Paracetamol (acetaminophen) is an over-the-counter analgesic and antipyretic, effective for mild to moderate pain (headache, muscle aches, fever). It is well tolerated at recommended doses, but the 4 g daily maximum must not be exceeded: in excess it can cause severe liver damage, especially with alcohol use or when combined with other paracetamol-containing medicines.
Also known as: Acetaminofeno
Isoniazid (a CYP2E1 inducer) increases formation of the toxic paracetamol metabolite — higher risk of hepatotoxicity, especially at high doses or with alcohol.
The isoniazid label documents a report of severe paracetamol (acetaminophen) toxicity in a patient taking isoniazid and proposes the molecular basis: "isoniazid induces P-450IIE1, a mixed-function oxidase enzyme that appears to generate the toxic metabolites in the liver", causing a greater proportion of ingested paracetamol to be converted into the toxic metabolite (NAPQI); rat studies demonstrated that isoniazid pretreatment potentiates paracetamol hepatotoxicity. The combination is very common (isoniazid is used in tuberculosis and paracetamol is the first-line analgesic/antipyretic), and the risk is mainly of additive hepatotoxicity in patients with liver disease, alcohol users or with high/prolonged paracetamol doses. Recommendations: use the lowest effective paracetamol dose, avoid alcohol, monitor transaminases in at-risk patients and watch for signs of liver injury (nausea, anorexia, jaundice, right upper quadrant pain).
Isoniazid + paracetamol: isoniazid induces CYP2E1 and increases toxic paracetamol metabolites. Monitor liver function and avoid overdose.
CYP2E1 induction with increased NAPQI (hepatotoxic) metabolite production.
Liver function (ALT/AST) in at-risk patients; signs of hepatitis.
Jaundice, nausea, right upper quadrant pain.
Limit paracetamol dose (2-3 g/day) and avoid alcohol during treatment.
DailyMed/FDA (NIH/NLM) — approved Isoniazid label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=93252cc8-c8d4-401b-bde5-ca8a3b57651e ; approved Paracetamol label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=bf001b70-6164-1ec9-e053-2a95a90a1274
Increased risk of renal injury and gastrointestinal symptoms with prolonged use or high doses of both analgesics. At usual short-term doses it is generally well tolerated.
Paracetamol and ibuprofen have different mechanisms, but chronic use of both at high doses increases the risk of nephrotoxicity (papillary necrosis, renal failure) and, according to some studies, the risk of gastrointestinal bleeding and cardiovascular events compared with each drug alone. For occasional analgesia the combination is acceptable (additive effect), but prolonged unsupervised use should be avoided, daily limits should be respected (paracetamol up to 3–4 g/day; ibuprofen per presentation) and renal function should be monitored in at-risk patients.
Ibuprofen + paracetamol: prolonged combined use at high doses increases the risk of renal injury and gastrointestinal bleeding. Respect daily limits and monitor renal function.
Additive effects: Ibuprofen inhibits renal prostaglandin synthesis and chronic use adds renal load. At therapeutic doses the combination does not potentiate paracetamol hepatotoxicity.
Renal function and signs of toxicity in at-risk patients or prolonged use. Avoid the combination in children without weight-adjusted dosing.
New flank pain, oedema, reduced urine output, rising blood pressure.
Use the lowest effective doses for the shortest time. Prefer a single analgesic. In patients with renal disease, hypertension or older age, reinforce monitoring.
DailyMed/FDA (NIH/NLM) — approved Paracetamol label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4c737cd6-fe56-4cef-887c-cd6cf83b254c ; approved Ibuprofen label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=14515409-736f-4119-b6a0-cb19ee2e948e
Regular, prolonged use of paracetamol may enhance the anticoagulant effect of warfarin (INR), especially with daily use.
Paracetamol is the preferred analgesic in anticoagulated patients because it lacks the gastrointestinal bleeding risk of NSAIDs, but at high doses or with prolonged use it can raise the INR: the mechanism involves glutathione depletion and interference with the synthesis of vitamin K-dependent coagulation factors (the NAPQI metabolite inhibits vitamin K-dependent carboxylation). Studies show INR elevations with doses ≥ 2 g/day maintained for several days. Use the lowest effective dose, do not exceed 2–3 g/day continuously and monitor the INR in patients using paracetamol chronically.
Paracetamol at high doses or with prolonged use (>2 g/day for days) can raise the INR. Use the lowest effective dose and monitor the INR; paracetamol is preferred over NSAIDs.
Not yet fully established: likely interference with vitamin K and clotting factor metabolism.
Regular INR monitoring in patients taking paracetamol daily for more than a week.
Unusual bleeding, spontaneous bruising, gum bleeding, melaena.
Not contraindicated as a single dose. In chronic use, monitor INR and adjust warfarin if needed.
DailyMed/FDA (NIH/NLM) — approved Paracetamol label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4c737cd6-fe56-4cef-887c-cd6cf83b254c ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057
Chronic alcohol consumption increases the risk of paracetamol hepatotoxicity, even at therapeutic doses.
Avoid alcohol; do not exceed the recommended daily paracetamol dose.
DailyMed/FDA (NIH/NLM) — approved Paracetamol label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4c737cd6-fe56-4cef-887c-cd6cf83b254c
Paracetamol can be taken with or without food; absorption may be slightly slower with food, without clinical relevance.
May be taken with or without food.
DailyMed/FDA (NIH/NLM) — approved Paracetamol label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4c737cd6-fe56-4cef-887c-cd6cf83b254c
Paracetamol is hepatotoxic at high doses; patients with liver disease are at increased risk of liver injury.
Reduce the maximum daily dose and avoid prolonged use in liver disease.
DailyMed/FDA (NIH/NLM) — approved Paracetamol label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4c737cd6-fe56-4cef-887c-cd6cf83b254c
Chronic alcohol consumption increases the risk of paracetamol hepatotoxicity, even at therapeutic doses.
Limit the maximum daily dose and inform the patient about the risk.
DailyMed/FDA (NIH/NLM) — approved Paracetamol label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4c737cd6-fe56-4cef-887c-cd6cf83b254c
Paracetamol is the analgesic/antipyretic of choice in pregnancy at usual doses.
May be used at the lowest effective dose for the shortest possible time.
Present in breast milk in small amounts; compatible with breastfeeding.
No specific contraception required.
DailyMed/FDA (NIH/NLM) — approved Paracetamol label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4c737cd6-fe56-4cef-887c-cd6cf83b254c
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
Analgesic and antipyretic with well-established efficacy in mild to moderate pain and fever; analgesic activity is predominantly central (the exact mechanism is not fully understood), with inhibition of prostaglandin synthesis in the CNS and actions on descending serotonergic pathways.
The analgesic mechanism involves inhibition of central cyclooxygenase (COX-3/COX-2) and modulation of descending inhibitory serotonergic pain pathways; at therapeutic doses it has little peripheral anti-inflammatory activity. In overdose, the reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI) depletes glutathione and causes hepatocellular necrosis.
Rapid, almost complete oral absorption in the small intestine, dependent on gastric emptying; peak concentrations occur 30-60 minutes after dosing. Bioavailability is about 75-85% (slight first-pass effect).
Extensive hepatic metabolism: glucuronide (~55%) and sulfate (~30%) conjugation and CYP-mediated oxidation (CYP2E1, CYP1A2, CYP3A4) forming the reactive metabolite NAPQI, normally conjugated with glutathione; in overdose NAPQI accumulates and damages hepatocytes. About 85% of the dose appears in urine within 24 hours, mainly as conjugates.
Plasma half-life of 1.9 to 2.5 hours at therapeutic doses (mean ~2 h), with a total clearance of 4.5-5.5 mL/min/kg; prolonged in liver disease and overdose.
Medicines from the same therapeutic group (ATC classification) or the same pharmacological class.
