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. |
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 | 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 is excreted into breast milk; M/P ratio 2.4; risk of infant CNS depression and apnea, especially in CYP2D6 ultra-rapid metabolizers. Promethazine is excreted in small amounts; may cause drowsiness. Use with caution; consider lowest effective dose and monitor infant for sedation and respiratory depression. |
| Teratogenic Risk |
■ 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 promethazine, codeine, or any component of the formulation; pediatric patients <2 years (promethazine); pediatric patients <12 years for cough and pain (codeine); pediatric patients <18 years after tonsillectomy/adenoidectomy (codeine); treatment of cough in pediatric patients <12 years (codeine); concomitant use of MAOIs or within 14 days; severe respiratory depression; acute or severe bronchial asthma; gastrointestinal obstruction; known CYP2D6 poor metabolizers; signs of respiratory depression in children
| Precautions |
Loading safety data…
| 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. |
| 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. |