ACTIFED W/ CODEINE
Clinical safety rating: avoid
CNS depressants including alcohol and benzodiazepines increase sedation risk Life-threatening respiratory depression may occur especially in CYP2D6 ultra-rapid metabolizers.
Codeine is a prodrug that is metabolized to morphine, which acts as a mu-opioid receptor agonist; triprolidine is an H1 receptor antagonist. The combination produces antitussive and antihistamine effects.
| Metabolism | Codeine is metabolized primarily via glucuronidation and O-demethylation to morphine by CYP2D6, and N-demethylation to norcodeine by CYP3A4. Triprolidine is metabolized by hepatic CYP450 enzymes. |
| Excretion | Renal: 60-80% (codeine and metabolites, primarily as codeine-6-glucuronide, norcodeine, and morphine); unchanged codeine <10%. Fecal: <10%. Biliary: minor. |
| Half-life | Codeine: 2.5-4 hours; pseudoephedrine: 5-8 hours; triprolidine: 3-6 hours. Context: Codeine half-life prolonged in hepatic impairment and CYP2D6 poor metabolizers; pseudoephedrine half-life increased with alkaline urine. |
| Protein binding | Codeine: 7-25% (primarily albumin); pseudoephedrine: negligible (<5%); triprolidine: approximately 85% (mainly albumin). |
| Volume of Distribution | Codeine: 3-6 L/kg; pseudoephedrine: 2.5-3.5 L/kg; triprolidine: 2-5 L/kg. Indicates extensive tissue distribution. |
| Bioavailability | Codeine: 50-70% (oral); pseudoephedrine: 100% (oral); triprolidine: approximately 50% (oral) due to first-pass metabolism. |
| Onset of Action | Oral: Codeine: 30-60 minutes; pseudoephedrine: 30-60 minutes; triprolidine: 1 hour. |
| Duration of Action | Codeine: 4-6 hours; pseudoephedrine: 4-6 hours; triprolidine: 4-6 hours. Note: Dose-dependent; sustained-release properties absent; duration may be shorter in rapid metabolizers. |
| Molecular Weight | 299.37 |
Adults: 10 mL orally every 4-6 hours as needed, not to exceed 4 doses in 24 hours. Each 10 mL contains 10 mg codeine, 4 mg triprolidine, 60 mg pseudoephedrine.
| Dosage form | SYRUP |
| Renal impairment | GFR 30-59 mL/min: administer every 6 hours; GFR <30 mL/min: administer every 12 hours or avoid use due to risk of accumulation of codeine and pseudoephedrine; hemodialysis: not recommended. |
| Liver impairment | Child-Pugh A (mild): no adjustment; Child-Pugh B (moderate): reduce dose by 50% or extend interval to every 8 hours; Child-Pugh C (severe): avoid use due to risk of central nervous system depression. |
| Pediatric use | Not recommended in children <12 years due to risk of respiratory depression. For children ≥12 years: 10 mL orally every 4-6 hours as needed, max 4 doses in 24 hours. Weight-based dosing not established. |
| Geriatric use | Start at lower dose (e.g., 5 mL orally every 6 hours) due to increased sensitivity to anticholinergic and sedative effects; monitor for confusion, urinary retention, and hypotension. |
| 1st trimester | Use only if potential benefit justifies risk; codeine is associated with risk of congenital malformations (e.g., heart defects) in some studies; first-trimester exposure should be minimized. |
| 2nd trimester | Use with caution; no well-controlled studies; potential for fetal dependence and respiratory depression. |
| 3rd trimester | Avoid near term; prolonged use may lead to neonatal opioid withdrawal syndrome (NOWS) and respiratory depression; use during labor may cause neonatal respiratory depression. |
Clinical note
CNS depressants including alcohol and benzodiazepines increase sedation risk Life-threatening respiratory depression may occur especially in CYP2D6 ultra-rapid metabolizers.
| FDA category | Positive |
| Placental transfer | Both codeine and triprolidine/pseudoephedrine cross the placenta; codeine undergoes placental transfer and is metabolized to morphine in the fetus. |
■ FDA Black Box Warning
WARNING: RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; ADDICTION, ABUSE, AND MISUSE; RISK EVALUATION AND MITIGATION STRATEGY (REMS); LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; CYP2D6 GENETIC VARIABILITY; INTERACTION WITH ALCOHOL; RISKS FROM CONCOMITANT USE OF CYP3A4 INHIBITORS; RISKS IN PATIENTS WITH GASTROINTESTINAL CONDITIONS; RISKS OF USE IN PATIENTS WITH ASTHMA OR OTHER RESPIRATORY DISEASE; LABEL FOR INFANTS AND CHILDREN.
| Common Effects | cough |
| Serious Effects |
Hypersensitivity to codeine, triprolidine, or pseudoephedrineSevere hypertensionCoronary artery diseaseConcurrent MAO inhibitor therapyRespiratory depressionAcute asthma attackObstructive bowel diseasePremature infants or during labor when delivery is imminent
| Precautions | Addiction, abuse, and misuse, Life-threatening respiratory depression, Neonatal opioid withdrawal syndrome, Risks from concomitant use with benzodiazepines or other CNS depressants, CYP2D6 genetic variability (ultrarapid metabolizers), Accidental ingestion, Interaction with alcohol, Use in patients with gastrointestinal conditions, Use in patients with asthma or other respiratory disease, Avoid use in children <12 years |
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| Breastfeeding | Codeine is excreted into breast milk; risk of infant opioid toxicity, especially in CYP2D6 ultra-rapid metabolizers (may produce toxic morphine levels). Use with caution; monitor infant for drowsiness, respiratory depression. Alternatives preferred. The antihistamine components may reduce milk supply. |
| Lactation Rating | L4 (Possibly Hazardous) |
| Teratogenic Risk | First trimester: Codeine is associated with increased risk of congenital malformations (OR 1.24–2.0), particularly cardiac defects, with a dose-response relationship. Triprolidine and pseudoephedrine are generally considered low risk, but pseudoephedrine may be associated with gastroschisis (OR 1.8). Second trimester: Codeine may cause fetal dependence; pseudoephedrine may reduce uteroplacental blood flow. Third trimester: Codeine can cause neonatal opioid withdrawal syndrome (NOWS) and respiratory depression at delivery; pseudoephedrine may exacerbate pregnancy-induced hypertension. Overall, avoid in pregnancy for non-severe indications. |
| Fetal Monitoring | Maternal: Assess blood pressure (pseudoephedrine can elevate BP), monitor for sedation and respiratory depression (codeine), and assess for signs of opioid dependence. Fetal/neonatal: Perform ultrasound for anomalies if exposure occurs in first trimester; monitor fetal heart rate and growth; assess neonate for NOWS (e.g., Finnegan scores) and respiratory status after delivery. |
| Fertility Effects | Codeine may impair fertility in both sexes via opioid-induced hypogonadism, leading to decreased libido, erectile dysfunction, and menstrual irregularities. Pseudoephedrine has no known significant effects on fertility. Triprolidine may cause dry mucous membranes but no direct fertility impairment. |
| Food/Dietary | Avoid grapefruit and grapefruit juice as they may increase codeine levels and risk of adverse effects. High-tyramine foods (aged cheese, cured meats, fermented products) may interact with pseudoephedrine, potentially causing hypertensive crisis. Alcohol is contraindicated due to additive CNS depression. |
| Clinical Pearls | Actifed w/ Codeine combines triprolidine, pseudoephedrine, and codeine. Due to codeine's prodrug metabolism via CYP2D6, ultra-rapid metabolizers risk toxicity; contraindicated in children <12 years, post-tonsillectomy/adenoidectomy, and breastfeeding. Pseudoephedrine may cause hypertensive crisis with MAOIs. Triprolidine's anticholinergic effects exacerbate glaucoma, urinary retention, and cognitive impairment in elderly. |
| Patient Advice | Do not exceed recommended dose; risk of serious breathing problems, especially in children. · Avoid alcohol and other CNS depressants (e.g., benzodiazepines, opioids) as they increase sedation and respiratory depression risk. · Store securely; codeine carries risk of dependence and misuse. · If pregnant or breastfeeding, consult prescriber; do not use while breastfeeding due to infant toxicity risk. · May cause drowsiness; avoid driving or operating heavy machinery until effects are known. · Inform healthcare provider of all medications, especially MAOIs (within 14 days), antidepressants, or blood pressure medications. · Discontinue and seek medical help if symptoms of allergic reaction (rash, itching, swelling, severe dizziness, trouble breathing) occur. · Use caution with high blood pressure, thyroid problems, diabetes, or enlarged prostate. |