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. |
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 | 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.
| FDA category | Positive |
| Breastfeeding | Hydrocodone is excreted into breast milk in low concentrations (M/P ratio approximately 0.2-0.5), but can accumulate in infants of ultrarapid CYP2D6 metabolizers. Chlorpheniramine is also excreted but levels are low. Use cautiously; monitor infant for sedation, respiratory depression, or poor feeding. The American Academy of Pediatrics considers hydrocodone compatible with breastfeeding with caution; chlorpheniramine is generally considered safe. |
■ 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 |
["Hypersensitivity to hydrocodone, chlorpheniramine, or any component","Significant respiratory depression","Acute or severe bronchial asthma in an unmonitored setting or without resuscitative equipment","Paralytic ileus","Concomitant use of MAOIs or within 14 days of such use","Known or suspected gastrointestinal obstruction"]
| Precautions | ["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"] |
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| 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. |