Head-to-head clinical analysis & difference comparison: details on mechanism of action, dosing, half-life, interactions, and maternal-fetal safety.
AZITHROMYCIN vs ACETAMINOPHEN AND CODEINE PHOSPHATE
Clinician-reviewed, head-to-head comparison of mechanism, dosing, pharmacokinetics, and safety profiles.
Last clinically reviewed: July 2026 · OpiCalc Medical Review Team
Binds to the 50S ribosomal subunit of susceptible bacteria, inhibiting m RNA translation and thus protein synthesis. Exhibits concentration-dependent bactericidal activity.
Acetaminophen: centrally acting analgesic and antipyretic, possibly via inhibition of cyclooxygenase (COX) and modulation of cannabinoid receptors. Codeine: prodrug converted to morphine; mu-opioid receptor agonist.
Acute bacterial exacerbations of chronic obstructive pulmonary disease due to H. influenzae, M. catarrhalis, or S. pneumoniae,Acute bacterial sinusitis due to H. influenzae, M. catarrhalis, or S. pneumoniae,Community-acquired pneumonia due to C. pneumoniae, H. influenzae, M. pneumoniae, or S. pneumoniae,Pharyngitis/tonsillitis due to S. pyogenes,Uncomplicated skin and skin structure infections due to S. aureus, S. pyogenes, or S. agalactiae,Urethritis/cervicitis due to C. trachomatis or N. gonorrhoeae,Genital ulcer disease due to H. ducreyi,Acute otitis media due to H. influenzae, M. catarrhalis, or S. pneumoniae,Prevention of disseminated M. avium complex disease in advanced HIV infection,Pertussis (off-label)
Mild to moderate pain,Pain accompanied by fever
500 mg orally once daily for 3 days, or 500 mg IV once daily for at least 2 days followed by 500 mg orally to complete 7-10 days of therapy for community-acquired pneumonia. For other indications, typical adult dose is 500 mg orally on day 1 then 250 mg orally once daily on days 2-5.
One or two tablets (acetaminophen 300 mg/codeine 30 mg per tablet) orally every 4-6 hours as needed for pain; maximum 12 tablets daily.
Terminal half-life of approximately 68 hours (range 35–96 h) after multiple doses, allowing once-daily dosing and a prolonged post-antibiotic effect.
Acetaminophen: 2–3 hours (prolonged in hepatic impairment). Codeine: 2.5–3.5 hours; metabolites: morphine 1.5–2.5 hours, codeine-6-glucuronide 3–4 hours. Clinical context: dosing interval every 4–6 hours.
Primarily hepatic, not via cytochrome P450 system. Partially metabolized to inactive metabolites. Eliminated via biliary excretion and renal excretion (<15% unchanged).
Acetaminophen: primarily glucuronidation and sulfation in liver; minor CYP450 (CYP2E1) to toxic NAPQI. Codeine: CYP2D6 to morphine; CYP3A4 to norcodeine; glucuronidation.
Primarily biliary/fecal (approx. 50% unchanged); renal excretion accounts for about 12% of the dose.
Acetaminophen: renal elimination of conjugated metabolites (glucuronide 60%, sulfate 30%, cysteine/mercapturate <5%), less than 5% unchanged. Codeine: renal elimination of codeine (5–15%), morphine (5–10%), norcodeine (10–20%), and conjugates; 90% excreted in urine within 24 hours.
7–51% (concentration-dependent); primarily binds to albumin.
Acetaminophen: 10–25% (albumin). Codeine: 7–25% (primarily albumin).
31.1 L/kg (range 23–50 L/kg), indicating extensive tissue penetration and sequestration (e.g., WBCs, liver, lung).
Acetaminophen: 0.9 L/kg. Codeine: 3–6 L/kg (extensive tissue distribution).
Oral: 37–40% (fasting); food may decrease absorption by ~50%.
Oral: acetaminophen 88% (variable first-pass); codeine 50–60% (first-pass metabolism to morphine, norcodeine, and conjugates).
No dose adjustment required for GFR ≥10 m L/min. For GFR <10 m L/min, caution advised; no specific dose recommendation, consider alternative agent.
GFR 30-50 m L/min: administer every 6 hours; GFR 10-29 m L/min: administer every 8 hours; GFR <10 m L/min: administer every 12 hours; hemodialysis: not recommended.
No dose adjustment required for mild to moderate hepatic impairment (Child-Pugh class A and B). Contraindicated in severe hepatic impairment (Child-Pugh class C).
Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 50% and extend interval to every 8 hours; Child-Pugh C: contraindicated.
For otitis media and community-acquired pneumonia: 10 mg/kg orally or IV on day 1 (max 500 mg), then 5 mg/kg (max 250 mg) once daily on days 2-5. For pharyngitis/tonsillitis: 12 mg/kg orally once daily for 5 days (max 500 mg/day).
For children ≥12 years: acetaminophen 10-15 mg/kg/dose and codeine 0.5-1 mg/kg/dose orally every 4-6 hours; maximum acetaminophen 75 mg/kg/day, codeine 6 mg/kg/day. For children <12 years: not recommended due to codeine safety concerns.
No specific dose adjustment required; use same dosing as younger adults. Monitor renal function due to age-related decline, but no modification needed unless severe renal impairment (Cr Cl <10 m L/min).
Start with lowest effective dose; acetaminophen component maximum 3 g/day; consider reduced codeine dose (e.g., 15 mg) due to increased sensitivity and risk of respiratory depression; extend dosing interval to every 6-8 hours.
None.
Risk of medication errors: confusion between milligram and milliliter doses, and between codeine and acetaminophen components. Contraindicated for postoperative pain management in children following tonsillectomy/adenoidectomy due to risk of respiratory depression and death.
Hepatotoxicity: hepatitis, cholestatic jaundice, hepatic necrosis, hepatic failure,QT prolongation and torsades de pointes (especially with concurrent use of other QT-prolonging agents, electrolyte abnormalities, bradycardia, or structural heart disease),Clostridioides difficile-associated diarrhea (CDAD),Aggravation of myasthenia gravis,Severe allergic reactions (angioedema, anaphylaxis, Stevens-Johnson syndrome),Infantile hypertrophic pyloric stenosis (IHPS) in neonates following oral azithromycin,Use in pregnancy: category B; avoid during breastfeeding due to potential for disruption of infant gut flora
Hepatotoxicity (acetaminophen overdose); respiratory depression; drug dependence; ultra-rapid metabolizers of codeine (CYP2D6) leading to morphine toxicity; concomitant CNS depressants; use in pediatric patients; avoid alcohol.
Hypersensitivity to azithromycin, erythromycin, or any macrolide antibiotic,History of cholestatic jaundice or hepatic dysfunction associated with prior azithromycin use,Concurrent use with ergotamine or dihydroergotamine (possible ergot toxicity)
Hypersensitivity to acetaminophen or codeine; severe respiratory depression; acute or severe asthma; paralytic ileus; post-operative pain management in children after tonsillectomy/adenoidectomy; breastfeeding (in ultra-rapid metabolizers); concomitant MAOIs.
Food does not significantly affect absorption; can be taken with or without food. However, avoiding high-fat meals may reduce minor GI side effects. No known specific food interactions.
Avoid alcohol; high-fat meals may delay absorption but not clinically significant.
FDA Category B. No evidence of teratogenicity in animal studies; limited human data show no increased risk of major malformations. First trimester: No significant association with birth defects. Second/third trimester: No reported fetal harm from short-term use for infections like chorioamnionitis. Use only if clearly needed.
Acetaminophen is considered low risk in all trimesters at therapeutic doses; chronic high doses may be associated with adverse outcomes. Codeine is associated with risk of respiratory depression and neonatal withdrawal if used near term; may cause neural tube defects and other malformations with first-trimester exposure, but data are conflicting. Use lowest effective dose for shortest duration.
Azithromycin is excreted into breast milk in low amounts. M/P ratio approximately 0.2-0.6. Relative infant dose estimated at 2-6% of maternal weight-adjusted dose. Generally considered compatible with breastfeeding; monitor infant for diarrhea or rash.
Acetaminophen is excreted into breast milk in low amounts (M/P ratio ~0.91-1.42) and is considered compatible with breastfeeding. Codeine is also excreted in breast milk; risk of infant opioid toxicity depends on maternal CYP2D6 phenotype. Ultra-rapid metabolizers may produce higher morphine levels. Use with caution, avoid in known CYP2D6 ultra-rapid metabolizers, and monitor infant for sedation and respiratory depression.
No dose adjustment required for pregnancy. Standard adult dosing (500 mg on day 1, then 250 mg daily for 4 days) is appropriate. Note: Pregnancy may increase volume of distribution, but pharmacokinetic studies suggest no significant decrease in AUC; no need for dose increase.
No routine dose adjustment needed for acetaminophen. Codeine pharmacokinetics are altered in pregnancy: increased clearance and volume of distribution may require dose adjustment; however, due to variability in CYP2D6 metabolism, individualize dosing and monitor for efficacy and toxicity. Avoid codeine in pregnancy unless alternative analgesics are ineffective.
Monitor for QTc prolongation especially in patients with preexisting cardiac conditions or those on other QT-prolonging drugs. Azithromycin has a long half-life (68 hours) allowing for shorter treatment courses. Use with caution in hepatic impairment; consider alternative in severe liver disease. Not recommended for pneumonia in patients with bacteremia due to increased mortality risk. Administer on an empty stomach or with food if GI upset occurs; however, absorption is unaffected by food.
For acute pain, limit codeine to 3 days; avoid in children under 12 due to CYP2D6 ultra-rapid metabolizer risk of fatal respiratory depression; monitor for constipation; assess liver function for acetaminophen hepatotoxicity; use with caution in renal impairment.
Take exactly as prescribed; do not skip doses or stop early even if you feel better.,Do not take antacids containing aluminum or magnesium within 2 hours before or after this medication.,Report any signs of liver problems (nausea, vomiting, dark urine, jaundice) or severe diarrhea (watery or bloody) immediately.,Azithromycin may cause dizziness; avoid driving or operating machinery until you know how it affects you.,Inform your doctor if you have a history of QT prolongation, heart rhythm problems, or electrolyte imbalances.,Store at room temperature away from moisture and heat; discard any unused liquid after 10 days.
Take exactly as prescribed; do not exceed 4000 mg acetaminophen per day.,Avoid alcohol while taking this medication.,Do not use with other acetaminophen-containing products.,May cause dizziness or drowsiness; avoid driving until you know how you react.,Common side effects include constipation, nausea, and drowsiness.,Seek emergency if signs of allergic reaction or difficulty breathing occur.
"Azithromycin, a macrolide antibiotic, is known to prolong the QT interval by blocking cardiac potassium channels (specifically IKr), which can lead to torsades de pointes. Mifepristone also poses a risk of QT prolongation, likely via similar mechanisms. Coadministration may result in additive QTc prolongation, increasing the risk of life-threatening ventricular arrhythmias, especially in patients with preexisting cardiac conditions or electrolyte disturbances."
"Lumiracoxib is a selective COX-2 inhibitor primarily metabolized by CYP2C9 and to a lesser extent by CYP3A4. Azithromycin, a macrolide antibiotic, is a known inhibitor of CYP3A4. Concomitant use may decrease the metabolism of azithromycin, leading to increased plasma concentrations and potential toxicity, such as QT prolongation and hepatotoxicity. Elevated azithromycin levels can also enhance its antibacterial effects but raise safety concerns."
"Azithromycin, a macrolide antibiotic, inhibits the cardiac potassium channel encoded by hERG (human Ether-à-go-go-Related Gene), leading to prolonged cardiac repolarization and increased risk of QTc interval prolongation. Arformoterol, a long-acting beta-2 agonist, can also prolong the QTc interval via beta-adrenergic receptor-mediated effects on cardiac ion channels. Concurrent use may result in additive QTc prolongation, predisposing patients to potentially fatal ventricular arrhythmias such as torsades de pointes."
"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 AZITHROMYCIN vs ACETAMINOPHEN AND CODEINE PHOSPHATE, answered by our medical review team.
AZITHROMYCIN is a Macrolide Antibiotic that works by Binds to the 50S ribosomal subunit of susceptible bacteria, inhibiting m RNA translation and thus protein synthesis. Exhibits concentration-dependent bactericidal activity.. ACETAMINOPHEN AND CODEINE PHOSPHATE is a Opioid Agonist that works by Acetaminophen: centrally acting analgesic and antipyretic, possibly via inhibition of cyclooxygenase (COX) and modulation of cannabinoid receptors. Codeine: prodrug converted to morphine; mu-opioid receptor agonist.. They differ in pharmacokinetic profiles, FDA-approved indications, and side effect profiles.
Potency comparisons between AZITHROMYCIN and ACETAMINOPHEN AND CODEINE PHOSPHATE depend on the specific clinical indication. These are agents from distinct pharmacological classes and are not directly interchangeable by dose. A physician or clinical pharmacist should guide any therapeutic switching decisions.
The standard adult dose of AZITHROMYCIN is: 500 mg orally once daily for 3 days, or 500 mg IV once daily for at least 2 days followed by 500 mg orally to complete 7-10 days of therapy for community-acquired pneumonia. For other indications, typical adult dose is 500 mg orally on day 1 then 250 mg orally once daily on days 2-5.. The standard adult dose of ACETAMINOPHEN AND CODEINE PHOSPHATE is: One or two tablets (acetaminophen 300 mg/codeine 30 mg per tablet) orally every 4-6 hours as needed for pain; maximum 12 tablets daily.. 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 AZITHROMYCIN and ACETAMINOPHEN AND CODEINE PHOSPHATE. The metabolism of Azithromycin can be decreased when combined with Acetaminophen. Consult your prescriber before combining these medications.
The maternal-fetal safety profiles differ. AZITHROMYCIN is classified as Category A/B. FDA Category B. No evidence of teratogenicity in animal studies; limited human data show no increased risk of major malformations. First trimester: No significant association with . ACETAMINOPHEN AND CODEINE PHOSPHATE is classified as Category D/X. Acetaminophen is considered low risk in all trimesters at therapeutic doses; chronic high doses may be associated with adverse outcomes. Codeine is associated with risk of respirat. Always consult a maternal-fetal medicine specialist before taking either drug during pregnancy or lactation.