Potential Drug-Drug Interactions Alcohol
The package label for adult TYLENOL® acetaminophen products contains an alcohol warning that states, "If you consume 3 or more alcoholic drinks every day, ask your doctor whether you should take acetaminophen or other pain relievers/fever reducers.
Acetaminophen may cause liver damage."
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.108-110 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.111-115
Healthcare professionals should alert their patients who regularly consume large amounts of alcohol not to exceed recommended doses of acetaminophen.
Anticonvulsants
Some reports have suggested that patients taking long-term anticonvulsants, who overdose on acetaminophen, may be at increased risk of hepatotoxicity because of accelerated metabolism of acetaminophen.137,138 Available data are conflicting. A 7-year retrospective study of acetaminophen overdose admissions indicates that the overall mortality rate was not significantly different for patients taking concomitant anticonvulsant medications.139 Hydantoins
At usual oral therapeutic doses of acetaminophen and hydantoins, no special dosage adjustment or monitoring is generally required. Pharmacokinetic studies indicate that phenytoin primarily induces the glucuronidation pathway, whereas glutathione-derived metabolites are not increased in patients on chronic phenytoin therapy.140 Additionally, recent data demonstrate that phenytoin is metabolized primarily by CYP2C9 and CYP2C19,141 whereas acetaminophen is primarily metabolized by CYP2E1. These data indicate that there is no increased risk from an acetaminophen overdose in patients on chronic hydantoin therapy.
Carbamazepine
At usual oral therapeutic doses of acetaminophen and carbamazepine, no special dosage adjustment is generally required. Carbamazepine is primarily metabolized by CYP3A4, whereas acetaminophen is metabolized primarily via CYP2E1.141 It is not known whether there is increased risk from an acetaminophen overdose in patients on chronic carbamazepine therapy.
Diflunisal
Professional literature from the manufacturer of diflunisal cautions that concomitant
administration with acetaminophen produces an approximate 50% increase in plasma levels of acetaminophen in normal volunteers.142 Acetaminophen had no effect on diflunisal plasma levels. The clinical significance of these findings has not been established. However, caution should be used with concomitant administration of diflunisal and acetaminophen and patients should be monitored carefully.
Isoniazid
Some reports suggest that patients on chronic isoniazid therapy may be at risk for developing hepatotoxicity from an acetaminophen overdose at doses that would not have been expected to produce toxicity.143-145 Since patients on isoniazid therapy may develop hepatic effects from isoniazid alone, data from individual case reports are unclear as to whether chronic administration of isoniazid may increase the risk of acetaminophen toxicity. Volunteer studies demonstrate that isoniazid inhibits the formation of the toxic metabolite of acetaminophen when taken concurrently, indicating that isoniazid could actually protect against
hepatotoxicity from an acetaminophen overdose.146,147 However, it also appears that isoniazid acetylation genotype may play a role in the activity of CYP2E1,148 and based on acetylation genotype, inhibition or induction may be present following discontinuation of isoniazid therapy. In two studies of induction, any evidence suggesting increase of activity was only seen during a brief period from 12 to 48 hours after discontinuation of isoniazid.147,148
Oral Anticoagulants
Many factors, including diet, medications, and environmental and physical states, may affect how a patient responds to anticoagulant therapy.142 There have been several reports that suggest that acetaminophen may produce hypoprothrombinemia (elevated international normalized ratio [INR] or prothrombin time) when administered with coumarin
149-151 152-154
55
WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Safety Perspectives, Toxicology, And Special Precautions a. Safety
Central Nervous System Effects
Acetaminophen at recommended doses has no obvious effects on central nervous system function.33 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.
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.82-85 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.86 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.
Gastrointestinal Effects
In recommended therapeutic doses, acetaminophen does not cause gastric irritation, gastric erosions, occult or overt gastrointestinal blood loss, or ulcers.87,88 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.89 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.90-92 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.93 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.94
Hematologic Effects
A case-controlled, multicenter study established that acetaminophen is not associated with agranulocytosis or aplastic anemia.95 Although there have been infrequent reports, primarily letters to the editor, in which thrombocytopenia was noted in patients receiving
acetaminophen, no causality was established.96-101 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.102 In another study, a single 1000-mg dose of acetaminophen was given to normal volunteers and did not affect bleeding time or platelet aggregation. 103 Patients with hemophilia receiving multiple doses of acetaminophen showed no significant changes in bleeding time.104,105
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 colleagues49 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 associates50 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 aceta-minophen-treated patients. In a large clinical study, Lesko and Mitchell106 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).
57 of severe chronic alcoholics and the dosages of acetaminophen most often exceed
recommended doses and often involve substantial overdose.108-110 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.111-115
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.116 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.
Hypersensitivity and 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.
Pregnancy/Teratogenicity
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.23 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.24 In the fetus, acetaminophen is effectively metabolized by sulfate conjugation.25 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.26-28 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.117
Renal Effects
Clinical data have established that acetaminophen in recommended doses is not nephrotoxic.33 In a single-blind study, Prescott and colleagues118 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 associates119 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.120
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.119,121-125
A National Kidney Foundation position paper notes that there is negligible clinical evidence to suggest that the habitual use of acetaminophen causes analgesic nephropathy.126 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.126 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.
b. Use in Certain Disease States or Conditions
Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency
In therapeutic doses, acetaminophen does not shorten the lifespan of red blood cells127,128 and does not produce any clinically perceptible destruction of circulating red blood cells.129 Use in Chronic Liver Disease
Acetaminophen can be used in patients with liver disease130 and has been studied in both one-time single (1500 mg) and multiple doses (4000 mg/d) in adult patients with chronic stable liver disease.131,132 Benson131 conducted a double-blind, two-period, crossover study that
59 significantly different.133 Although the plasma half-life of acetaminophen was prolonged in patients with severe liver disease, there were no significant differences in the 24-hour (adult) and 36-hour (children) urinary excretion of acetaminophen or its conjugates (eg, glucuronide, sulfate, cysteine, mercapturic acid).
Use in Renal Disease
Based on available clinical data, acetaminophen can be used in patients with chronic renal disease without dosage adjustment. In a single-dose study, Prescott and colleagues134 compared the disposition and metabolite kinetics of 1000 mg of acetaminophen in patients with renal disease and in healthy volunteers. The fractional urinary recovery of
acetaminophen and its conjugates (eg, glucuronide, sulfate, cysteine, mercapturate) was similar in healthy volunteers and in patients with moderate renal failure. In a 10-day, multi-dose study, Martin and associates135 evaluated the disposition of acetaminophen 3000 mg daily in healthy volunteers compared with patients with chronic renal failure. A slight increase in predose trough acetaminophen levels was noted in patients with renal failure (3.1 µg/mL) compared with controls (1.1 µg/mL), but there was no evidence of accumulation of the glutathione-derived metabolites of acetaminophen (eg, cysteine, mercapturate). Although mean daily predose plasma concentrations of sulfate and glucuronide conjugates were higher in patients with chronic renal disease, these conjugates disappeared rapidly when
acetaminophen was discontinued. There is no significant risk of acetaminophen toxicity in patients with moderate to severe renal failure.
A National Kidney Foundation position paper notes that physicians preferentially recommend acetaminophen to patients with renal failure because of the bleeding complications associated with aspirin in these individuals.126 In this position paper, acetaminophen was recommended as the non-narcotic analgesic of choice for episodic use in patients with underlying renal disease.
Use in Older Patients
No adjustment in labeled dosage is necessary for older patients who require acetaminophen therapy. Those who require therapy for longer than 10 days should consult their physician for condition monitoring; however, no reduction in recommended dosage is necessary. The American Geriatrics Society Clinical Practice Guidelines for the Management of Chronic Pain in Older Persons136 recommend acetaminophen as the drug of choice for relieving mild to moderate musculoskeletal pain, with the maximum dosage not to exceed 4000 mg daily.
Carcinogenicity/Mutagenicity (Animal)
Various animal bioassays on a weight-of-evidence basis have demonstrated no evidence of carcinogenic potential for acetaminophen. The International Agency for Research on Cancer (IARC) found only limited evidence in animals for carcinogenicity and the US National Toxicology Program (NTP) found no evidence for carcinogenicity in mice and male rats and only equivocal evidence for carcinogenicity in female rats.161,162 The equivocal results were based on a few studies with serious methodological problems. Negative results have been demonstrated in rodent bioassays of acetaminophen.163
Carcinogenicity (Human)
Although it has been hypothesized that long-term use of analgesics may be associated with a slight increase in urinary tract tumors and renal cell cancer in man, a number of population-based, case-controlled studies have shown that it is not likely that acetaminophen use plays a major role in renal cell cancer.164-166
A comprehensive and conclusive review, accepted by the Committee for Proprietary Medicinal Products (CPMP) of the European Union, considered the genotoxic and
carcinogenic properties of acetaminophen.167 This review concluded that genotoxic effects of acetaminophen are not reached at therapeutic dosage.
Reproductive and Teratogenic Effects (Animal)
There was no effect on pregnancy or offspring when acetaminophen was given at dose levels of 600 mg/kg/d in the diet of male rats for 60 days prior to mating and to female rats from 14 days before mating to the end of pregnancy. An oral dose of 600 mg/kg/d produced no teratogenicity or embryotoxicity when given from days 6 through 15 of pregnancy. When acetaminophen was given from day 16 of pregnancy through a 3-week lactation period, no deleterious effect was noted on pregnancy rate or on percent of live births, but a decrease in body weight gain and survival rate was noted among offspring of drug-treated females.168,169 In another study, acetaminophen 250 mg/kg/d did not affect fetal length or weight, incidence of resorptions, or placental weight.170
Potential Laboratory Test Interferences
Using the most current analytic systems, acetaminophen does not cause laboratory test interferences. However, there are certain methods with which the possibility of laboratory changes exists, as described below:
Blood Tests
Acetaminophen at recommended doses does not appear to interfere with glucose analysis using currently marketed blood glucose meters. For further detail, it may be advisable to contact the specific laboratory instrumentation manufacturer.
Urine Tests
Acetaminophen in therapeutic doses may interfere with the determination of
5-hydroxyindoleacetic acid (5HIAA), causing false-positive results. False determinations may be eliminated by avoiding acetaminophen ingestion several hours before and during the collection of the urine specimen.155
OVERDOSE
61 in the course of treatment, in reducing morbidity and virtually eliminating mortality
associated with even a massive acetaminophen overdose.
McNeil Consumer Healthcare continues to sponsor a toll-free telephone number (1-800-525-6115), available 24 hours a day, at the Rocky Mountain Poison and Drug Center. Please do not hesitate to call this number if you need individualized consultation on managing a patient with an acetaminophen overdose.
a. Acute Overdose Management
Acute acetaminophen overdose is defined as an ingestion of a toxic amount of acetaminophen occurring within a period of 8 hours or less.* A number of steps in the management of such an overdose are important to achieve an optimal clinical outcome. This section outlines basic steps in managing acute acetaminophen overdose, consistent with FDA-approved labeling of acetylcysteine. A flowchart outlining a stepwise approach, and a nomogram are provided (Figures 3 and 4, respectively).
FIGURE 3. Flowchart: Stepwise Management of Acute Acetaminophen Overdose
Assessment
Adults or adolescents ( ≥ 12 years of age), who may have ingested acetaminophen in a purposeful overdose, independent of the amount reported to have been ingested, should be referred for evaluation and have a plasma acetaminophen level determined. Any individual presenting with an unknown amount of acetaminophen ingested or with a questionable or unreliable history about the time of ingestion should have a plasma acetaminophen level drawn and be treated with acetylcysteine. (For management of acetaminophen overdose in young children, see Special Populations, Young Children.)
Estimate as carefully as possible the quantity and dosage form (see also Special
Considerations: Extended-Release Acetaminophen) of acetaminophen ingested and the time of ingestion. In adults and adolescents, hepatic toxicity 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) with overdoses less than 15 g (ie, 45 regular-strength or 30 extra-strength caplets or tablets).
Gastric Decontamination/Prevention of Absorption
Gastric decontamination should be carried out according to standard treatment guidelines.
Gastric decontamination should be carried out according to standard treatment guidelines.