Head-to-head clinical analysis & difference comparison: details on mechanism of action, dosing, half-life, interactions, and maternal-fetal safety.
ACETAMINOPHEN; OXYCODONE HYDROCHLORIDE vs ACTIFED W/ CODEINE
Clinician-reviewed, head-to-head comparison of mechanism, dosing, pharmacokinetics, and safety profiles.
Last clinically reviewed: June 2026 · OpiCalc Medical Review Team
Acetaminophen: cyclooxygenase (COX) inhibitor, primarily in the CNS, reducing prostaglandin synthesis; analgesic and antipyretic. Oxycodone: mu-opioid receptor agonist, inhibiting ascending pain pathways and altering pain perception.
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.
Management of moderate to moderately severe pain,Acute pain,Chronic pain
Symptomatic relief of cough and upper respiratory symptoms associated with allergy or cold
1-2 tablets (equivalent to 325-650 mg acetaminophen / 5-10 mg oxycodone) every 4-6 hours as needed for pain; maximum 12 tablets per day (acetaminophen limit 3900 mg/day or lower if hepatic risk).
Adults: 10 m L orally every 4-6 hours as needed, not to exceed 4 doses in 24 hours. Each 10 m L contains 10 mg codeine, 4 mg triprolidine, 60 mg pseudoephedrine.
Acetaminophen: 2-3 hours (prolonged in hepatic impairment or overdose); Oxycodone: 3-5 hours (immediate-release), 4.5-8 hours (extended-release); Clinical context: Terminal half-life of oxycodone may be prolonged in elderly or patients with renal/hepatic impairment.
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.
Acetaminophen: primarily hepatic via glucuronidation (UGT1A1, UGT1A6, UGT1A9), sulfation (SULT1A1), and minor CYP450 (CYP2E1, CYP3A4) to toxic NAPQI. Oxycodone: hepatic via CYP3A4 (major) and CYP2D6 (minor) to active metabolites (noroxycodone, oxymorphone).
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.
Acetaminophen: renal excretion of metabolites (glucuronide 45-55%, sulfate 20-30%, cysteine and mercapturate conjugates 5-10%) and unchanged drug (<5%); Oxycodone: renal excretion of unchanged drug (approximately 10-19%) and metabolites (noroxycodone, oxymorphone, and their glucuronides) (total renal elimination ~60-87%); fecal elimination of Oxycodone is minimal (<10%).
Renal: 60-80% (codeine and metabolites, primarily as codeine-6-glucuronide, norcodeine, and morphine); unchanged codeine <10%. Fecal: <10%. Biliary: minor.
Acetaminophen: 20-30% (albumin); Oxycodone: 45-50% (albumin).
Codeine: 7-25% (primarily albumin); pseudoephedrine: negligible (<5%); triprolidine: approximately 85% (mainly albumin).
Acetaminophen: 0.9-1.0 L/kg (suggests distribution into total body water); Oxycodone: 2.6-4.0 L/kg (suggests extensive tissue distribution).
Codeine: 3-6 L/kg; pseudoephedrine: 2.5-3.5 L/kg; triprolidine: 2-5 L/kg. Indicates extensive tissue distribution.
Acetaminophen: Oral 85-90%; Oxycodone: Oral 60-87% (first-pass metabolism), Rectal (oxycodone suppository) ~60-80%.
Codeine: 50-70% (oral); pseudoephedrine: 100% (oral); triprolidine: approximately 50% (oral) due to first-pass metabolism.
e GFR 30-60 m L/min: start with 50% of usual dose, increase cautiously; e GFR <30 m L/min: start with 25% of usual dose, extend dosing interval to every 8-12 hours; avoid in dialysis due to oxycodone accumulation.
GFR 30-59 m L/min: administer every 6 hours; GFR <30 m L/min: administer every 12 hours or avoid use due to risk of accumulation of codeine and pseudoephedrine; hemodialysis: not recommended.
Child-Pugh A: no adjustment; Child-Pugh B: start with 50% of usual dose, maximum acetaminophen 2000 mg/day; Child-Pugh C: contraindicated.
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.
Weight-based: oxycodone 0.05-0.15 mg/kg/dose (max 5 mg/dose) with acetaminophen 10-15 mg/kg/dose every 4-6 hours; maximum acetaminophen 75 mg/kg/day (not to exceed 4000 mg/day).
Not recommended in children <12 years due to risk of respiratory depression. For children ≥12 years: 10 m L orally every 4-6 hours as needed, max 4 doses in 24 hours. Weight-based dosing not established.
Start with lowest dose (e.g., half of adult dose), titrate slowly; avoid in patients with impaired renal/hepatic function or those at risk for falls; monitor for respiratory depression and constipation.
Start at lower dose (e.g., 5 m L orally every 6 hours) due to increased sensitivity to anticholinergic and sedative effects; monitor for confusion, urinary retention, and hypotension.
Risk of addiction, abuse, and misuse; life-threatening respiratory depression; accidental ingestion of acetaminophen may cause hepatotoxicity; neonatal opioid withdrawal syndrome; CYP3A4 interaction with benzodiazepines or other CNS depressants.
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.
Addiction, abuse, misuse; respiratory depression; accidental exposure; neonatal opioid withdrawal syndrome; hepatotoxicity (acetaminophen); interactions with CNS depressants; elderly or debilitated patients; renal impairment; severe hypotension; adrenal insufficiency; use in patients with head injury.
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
Hypersensitivity to acetaminophen or oxycodone; significant respiratory depression; acute or severe bronchial asthma; GI obstruction (e.g., paralytic ileus); severe hepatic impairment; concurrent use with MAOIs or within 14 days.
Hypersensitivity to codeine, triprolidine, or any component,Children <12 years,Postoperative management in children <18 years after tonsillectomy and/or adenoidectomy,Significant respiratory depression,Acute or severe bronchial asthma,Concurrent use of monoamine oxidase inhibitors (MAOIs) or within 14 days,Paralytic ileus,Known CYP2D6 ultrarapid metabolizers
Avoid alcohol. Grapefruit juice may increase oxycodone levels; limit or avoid grapefruit products. High-fat meals may delay absorption of oxycodone. Maintain adequate hydration to prevent constipation.
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.
Acetaminophen: Generally considered low risk; no consistent association with major malformations. Oxycodone: First trimester: No increased risk of major malformations in human studies. Second and third trimesters: Risk of neonatal opioid withdrawal syndrome (NOWS) with chronic use; respiratory depression at delivery. No specific human data for combination; extrapolated from individual components.
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.
Acetaminophen: Compatible; M/P ratio ~1.0 (low transfer). Oxycodone: Low levels in milk; M/P ratio ~3.6 (relative infant dose 1.7–6.3% of maternal weight-adjusted dose). Monitor infant for drowsiness, respiratory depression. Use lowest effective dose, shortest duration.
Codeine and pseudoephedrine are excreted into breast milk. M/P ratio for codeine is ~2.5; for pseudoephedrine, ~2.6–3.5. Use is contraindicated in breastfeeding due to risk of neonatal opioid toxicity (especially in CYP2D6 ultra-rapid metabolizers) and potential irritability/poor feeding from pseudoephedrine. Triprolidine has limited data but is considered compatible in low doses.
Acetaminophen: No dose adjustment needed; use lowest effective dose. Oxycodone: Pharmacokinetic changes in pregnancy include increased clearance (due to enhanced hepatic metabolism and renal blood flow) and increased volume of distribution, potentially reducing plasma concentrations. Dose may need to be increased (monitor for efficacy and avoid withdrawal); however, use lowest effective dose to minimize neonatal risks. Consider non-opioid alternatives.
No specific dose adjustments are established; however, due to increased renal clearance of pseudoephedrine in pregnancy, standard doses may be less effective. Codeine metabolism via CYP2D6 is variably affected by pregnancy (increased clearance ≈30–50% in second/third trimester), potentially requiring dose titration. Avoid use entirely in pregnancy; use alternative agents if needed.
Monitor for acetaminophen hepatotoxicity; maximum daily acetaminophen intake should not exceed 4000 mg. Oxycodone has high abuse potential; consider prescribing naloxone for patients at risk of opioid overdose. Avoid concurrent use of other CNS depressants. Use with caution in elderly or renally impaired patients.
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.
Do not exceed 4000 mg of acetaminophen per day from all sources.,This medication can cause drowsiness; avoid driving or operating machinery until you know how it affects you.,Do not consume alcohol while taking this medication.,Take exactly as prescribed; do not crush, chew, or break extended-release tablets.,Store securely out of reach of children and dispose of unused medication properly.,Seek emergency medical attention if you experience difficulty breathing, severe drowsiness, or signs of an allergic reaction.
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.
"Phenobarbital, a potent inducer of cytochrome P450 (CYP) enzymes, particularly CYP3A4 and CYP2D6, significantly increases the hepatic metabolism of oxycodone, a prodrug that requires CYP3A4-mediated N-demethylation to noroxycodone and CYP2D6-mediated O-demethylation to oxymorphone for its analgesic effects. This induction reduces the systemic exposure and peak plasma concentration of active oxycodone and its active metabolite oxymorphone, leading to diminished analgesic efficacy and potential opioid withdrawal symptoms in patients on chronic opioid therapy. Clinically, patients may require substantially higher doses of oxycodone to achieve pain relief, increasing the risk of dose-related adverse effects if the interaction is not recognized."
"The co-administration of oxycodone, a mu-opioid receptor agonist, and gamma-hydroxybutyric acid (GHB), a central nervous system depressant with activity at GABA-B and GHB receptors, results in additive or synergistic respiratory depression and CNS depression. This interaction potentiates the risk of severe hypoventilation, coma, and fatal overdose, especially in non-tolerant users or at therapeutic doses. The combined sedation also increases the likelihood of hypotension, bradycardia, and impaired psychomotor function, necessitating extreme caution."
"The coadministration of oxycodone, a mu-opioid receptor agonist with central nervous system (CNS) depressant effects, and perampanel, a noncompetitive AMPA receptor antagonist that also causes CNS depression, produces additive sedative and respiratory depressant effects. This synergy increases the risk of excessive sedation, impaired cognitive function, and potentially life-threatening respiratory depression. Patients may experience profound somnolence, confusion, and an increased fall risk, necessitating dose adjustments or avoidance."
"Pirenzepine, a selective M1 muscarinic antagonist, reduces gastrointestinal motility and secretions, while codeine, an opioid agonist, also decreases gastrointestinal motility via mu-opioid receptors. Concurrent use leads to additive anticholinergic and opioid effects, resulting in enhanced risk of severe constipation, paralytic ileus, and central nervous system depression. Clinically, patients may experience exacerbated sedation, respiratory depression, and urinary retention."
"Ropinirole, a non-ergoline dopamine agonist used in Parkinson's disease and restless legs syndrome, may reduce the analgesic efficacy of codeine. This is likely due to pharmacodynamic antagonism at central dopamine and opioid receptors, as well as potential pharmacokinetic interactions that decrease the conversion of codeine to its active metabolite morphine via CYP2D6 inhibition by ropinirole. The resultant blunted opioid response can lead to inadequate pain control, necessitating dose adjustment or alternative therapy."
"Vemurafenib induces CYP3A4, significantly reducing the plasma concentrations of codeine, which is metabolized via CYP3A4 to its active metabolite morphine. This may diminish codeine's analgesic efficacy, potentially leading to inadequate pain control. Additionally, reduced formation of morphine may lower the risk of opioid-related adverse effects."
Explore head-to-head clinical comparisons of other medications in the same therapeutic classes.
Common clinical questions about ACETAMINOPHEN; OXYCODONE HYDROCHLORIDE vs ACTIFED W/ CODEINE, answered by our medical review team.
ACETAMINOPHEN; OXYCODONE HYDROCHLORIDE is a Opioid Agonist that works by Acetaminophen: cyclooxygenase (COX) inhibitor, primarily in the CNS, reducing prostaglandin synthesis; analgesic and antipyretic. Oxycodone: mu-opioid receptor agonist, inhibiting ascending pain pathways and altering pain perception.. ACTIFED W/ CODEINE is a Opioid Agonist that works by 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.. They differ in pharmacokinetic profiles, FDA-approved indications, and side effect profiles.
Potency comparisons between ACETAMINOPHEN; OXYCODONE HYDROCHLORIDE and ACTIFED W/ CODEINE depend on the specific clinical indication. These are both Opioid Agonist agents and are not directly interchangeable by dose. A physician or clinical pharmacist should guide any therapeutic switching decisions.
The standard adult dose of ACETAMINOPHEN; OXYCODONE HYDROCHLORIDE is: 1-2 tablets (equivalent to 325-650 mg acetaminophen / 5-10 mg oxycodone) every 4-6 hours as needed for pain; maximum 12 tablets per day (acetaminophen limit 3900 mg/day or lower if hepatic risk).. The standard adult dose of ACTIFED W/ CODEINE is: Adults: 10 m L orally every 4-6 hours as needed, not to exceed 4 doses in 24 hours. Each 10 m L contains 10 mg codeine, 4 mg triprolidine, 60 mg pseudoephedrine.. Dosing should always be individualized based on indication, renal and hepatic function, age, and other patient factors.
A moderate-severity drug interaction has been identified when combining ACETAMINOPHEN; OXYCODONE HYDROCHLORIDE and ACTIFED W/ CODEINE. The risk or severity of adverse effects can be increased when Codeine is combined with Oxycodone. Consult your prescriber before combining these medications.
The maternal-fetal safety profiles differ. ACETAMINOPHEN; OXYCODONE HYDROCHLORIDE is classified as Category D/X. Acetaminophen: Generally considered low risk; no consistent association with major malformations. Oxycodone: First trimester: No increased risk of major malformations in human stud. ACTIFED W/ CODEINE is classified as Category D/X. 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 . Always consult a maternal-fetal medicine specialist before taking either drug during pregnancy or lactation.