APAP-related Prescribing Precautions

A Food and Drug Administration (FDA) Drug Safety Communication published on January 13, 2014 states that “acetaminophen-containing prescription products are safe and effective when used as directed, though all medications carry some risks”.57 Indeed, during the past decade, APAP has been identified as the leading cause of acute liver failure (ALF) in the United States and up to 50% of the cases are due to unintentional overdose.58-61

Concerns about the incidence of ALF prompted the FDA to require a Boxed Warning highlighting the potential for severe liver toxicity with APAP. The FDA also mandated that the Boxed Warning highlight the potential for allergic reactions and for severe liver injury in patients who drank alcohol while taking APAP containing products.57 Manufactures were also instructed to revise their labeling (package insert) to include a warning about potential increased bleeding in patients taking warfarin.62

The FDA also set a limit of 325 mg of APAP per tablet, capsule, or other dosage units in prescription drug products, e.g., opioid analgesics w/APAP. The FDA also called upon healthcare professionals to discontinue prescribing combination drug products containing more than 325 mg of APAP (may still prescribe 650 mg per dose).57,63 On March 26, 2014 the FDA formally mandated the withdrawal of all prescription combination drug products from the market containing more than 325 mg of APAP.64

Recent evidence also suggests that APAP is a hormone disrupter, e.g., it interferes with reproductive and thyroid hormone functions essential for normal brain development. APAP taken during pregnancy has been associated with an increased risk of attention-deficit/hyperactivity disorder (ADHD)-like behavioral problems or hyperkinetic disorders (HKDs) in children.65 A summary of potential ADRs associated with the use of APAP is presented in Table 6.

Table 6. Potential APAP-associated Adverse Drug Reactions.

Potential ADRsComments
AllergySwelling of the face, mouth, and throat; difficulty breading; and itching and/or a rash; rare cases of anaphylaxis.
Stevens-Johnson syndrome and toxic epidermal necrolysisReddening of the skin, a rash, blisters, and detachment of the upper surface of the skin.
AsthmaIncreased risk of asthma and wheezing in both children and adults.
Possible causal relationship between wheezing or asthma in offspring and maternal use of APAP during pregnancy.
Acute liver failure (ALF)Nausea, vomiting, anorexia, diarrhea, and abdominal pain within the first 24 hours.
  • Clinical evidence of hepatic damage in 2 to 6 days. When the drug’s half-life exceeds 12 hours, hepatic coma and death are likely.
    • The hepatotoxic single dose of APAP in healthy adults is between 23 to 30 regular-strength (325 mg) doses; for children it is 150 mg/kg.
    • In patients with liver disease, alcohol and malnutrition (even with therapeutic doses of APAP) may enhance this toxicity.
Hematologic malignanciesChronic users of APAP (≥ 4 days/week for ≥ 4 years) have a two-fold increased risk of developing lymphomas and myelodysplastic syndrome.
CryptorchidismIncreased risk with APAP use for more than 4 weeks during pregnancy, especially during the first and second trimesters.
Attention-deficit/hyperactivity disorders and hyperkinetic disorders in childrenIncreases the risk with increased frequency of maternal APAP use during pregnancy.
Drug-drug interactionsPotential interaction between APAP and warfarin sodium.
  • Long-term concurrent use of APAP (i.e., 2 to 4 g daily for 4 weeks) and warfarin sodium increases the International Normalized Ratio and the risk of bleeding.