PROMETHAZINE HYDROCHLORIDE; CODEINE PHOSPHATE
Clinical safety rating: safe
CNS depressants may enhance sedative effects Can cause respiratory depression in children and extrapyramidal symptoms.
Promethazine is a phenothiazine derivative that acts as a histamine H1 receptor antagonist, antiemetic, and sedative via blockade of central and peripheral H1 receptors and antagonism of dopamine D2 receptors. Codeine is an opioid agonist that binds to mu-opioid receptors in the CNS, producing analgesia and cough suppression; it also has antitussive effects via central action.
| Metabolism | Promethazine is extensively metabolized in the liver via CYP2D6 and other pathways; codeine is metabolized by CYP2D6 to morphine (active), and by CYP3A4 to norcodeine. |
| Excretion | Promethazine: Renal (70-80% as metabolites, <1% unchanged); Codeine: Renal (70-90% as metabolites, 5-15% unchanged). Biliary/feces: Minor (<10% total). |
| Half-life | Promethazine: 10-19 hours (terminal); Codeine: 2.4-4 hours (terminal), prolonged in hepatic impairment. Clinical context: Dosing interval typically 4-6 hours for codeine; promethazine accumulates with repeated dosing. |
| Protein binding | Promethazine: 88-93% bound primarily to albumin; Codeine: 7-25% bound primarily to albumin. |
| Volume of Distribution | Promethazine: 13-18 L/kg (extensive tissue distribution); Codeine: 3-6 L/kg (moderate distribution). Clinical meaning: Large Vd indicates extensive tissue uptake. |
| Bioavailability | Promethazine: Oral 25% (extensive first-pass), IM 85-90%, rectal 70-80%; Codeine: Oral 50-60% (first-pass metabolism), IM 80-90%. |
| Onset of Action | Promethazine: Oral 20-30 min, IM/IV 15-20 min, rectal 20-30 min; Codeine: Oral 30-60 min, IM 10-30 min. |
| Duration of Action | Promethazine: 4-12 hours (antiemetic, sedative); Codeine: 4-6 hours (analgesic). Clinical notes: Promethazine duration longer for sedation; codeine duration dose-dependent. |
Promethazine hydrochloride 6.25-25 mg / codeine phosphate 10-20 mg (based on codeine component) orally every 4-6 hours as needed. Maximum codeine dose: 60 mg per dose, 120 mg per day.
| Dosage form | SYRUP |
| Renal impairment | GFR 30-59 mL/min: Use with caution; consider reducing codeine dose by 25-50% or extending interval. GFR <30 mL/min: Avoid use; codeine accumulation risk. |
| Liver impairment | Child-Pugh Class A: No adjustment. Class B: Reduce codeine dose by 50% or extend interval. Class C: Avoid use; risk of toxicity. |
| Pediatric use | Children ≥12 years: 5-10 mL (containing promethazine 6.25 mg/ codeine 10 mg per 5 mL) orally every 4-6 hours as needed. Maximum: 30 mL/day. Not recommended for children <12 years due to respiratory depression risk. |
| Geriatric use | Initiate at lowest effective dose (e.g., promethazine 6.25 mg / codeine 10 mg) every 6 hours; monitor for sedation, confusion, and respiratory depression. Avoid in patients with significant hepatic or renal impairment. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
CNS depressants may enhance sedative effects Can cause respiratory depression in children and extrapyramidal symptoms.
| FDA category | Animal |
| Breastfeeding | Codeine is excreted into breast milk; M/P ratio approximately 2.5 (range 1.5-4.0). Risk of infant opioid toxicity, especially in CYP2D6 ultra-rapid metabolizers. Promethazine is excreted in small amounts; M/P ratio unknown. Generally not recommended due to potential for infant sedation and respiratory depression. If used, monitor infant for excess sleepiness, difficulty breathing, or poor feeding. |
| Teratogenic Risk |
■ FDA Black Box Warning
WARNING: RISK OF RESPIRATORY DEPRESSION IN CHILDREN; CODEINE USE POST-ADENOTONSILLECTOMY CONTRANDICATED; CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS MAY RESULT IN PROFOUND SEDATION, RESPIRATORY DEPRESSION, COMA, AND DEATH; PROLONGED USE DURING PREGNANCY MAY RESULT IN NEONATAL OPIOID WITHDRAWAL SYNDROME.
| Common Effects | nausea/vomiting |
| Serious Effects |
Hypersensitivity to promethazine or codeine, severe respiratory depression, acute asthma, status asthmaticus, GI obstruction, concurrent use of MAOIs or within 14 days, breastfeeding (codeine), children <6 years (due to FDA boxed warning), post-adenotonsillectomy in children (codeine), severe hepatic/renal impairment.
| Precautions | Respiratory depression (especially in children), CNS depression, risk of opioid addiction/abuse, potential for serotonin syndrome, severe hypotension, extrapyramidal symptoms, neuroleptic malignant syndrome, lowered seizure threshold, anticholinergic effects, interaction with MAOIs or other serotonergic drugs, impaired ability to drive/operate machinery. |
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| First trimester: Codeine is associated with increased risk of congenital malformations (specifically cardiac defects) based on some epidemiological studies; promethazine has not shown consistent teratogenic risk. Second trimester: No specific major risks identified, but opioid exposure may affect fetal growth. Third trimester: Prolonged use of codeine may cause neonatal opioid withdrawal syndrome (NOWS) and respiratory depression; promethazine may increase risk of neonatal respiratory depression if used near term. |
| Fetal Monitoring | Monitor maternal respiratory rate, sedation level, blood pressure. Fetal heart rate monitoring during labor if used. Assess neonatal for signs of opioid withdrawal (NOWS) using Finnegan scoring. Monitor infant for respiratory depression if used near delivery. For prolonged use, assess fetal growth via ultrasound. |
| Fertility Effects | Codeine may inhibit ovulation by increasing prolactin levels (mechanism uncertain). Promethazine may cause galactorrhea and menstrual irregularities via prolactin elevation. Effects on male fertility unknown but theoretically may affect sperm quality due to anticholinergic properties. |