Warning and Precautions

• Acetaminophen is the leading cause of serious liver injury in Canada, mostly due to unintentional overdoses. High-risk populations include those with pre-existing liver disease, alcoholism, malnutrition, chronic users of acetaminophen and the pediatric population. Because of the risk of hepatotoxicity, patients should be cautioned against the inadvertent administration of excessive doses of acetaminophen that can occur through concomitant use of multiple acetaminophen-containing products, such as cough and cold remedies, analgesic or arthritis formulations, antipyretics or products for relief of menstrual symptoms or muscle spasm. Patients in high-risk populations should be advised to use doses lower than the daily maximum of acetaminophen and for shorter periods of time.
• Acetaminophen is one of the most frequent causes of accidental poisoning in young children. Administration of acetaminophen to children may be especially prone to error due to the many concentrations and strengths of products available. To avoid dosing errors, all product labels should be checked carefully to ensure accurate calculation of the amount of acetaminophen to be given. Weight-based dosing and calibrated measuring devices such as oral syringes should always be used.

Dermatologic

Severe hypersensitivity reactions have been reported rarely (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, urticaria, rash, pruritus, angioedema); immediately discontinue and seek urgent care if such reactions occur.

Hepatic/Biliary/Pancreatic

Potentially fatal hepatotoxicity can result from acetaminophen overdose (see Overdosage). However, hepatotoxicity has occurred in patients receiving high or excessive doses with therapeutic intent. Certain patients may be more susceptible to acetaminophen hepatotoxicity, e.g., chronic alcoholics, patients with liver disease or those who are malnourished or taking other drugs that induce hepatic enzymes (see also Serious Warnings and Precautions).

Immune

Severe hypersensitivity reactions have occurred rarely (e.g., anaphylaxis, respiratory distress); immediately discontinue and seek urgent care if such reactions occur.

Respiratory

Acetaminophen use in a child’s first year of life has been associated with a higher risk of developing asthma [Lancet 2008;372(9643):1039-48]. However, acetaminophen likely remains a safe treatment option for pain and fever in children with asthma [N Engl J Med 2016;375(7):619-30].

Contraindications

• Severe hepatic impairment or liver disease
• Hypersensitivity to acetaminophen or any component of the formulation;
• acetaminophen-induced liver disease.

Special Populations

Pregnant Women

Acetaminophen is considered to be safe for the short-term treatment of fever and pain during pregnancy; it is often the drug of first choice in pregnant women. Long term use or supratherapeutic doses may be associated with fetal liver toxicity. Observational studies have demonstrated potential associations between acetaminophen use during pregnancy and greater risk of developing asthma or behavioural problems in offspring, however firm conclusions cannot be made. Nevertheless, experts recommend acetaminophen as the drug of choice in pregnancy for short-term or intermittent use; and recommend against the routine use of any medication in pregnancy, including acetaminophen.

Nursing Women

Acetaminophen is considered to be safe for the short-term treatment of fever and pain during pregnancy; it is the drug of first choice in nursing women. A nursing infant receives an average of 1–2% of the maternal dosage, which is much less than usual infant doses of acetaminophen. There is one case report of a rash developing in an infant exposed to acetaminophen via breast milk; the rash subsided upon drug discontinuation.

Pediatrics

Acetaminophen is one of the most frequent causes of accidental poisoning in infants and toddlers. Acetaminophen-containing products should be kept well out of reach of children and stored in locked cabinets (see also Serious Warnings and Precautions).

Geriatrics

The elderly population is likely to have compromised renal and hepatic function; thus they may display increased sensitivity to chronic use or high dosages of acetaminophen. Use with caution.

Renal Impairment

• ClCr >50 mL/min: 4 hour dosage interval
• ClCr 10–50 mL/min: 6 hour dosage interval
• ClCr <10 mL/min: 8 hour dosage interval

Hepatic Impairment

Consider dosage reduction in patients with hepatic impairment; acetaminophen is contraindicated in patients with severe hepatic impairment or liver disease.

Adverse Drug Reactions

Adverse reactions are uncommon when acetaminophen is used at regular doses for short-term use in low-risk populations.

Dermatologic

Although uncommon, cutaneous reactions have been reported with acetaminophen (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, urticaria, rash, pruritus, angioedema).

Endocrine and Metabolism

Decreased serum bicarbonate, calcium and sodium have occurred, in addition to hyperchloremia, hyperuricemia and elevated blood glucose.

Hematologic

Neutropenia, thrombocytopenia purpura, hemolytic anemia, agranulocytosis have been reported.

Hepatic

Potentially fatal hepatotoxicity can result from acetaminophen overdose (see Overdosage). However, hepatotoxicity has occurred in patients receiving high or excessive doses with therapeutic intent. Certain patients may be more susceptible to acetaminophen hepatotoxicity, e.g., chronic alcoholics, patients with liver disease or those who are malnourished or taking other drugs that induce hepatic enzymes (see also Serious Warnings and Precautions).

Hypersensitivity

Reactions including laryngeal edema, angioedema, bronchospasm and/or anaphylaxis have occurred rarely. Dose-dependent cross-sensitivity to acetaminophen is reported to occur in up to 34% of ASA-sensitive asthmatic patients. Low initial doses of acetaminophen (<1000 mg) are recommended in these patients, with monitoring for about 3 hours following initial doses. Some acetaminophen formulations may contain additives such as sulfite or propylene glycol, which can induce severe hypersensitivity reactions in susceptible individuals.

Neurologic

If acetaminophen is used for the treatment of headache for >15 days/month, medication overuse headache may result; limit use to <15 days/month.

Renal

Nephropathy, including papillary renal failure has been reported following chronic consumption of large amounts of acetaminophen. Renal tubular necrosis has been associated occasionally with hepatic injury produced by acetaminophen overdose.

Other

Transient hypothermia has been rarely reported in children and adults following both therapeutic and supratherapeutic doses of acetaminophen.

Abnormal Hematologic and Clinical Chemistry Findings

Liver function tests (LFTs) Small and clinically unimportant elevations in ALT have been reported at doses of 2–4 grams/day. Small elevations are likely transient and not clinically important.