HYDROCODONE BITARTRATE, CHLORPHENIRAMINE MALEATE AND PSEUDOEPHEDRINE HYDROCHLORIDE
Clinical safety rating: safe
MAOIs can cause hypertensive crisis Can cause insomnia and tachycardia.
Hydrocodone: mu-opioid receptor agonist; Chlorpheniramine: histamine H1 receptor antagonist; Pseudoephedrine: sympathomimetic amine, alpha- and beta-adrenergic receptor agonist.
| Metabolism | Hydrocodone: CYP3A4 and CYP2D6; Chlorpheniramine: CYP2D6 and other CYP enzymes; Pseudoephedrine: partially hepatic metabolism, primarily renal excretion. |
| Excretion | Hydrocodone: primarily renal (as conjugated metabolites, norhydrocodone, and unchanged drug); <5% fecal. Chlorpheniramine: renal (as metabolites, ~20% unchanged) and fecal. Pseudoephedrine: renal (>90% unchanged via active tubular secretion). |
| Half-life | Hydrocodone: 3.8-6 hours; Chlorpheniramine: 14-25 hours (prolonged in children); Pseudoephedrine: 5-8 hours (pH-dependent urinary excretion). |
| Protein binding | Hydrocodone: ~30% (primarily albumin); Chlorpheniramine: 70-72% (albumin); Pseudoephedrine: negligible (<20%). |
| Volume of Distribution | Hydrocodone: 3.3-4.7 L/kg; Chlorpheniramine: 7-10 L/kg; Pseudoephedrine: 2.6-3.3 L/kg. High Vd indicates extensive tissue distribution. |
| Bioavailability | Oral: Hydrocodone 70% (first-pass metabolism); Chlorpheniramine 25-50% (significant first-pass); Pseudoephedrine 100% (well absorbed, minimal first-pass). |
| Onset of Action | Oral: Hydrocodone 30-60 min; Chlorpheniramine 1-2 hours; Pseudoephedrine 30-60 min. |
| Duration of Action | Hydrocodone: 4-6 hours; Chlorpheniramine: 4-6 hours (up to 12-24 hours for sustained-release if present); Pseudoephedrine: 4-6 hours (up to 12 hours for sustained-release). Note: Duration may be extended in hepatic/renal impairment. |
| Molecular Weight | 406.9 |
| Action Class | Combination: Opioid agonist, Antihistamine (H1-receptor antagonist), Sympathomimetic (alpha-adrenergic agonist) |
1 tablet (Hydrocodone 5 mg / Chlorpheniramine 4 mg / Pseudoephedrine 60 mg) orally every 4-6 hours as needed for cough and congestion; maximum 4 tablets per day.
| Dosage form | SOLUTION |
| Renal impairment | Avoid use in severe renal impairment (GFR < 30 mL/min) due to accumulation of hydrocodone and chlorpheniramine. For moderate impairment (GFR 30-50 mL/min), consider extended intervals (every 8-12 hours) and monitor for CNS depression. |
| Liver impairment | Contraindicated in Child-Pugh class C (severe hepatic impairment). For class A (mild) or B (moderate), reduce dose to 1 tablet every 8-12 hours; monitor for sedation and respiratory depression. |
| Pediatric use | Not recommended for children under 6 years. For children 6-11 years: 1/2 tablet (hydrocodone 2.5 mg / chlorpheniramine 2 mg / pseudoephedrine 30 mg) every 6 hours; max 2 tablets/day. For children ≥12 years: same as adult dosing. |
| Geriatric use | Initiate with 1 tablet every 8-12 hours; reduce total daily dose due to increased risk of sedation, confusion, and anticholinergic effects. Maximum 2 tablets per day. |
| 1st trimester | Avoid in first trimester due to risk of congenital malformations (e.g., neural tube defects) associated with pseudoephedrine and potential opioid-related effects. Hydrocodone may cause neonatal withdrawal with prolonged use. |
| 2nd trimester | Use only if clearly needed; opioid exposure may lead to fetal dependence and withdrawal. Pseudoephedrine may decrease placental blood flow. |
| 3rd trimester | Avoid due to risk of neonatal opioid withdrawal syndrome (NOWS), premature labor from pseudoephedrine, and potential respiratory depression in neonates near term. |
Clinical note
MAOIs can cause hypertensive crisis Can cause insomnia and tachycardia.
| FDA category | Animal |
| Placental transfer | Hydrocodone and pseudoephedrine cross the placenta; chlorpheniramine likely crosses to a lesser extent. Hydrocodone is detected in umbilical cord blood. Risk of fetal effects increases with dose and duration. |
■ FDA Black Box Warning
Risk of opioid addiction, abuse, and misuse; life-threatening respiratory depression; accidental ingestion; neonatal opioid withdrawal syndrome; risk with concomitant use of benzodiazepines or other CNS depressants.
| Common Effects | Insomnia |
| Serious Effects | Respiratory depression, Addiction, abuse, and misuse, Neonatal opioid withdrawal syndrome, Adrenal insufficiency, Severe hypotension, Serotonin syndrome (with concomitant serotonergic drugs), QT prolongation and torsades de pointes (chlorpheniramine), Hypertensive crisis (pseudoephedrine), Seizures, Urinary retention |
Hypersensitivity to any componentSevere hypertension or coronary artery disease (pseudoephedrine)Concurrent use or within 14 days of MAO inhibitors (potential hypertensive crisis)Narrow-angle glaucomaUrinary retentionSevere hepatic impairmentRespiratory depression (opioid-related)
| Precautions | Respiratory depression, drug dependence, CNS depression, severe hypertension, increased intraocular pressure, hyperthyroidism, diabetes, prostatic hyperplasia, urinary retention, impaired renal/hepatic function. |
Loading safety data…
| Breastfeeding | Hydrocodone is excreted into breast milk in small amounts; risk of infant sedation and respiratory depression, especially in CYP2D6 ultra-rapid metabolizers. Chlorpheniramine and pseudoephedrine may reduce milk supply and cause irritability or drowsiness in infants. Avoid or use with caution; alternative agents preferred. |
| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | First trimester: Hydrocodone is associated with neural tube defects, heart defects, and gastroschisis (limited data). Chlorpheniramine is generally considered low risk but some studies suggest a slight increase in cleft palate. Pseudoephedrine is associated with gastroschisis and small intestinal atresia when used in first trimester. Second and third trimesters: Chronic hydrocodone use can lead to neonatal opioid withdrawal syndrome (NOWS) and respiratory depression at birth. Pseudoephedrine may reduce uterine blood flow and cause fetal tachycardia. Chlorpheniramine has no known major risks in later trimesters. |
| Fetal Monitoring | Monitor maternal blood pressure and heart rate due to pseudoephedrine. Assess fetal heart rate and uterine activity if used near term. In neonates exposed chronically, monitor for signs of NOWS. Observe for maternal sedation or respiratory depression. Periodic growth ultrasound if used long-term. |
| Fertility Effects | Opioids may cause menstrual irregularities and reduce fertility due to prolactin elevation. Antihistamines may cause minimal effects. Pseudoephedrine may theoretically affect spermatogenesis but clinical data lacking. No significant permanent effects expected. |
| Food/Dietary | Avoid high-tyramine foods (e.g., aged cheeses, cured meats) if taking MAOIs (contraindicated). Grapefruit juice may increase hydrocodone levels; limit consumption. Alcohol potentiates CNS depression; avoid concurrent use. |
| Clinical Pearls | Hydrocodone bitartrate is an opioid antitussive; chlorpheniramine maleate is a first-generation antihistamine; pseudoephedrine hydrochloride is a sympathomimetic decongestant. Avoid use in patients with severe hypertension, coronary artery disease, or MAOI use within 14 days. Monitor for CNS depression, respiratory depression, and urinary retention. In elderly patients, risk of anticholinergic effects (chlorpheniramine) and opioid sensitivity is increased. Pseudoephedrine may cause tachyphylaxis with prolonged use. |
| Patient Advice | Do not exceed recommended dose or frequency; risk of addiction and respiratory depression with hydrocodone. · Avoid alcohol and other CNS depressants (e.g., benzodiazepines) due to additive sedation and respiratory depression. · Report symptoms of high blood pressure, fast/irregular heartbeat, or difficulty urinating. · May cause drowsiness or dizziness; avoid driving or operating heavy machinery until response is known. · Do not crush or chew extended-release formulations; take with a full glass of water. · Antihistamine may cause dry mouth; use sugarless candy or ice chips for relief. |