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. |
| Molecular Weight | Promethazine HCl: 320.9 Da; Codeine Phosphate: 406.4 Da (salt form); Codeine base: 299.4 Da |
| Action Class | Antihistamine / Antiemetic (promethazine); Opioid agonist (codeine) |
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 | Avoid in first trimester unless absolutely necessary; risk of teratogenicity not definitively established, but codeine is associated with congenital malformations in some studies. |
| 2nd trimester | Use with caution; may cause respiratory depression in fetus if used near term. |
| 3rd trimester | Avoid in third trimester, especially near delivery; may cause neonatal respiratory depression, withdrawal syndrome, and codeine is metabolized to morphine which can cross placenta. |
Clinical note
CNS depressants may enhance sedative effects Can cause respiratory depression in children and extrapyramidal symptoms.
| FDA category | Animal |
| Placental transfer | Both promethazine and codeine cross the placenta; codeine is metabolized to morphine which also crosses. Fetal concentrations can be similar to maternal levels. |
■ 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 | Respiratory depression, Severe hypotension, Neuroleptic malignant syndrome, Seizures, QT prolongation / torsades de pointes, Severe bone marrow suppression (agranulocytosis, leukopenia), Paradoxical CNS stimulation (especially in children), Serotonin syndrome (when combined with other serotonergic drugs), Physical dependence and withdrawal (codeine), Hepatotoxicity (with high doses or overdose) |
Hypersensitivity to promethazine, codeine, or any componentComatose statesSevere respiratory depression (without resuscitation equipment)Acute or severe bronchial asthma (codeine)Paralytic ileusConcurrent use of MAOIs (or within 14 days)Children < 6 years (risk of respiratory depression from codeine; promethazine contraindicated in children <2 years due to risk of fatal respiratory depression)Breastfeeding in CYP2D6 ultra-rapid metabolizers (codeine)
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| Breastfeeding | Codeine is excreted into breast milk; risk of infant opioid toxicity, especially in CYP2D6 ultra-rapid metabolizers. Promethazine may cause drowsiness in infant. Use lowest effective dose for shortest duration; monitor infant for sedation and respiratory depression. Alternative analgesics preferred. |
| Lactation Rating | L4 (Possibly Hazardous) |
| Teratogenic Risk | 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. |
| 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. |
| Food/Dietary | Avoid alcohol and foods containing alcohol (e.g., wine, beer, some desserts). Limit consumption of high-fat meals as they may delay absorption. Avoid large amounts of caffeine; increased CNS stimulation may occur. No other specific food interactions known. |
| Clinical Pearls | Promethazine is a phenothiazine antiemetic with strong sedative effects; codeine is an opioid antitussive. Use with caution in children <6 years old due to risk of fatal respiratory depression. Avoid in patients with asthma or COPD. Monitor for CNS depression and constipation. Do not exceed recommended doses; codeine is a prodrug metabolized by CYP2D6 to morphine, so ultrarapid metabolizers risk toxicity. Promethazine can cause extrapyramidal symptoms, especially in elderly. Do not use in patients with known hypersensitivity to phenothiazines. IV administration can cause tissue necrosis; give deep IM only. |
| Patient Advice | This medication can cause drowsiness; avoid driving or operating machinery until you know how it affects you. · Do not drink alcohol or use other sedatives while taking this drug. · Take only the prescribed dose; do not increase or take more frequently without consulting your doctor. · May cause constipation; increase fluid intake and dietary fiber. · Avoid prolonged sun exposure; may cause photosensitivity. · If you are pregnant or breastfeeding, discuss risks with your doctor. · Seek emergency care if you experience slow breathing, confusion, or severe dizziness. · Do not give to children under 6 years of age. · Use sugar-free products if you have diabetes (syrup may contain sugar). |