PHERAZINE 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.
Promethazine is a phenothiazine derivative that acts as a histamine H1 receptor antagonist, antiemetic, and sedative. It also exerts anticholinergic and antidopaminergic effects, particularly at D2 receptors. Codeine is an opioid agonist primarily at mu-opioid receptors, leading to analgesia and antitussive effects. The combination enhances sedation and antiemetic action.
| Metabolism | Promethazine is extensively metabolized in the liver via oxidation and glucuronidation, primarily by CYP2D6 and to a lesser extent CYP1A2, CYP2B6, and CYP2C19. Codeine is metabolized by CYP2D6 to morphine (active), CYP3A4 to norcodeine (active), and by glucuronidation. |
| Excretion | Renal (50-70% as unchanged promethazine and metabolites; codeine and its metabolites, primarily morphine and codeine-6-glucuronide, are excreted renally). Biliary/fecal elimination accounts for less than 10%. |
| Half-life | Promethazine: 9-16 hours in adults; codeine: 2.5-3.5 hours; morphine: 1.5-2 hours. Clinical context: The half-life of codeine is shorter, but its active metabolite morphine contributes to analgesia. Accumulation may occur with repeated dosing. |
| Protein binding | Promethazine: ~93% bound to plasma proteins (primarily albumin). Codeine: ~7-25% bound to albumin. |
| Volume of Distribution | Promethazine: 14-22 L/kg (large Vd indicating extensive tissue distribution). Codeine: 3-6 L/kg. Clinical meaning: Promethazine distributes widely, including across the blood-brain barrier. |
| Bioavailability | Oral promethazine: ~25% due to extensive first-pass metabolism. Oral codeine: ~50-90% (varies by formulation; first-pass metabolism to morphine accounts for 10-15% of the dose). |
| Onset of Action | Oral: 20-30 minutes for analgesic effects (codeine); antihistaminic/sedative effects of promethazine begin within 15-30 minutes. Peak effects occur at 60-90 minutes. |
| Duration of Action | Analgesic effects of codeine: 4-6 hours; sedative effects of promethazine: up to 6-8 hours. Clinical note: Duration varies with dose and patient factors; caution for CNS depression. |
| Molecular Weight | 339.82 |
One tablet (promethazine 6.25 mg / codeine 10 mg) orally every 4-6 hours as needed; maximum 4 tablets in 24 hours.
| Dosage form | SYRUP |
| Renal impairment | GFR 30-60 mL/min: extend dosing interval to every 8-12 hours; GFR 10-29 mL/min: administer every 12-18 hours; GFR <10 mL/min: use not recommended. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: administer with caution, reduce dose by 25-50%; Child-Pugh C: contraindicated. |
| Pediatric use | Weight-based: promethazine 0.25-0.5 mg/kg and codeine 0.5-1 mg/kg per dose orally every 4-6 hours; maximum 4 doses per day. Not recommended in children <2 years due to risk of respiratory depression. Use lowest effective dose. |
| Geriatric use | Start at lowest effective dose (half tablet orally every 6 hours) due to increased sensitivity to anticholinergic effects and respiratory depression; maximum 3 tablets per 24 hours; monitor closely for sedation and confusion. |
| 1st trimester | Avoid unless absolutely necessary; codeine may cause neural tube defects in animal studies, but human data limited. Use only if benefit outweighs risk. |
| 2nd trimester | Caution; prolonged use may lead to maternal opioid dependence and neonatal withdrawal. Use lowest effective dose for shortest duration. |
| 3rd trimester | Avoid near term; risk of neonatal respiratory depression and opioid withdrawal syndrome. Codeine is metabolized to morphine; neonatal toxicity 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 | Codeine and its active metabolite morphine cross the placenta readily; fetal concentrations may reach maternal levels. Evidence: significant transfer documented. |
■ FDA Black Box Warning
Respiratory depression in children: Promethazine is contraindicated in children younger than 2 years. Use in children 2 years and older with caution and at the lowest effective dose. Risk of respiratory depression and death with promethazine in pediatric patients. Codeine is contraindicated in children younger than 12 years for cough and pain, and in children younger than 18 years after tonsillectomy/adenoidectomy due to risk of respiratory depression and death.
| Common Effects | cough |
| Serious Effects |
Hypersensitivity to codeine, promethazine, or any componentSevere respiratory depressionBronchial asthma (acute or severe)Acute or postoperative pain in children undergoing tonsillectomy/adenoidectomy (risk of fatal respiratory depression)Concurrent use of MAOIs (or within 14 days)Pediatric patients < 6 years of age (due to promethazine risk of fatal respiratory depression)Pregnancy (especially third trimester) and laborLactation (especially with CYP2D6 ultra-rapid metabolizer status)CNS depression, coma, head injury, increased intracranial pressureGastrointestinal obstruction, paralytic ileus, known or suspected COPDAsthma attack, acute febrile illness, Reye's syndrome (promethazine should not be used in children with these)Liver failure, severe hepatic impairment
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| Breastfeeding | Codeine is excreted in breast milk; risk of infant sedation, respiratory depression, and opioid toxicity. Contraindicated in women who are ultra-rapid metabolizers of CYP2D6. Avoid use during breastfeeding; if necessary, monitor infant for drowsiness and difficulty breathing. |
| Lactation Rating | L4 (Hazardous - potentially dangerous; if used, closely monitor infant for adverse effects). |
| Teratogenic Risk | First trimester: limited human data; codeine associated with respiratory depression and withdrawal in neonates; promethazine not associated with major malformations but may cause fetal CNS depression. Second/third trimester: chronic use may lead to neonatal opioid withdrawal syndrome (NOWS) and respiratory depression. Avoid in third trimester due to risk of prolonged labor and neonatal respiratory depression. |
| Fetal Monitoring | Monitor maternal respiratory rate, sedation level, and bowel function. Fetal monitoring for heart rate variability and decelerations. In neonates, observe for signs of opioid withdrawal (e.g., irritability, poor feeding, tremors) and respiratory depression. Consider umbilical cord drug testing if chronic use. |
| Fertility Effects | Codeine may impair female fertility via disruption of menstrual cycle and ovulation. Promethazine may cause hyperprolactinemia and galactorrhea, potentially affecting fertility. No adequate studies in males; possible sperm abnormalities with chronic opioid use. |
| Precautions | Respiratory depression, especially in children; increased risk of CNS depression with alcohol or other CNS depressants; anticholinergic effects (dry mouth, blurred vision, urinary retention); extrapyramidal reactions; tardive dyskinesia with long-term use; neuroleptic malignant syndrome (rare); hypotension; caution in patients with asthma, COPD, sleep apnea, or other respiratory conditions; risk of serotonin syndrome with serotonergic drugs; adrenal insufficiency with prolonged use; opioid-induced hyperalgesia; increased intracranial pressure; severe hypotension; hepatotoxicity; pancreatitis; bone marrow suppression; caution in patients with glaucoma, prostatic hypertrophy, or urinary retention. |
| Food/Dietary | Avoid alcohol and caffeine. Grapefruit juice may alter codeine metabolism. High-fat meals may increase absorption of codeine. May cause food intolerance due to sedation. |
| Clinical Pearls | Promethazine is a phenothiazine with antihistaminic and antiemetic properties; codeine is an opioid prodrug. This combination is used for cough and cold symptoms. Beware of respiratory depression, especially in children and elderly. Codeine metabolism via CYP2D6; poor metabolizers may have reduced efficacy, ultra-rapid metabolizers risk toxicity. Avoid in children <12 years (FDA black box). May cause dystonic reactions, neuroleptic malignant syndrome. Do not use concurrently with other CNS depressants. |
| Patient Advice | Do not exceed recommended dose; can cause severe drowsiness or breathing problems. · Avoid alcohol and other sedatives while taking this medication. · Do not use in children under 12 years of age; risk of fatal respiratory depression. · May cause dizziness; avoid driving or operating machinery. · Stop and seek medical attention if you experience slow or shallow breathing, confusion, or severe drowsiness. · Inform your doctor if you have asthma, COPD, or liver/kidney disease. · Do not crush or chew extended-release formulations. Take only as directed. · May cause constipation; increase fluid and fiber intake. · Do not stop suddenly; withdrawal may occur. Consult doctor for tapering. · Store safely away from children; overdose can be fatal. |