BROMODIPHENHYDRAMINE HYDROCHLORIDE AND CODEINE PHOSPHATE
Clinical safety rating: safe
CNS depressants may enhance sedative effects May cause marked drowsiness and impair mental and physical abilities.
Bromodiphenhydramine hydrochloride is a first-generation antihistamine that antagonizes histamine H1 receptors, reducing allergic symptoms. Codeine phosphate is an opioid agonist at mu-opioid receptors, producing analgesia and antitussive effects. Combination provides enhanced cough suppression.
| Metabolism | Bromodiphenhydramine undergoes hepatic metabolism via CYP450 enzymes, primarily CYP2D6 and CYP3A4. Codeine is metabolized by CYP2D6 to morphine (active), CYP3A4 to norcodeine, and glucuronidation. |
| Excretion | Renal: 70-80% as metabolites (codeine ~10% unchanged; diphenhydramine <5% unchanged). Biliary/fecal: 20-30%. |
| Half-life | Codeine: 2.5-3.5 h (adults), prolonged in hepatic impairment. Diphenhydramine: 4-8 h (adults), extended in elderly. |
| Protein binding | Codeine: 7-25% (albumin). Diphenhydramine: 80-85% (albumin, alpha-1-acid glycoprotein). |
| Volume of Distribution | Codeine: 3-6 L/kg. Diphenhydramine: 4-8 L/kg; extensive tissue distribution. |
| Bioavailability | Oral: codeine 90% (extensive first-pass metabolism). Diphenhydramine: 40-60%. |
| Onset of Action | Oral: codeine 30-60 min, diphenhydramine 15-30 min. |
| Duration of Action | Codeine: 4-6 h (analgesia). Diphenhydramine: 4-6 h (antihistamine), 6-8 h (sedation). |
5 mL of oral solution (containing bromodiphenhydramine hydrochloride 12.5 mg and codeine phosphate 10 mg) every 4-6 hours as needed; maximum 4 doses in 24 hours.
| Dosage form | SYRUP |
| Renal impairment | GFR >50 mL/min: no adjustment; GFR 10-50 mL/min: administer every 6 hours; GFR <10 mL/min: not recommended. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 50% or extend interval; Child-Pugh C: contraindicated. |
| Pediatric use | Children 6-11 years: 2.5-5 mL every 4-6 hours; maximum 4 doses/day. Children 12-17 years: same as adult dosing. Weight-based: codeine 0.5-1 mg/kg/dose every 4-6 hours; not recommended in children <6 years. |
| Geriatric use | Start with half the adult dose (2.5 mL) every 6 hours; monitor for CNS depression and constipation; avoid in patients with impaired renal or hepatic function. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
CNS depressants may enhance sedative effects May cause marked drowsiness and impair mental and physical abilities.
| FDA category | Animal |
| Breastfeeding | Bromodiphenhydramine: Excreted into breast milk; concentration unknown; may cause sedation or irritability in infant; avoid due to anticholinergic effects. Codeine: M/P ratio approximately 2.5 for morphine (active metabolite); infant exposure depends on maternal CYP2D6 metabolism; risk of central nervous system depression in breastfed infants; use is generally contraindicated due to potential for opioid toxicity, especially in ultra-rapid metabolizers. Alternate analgesics recommended. |
■ FDA Black Box Warning
Codeine is contraindicated in children younger than 12 years for cough treatment due to risk of respiratory depression and death. Avoid use in children <18 years with risk factors for respiratory depression.
| Common Effects | insomnia |
| Serious Effects |
Hypersensitivity to any component; children <12 years; significant respiratory depression; acute asthma; obstructive airway disease; concurrent MAOI use or within 14 days; severe hypertension; coronary artery disease; urinary retention; glaucoma; breastfeeding.
| Precautions | Respiratory depression risk, especially in children and CYP2D6 ultra-rapid metabolizers; CNS depression; addiction potential; sedation; anticholinergic effects; exacerbated glaucoma, urinary retention, hyperthyroidism, cardiovascular disease; avoid alcohol. |
| Food/Dietary |
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| Teratogenic Risk |
| First trimester: Limited data; bromodiphenhydramine is an antihistamine with potential anticholinergic effects; codeine is an opioid and prodrug to morphine; animal studies with codeine show increased risk of cleft palate, but human data are insufficient to confirm teratogenicity. Second trimester: No specific structural defects attributed; pharmacological effects may persist but risk appears low. Third trimester: Chronic maternal opioid use can cause neonatal opioid withdrawal syndrome (NOWS) and respiratory depression at birth; codeine use near term may lead to neonatal respiratory depression due to placental transfer of morphine. Overall, use only if benefit outweighs risk. |
| Fetal Monitoring | Maternal: Monitor for respiratory depression, sedation, constipation, urinary retention, and signs of histamine release. Fetal: Ultrasound for growth restriction if chronic use; third trimester: fetal heart rate monitoring and biophysical profile to assess well-being; neonatal: observe for respiratory depression and withdrawal symptoms (NOWS) after delivery. |
| Fertility Effects | Limited data; antihistamines like bromodiphenhydramine are not known to impair fertility. Codeine may affect hormonal regulation via opioid receptor modulation; chronic use can disrupt menstrual cycle and reduce fertility in females; in males, may alter sperm parameters (decreased motility/ count) — typically reversible upon discontinuation. |
| Avoid alcohol and grapefruit juice; alcohol potentiates central nervous system depression, and grapefruit juice may affect codeine metabolism. No significant food restrictions otherwise. |
| Clinical Pearls | Bromodiphenhydramine is a first-generation antihistamine with sedative properties; codeine is an opioid antitussive. This fixed-dose combination exploits central antitussive synergy but increases central nervous system depression risk. Use cautiously in patients with respiratory compromise, asthma, or chronic obstructive pulmonary disease. Avoid in children under 12 years due to codeine's risk of respiratory depression. Monitor for serotonin syndrome when co-administered with serotonergic drugs. Codeine is a prodrug requiring CYP2D6 metabolism for activation; ultra-rapid metabolizers risk toxicity. |
| Patient Advice | This medication may cause severe drowsiness; avoid driving or operating heavy machinery until you know how it affects you. · Do not consume alcohol or other sedatives while taking this drug. · Take exactly as prescribed; do not increase dose or frequency due to risk of dependence and respiratory depression. · If you have difficulty breathing, shallow breathing, or extreme drowsiness, seek emergency help immediately. · Do not use this medication in children under 12 years old. |