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Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration, with peak plasma concentration attained within 10–60 minutes (immediate-release preparations) or 60–120 minutes (extended-release preparations).

Poor or variable absorption following rectal administration; considerable variation in peak plasma concentrations attained; time to reach peak plasma concentration is substantially longer than after oral administration.

Food

Food may delay absorption following administration as extended-release tablets.

Distribution

Extent

Rapidly distributed to most body tissues. Crosses placenta and is distributed into breast milk.

Plasma Protein Binding

25%.

Elimination

Metabolism

Metabolized principally by sulfate and glucuronide conjugation; small amounts (5–10%) oxidized by CYP-dependent pathways (mainly CYP2E1 and CYP3A4) to a toxic metabolite, N-acetyl-p-benzoquinoneimine (NAPQI). NAPQI is detoxified by glutathione and eliminated; any remaining toxic metabolite may bind to hepatocytes and cause cellular necrosis.

Elimination Route

Mainly excreted in urine as conjugates.

Half-life

1.25–3 hours.

Special Populations

Following toxic doses or in patients with liver damage, plasma half-life may be prolonged.

In patients with moderate to severe renal impairment, acetaminophen conjugates may accumulate.

Stability

Storage

Oral

Tablets

Room temperature. Protect orally disintegrating tablets (Tylenol^® Meltaways) from high humidity. Protect grape-flavored orally disintegrating tablets from light.

Suspension/Solution

Room temperature.

Actions

• Exhibits analgesic and antipyretic activity.
• Weak, reversible, isoform-nonspecific cyclooxygenase inhibitor at dosages of 1 g daily. Inhibitory effect on cyclooxygenase-1 is limited; does not inhibit platelet function.

Advice to Patients

• Risk of severe hepatic damage with use of excessive dosages, with concomitant use of multiple acetaminophen-containing preparations, and in those consuming substantial amounts of alcohol (e.g., ≥3 alcohol-containing drinks per day) concomitantly.
• When used for self-medication, importance of reading the product labeling. Importance of not exceeding the recommended daily dosage and of not using other acetaminophen-containing products (e.g., some cold and cough products) concomitantly.
• When used for self-medication in pediatric patients, importance of basing the dose on the child’s weight; importance of not exceeding the recommended daily dosage.
• Importance of advising parents and caregivers about the appropriate dose, frequency, duration of therapy, and specific strength and formulation for an individual pediatric patient. Advise of the danger of substituting alternative dosage forms, particularly adult for pediatric formulations.
• Importance of ensuring that the correct amount of medication required for the intended dose is administered (e.g., importance of using only the calibrated measuring device provided with the particular formulation for measuring the dose, importance of ensuring that the strength and number of dosage units correspond to the intended dose).
• Importance of seeking quick medical attention if ingested dosage exceeds recommended dosage.
• Importance of limiting alcohol intake.
• Importance of not administering cough/cold preparations to children <2 years of age without first consulting a clinician; when administering these preparations, follow clinician’s instructions precisely.
• Advise patients that paracetamol and APAP are other names for acetaminophen.
• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (e.g., cough/cold preparations) as well as any concomitant illnesses.
• Importance of informing patients of other important precautionary information. (See Cautions.)