AMBENYL
Clinical safety rating: caution
Comprehensive clinical and safety monograph for AMBENYL (AMBENYL).
AMBENYL is a combination product containing codeine (opioid agonist) and bromodiphenhydramine (antihistamine). Codeine binds to mu-opioid receptors in the CNS, inhibiting ascending pain pathways and altering pain perception; bromodiphenhydramine antagonizes histamine H1 receptors, producing antitussive and sedative effects.
| Metabolism | Codeine is metabolized via CYP2D6 to morphine (active), CYP3A4 to norcodeine, and to a lesser extent via glucuronidation; bromodiphenhydramine is metabolized via CYP450 enzymes, primarily CYP2D6. |
| Excretion | Renal: 60% unchanged codeine, 20% codeine-6-glucuronide; biliary/fecal: 20% as metabolites. Guaifenesin: renal 95% as unchanged drug and metabolites. |
| Half-life | Codeine: 2.5-3.5 h (terminal) with CYP2D6 poor metabolizers up to 6 h. Guaifenesin: 1-2 h. |
| Protein binding | Codeine: 7-25% (albumin). Guaifenesin: negligible. |
| Volume of Distribution | Codeine: 3-6 L/kg (extensive tissue distribution). Guaifenesin: 1-2 L/kg. |
| Bioavailability | Codeine: oral 90% (first-pass metabolism). Guaifenesin: oral 100% (well absorbed). |
| Onset of Action | Codeine: oral 30-60 min. Guaifenesin: oral 30 min. |
| Duration of Action | Codeine: 4-6 h (analgesic/antitussive). Guaifenesin: 4-6 h (expectorant). |
Each 5 mL contains codeine phosphate 10 mg and diphenhydramine hydrochloride 12.5 mg. Adults: 10 mL (2 teaspoonfuls) orally every 4-6 hours as needed; maximum 40 mL per day.
| Dosage form | SYRUP |
| Renal impairment | GFR 30-50 mL/min: use with caution, reduce dose by 25-50% and monitor for CNS depression. GFR <30 mL/min: avoid use or use with extreme caution; codeine accumulation risk. |
| Liver impairment | Child-Pugh A: no adjustment needed. Child-Pugh B: use with caution, consider 50% dose reduction. Child-Pugh C: avoid use. |
| Pediatric use | Not recommended for children under 6 years. Children 6-12 years: 5 mL (1 teaspoonful) orally every 4-6 hours; maximum 20 mL per day. Children >12 years: adult dosing. |
| Geriatric use | Initiate at 5 mL every 6 hours due to increased sensitivity to anticholinergic and CNS depressant effects; monitor for confusion, sedation, and urinary retention. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for AMBENYL (AMBENYL).
| Breastfeeding | Codeine is excreted in breast milk (M/P ratio ~2.5); risk of neonatal opioid toxicity (CNS depression). Diphenhydramine may inhibit lactation and cause drowsiness in infant. Contraindicated during breastfeeding due to possible severe adverse reactions in neonates. |
| Teratogenic Risk | FDA Pregnancy Category C. First trimester: Limited data; potential for fetal malformations (cleft palate, cardiac defects) based on animal studies with high-dose antihistamines. Second and third trimesters: Risk of neonatal respiratory depression, irritability, and withdrawal if used near term. Avoid in third trimester due to risk of premature closure of ductus arteriosus (codeine component). |
■ FDA Black Box Warning
Risk of respiratory depression, especially in children; risk of opioid addiction, abuse, and misuse; risk of neonatal opioid withdrawal syndrome with prolonged use during pregnancy; CYP2D6 ultra-rapid metabolizers may convert codeine to morphine at higher rates, leading to fatal respiratory depression.
| Serious Effects |
Children <12 years; post-operative management in children <18 years after tonsillectomy/adenoidectomy; respiratory depression; acute or severe bronchial asthma; known hypersensitivity to codeine, bromodiphenhydramine, or any component; concurrent use of monoamine oxidase inhibitors (MAOIs) or within 14 days; gastrointestinal obstruction; paralytic ileus.
| Precautions | Respiratory depression; use in children <12 years contraindicated; risk of opioid-induced hyperalgesia; central nervous system depression; sedation; constipation; urinary retention; hypotension; anticholinergic effects; potential for misuse, abuse, and addiction; serotonin syndrome if used with other serotonergic drugs; adrenal insufficiency; risk of severe hypotension in volume-depleted patients; interactions with CNS depressants. |
| Food/Dietary |
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| Fetal Monitoring | Monitor maternal respiratory rate, sedation level, and bowel function (constipation). Fetal monitoring for heart rate variability and growth restriction if used chronically. Neonatal monitoring for withdrawal symptoms (irritability, poor feeding) if used near delivery. |
| Fertility Effects | Limited data. Codeine may impair male fertility via hormonal disruption and sperm motility reduction. Diphenhydramine may cause galactorrhea and menstrual irregularities via prolactin elevation. No established impact on female fertility. |
| Zolpidem absorption is delayed and reduced when taken with food, especially high-fat meals. To achieve rapid onset of sleep, take on an empty stomach. Avoid grapefruit juice as it may increase zolpidem levels. |
| Clinical Pearls | Ambien (zolpidem) is a non-benzodiazepine sedative-hypnotic used primarily for short-term insomnia. Avoid co-administration with alcohol or other CNS depressants. Use the lowest effective dose, especially in elderly patients, due to increased risk of falls and cognitive impairment. Monitor for complex sleep behaviors (e.g., sleep-driving). Tablet should be taken immediately before bedtime, not with or after a meal to avoid delayed onset. |
| Patient Advice | Take zolpidem exactly as prescribed, only when you have at least 7-8 hours to devote to sleep. · Do not take zolpidem with alcohol or other sedatives as this can cause severe drowsiness and dangerous side effects. · Avoid driving or operating machinery the morning after taking zolpidem, as it may cause drowsiness, dizziness, or impaired coordination. · Report any unusual behaviors during sleep, such as walking, eating, or driving, to your doctor immediately. · Do not crush, chew, or split the extended-release tablets; swallow them whole. |