Acetaminophen/salicylamide Disease Interactions

Chronic alcohol abusers may be at increased risk of hepatotoxicity during treatment with acetaminophen (APAP). Severe liver injury, including cases of acute liver failure resulting in liver transplant and death, has been reported in patients using acetaminophen. Therapy with acetaminophen should be administered cautiously, if at all, in patients who consume three or more alcoholic drinks a day. In general, patients should avoid drinking alcohol while taking acetaminophen-containing medications. Patients should be warned not to exceed the maximum recommended total daily dosage of acetaminophen (4 g/day in adults and children 12 years of age or older), and to read all prescription and over-the-counter medication labels to ensure they are not taking multiple acetaminophen-containing products, or check with a healthcare professional if they are unsure. They should also be advised to seek medical attention if they experience signs and symptoms of liver injury such as fever, rash, anorexia, nausea, vomiting, fatigue, right upper quadrant pain, dark urine, and jaundice.

Acetaminophen is contraindicated in patients with severe hepatic impairment or severe active liver disease. Patients with hepatic impairment may be at increased risk of toxicity. Severe liver injury, including cases of acute liver failure and death, have been reported in patients using this drug. Clinical monitoring of hepatic function is recommended. Caution is advised if using acetaminophen in patients with chronic malnutrition or severe hypovolemia. Instruct patients to avoid drinking alcohol while taking acetaminophen-containing medications. Patients should be warned not to exceed the maximum recommended total daily dosage of acetaminophen (4 g/day in adults and children 12 years of age or older), and to read all prescription and over-the-counter medication labels to ensure they are not taking multiple acetaminophen-containing products, or check with a healthcare professional if they are unsure.

Salicylates, particularly aspirin, can cause dose-related gastrointestinal bleeding and mucosal damage, which may occur independently of each other. Occult, often asymptomatic GI blood loss is quite common with usual dosages of aspirin and stems from the drug's local effect on the GI mucosa. During chronic therapy, this type of bleeding may occasionally produce iron deficiency anemia. In contrast, major upper GI bleeding rarely occurs except in patients with active peptic ulcers or recent GI bleeding. However, these patients generally do not experience greater occult blood loss than healthy patients following small doses of aspirin. Mucosal damage associated with the use of salicylates may lead to development of peptic ulcers with or without bleeding, reactivation of latent ulcers, and ulcer perforation. Therapy with salicylates and related agents such as salicylamide should be considered and administered cautiously in patients with a history of GI disease or alcoholism, particularly if they are elderly and/or debilitated, since such patients may be more susceptible to the GI toxicity of these drugs and seem to tolerate ulceration and bleeding less well than other individuals. Extreme caution and thorough assessment of risks and benefits are warranted in patients with active or recent GI bleeding or lesions. Whenever possible, especially if prolonged use is anticipated, treatment with non-ulcerogenic agents should be attempted first. If salicylates are used, close monitoring for toxicity is recommended. Some adverse GI effects may be minimized by administration with high dosages of antacids, use of enteric-coated or extended-release formulations, and/or concurrent use of a histamine H2-receptor antagonist or a cytoprotective agent such as misoprostol. Patients with active peptic ulceration or GI bleeding treated with salicylates should generally be administered a concomitant anti-ulcer regimen.

The use of salicylates, primarily aspirin, in children with varicella infections or influenza-like illnesses has been associated with an increased risk of Reye's syndrome. Although a causal relationship has not been established, the majority of evidence to date seems to support the association. Most authorities, including the American Academy of Pediatrics Committee on Infectious Diseases, recommend avoiding the use of salicylates in children and teenagers with known or suspected varicella or influenza and during presumed outbreaks of influenza. If antipyretic or analgesic therapy is indicated under these circumstances, acetaminophen may be an appropriate alternative. The same precautions should also be observed with related agents such as salicylamide or diflunisal because of their structural and pharmacological similarities to salicylate.

Several oral acetaminophen and acetaminophen-combination products, particularly flavored chewable tablets, contain the artificial sweetener, aspartame (NutraSweet). Aspartame is converted to phenylalanine in the gastrointestinal tract following ingestion. Chewable and effervescent formulations of acetaminophen products may also contain phenylalanine. The aspartame/phenylalanine content should be considered when these products are used in patients who must restrict their intake of phenylalanine (i.e. phenylketonurics).

Occult, often asymptomatic GI blood loss occurs quite frequently with the use of normal dosages of aspirin and stems from the drug's local effect on the GI mucosa. During chronic therapy, this type of bleeding may occasionally produce iron deficiency anemia. Other salicylates reportedly cause little or no GI blood loss at usual dosages, but may do so at high dosages. Prolonged therapy with salicylates, particularly aspirin, should be administered cautiously in patients with or predisposed to anemia. Periodic monitoring of hematocrit is recommended. The same precautions should also be observed with the use of related agents such as salicylamide because of their structural and pharmacological similarities to salicylate.

All salicylates can interfere with the action of vitamin K and induce a dose-dependent alteration in hepatic synthesis of coagulation factors VII, IX and X. At usual recommended dosages, a slight increase in prothrombin time (PT) may occur. Therapy with salicylates, especially if given in high dosages, should be administered cautiously in patients with significant active bleeding or a hemorrhagic diathesis, including hemostatic and/or coagulation defects associated with hemophilia, vitamin K deficiency, hypoprothombinemia, thrombocytopenia, thrombocytopathy, or severe hepatic impairment. The same precaution should also be observed with the use of related agents such as salicylamide because of their structural and pharmacological similarities to salicylate.

Salicylates, particularly aspirin, may cause or aggravate hemolysis in patients with pyruvate kinase or glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. However, this effect has not been clearly established. Until more data are available, therapy with salicylates should be administered cautiously in patients with G-6-PD deficiency. The same precaution should also be observed with the use of related agents such as salicylamide because of their structural and pharmacological similarities to salicylate.

The use of salicylates has occasionally been associated with acute, reversible hepatotoxicity, primarily manifested as elevations of serum transaminases, alkaline phosphatase and/or, rarely, bilirubin. Hepatic injury consistent with chronic active hepatitis has also been reported in a few patients, which resulted rarely in encephalopathy or death. Salicylate-induced hepatotoxicity appears to be dependent on serum salicylate concentration (> 25 mg/dL) and has occurred most frequently in patients with juvenile arthritis, active systemic lupus erythematosus, rheumatic fever, or preexisting hepatic impairment. Therapy with salicylates, particularly when given in high dosages, should be administered cautiously in these patients, and periodic monitoring of liver function is recommended. The same precautions should also be observed with the use of related agents such as salicylamide because of their structural and pharmacological similarities to salicylate. A dosage reduction may be necessary if liver function abnormalities develop and serum salicylate concentration exceeds 25 mg/dL, although serum transaminase elevations may sometimes be transient and return to pretreatment values despite continued therapy without dosage adjustment.