HYDROCODONE BITARTRATE AND CHLORPHENIRAMINE MALEATE
Clinical safety rating: avoid
CNS depressants including alcohol and benzodiazepines increase sedation risk Life-threatening respiratory depression may occur.
Hydrocodone is a full mu-opioid receptor agonist, exerting analgesic and antitussive effects by binding to opioid receptors in the CNS and cough center. Chlorpheniramine is a first-generation antihistamine that antagonizes histamine H1 receptors, reducing allergic symptoms.
| Metabolism | Hydrocodone is primarily metabolized by CYP3A4 and CYP2D6 to hydromorphone (active) and norhydrocodone. Chlorpheniramine is metabolized by CYP2D6 and other pathways. |
| Excretion | Hydrocodone: primarily renal excretion as unchanged drug and conjugated metabolites (approx. 26% unchanged); minor biliary/fecal elimination. Chlorpheniramine: renal excretion of metabolites and unchanged drug (approx. 30% unchanged), with some fecal elimination. |
| Half-life | Hydrocodone: 3.8-8.5 hours (mean 5.3 hours); context: immediate-release, dosing intervals typically 4-6 hours. Chlorpheniramine: terminal half-life 12-43 hours (mean 21 hours); context: longer half-life supports twice-daily dosing, but effects may not correlate linearly. |
| Protein binding | Hydrocodone: 19-45% bound to plasma proteins (mainly albumin). Chlorpheniramine: approximately 70% bound to plasma proteins (mainly albumin and alpha-1-acid glycoprotein). |
| Volume of Distribution | Hydrocodone: Vd 4.7 L/kg (total body water distribution, moderate tissue binding). Chlorpheniramine: Vd 3-7 L/kg (extensive tissue distribution, high tissue binding). |
| Bioavailability | Oral: Hydrocodone bioavailability approximately 50-70% (first-pass metabolism). Chlorpheniramine bioavailability 25-50% (significant first-pass metabolism). |
| Onset of Action | Oral: Hydrocodone onset 30-60 minutes; Chlorpheniramine onset 30-60 minutes. |
| Duration of Action | Oral: Hydrocodone duration 4-6 hours (analgesic effect). Chlorpheniramine duration 4-6 hours for allergy symptoms, but may persist longer due to half-life. |
| Molecular Weight | Hydrocodone bitartrate: 449.5 Da; Chlorpheniramine maleate: 390.9 Da (as combined: weight not additive, specify each active ingredient separately) |
| Action Class | Opioid Agonist; Antihistamine (First-generation H1 receptor antagonist) |
1 tablet (hydrocodone 5 mg/chlorpheniramine 4 mg) orally every 4-6 hours as needed; maximum 6 tablets per day.
| Dosage form | SOLUTION |
| Renal impairment | GFR 30-50: administer every 6 hours; GFR <30: avoid use due to accumulation of hydrocodone metabolites and risk of CNS depression. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B or C: avoid use or reduce dose by 50% and monitor for excessive sedation. |
| Pediatric use | Not recommended for children under 18 years of age due to risk of respiratory depression from hydrocodone. |
| Geriatric use | Initiate with half the usual adult dose, extend dosing interval to every 6 hours, and monitor closely for sedation and respiratory depression. |
| 1st trimester | Avoid: Risk of fetal malformations (e.g., respiratory defects, cardiac defects) associated with opioid use in first trimester. |
| 2nd trimester | Avoid: Risk of fetal dependence and neonatal abstinence syndrome; consider only if clearly needed. |
| 3rd trimester | Avoid: Prolonged use may cause neonatal opioid withdrawal syndrome; avoid during labor due to risk of respiratory depression in neonate. |
Clinical note
CNS depressants including alcohol and benzodiazepines increase sedation risk Life-threatening respiratory depression may occur.
| FDA category | Positive |
| Placental transfer | Both hydrocodone and chlorpheniramine cross the placenta; hydrocodone is known to produce fetal dependence and withdrawal. |
| Breastfeeding |
■ FDA Black Box Warning
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; CYTOCHROME P450 3A4 INTERACTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; INTERACTION WITH ALCOHOL; RISK OF MEDICATION ERRORS; NEONATAL OPIOID WITHDRAWAL SYNDROME; and RISKS OF CONCOMITANT USE WITH MAOIs.
| Common Effects | Cough |
| Serious Effects | Respiratory depression, Addiction, abuse, and misuse, Neonatal opioid withdrawal syndrome, Adrenal insufficiency, Severe hypotension, Seizures, Serotonin syndrome (with concomitant serotonergic drugs), Anticholinergic toxicity (e.g., delirium, hyperthermia, tachycardia) |
Hypersensitivity to hydrocodone, chlorpheniramine, or any componentSignificant respiratory depressionAcute or severe bronchial asthma in an unmonitored settingParalytic ileusConcurrent use of MAO inhibitors or within 14 days of stopping MAOIsKnown or suspected gastrointestinal obstructionNewborns and premature infantsNarrow-angle glaucomaSevere hypertension or coronary artery diseaseUrinary retention
| Precautions |
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| Hydrocodone and chlorpheniramine are excreted into breast milk. Hydrocodone may cause infant drowsiness, respiratory depression, and withdrawal symptoms. Chlorpheniramine may cause CNS stimulation or irritability in infants. Use only if clearly needed and monitor infant for adverse effects. |
| Lactation Rating | L4 (Possibly Hazardous) |
| Teratogenic Risk | First trimester: Opioid exposure associated with neural tube defects, congenital heart defects, and gastroschisis in some studies; antihistamine not associated with major malformations. Second/third trimester: Chronic use may lead to fetal opioid dependence, placental insufficiency, preterm labor, and intrauterine growth restriction. At delivery: Neonatal opioid withdrawal syndrome (NOWS) is expected if maternal use near term. |
| Fetal Monitoring | Assess fetal growth via ultrasound due to risk of intrauterine growth restriction; monitor for signs of preterm labor. During labor, monitor fetal heart rate tracing. Neonatal observation for opioid withdrawal signs for at least 48-72 hours after delivery. Maternal monitoring includes respiratory rate, sedation level, and signs of constipation. |
| Fertility Effects | Opioids may suppress gonadotropin-releasing hormone, leading to reduced libido, anovulation, and oligomenorrhea. Antihistamines may cause hyperprolactinemia, but clinical significance is low. Chronic use may impair fertility; effects are typically reversible upon discontinuation. |
| Addiction, abuse, and misuse, Life-threatening respiratory depression, Accidental ingestion, Cytochrome P450 3A4 interaction, Risks from concomitant use with benzodiazepines or other CNS depressants, Interaction with alcohol, Medication errors, Neonatal opioid withdrawal syndrome, Risks of concomitant use with MAOIs, Adrenal insufficiency, Severe hypotension, Risks in patients with head injury or increased intracranial pressure, Seizures, Cough reflex suppression, Anticholinergic effects, Urinary retention, Avoid other anticholinergics |
| Food/Dietary | Avoid alcohol and any foods or drinks containing alcohol (e.g., beer, wine, liquor, some mouthwashes, and desserts with alcohol) due to additive CNS depression. Grapefruit juice may alter hydrocodone metabolism; consider avoiding. No specific restrictions for chlorpheniramine. |
| Clinical Pearls | Hydrocodone/chlorpheniramine is a fixed-dose combination antitussive/antihistamine. The hydrocodone component has opioid agonist activity; monitor for respiratory depression, especially in COPD or sleep apnea. Chlorpheniramine is a first-generation antihistamine with anticholinergic effects; avoid in narrow-angle glaucoma, urinary retention, and prostatic hypertrophy. Note that the combination product is Schedule II due to hydrocodone content. Use with caution in patients on MAOIs or within 14 days of discontinuation due to risk of hypertensive crisis. |
| Patient Advice | This medication contains hydrocodone, an opioid, which can lead to addiction, abuse, and misuse. · Do not take with alcohol or other CNS depressants (e.g., sedatives, tranquilizers) as it may cause severe drowsiness or breathing problems. · May cause drowsiness; avoid driving or operating heavy machinery until you know how it affects you. · Avoid use of other antihistamines or cold medicines without consulting your healthcare provider. · Take exactly as prescribed; do not increase dose or frequency. · Constipation is common; increase fluid and fiber intake. If severe, contact your doctor. · Keep out of reach of children; accidental ingestion can be fatal. |