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. |
| Molecular Weight | Codeine: 299.36 g/mol; Promethazine: 284.42 g/mol; Phenylephrine: 167.21 g/mol. For the combination product, typical molecular weight is variable; codeine component is primary concern. |
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 | Avoid unless absolutely necessary; studies suggest increased risk of congenital malformations with codeine use, though data is limited for the combination. Use lowest effective dose for shortest duration. |
| 2nd trimester | Use with caution; risk of fetal dependence and respiratory depression with codeine. Avoid prolonged use, especially near term. May cause maternal and fetal adverse effects. |
| 3rd trimester | Avoid; codeine can cause neonatal respiratory depression and withdrawal. Promethazine may cause extrapyramidal symptoms and possible respiratory depression in neonates. Use only if maternal benefit outweighs fetal risk. |
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 codeine and promethazine cross the placenta. Codeine reaches fetal plasma concentrations similar to maternal levels. Promethazine crosses readily and can accumulate in fetal tissues. |
■ 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 componentSevere asthma or COPD with respiratory compromiseUpper airway obstructionAcute or severe bronchial asthmaConcurrent use of MAOIs or within 14 days of MAOI useNeonatal or premature infants (especially regarding promethazine)Use in children < 2 years (risk of fatal respiratory depression with codeine, especially post-tonsillectomy/adenoidectomy for obstructive sleep apnea)
| 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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| Breastfeeding | Both codeine and promethazine are excreted into breast milk. Codeine is metabolized to morphine; risk of infant sedation, respiratory depression, and apnea in CYP2D6 ultra-rapid metabolizer mothers. Promethazine may cause drowsiness and irritability in infants. Avoid use during breastfeeding if possible. If used, monitor infant for excessive sleepiness, difficulty feeding, or respiratory depression. |
| Lactation Rating | L4 - Possibly Hazardous |
| Teratogenic Risk | 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. |
| Food/Dietary | Avoid alcohol and grapefruit juice (may increase codeine effects). No specific food interactions for pheniramine or phenylephrine. Maintain adequate fluid intake to help loosen secretions. |
| Clinical Pearls | PHERAZINE VC W/ CODEINE is a combination expectorant, decongestant, and antitussive. Monitor for CNS depression, especially when co-administered with other depressants. Avoid in patients with MAOI use within 14 days. Codeine is a prodrug metabolized by CYP2D6 to morphine; ultrarapid metabolizers risk toxicity. Use with caution in respiratory compromise, cough reflex suppression may be hazardous. Not recommended in children under 12 due to risk of respiratory depression. |
| Patient Advice | Take exactly as prescribed; do not exceed recommended dose or duration. · Do not take with alcohol, sedatives, or other CNS depressants without consulting your doctor. · May cause drowsiness or dizziness; avoid driving or operating machinery until effects are known. · Do not use for persistent or chronic cough, or with high fever, rash, or persistent headache. · Notify your doctor if cough lasts more than 5 days, returns, or occurs with fever, rash, or headache. · Keep out of reach of children; accidental overdose can be fatal. · If pregnant or breastfeeding, consult healthcare provider before use. · Rapid heartbeat, shortness of breath, or severe dizziness may indicate overdose; seek emergency help. |