Acetaminophen Safety Overview: Clinical Data by System

Data from almost 500 clinical trials underscore the safety profile of acetaminophen. Below are some results of interest. An overview of the safety profile is also available in the TYLENOL® product monograph.
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Central Nervous System Effects

Acetaminophen at recommended doses has no obvious effects on central nervous system function. In an overdose situation, central nervous system effects are uncommon. Coma or other evidence of central nervous system depression usually is not present unless the patient has taken a massive overdose, has taken other central nervous system-active agents concomitantly, or is experiencing central nervous system effects secondary to fulminant hepatic failure.

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Cross-Reactivity of Acetaminophen with Aspirin and NSAIDs

Most studies do not show any cross-reactivity with the use of acetaminophen in aspirin-sensitive patients. In one study, when asthmatic patients who were sensitive to very low doses of aspirin were challenged with doses of 1000 to 1500 mg of acetaminophen, a proportion had evidence of decreased pulmonary forced expiratory volume at 1 second (FEV1), but, in contrast to the aspirin reactions, the reactions to acetaminophen were generally mild and easily reversed. No reactions were seen with acetaminophen at doses of 650 mg or less. Acetaminophen is recommended as the analgesic/antipyretic of choice in aspirin/NSAID-sensitive patients.

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Gastrointestinal Effects

In recommended therapeutic doses, acetaminophen does not cause gastric irritation, gastric erosions, occult or overt gastrointestinal blood loss, or ulcers. In a placebo-controlled, randomized, double-blind, crossover, endoscopy study in 12 healthy volunteers, 1000 mg of aspirin evoked a lesion score of 2.5 (possible scores ranged from 0 [no mucosal lesions] to 3 [more than 10 petechiae or free blood in the lumen]), whereas 1000 mg of acetaminophen and placebo resulted in scores of 1.0 and 0.92, respectively. Several case-controlled studies have established that gastrointestinal bleeding is a significant risk with both regular and occasional aspirin or NSAID use, whereas acetaminophen is not associated with a risk for gastrointestinal bleeding. A case-controlled study evaluating first-time peptic ulcer patients found no significant risk associated with acetaminophen use prior to gastric ulcer occurrence, whereas this was not the case with aspirin. An American College of Gastroenterology survey found that OTC aspirin and NSAIDs were used significantly more often by patients in the gastrointestinal bleeding population than in controls. However, this was not the case with acetaminophen.

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Hematologic Effects

A case-controlled, multicenter study established that acetaminophen is not associated with agranulocytosis or aplastic anemia. Although there have been infrequent reports, primarily letters to the editor, in which thrombocytopenia was noted in patients receiving acetaminophen, no causality was established.

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Hemostatic Effects

In various clinical conditions, acetaminophen may be preferred because it does not have any immediate or delayed effects on small-vessel hemostasis, as measured by bleeding time. In normal volunteers receiving a single dose of acetaminophen (975 or 1950 mg) or multiple doses of acetaminophen (1950 mg daily for 6 weeks), no change in bleeding time or platelet aggregation was observed. In another study, a single 1000-mg dose of acetaminophen was given to normal volunteers and did not affect bleeding time or platelet aggregation. Patients with hemophilia receiving multiple doses of acetaminophen showed no significant changes in bleeding time.

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Hepatic Effects

In clinical studies in adults, acetaminophen when taken in therapeutic doses of up to 4000 mg/d demonstrated no adverse hepatic effects. Two double-blind, randomized, controlled trials have demonstrated the safety of acetaminophen with chronic use. In one study, Bradley and colleagues compared acetaminophen (4000 mg/d) with analgesic (1200 mg/d) and anti-inflammatory (2400 mg/d) doses of ibuprofen for 4 weeks. In the second study, Williams and associates evaluated the relative safety and efficacy of acetaminophen (2600 mg/d) compared with naproxen (750 mg/d) for up to 2 years. In both of these studies, no clinically important hepatic events occurred in acetaminophen-treated patients. In a large clinical study, Lesko and Mitchell enrolled more than 84,000 febrile children in a randomized, double-blind, acetaminophen-controlled trial to assess the risks of rare but serious adverse events following use of pediatric ibuprofen. Of the children included in the analysis, 28,130 received acetaminophen and none experienced serious adverse hepatic effects.

Acetaminophen in massive overdosage may cause hepatotoxicity in some patients. In adults and adolescents, hepatotoxicity may occur following ingestion of greater than 7.5 to 10 g (ie, 24 regular strength or 15 extra-strength caplets or tablets) over a period of 8 hours or less. Fatalities are infrequent (less than 3% to 4% of untreated cases) and have rarely been reported with overdoses less than 15 g (ie, 45 regular-strength or 30 extra-strength caplets or tablets). In children, amounts less than 150 mg/kg are highly unlikely to produce hepatotoxicity. In both adults and children, toxicity associated with acetaminophen is almost invariably caused by ingestion of quantities of the drug that are significantly above the recommended dosage range. Hepatotoxicity, ranging from transient sharp transaminase elevations to fatal, fulminant hepatic failure, is the most common result of clinically significant overdosage.

Chronic heavy alcohol abusers may be at increased risk of liver toxicity from excessive acetaminophen use, although reports of this event are rare. Although some authors suggest that alcoholics may be at increased risk from therapeutic doses, reports usually involve cases of severe chronic alcoholics and the dosages of acetaminophen most often exceed recommended doses and often involve substantial overdose. Studies evaluating the metabolism of doses up to 20 mg/kg of acetaminophen in chronic alcohol abusers and a study evaluating the effects of 2 days of acetaminophen dosing at 4000 mg daily in chronic alcoholics undergoing detoxification do not support an increased risk of hepatotoxicity with recommended doses of acetaminophen.

A report has suggested that hepatotoxicity following greater than the recommended dose of acetaminophen may be enhanced by both fasting and/or chronic alcohol ingestion. Review of this case series revealed that all patients reported taking overdoses of acetaminophen, most had reported prolonged periods of fasting, and the majority had a history of the abuse of alcohol.

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Hypersensitivity/Allergy

Allergic reactions (primarily skin rash) or reports of hypersensitivity secondary to acetaminophen are rare and generally are controlled by discontinuation of the drug and, when necessary, symptomatic treatment.

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Pregnancy

Acetaminophen labeling, like all OTC medications, instructs consumers who are pregnant or nursing a baby to contact their doctor before use. Acetaminophen has been used for over 40 years and available data indicate that acetaminophen in therapeutic doses does not adversely affect the pregnant mother or the fetus.

Transplacental Passage

Analysis of urine samples has demonstrated the passage of unconjugated acetaminophen via placental transfer. When given to the mother in therapeutic doses, acetaminophen crosses the placenta into fetal circulation as early as 30 minutes after ingestion, although the difference in serum concentration between maternal and cord blood is not statistically significant. In the fetus, acetaminophen is effectively metabolized by sulfate conjugation.

Nursing

Maternal ingestion of acetaminophen in recommended analgesic doses does not present a risk to the nursing infant. Amounts in milk range from 0.1% to 1.85% of the ingested maternal dose. These studies have established that, even at the time of peak acetaminophen concentration in human breast milk, the nursing infant would receive less than 2% of the maternal dose. Accordingly, breast feeding need not be interrupted because of maternal medication with recommended doses of acetaminophen.

Overdose

One study that evaluated the subsequent outcome of pregnancy in women who had taken an acetaminophen overdose during the period from 1984 to 1992 demonstrated no increased risk for fetal malformation. Acetaminophen overdose alone is not an indication for termination of pregnancy.

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Renal Effects

Clinical data have established that acetaminophen in recommended doses is not nephrotoxic. In a single-blind study, Prescott and colleagues compared the effect of acetaminophen (4000 mg/d) with indomethacin (150 mg/d) and placebo on renal function in healthy volunteers. Acetaminophen did not have the adverse renal effects generally associated with NSAIDs. Edwards and associates measured renal function in patients taking at least 1000 mg of acetaminophen daily for at least 1 year. There was no evidence of clinically significant renal impairment in 18 patients who each consumed a cumulative total of 2 to 30 kg of acetaminophen over prolonged periods.

Acute nephrotoxicity has been reported following massive overdose either as a sequela of hepatic failure or, occasionally, in the absence of hepatic failure.

Some studies suggest an association between the chronic long-term use of acetaminophen and renal effects. Results, however, are conflicting, limited by recall bias and confounded by the inability to determine whether analgesic use preceded or followed the onset of renal disease.

A National Kidney Foundation position paper notes that there is negligible clinical evidence to suggest that the habitual use of acetaminophen causes analgesic nephropathy. However, use of antipyretic analgesic combinations (ie, analgesics that contain aspirin and acetaminophen combined with caffeine or codeine) in large doses for prolonged periods of time is thought to be associated with an increased risk of renal papillary necrosis resulting in analgesic nephropathy. The panel concludes that acetaminophen has been preferentially recommended by physicians to patients with renal failure and that there is no evidence that occasional use of acetaminophen causes renal injury. In this position paper, acetaminophen was recommended as the non-narcotic analgesic of choice for episodic use in patients with underlying renal disease.

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