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Safety Perspectives, Toxicology, And Special Precautions
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.
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
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
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
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). 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.107
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
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.
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.
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
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.
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
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 evaluated the use of 4000 mg/d of acetaminophen for 13 days in patients with stable chronic liver disease. There were no abnormalities indicative of an adverse reaction to acetaminophen. Forrest and associates132 compared acetaminophen metabolism following a single 1500-mg dose in normal subjects, patients with mild liver disease, and patients with severe liver disease. There were no significant differences in overall 24-hour urinary excretion of acetaminophen and glucuronide, sulfate, cysteine, and mercapturic acid conjugates of acetaminophen. Following a single (10 mg/kg) dose of acetaminophen, the pharmacokinetic profiles in pediatric patients with mild, moderate, or severe liver disease were not 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.
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
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:
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.
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
23. Levy G, Garrettson LK, Soda DM. Evidence of placental transfer of acetaminophen (letter). Pediatrics. 1975;55:895.
24. Naga Rani MA, Joseph T, Narayanan R. Placental transfer of paracetamol. J Indian Med Assoc. 1989; 87:182-183.
25. Rollins DE, von Bahr C, Glaumann H, Moldeus P, Rane A. Acetaminophen: potentially toxic metabolite formed by human fetal and adult liver microsomes and isolated fetal liver cells.Science. 1979;205:1414-1416.
26. Berlin CM Jr, Yaffe SJ, Ragni M. Disposition of acetaminophen in milk, saliva, and plasma of lactating women. Pediatr Pharmacol. 1980;1:135-141.
27. Bitzen PO, Gustafsson B, Jostell KG, Melander A, Wahlin-Boll E. Excretion of paracetamol in human breast milk. Eur J Clin Pharmacol. 1981;20:123-125.
28. Notarianni LJ, Oldham HG, Bennett PN. Passage of paracetamol into breast milk and its subsequent metabolism by the neonate. Br J Clin Pharmacol. 1987;24:63-67.
29. Mitchell JR, Thorgeirsson SS, Potter WZ, Jollow DJ, Keiser H. Acetaminophen-induced hepatic injury: protective role of glutathione in man and rationale for therapy. Clin Pharmacol Ther. 1974;16:676-684.
30. Patten CJ, Thomas PE, Guy RL, et al. Cytochrome P450 enzymes involved in acetaminophen activation by rat and human liver microsomes and their kinetics. Chem Res Toxicol. 1993;6:511-518.
33. Prescott L. Paracetamol: A Critical Bibliographic Review. London: Taylor and Francis, Ltd; 1996.
49. Bradley J D, Brandt KD, Katz BP, Kalasinski LA, Ryan SI. Comparison of an anti-inflammatory dose of ibuprofen, an analgesic dose of ibuprofen, and acetaminophen in the treatment of patients with osteoarthritis of the knee. N Engl J Med. 1991;325: 87-91.
50. Williams HJ, Ward JR, Egger MJ, et al. Comparison of naproxen and acetaminophen in a two-year study of treatment of osteoarthritis of the knee. Arthritis Rheum. 1993;36:1196-1206.
82. Falliers CJ. Acetaminophen and aspirin challenges in subgroups of asthmatics. J Asthma. 1983; 20(suppl 1):39-49.
83. Quiralte J, Blanco C, Castillo R, Delgado J, Carrillo T. Intolerance to nonsteroidal anti-inflammatory drugs: results of controlled drug challenges in 98 patients. J Allergy Clin Immunol. 1996;98:678-685.
84. Spector SL, Wangaard CH, Farr RS. Aspirin and concomitant idiosyncrasies in adult asthmatic patients. J Allergy Clin Immunol. 1979;64:500-506.
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86. Settipane RA, Schrank PJ, Simon RA, Mathison DA, Christiansen SC, Stevenson DD. Prevalence of cross-sensitivity with acetaminophen in aspirin-sensitive asthmatic subjects. J Allergy Clin Immunol. 1995;96:480-485.
87. Hoftiezer JW, O'Laughlin JC, Ivey KJ. Effects of 24 hours of aspirin, Bufferin, paracetamol and placebo on normal human gastroduodenal mucosa. Gut. 1982; 23:692-697.
88. Johnson PC, Driscoll T. Comparison of plain and buffered aspirin with acetaminophen in regard to gastrointestinal bleeding. Curr Ther Res. 1981;30: 79-84.
89. Muller P, Simon B, Weise D, Dammann HG. Endoscopic studies on the gastric tolerance of paracetamol and acetylsalicylic acid: a placebo-controlled double-blind study in healthy volunteers. Arzneimittelforschung. 1990;40:316-318.
90. Begaud B, Chaslerie A, Carne X, et al. Upper gastrointestinal bleeding associated with analgesics and NSAID use: a case-control study (letter). J Rheumatol. 1993;20:1443-1444.
91. Laporte JR, Carne X, Vidal X, Moreno V, Juan J. Upper gastrointestinal bleeding in relation to previous use of analgesics and nonsteroidal anti-inflammatory drugs. Lancet. 1991;337:85-89.
92. Levy M, Miller DR, Kaufman DW, et al. Major upper gastrointestinal tract bleeding: relation to the use of aspirin and other nonnarcotic analgesics. Arch Intern Med. 1988;148:281-285.
93. McIntosh JH, Fung CS, Berry G, Piper DW. Smoking, nonsteroidal anti-inflammatory drugs, and acetaminophen in gastric ulcer: a study of associations and the effects of previous diagnosis on exposure patterns. Am J Epidemiol. 1988;128:761-770.
94. Peura DA, Lanza FL, Gostout CJ, Foutch PG, and contributing ACG member and fellows. Report of the American College of Gastroenterology Institute for Clinical Research and Education: The American College of Gastroenterology Bleeding Registry: Preliminary Findings. Am J Gastroenterol. 1997;92:924-928.
95. Kaufman DW. The Drug Etiology of Agranulocytosis and Aplastic Anemia. New York, NY: Oxford Press; 1991:200-201.
96. Eisner EV, Shahidi NT. Immune thrombocytopenia due to drug metabolite. N Engl J Med. 1972;287:376-381.
97. Font J, Nomdedeu B, Martinez-Orozco F, Ingelmo M, Balcells A. Amegakaryocytic thrombocytopenia and an analgesic (letter). Ann Intern Med. 1981;95:783.
98. Kornberg A, Polliack A. Paracetamol-induced thrombocytopenia and haemolytic anemia (letter). Lancet. 1978;2:1159.
99. Scheinberg IH. Thrombocytopenic reaction to aspirin and acetaminophen (letter). N Engl J Med. 1979; 300:678.
100. Shoenfeld Y, Shaklai M, Livni E, Pinkhas J. Thrombocytopenia from acetaminophen (letter). N Engl J Med. 1980;303:47.
101. Skokan JD, Hewlett JS, Hoffman GC. Thrombocytopenic purpura associated with ingestion of acetaminophen (Tylenol (acetaminophen) ). Cleve Clin Quarterly. 1973;40:89-91.
102. Mielke CH Jr, Heiden D, Britten AF, Ramos J, Flavell P. Hemostasis, antipyretics, and mild analgesics: acetaminophen versus aspirin. JAMA. 1976;235:613-616.
103. Seymour RA, Williams FM, Oxley A, et al. A comparative study of the effects of aspirin and paracetamol (acetaminophen) on platelet aggregation and bleeding time. Eur J Clin Pharmacol. 1984;26:567-571.
104. Kasper CK, Rapaport SI. Bleeding times and platelet aggregation after analgesics in hemophilia. Ann Intern Med. 1972;77:189-193.
105. Mielke CH Jr. Comparative effects of aspirin and acetaminophen on hemostasis. Arch Intern Med. 1981;141:305-310.
106. Lesko SM, Mitchell AA. An assessment of the safety of pediatric ibuprofen: a practitioner-based randomized clinical trial. JAMA. 1995;273:929-933.
107. Linden CH, Rumack BH. Acetaminophen overdose. Emerg Med Clin North Am. 1984;2:103-119.
108. Schøidt FV, Rochling FA, Casey DL, Lee WM. Acetaminophen toxicity in an urban county hospital. N Engl J Med. 1997;337:1112-1117.
109. Seeff LB, Cuccherini BA, Zimmerman HJ, Adler E, Benjamin SB. Acetaminophen hepototoxicity in alcoholics: a therapeutic misadventure. Ann Intern Med. 1986;104:399-404.
110. Zimmerman HJ, Maddrey WC. Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: analysis of instances of therapeutic misadventure. Hepatology. 1995;22:767-773.
111. Critchley JA, Dyson EH, Scott AW, Jarvie DR, Prescott LF. Is there a place for cimetidine or ethanol in the treatment of paracetamol poisoning? Lancet. 1983;1:1375-1376.
112. Critchley JA, Cregeen RJ, Balali-Mood M, Pentland B, Prescott LF. Paracetamol metabolism in heavy drinkers. Br J Clin Pharmacol. 1982;13:276P-277P.
113. Kuffner E, Bogdan GM, Dart RC. Evaluation of hepatotoxicity in alcoholics from therapeutic doses of acetaminophen (abstract). J Toxicol Clin Toxicol. 1997;35:561.
114. Skinner MH, Matano R, Hazle W, Blaschke TF. Acetaminophen metabolism in recovering alcoholics. Methods Find Exp Clin Pharmacol. 1990;12:513-515.
115. Villeneuve JP, Raymond G, Bruneau J, Colpron L, Pomier-Layrargues G. Pharmacokinetics and metabolism of acetaminophen in normal, alcoholic, and cirrhotic subjects. Gastroenterol Clin Biol. 1983;7:898-902.
116. Whitcomb DC, Block GD. Association of acetaminophen hepatotoxicity with fasting and ethanol use. JAMA. 1994;272:1845-1850.
117. McElhatton PR, Sullivan FM, Volans GN. Paracetamol overdose in pregnancy analysis of the outcomes of 300 cases referred to the Teratology Information Service. Reprod Toxicol. 1997;11:85-94.
118. Prescott LF, Mattison P, Menzies DG, Manson LM. The comparative effects of paracetamol and indomethacin on renal function in healthy female volunteers. Br J Clin Pharmacol. 1990;29:403-412.
119. Edwards OM, Edwards P, Huskisson EC, Taylor RT. Paracetamol and renal damage. Br Med J. 1971;2: 87-89.
120. Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics. 1975;55:871-876.
121. Gates TN, Temple AR. Analgesic use and chronic renal disease (letter). N Engl J Med. 1989;321:1125.
122. Murray TG, Stolley PD, Anthony JC, Schinnar R, Hepler-Smith E, Jeffreys JL. Epidemiologic study of regular analgesic use and end-stage renal disease. Arch Intern Med. 1983;143:1687-1693.
123. Nelson EB. Kidney failure and analgesic drugs (letter). N Engl J Med. 1995;332:1514-1515.
124. Perneger TV, Whelton PK, Klag MJ. Risk of kidney failure associated with the use of acetaminophen, aspirin, and nonsteroidal anti-inflammatory drugs. N Engl J Med. 1994;331:1675-1679.
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126. Henrich WL, Agodoa LE, Barrett B, et al. Analgesics and the kidney: summary and recommendations to the Scientific Advisory Board of the National Kidney Foundation from an Ad Hoc Committee of the National Kidney Foundation. Am J Kidney Dis. 1996;27:162-165.
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128. Cottafava F, Neiri S, Franzone G, Sanguinetti M, Bertolazzi L, Ravera G. Double-blind controlled comparison of placebo and paracetamol in patients with G-6-PD-deficiency. Pediatr Med Chir. 1990;12:633-638.
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130. Benson GD. Hepatotoxicity following the therapeutic use of antipyretic agents. Am J Med. 1983;75(suppl 5A):85-93.
131. Benson GD. Acetaminophen in chronic liver disease. Clin Pharmacol Ther. 1983;33:95-101.
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133. al-Obaidy SS, McKiernan PJ, Li Wan Po A, Glasgow JF, Collier PS. Metabolism of paracetamol in children with chronic liver disease. Eur J Clin Pharmacol. 1996;50:69-76.
134. Prescott LF, Speirs GC, Critchley JA, Temple RM, Winney RJ. Paracetamol disposition and metabolite kinetics in patients with chronic renal failure. Eur J Clin Pharmacol. 1989;36:291-297.
135. Martin U, Temple RM, Winney RJ, Prescott LF. The disposition of paracetamol and the accumulation of its glucuronide and sulphate conjugates during multiple dosing in patients with chronic renal failure. Eur J Clin Pharmacol. 1991;41:43-46.
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