine passes into milk; may cause infant drowsiness, irritability, or apnea. Use caution; consider safer alternatives. M/P ratio for promethazine not well-defined. |
| Teratogenic Risk |
■ FDA Black Box Warning
Codeine: Risk of respiratory depression, addiction, abuse, and misuse; life-threatening respiratory depression in children with CYP2D6 ultra-rapid metabolizer phenotype; neonatal opioid withdrawal syndrome with prolonged use during pregnancy.
| Common Effects | cough |
| Serious Effects |
Hypersensitivity to any component; premature infants; neonates; severe hypertension; narrow-angle glaucoma; prostatic hypertrophy; concurrent MAOI use; known CYP2D6 ultra-rapid metabolizer (codeine); breastfeeding (codeine); severe respiratory depression.
| Precautions | Respiratory depression; drug dependence; CNS depression; risk of serotonin syndrome with serotonergic drugs; anticholinergic effects; prolonged QT interval; hypotension; paradoxical excitation; not for use in children < 6 years (codeine); avoid with MAOIs. |
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| First trimester: Codeine crosses placenta; risk of congenital malformations not significantly increased at therapeutic doses, but chronic high doses may cause neonatal opioid withdrawal. Phenerazine (promethazine) has limited data; no major malformation signal, but caution with high doses near term. Second/third trimester: Codeine may cause fetal respiratory depression, neonatal withdrawal syndrome, and preterm birth. Promethazine may cause maternal hypotension, reduced placental perfusion, and neonatal respiratory depression if given near term. Avoid in third trimester. |
| Fetal Monitoring | Monitor maternal respiratory rate, oxygen saturation, sedation level; fetal heart rate monitoring during labor; neonatal monitoring for opioid withdrawal (NACS scale), respiratory depression, and excessive sedation for at least 24-48 hours postpartum. Avoid concurrent CNS depressants. |
| Fertility Effects | Codeine may impair male fertility (reduced sperm motility/morphology) and female fertility (menstrual irregularities, ovulatory dysfunction) at high doses; promethazine has no known significant impact on fertility. |