PROMETH HYDROCHLORIDE,PHENYLEPHRINE HYDROCHLORIDE W/CODEINE PHOSPHATE
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 that acts as a histamine H1 receptor antagonist, anticholinergic, and antiemetic; phenylephrine is an alpha-1 adrenergic receptor agonist causing vasoconstriction; codeine is an opioid agonist at mu-opioid receptors, producing analgesia and antitussive effects.
| Metabolism | Promethazine: liver via CYP2D6; codeine: liver via CYP2D6 and CYP3A4 to morphine (active); phenylephrine: primarily metabolized by monoamine oxidase (MAO) and sulfate conjugation. |
| Excretion | Codeine: renal (10-30% unchanged, 40-70% as codeine-6-glucuronide, 5-15% as morphine and norcodeine conjugates); Promethazine: renal (70-80% as metabolites); Phenylephrine: renal (80-90% unchanged and as sulfate conjugates). |
| Half-life | Codeine: 2.5-3.5 hours (neonates: 4.5 hours); Promethazine: 9-16 hours (metabolites up to 24 hours); Phenylephrine: 2-3 hours (oral) or 30-60 minutes (IV). |
| Protein binding | Codeine: 7-25% (primarily albumin); Promethazine: 93% (plasma proteins); Phenylephrine: 95% (primarily albumin and alpha-1 acid glycoprotein). |
| Volume of Distribution | Codeine: 3.5-6 L/kg; Promethazine: 9-18 L/kg; Phenylephrine: 0.6-1.3 L/kg. |
| Bioavailability | Codeine: oral 53% (wide range 26-81%); Promethazine: oral 25% (extensive first-pass), IM 70-80%, rectal 15-20%; Phenylephrine: oral 38% (extensive first-pass), IM 100%, IV 100%. |
| Onset of Action | Codeine: oral 30-45 min, IM 10-30 min; Promethazine: oral 20-30 min, IM 20 min, rectal 30-60 min; Phenylephrine: oral 15-20 min, IM 10-15 min, IV immediate (seconds to 1 min). |
| Duration of Action | Codeine: 4-6 hours (analgesia), 3-4 hours (antitussive); Promethazine: 4-6 hours (antihistamine), up to 12 hours (sedation); Phenylephrine: oral 2-4 hours, IM 30-60 min, IV 15-20 min. |
Promethazine 6.25 mg/phenylephrine 5 mg/codeine 10 mg per 5 mL oral solution: 5 mL every 4 hours as needed; max 30 mL/day.
| Dosage form | SYRUP |
| Renal impairment | GFR 30-50 mL/min: use with caution; GFR <30 mL/min: avoid due to risk of codeine accumulation and CNS depression. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: use with caution, consider dose reduction; Child-Pugh C: contraindicated. |
| Pediatric use | Children ≥6 years: 0.25-0.5 mL/kg/dose (max 10 mL/dose) every 6 hours as needed; max 2.5 mg/kg/day of codeine component. |
| Geriatric use | Initiate at half the adult dose; monitor for CNS depression, respiratory depression, and falls; avoid in patients with cognitive impairment or COPD. |
| 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: Excreted in breast milk (M/P ratio 2.3 for morphine). Risk of infant sedation and respiratory depression; contraindicated in mothers who are ultra-rapid metabolizers of CYP2D6. Phenylephrine: Possibly excreted in breast milk (unknown M/P ratio); may reduce milk production due to vasoconstriction. Promethazine: Excreted in breast milk (M/P ratio not established); may cause drowsiness or irritability in infant. Breastfeeding not recommended. |
■ FDA Black Box Warning
Respiratory depression in children; avoid use in children younger than 6 years. Codeine should not be used in children for postoperative pain management after tonsillectomy/adenoidectomy due to risk of fatal respiratory depression from CYP2D6 ultra-rapid metabolizers.
| Common Effects | cough |
| Serious Effects |
Hypersensitivity to any component; children younger than 6 years; postoperative pain management in children after tonsillectomy/adenoidectomy; severe hypertension; coronary artery disease; patients taking MAOIs or within 14 days; respiratory depression; status asthmaticus; premature infants or neonates; breastfeeding (codeine).
| Precautions | Risk of respiratory depression, especially in children; avoid in patients with asthma, COPD, or respiratory compromise. Caution in patients with glaucoma, prostatic hypertrophy, urinary retention, or severe hepatic/renal impairment. May impair mental/physical abilities. Risk of serotonin syndrome with other serotonergic drugs. Avoid concurrent use of MAOIs. Codeine may cause dependence, abuse, or misuse. |
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| Teratogenic Risk |
| Codeine phosphate is contraindicated in pregnancy due to risk of neonatal opioid withdrawal syndrome (NOWS) and respiratory depression. First trimester: No adequate studies; potential for neural tube defects (animal data). Second and third trimesters: Prolonged use may cause NOWS; high doses near term may cause neonatal respiratory depression. Phenylephrine: First trimester: Possible risk of minor malformations (case-control studies). Second and third trimesters: May reduce uteroplacental blood flow; use with caution. Promethazine: First trimester: Limited data; possible association with congenital anomalies (retrospective studies). Second and third trimesters: May cause extrapyramidal symptoms or respiratory depression in neonate if used near term. |
| Fetal Monitoring | Maternal: Blood pressure, heart rate, respiratory rate, oxygen saturation, and level of sedation. Fetal: Heart rate monitoring (non-stress test or biophysical profile) in third trimester during prolonged use; ultrasound for growth restriction if phenylephrine used. Neonatal: Monitor for respiratory depression, sedation, and withdrawal symptoms (irritability, poor feeding) after delivery if codeine used near term. |
| Fertility Effects | Codeine: May impair fertility via opioid-mediated suppression of gonadotropin-releasing hormone (GnRH) and increased prolactin levels. Promethazine: Limited data; histamine H1 receptor antagonism may affect uterine contractility and implantation. Phenylephrine: No known direct fertility effects. Overall combination: No adequate studies; potential for transient reduction in fertility due to opioid and antihistamine effects. |