General Administration Information
For storage information, see the specific product information within the How Supplied section.
-All preparations: Administer with food or large amounts (240 ml) of water or milk to minimize GI irritation.
Oral Solid Formulations
-Film-coated tablets: May help to reduce the unpleasant taste or aftertaste, burning in the throat, or difficulty in swallowing associated with uncoated tablets.
-Enteric-coated or extended-release tablets: Swallow whole; do not crush, cut, or chew. May help to reduce gastric irritation and/or symptomatic GI disturbances associated with uncoated tablets.
-Chewable tablets: May be chewed, crushed, and/or dissolved in a liquid, or swallowed whole, followed by approximately 120 ml of water, milk, or fruit juice immediately after administration.
-For use in patients unable to take or retain oral aspirin; however, absorption may be slow and incomplete. Do not use aspirin tablets rectally because they are likely to cause irritation and erosion of rectal mucosa.
-Instruct patient or caregiver on proper use of suppository.
-Prior to insertion, carefully remove the wrapper. Avoid excessive handling as to avoid melting of the suppository.
-If suppository is too soft to insert, chill in the refrigerator for 30 minutes or run cold water over it before removing the wrapper.
-Moisten the suppository with cool water prior to insertion.
-Have patient lie down on their side, usually in the Sim's lateral position to provide support and comfort.
-Apply gentle pressure to insert the suppository completely into the rectum, pointed end first, using a gloved, lubricated index finger.
-After insertion, keep the patient lying down to aid retention and gently hold the buttock cheeks close to keep the child from immediately expelling the suppository. The suppository must be retained in rectum to ensure complete absorption.
Gastrointestinal (GI) disturbances are the most common adverse events reported in children treated with aspirin. Most GI effects are mild and include nausea, vomiting, dyspepsia, abdominal pain, pyrosis (heartburn), and gastritis. Symptoms of gastric distress can be reduced if aspirin is taken with food or a full glass of water. In patients receiving chronic aspirin therapy, preventative agents, such as proton pump inhibitors or H2-antagonists, may be needed for protective effect on the gastric mucosa. Diarrhea or constipation may also occur. Melena, hemorrhoids, and rectal hemorrhage have occurred with aspirin therapy. Rare cases of esophagitis have been reported in patients receiving aspirin. Aspirin-induced esophagitis is characterized by sudden onset odynophagia, retrosternal pain, and dysphagia. Severe complications such as GI perforation, esophageal ulceration, esophageal stricture, and GI bleeding, have been reported rarely, including in children. Risk factors for aspirin-induced esophageal effects include taking the medication without water and at night. Symptoms usually resolve within days to weeks after stopping the medication. Penetration of the gastric or esophageal mucosal cell by unionized molecules is one mechanism by which aspirin causes mucosal damage. Raising the intragastric pH increases the amount of aspirin in the unionized form, and some data indicate that agents such as cimetidine or antacids can reduce mucosal injury from aspirin. Chronic aspirin therapy may induce peptic ulcer disease. Gastric or peptic ulcers up to 1 cm in diameter induced by salicylates may heal despite continued therapy when oral cimetidine or high dose antacids are used concomitantly. Duodenal mucosal damage appears to be less common when enteric-coated tablets are used when compared with buffered or uncoated tablets. GI bleeding or erosive gastritis can be minor or life-threatening and may result from a combination of direct irritant action on the stomach mucosa and an increased bleeding time. In general, the severity of GI bleeding with aspirin is dose-related. Occult GI bleeding occurs in many patients and is not necessarily correlated with GI distress. While the amount of blood lost is usually not significant, blood loss can result in iron deficiency anemia. GI bleeding is more common with aspirin than with other salicylates and is not reduced by administering aspirin with food.
Tinnitus and hearing loss may occur in patients receiving high-dose and/or long-term aspirin therapy. These effects are early manifestations of salicylate toxicity. However, hearing loss has occurred in patients at low serum salicylate levels. Tinnitus and hearing loss are usually dose-related and reversible upon dose reduction or discontinuation. Tinnitus is commonly associated with salicylate levels > 200-300 mcg/ml. Maximum hearing loss occurs most frequently at salicylate levels of >= 400 mcg/ml.
Anaphylactoid reactions, including angioedema, laryngeal edema, and acute bronchospasm, may occur with aspirin therapy. Most allergic reactions occur within minutes and almost always within an hour of ingestion, although delayed reactions have been noted. Aspirin hypersensitivity may manifest as a respiratory reaction including rhinitis and/or asthma or with urticaria and angioedema. Aspirin hypersensitivity is uncommon and occurs in only 0.5-1.9% of the general population. Hypersensitivity reactions to aspirin are reported less frequently in children with a rate of approximately 0.3%. In children with asthma, aspirin sensitivity is approximately 5%. Prevalence among adult patients with asthma or chronic urticaria has been reported to range from 4-11% and 27-35%, respectively. Sensitivity is manifested primarily as bronchospasm in asthmatic patients and is most commonly associated with nasal polyps. The correlation of aspirin hypersensitivity, asthma, and nasal polyps is known as the aspirin triad. Hypersensitivity reactions are more common with aspirin than other salicylates. Patients sensitive to aspirin may develop cross-sensitivity to other analgesics, NSAIDs, and azo dyes such as tartrazine. Acetaminophen and other salicylate salts are not cross-sensitive and may be used cautiously in patients with aspirin-induced asthma.
Salicylates, such as aspirin, may cause reversible hepatotoxicity primarily manifested as mild focal hepatic necrosis and portal hypertension with elevated hepatic enzymes (usually transaminases) and hyperbilirubinemia. Transaminase elevations have been commonly reported in children with rheumatic diseases treated with aspirin. Jaundice has been reported in some patients. Rarely, salicylates are associated with hypoprothrombinemia resulting in a prolonged prothrombin time and chronic hepatitis. Usually salicylate-induced hepatotoxicity is mild, but in some cases fatalities or hepatic encephalopathy have occurred. The occurrence of these events appears to be dose and duration related.
Reye's syndrome, a potentially fatal disease, has been associated with aspirin use in children following active varicella infection or other viral illnesses. Reye's syndrome has been reported in children of all ages; however, most of the reported cases have occurred in children 5-10 years of age. Data are not strong to support a dose-dependent association with Reyes's syndrome ; however, one case-controlled study reported that patients who developed Reye's syndrome (n = 27) had received larger doses for a longer duration compared with controls who did not develop Reye's syndrome. Of the patients who developed Reye's syndrome, 67% were receiving > 20 mg/kg/day of salicylates compared with only 22% of controls. Reye's syndrome is a multisystem disorder evidenced by persistent vomiting, altered sensorium, elevated hepatic enzymes, hypoprothrombinemia, hyperammonemia, convulsions, and encephalopathy.
Dermatologic reactions are uncommon; usually reported in patients who receive salicylate therapy for > 1 week continually or with overdosage. These reactions include acneiform rash, erythema nodosum, maculopapular rash, pruritus, purpura, and urticaria. Rarely, aspirin has been associated with Stevens-Johnson syndrome and toxic epidermal necrolysis. Aspirin (acetylsalicylic acid) has been associated with acute generalized exanthematous pustulosis (AGEP). The non-follicular, pustular, erythematous rash starts suddenly and is associated with fever above 38 degrees C. Drugs are the main cause of AGEP. A period of 2-3 weeks after an inciting drug exposure appears necessary for a first episode of AGEP; unintentional reexposure may cause a second episode within 2 days.
Aspirin therapy causes platelet dysfunction by inhibiting platelet aggregation resulting in a prolonged bleeding time; this effect is a common and expected pharmacologic effect of the drug leading to drug efficacy. Infrequently this effect on platelet aggregation may result in minor bleeding episodes such as epistaxis or hematoma or gingival bleeding. Leukopenia, pancytopenia, thrombocytopenia, agranulocytosis, aplastic anemia, and disseminated intravascular coagulation (DIC) have been reported rarely with salicylates. Leukocytosis has occurred in patients with salicylate overdose. If hemolytic anemia occurs in patients receiving aspirin, it almost always occurs in G6PD-deficient individuals. It appears that aspirin can induce hemolysis at therapeutic concentrations if other oxidative stressors are present. Otherwise, hemolysis only occurs at much higher concentrations.
With chronic, high-dose aspirin use, analgesic abuse, or salicylate overdose, a marked reduction in creatinine clearance, renal papillary necrosis, interstitial nephritis, or renal tubular necrosis with renal failure (unspecified) may be seen; however, in usual doses, salicylates rarely cause clinically significant renal effects in patients with normal renal function. The incidence of nephrotoxicity appears to be low in pediatric patients. Salicylates may cause transient urinary excretion of renal tubular epithelial cells, azotemia, albuminuria, and proteinuria.
Salicylates, such as aspirin, have dose-dependent effects on plasma uric acid levels. At low doses (1-2 g/day) decreased urate excretion and hyperuricemia may be seen. Intermediate salicylate doses (2-3 g/day) usually do not alter urate excretion, and large doses of salicylates (> 3 g/day) induce uricosuria and lower plasma uric acid levels. Small doses of salicylates can block the effects of probenecid and other uricosuric agents that decrease the tubular reabsorption of uric acid.
At therapeutic doses, salicylates such as aspirin cause changes in acid/base balance and electrolytes resulting in respiratory alkalosis. In patients with normal renal and respiratory function, this is usually compensated for appropriately. Severe acid/base disturbances may occur during salicylate toxicity. Infants and children with salicylate toxicity rarely present clinically with respiratory alkalosis. As salicylate toxicity progresses, changes resembling metabolic acidosis are present (e.g., low blood pH, low plasma bicarbonate levels, and normal or nearly normal plasma PaCO2). In reality, a combination of respiratory acidosis and metabolic acidosis is present. Alterations in water and electrolyte balance also occur in salicylate toxicity. Dehydration due to salicylate-induced diaphoresis and hyperventilation occurs. Since more water than electrolytes are loss, dehydration is associated with hypernatremia. Other laboratory changes noted in salicylate toxicity include hyperglycemia or hypoglycemia (especially in children), ketonuria, hypokalemia, and proteinuria. Prolonged exposure to high doses of salicylates also causes hypokalemia through both renal and nonrenal losses. Hyperventilation occurs due to direct stimulation of the respiratory center in the medulla. At high salicylate plasma concentrations (>= 350 mcg/ml), marked hyperventilation will occur and at serum concentrations of about 500 mcg/ml, hyperpnea will be seen. At high or prolonged doses, salicylates also have a depressant effect on the medulla. Toxic doses of salicylates cause central respiratory depression as well as cardiovascular collapse secondary to vasomotor depression. Since enhanced CO2 production continues, respiratory acidosis occurs.
Moderate-to-severe noncardiogenic pulmonary edema may occur during aspirin associated acute or chronic salicylic acid toxicity.
Intracranial bleeding may occur in patients at risk who are taking aspirin. This is rarely observed in children when aspirin is used alone, but the risk is significantly increased with concomitant use of other antithrombotics, anticoagulants, or thrombolytics.
Headache is a reported neurologic adverse reaction with NSAID use. Overuse of aspirin (defined as taking 3 or more doses per day more often than 5 days per week) by headache-prone patients frequently produces drug-induced rebound headache or medication overuse headache accompanied by dependence on symptomatic medication, tolerance (refractoriness to prophylactic medication), and withdrawal symptoms.
Dizziness, drowsiness, headache, lightheadedness, and lethargy may be signs of salicylism, mild salicylate toxicity. Other symptoms of salicylism include uncontrollable flapping movements of the hands, increased thirst, and visual impairment. In severe aspirin overdose, seizures, hallucinations, severe nervousness, excitement, confusion, wheezing or shortness of breath, and unexplained fever may occur. In young children, the only signs of overdose may be behavioral changes.
Aspirin use is contraindicated in patients with hypersensitivity to other medications for pain or fever, including those with salicylate hypersensitivity or NSAID hypersensitivity. The risk of cross-sensitivity with other nonsteroidal antiinflammatory drugs is significantly greater with aspirin than other salicylates. Patients with nasal polyps or with allergic reactions (e.g. urticaria) to aspirin are at risk of developing bronchoconstriction or anaphylaxis and should not receive aspirin. Patients with asthma are at risk of developing severe and potentially fatal exacerbations of asthma after taking aspirin. Aspirin should be avoided in asthmatics with a history of aspirin-induced acute bronchospasm.
Aspirin has been associated with the occurrence of Reye's syndrome when given to children with varicella (i.e., chickenpox) or influenza. Although a causal relationship has not been confirmed, most authorities advise against the use of aspirin in children with varicella, influenza, or other viral infection. If children are receiving chronic aspirin therapy, aspirin should be discontinued immediately if a fever develops, and not resumed until diagnosis confirms that the febrile viral illness has run its course and the absence of Reye's syndrome. Following varicella vaccination, aspirin use should generally be avoided for 6 weeks. Children receiving long-term aspirin therapy should receive the annual influenza vaccine.
Aspirin can induce gastric or intestinal ulceration that can occasionally be accompanied by iron-deficiency anemia or other anemia from the resultant blood loss. Aspirin should be used cautiously, if at all, in patients with a history of or active GI disease including erosive gastritis, esophagitis, GI bleeding, peptic ulcer disease, or previous NSAID-induced bleeding. Such patients should be monitored closely, with special caution in adolescent patients who may have alcoholism or who are tobacco smoking. All patients receiving chronic treatment should be routinely monitored for potential GI ulceration and bleeding. In patients who develop gastric or duodenal ulcers during aspirin treatment, the drug should be discontinued due to an increased risk of bleeding and/or perforation. Hematocrit should be monitored periodically in patients receiving prolonged or high-dose aspirin therapy since iron deficiency anemia may occur. Aspirin is generally recommended to be discontinued for a time interval (e.g., 1 week) prior to surgery to minimize postoperative bleeding; however, the decision to discontinue aspirin therapy prior to surgery should include a careful evaluation of the overall risks and benefits given the patient's coexisting conditions and the type of surgery or procedure.
Since even low doses of aspirin inhibit platelet aggregation and increase bleeding time, aspirin should be used cautiously in patients with coagulopathy, hemophilia, pre-existing thrombocytopenia, thrombotic thrombocytopenic purpura (TTP), or in patients receiving anticoagulant therapy or thrombolytic therapy. Neonates have a slower clearance of aspirin and therefore are at higher risk for bleeding. Medical evaluation of the potential risks versus benefits of aspirin therapy is needed in patients with aplastic anemia, agranulocytosis, or pancytopenia. Aspirin should be used with caution in patients with immunosuppression or neutropenia following myelosuppressive chemotherapy. Aspirin may mask signs of infection, such as fever and pain, in patients with bone marrow suppression.
Because of the possibility of interference with platelet function , aspirin should be avoided in patients with potential for intracranial bleeding (e.g., subarachnoid aneurysm, head trauma, increased intracranial pressure).
Because salicylates may cause or aggravate hemolysis in patients with G6PD deficiency, some reference texts state that aspirin should be used cautiously in these patients. If hemolytic anemia occurs in patients receiving aspirin, it almost always occurs in G6PD-deficient individuals. Otherwise, hemolysis only occurs at high concentrations.
Aspirin used should be avoided in children with hepatic disease as aspirin is primarily metabolized in the liver. Liver function should be monitored in patients receiving large doses of aspirin (e.g., for treatment of Kawasaki disease) or in patients with preexisting hepatic impairment in order to prevent reversible, dose-dependent hepatotoxicity. Large doses also can cause hypoprothrombinemia, which can be reversed by vitamin K. Patients with vitamin K deficiency should be closely monitored if taking large doses of aspirin.
Use aspirin with caution in patients with renal impairment; patients with renal insufficiency may be at increased risk of developing salicylate-induced nephrotoxicity. Because salicylic acid and its metabolites are excreted in the urine, regular- and high-dose aspirin should be avoided in patients with advanced, chronic renal failure. Monitor renal function periodically in all patients receiving prolonged or high-dose salicylate therapy. Although data are limited in pediatric patients with chronic kidney disease, use of low-dose aspirin for the prevention of atherosclerotic events in adults with concomitant cardiovascular disease is recommended. Similar consideration of benefits and risks should be made for pediatric patients who would typically receive low-dose aspirin therapy for chronic cardiovascular conditions. In general, the risk of nephrotoxicity in the pediatric population is low. In addition, use salicylates cautiously in patients with systemic lupus erythematosus (SLE) or other renal disease due to the risk of decreased glomerular filtration rate in these patients.
Caution is advised with aspirin use in sodium-restricted patients or patients with hypovolemic states (e.g., ascites, dehydration, heart failure, hypertension, or hypovolemia) as they may be more susceptible to adverse renal effects of salicylate therapy. Patients with sodium-retaining states, such as congestive heart failure or renal failure, should avoid sodium-containing buffered aspirin preparations because of their high sodium content.
The respiratory effects of salicylates, such as aspirin, may contribute to serious acid/base imbalance in patients with underlying acid/base disorders (e.g., metabolic acidosis, metabolic alkalosis, respiratory acidosis, or respiratory alkalosis) or in overdose situations. Salicylates primarily alter acid-base balance by causing metabolic acidosis and respiratory alkalosis, either alone or mixed.
In patients with gout, salicylates such as aspirin may increase serum uric acid levels, resulting in hyperuricemia, and interfere with the efficacy of uricosuric agents.
Description: Aspirin, the salicylic ester of acetic acid, is used for its analgesic, antiinflammatory, antipyretic, and antithrombotic effects. The antiinflammatory and analgesic effects of aspirin are roughly equivalent to those of many other NSAIDs. The use of aspirin in children is primarily limited to the treatment of Kawasaki disease, for thrombosis prophylaxis, particularly in children with congenital heart disease following cardiac surgery, and for the treatment and secondary prevention of arterial ischemic stroke (AIS). Reye's syndrome, a potentially fatal disease, has been associated with aspirin use following active varicella infection or other viral illnesses in children. Since this association, aspirin use has declined significantly and other NSAIDs and acetaminophen have replaced aspirin for mild analgesia and fever in children. Clinical guidelines for the treatment of juvenile idiopathic arthritis do not recommend aspirin as a treatment option due to the availability of other NSAIDs (i.e., ibuprofen, naproxen) that are just as effective, safer, and better tolerated. Aspirin is an OTC drug and is labeled for use as an analgesic in children >= 12 years of age ; however, aspirin is used off-label in children as young as neonates for its antiplatelet effects.
For the treatment of acute ischemic stroke*:
Oral or Rectal dosage:
Neonates: Not recommended. The ACCP pediatric antithrombotic therapy guidelines recommend supportive care over anticoagulation or aspirin therapy in neonates with arterial ischemic stroke in the absence of a documented ongoing cardioembolic source.
Infants, Children, and Adolescents: 5 mg/kg/dose PO once daily has been recommended. 1-5 mg/kg/day is the general dosage range recommended for aspirin when used as antiplatelet therapy in the ACCP pediatric antithrombotic therapy guidelines. There are limited data available for aspirin use in pediatric arterial ischemic stroke (AIS). Dosing recommendations and treatment guidelines in children are mainly based on extrapolation of data from use in adult AIS. The ACCP pediatric antithrombotic therapy guidelines recommend unfractionated heparin, low-molecular-weight heparin, or aspirin as initial therapy until dissection and embolic causes have been excluded. Secondary prevention with aspirin should follow acute therapy. The same dose of aspirin can be given rectally for those unable to tolerate oral aspirin ; however, absorption of aspirin suppositories is highly variable and effective serum concentrations may not be reached.
For the secondary prevention of acute ischemic stroke (i.e., stroke prophylaxis*):
Oral or Rectal dosage:
Neonates: Neonatal doses not specifically defined. 1-5 mg/kg/dose PO once daily is the general dosage range when used as antiplatelet therapy. However, pediatric studies have not been performed on the optimal dose for adequate platelet inhibition and dosing recommendations are based on extrapolation from adult data. 3-5 mg/kg/dose PO once daily is recommended as the initial dose for secondary prevention in the guidelines for stroke management in infants and children. If this dose is not tolerated, a dose reduction to 1-3 mg/kg/dose PO once daily may be considered. Aspirin prophylaxis is recommended for at least 2 years following acute arterial ischemic stroke.
Infants, Children, and Adolescents: 1-5 mg/kg/dose PO once daily is the general dosage range when used as antiplatelet therapy. However, pediatric studies have not been performed on the optimal dose for adequate platelet inhibition and dosing recommendations are based on extrapolation from adult data. 3-5 mg/kg/dose PO once daily is recommended as the initial dose for secondary prevention in the guidelines for stroke management in infants and children. If this dose is not tolerated, a dose reduction to 1-3 mg/kg/dose PO once daily may be considered. Aspirin prophylaxis is recommended for at least 2 years following acute arterial ischemic stroke. Rectal dosing is an option for those unable to tolerate oral aspirin ; however, absorption of aspirin suppositories is highly variable and effective serum concentrations may not be reached.
For arterial thromboembolism prophylaxis* (i.e., thrombosis prophylaxis*):
Oral or Rectal dosage:
Neonates: 1-5 mg/kg/dose PO once daily is the general dosage range when used as antiplatelet therapy. However, pediatric studies have not been performed on the optimal dose for adequate platelet inhibition and dosing recommendations are based on extrapolation from adult data. Higher doses (up to 15 mg/kg/day) have been reported in neonates after cardiac surgery. In a study in 34 neonates (>= 35 weeks gestational age and >= 2 kg) and 39 infants/children 30 days-24 months with cardiac conditions receiving clopidogrel to prevent thrombotic events, 79% of patients were receiving aspirin at a mean dose of 8.8 mg/kg/day (range 1.3-87.6 mg/kg/day). In another study in 906 infants (<= 92 days of age) with cyanotic congenital heart disease and a systemic-to-pulmonary-artery shunt receiving clopidogrel to prevent thrombotic events, 87.9% of patients were receiving concomitant aspirin at doses of <= 3 mg/kg/day (n = 137), > 3 to <= 5 mg/kg/day (n = 309), > 5 to <= 10 mg/kg/day (n = 310), and > 10 mg/kg/day (n = 35).
Infants, Children, and Adolescents: 1-5 mg/kg/dose PO once daily is the general dosage range when used as antiplatelet therapy. However, pediatric studies have not been performed on the optimal dose for adequate platelet inhibition and dosing recommendations are based on extrapolation from adult data. Higher doses (up to 10 mg/kg/day PO) have been reported in patients following cardiac surgery. In a study in 34 neonates and 39 infants/children 30 days-24 months with cardiac conditions receiving clopidogrel to prevent thrombotic events, 79% of patients were receiving aspirin at a mean dose of 8.8 mg/kg/day (range 1.3-87.6 mg/kg/day). In another study in 906 infants (<= 92 days of age) with cyanotic congenital heart disease and a systemic-to-pulmonary-artery shunt receiving clopidogrel to prevent thrombotic events, 87.9% of patients were receiving concomitant aspirin at doses of <= 3 mg/kg/day (n = 137), > 3 to <= 5 mg/kg/day (n = 309), > 5 to <= 10 mg/kg/day (n = 310), and > 10 mg/kg/day (n = 35). Rectal dosing can be used for those unable to tolerate oral aspirin ; however, absorption of aspirin suppositories is highly variable and effective serum concentrations may not be reached.
For the treatment of Kawasaki disease*:
Infants, Children, and Adolescents: 80 to 100 mg/kg/day PO in 4 divided doses during the acute phase (often until patient has been afebrile for 24 to 72 hours, for up to 14 days), then decrease to 3 to 5 mg/kg/day PO once daily (Max: 325 mg/day) until 4 to 6 weeks after the onset of illness. High-dose IVIG (2 grams/kg IV as a single dose) should be given concurrently within 10 days of illness onset but as soon as possible after diagnosis. For those who develop coronary artery abnormalities (CAA), low-dose aspirin may continue indefinitely. Duration of high-dose aspirin varies in clinical practice; while many clinicians reduce the aspirin dose after the patient is afebrile for 24 to 72 hours, others continue high-dose aspirin until day 14 of illness and at least 48 to 72 hours after cessation of fever. There is also debate over the optimal dose of aspirin in the acute phase of treatment. High-dose is recommended in the ACCP and AHA clinical guidelines. However, moderate doses (30 to 50 mg/kg/day) are commonly used in Asia and Western Europe during the acute phase to minimize aspirin toxicity. There are no data to suggest either dose is superior. Additionally, some data suggests low-dose aspirin (3 to 5 mg/kg/day or less than 10 mg/kg/day) is not inferior to high-dose aspirin (80 mg/kg/day or more than 10 mg/kg/day) in reducing the risk of CAA when given concomitantly with IVIG during the acute phase.
For the management of multisystem inflammatory syndrome in children (MIS-C) post SARS-CoV-2 exposure*:
Infants, Children, and Adolescents: Available data are limited, and efficacy has not been established. Doses varying from 3 to 5 mg/kg/day PO (low dose) to 30 to 100 mg/kg/day PO (moderate to high dose) have been reported and are being used in combination with IVIG with or without methylprednisolone. Although ranges are provided in clinical studies, the optimal duration of treatment or recommendations on dividing larger doses is not always described. However, when treating other conditions, high doses of aspirin are divided into 2 to 4 doses. At a minimum, low dose aspirin is recommended for patients with Kawasaki disease-like syndrome. In 1 institutional protocol, aspirin 20 to 25 mg/kg/dose every 6 hours (80 to 100 mg/kg/day) is recommended in patients with Kawasaki disease-like illness, evidence of excessive inflammation (ferritin more than 700 ng/mL, CRP more than 300 g/dL, or multisystem organ failure), or cardiac involvement. Once patients are afebrile for 24 hours or more, the aspirin dose is reduced to 3 to 5 mg/kg/day. Low dose aspirin (3 to 5 mg/kg/day; max 81 mg/day) has been recommended in patients with MIS-C and Kawasaki disease-like features and/or thrombocytosis (platelet count 450,000/microliter or more). Continuation is recommended until platelet count and coronary arteries are normal for at least 4 weeks after diagnosis with avoidance in patients with a platelet count of 80,000/microliter or less. Additionally, it is recommended that patients with coronary artery aneurysms and a maximal z-score of 2.5 to 10 be treated with low dose aspirin, whereas patients with a z-score of 10 or more be treated with low dose aspirin and therapeutic anticoagulation with enoxaparin or warfarin. In a prospective observational study, 21 patients received low dose aspirin 3 to 5 mg/kg/day in combination with IVIG. In retrospective studies and case series, 30 to 100 mg/kg/day PO (moderate to high dose) was usually administered initially, followed by 3 to 5 mg/kg/day PO (low dose). In 1 study, moderate to high dose aspirin was continued until 48 hours after defervescence and then continued at a low dose for 8 weeks.
Therapeutic Drug Monitoring:
Most patients experience signs of acute salicylate toxicity when the total salicylate level is > 300 mcg/ml. In chronic salicylism, signs of toxicity may occur at lower concentrations (>= 150 mcg/ml).
Maximum Dosage Limits:
Aspirin dosage must be individualized and is highly variable depending on the indication, coexisting conditions, and on patient response.
Usual maximum dose of 5 mg/kg/day PO for antiplatelet therapy; however, doses up to 15 mg/kg/day PO have been used for thrombosis prophylaxis.
Usual maximum dose of 5 mg/kg/day PO for antiplatelet therapy; however, doses up to 10 mg/kg/day PO have been used for thrombosis prophylaxis. 100 mg/kg/day PO during febrile phase of Kawasaki disease.
Usual maximum dose of 5 mg/kg/day PO for antiplatelet therapy; however, doses up to 10 mg/kg/day PO have been used for thrombosis prophylaxis. 100 mg/kg/day PO during febrile phase of Kawasaki disease.
Usual maximum dose of 5 mg/kg/day PO for antiplatelet therapy; however, doses up to 10 mg/kg/day PO have been used for thrombosis prophylaxis. 100 mg/kg/day PO during febrile phase of Kawasaki disease.
Patients with Hepatic Impairment Dosing
Avoid aspirin in patients with severe hepatic insufficiency. Patients with any degree of hepatic disease are at increased risk of salicylate-induced adverse reactions.
Patients with Renal Impairment Dosing
CrCl < 10 mL/minute/1.73 m2: Avoid regular- or high-dose aspirin. While pediatric-specific recommendations are not available, low-dose aspirin therapy is recommended for the prevention of atherosclerotic events in adults patients with cardiovascular disease. Similar consideration of benefits and risks should be made for pediatric patients who would typically receive low-dose aspirin therapy for chronic cardiovascular conditions.
Avoid regular- or high-dose aspirin. While pediatric-specific recommendations are not available, low-dose aspirin therapy is recommended for the prevention of atherosclerotic events in adults patients with cardiovascular disease. Similar consideration of benefits and risks should be made for pediatric patients who would typically receive low-dose aspirin therapy for chronic cardiovascular conditions. If use is necessary, doses should be administered after hemodialysis; aspirin is 50% to 100% dialyzable.
Continuous Ambulatory Peritoneal Dialysis (CAPD)
Avoid regular- or high-dose aspirin. While pediatric-specific recommendations are not available, low-dose aspirin therapy is recommended for the prevention of atherosclerotic events in adults patients with cardiovascular disease. Similar consideration of benefits and risks should be made for pediatric patients who would typically receive low-dose aspirin therapy for chronic cardiovascular conditions.
Continuous Renal Replacement Therapy (CRRT)
No dosage adjustment needed; monitor serum salicylate concentrations if possible and clinically appropriate.
Monograph content under development
Mechanism of Action: The activity of aspirin is due to its ability to inhibit cyclooxygenase (COX). Cyclooxygenase is responsible for the conversion of arachidonic acid to prostaglandin G2 (PGG-2), the first step in prostaglandin synthesis and precursor to prostaglandins of the E and F series. Cyclooxygenase exists in 2 isozymes: cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). In vivo, aspirin is hydrolyzed to salicylic acid and acetate. However, hydrolysis is not required for aspirin activity. Aspirin irreversibly inhibits COX by acetylation of a specific serine moiety (serine 530 of COX-1 and serine 516 of COX-2). Aspirin is about 170-times more potent in inhibiting COX-1 than COX-2. In comparison, salicylic acid has little or no ability to inhibit COX in vitro despite inhibiting prostaglandin synthesis at the site of inflammation in vivo. The exact mechanism of prostaglandin inhibition by salicylic acid is unclear; however, salicylates produce the majority of classic NSAID effects. Theories regarding the potential mechanism for salicylic acid include inactivation of transcriptional regulatory proteins (e.g., NF-kappaB), which regulate expression of inflammatory proteins. Aspirin appears to inhibit COX through two pathways and seems to have a different mechanism of action than other salicylates. Aspirin does not inhibit the peroxidase activity of COX and does not suppress leukotriene synthesis by lipoxygenase pathways.
-Antithrombotic Actions: Aspirin-induced inhibition of thromboxane A2 (TXA2) and prostacyclin (PGI-2) has opposing effects on hemostasis. TXA2 is a potent vasoconstrictor and platelet agonist, while PGI-2 inhibits platelet aggregation and vascular smooth muscle contraction. However, data suggest that the effects of aspirin-induced TXA2 inhibition predominate clinically. This may be due to the ability of vascular endothelial cells to regenerate new COX and recover normal function, while COX inhibition in platelets is irreversible due to the limited amount of mRNA and protein synthesis in these cells. This distinction also allows for the use of very low doses of aspirin to retard platelet aggregation. The antithrombotic actions of aspirin are primarily mediated by COX-1 inhibition; COX-1 produces TXA2. Aspirin may also inhibit platelet activation by neutrophils. The antiplatelet effects of aspirin result in a prolonged bleeding time, which returns to normal roughly 36 hours after the last dose of the drug. Antiplatelet effects occur before acetylsalicylic acid is detectable in the peripheral blood due to exposure of platelets in the portal circulation. In very high and toxic doses, aspirin also exerts a direct inhibitory effect on vitamin K-dependent hemostasis by inhibiting the synthesis of vitamin K-dependent clotting factors. Prothrombin synthesis is impaired, resulting in hypoprothrombinemia.
-Anti-inflammatory Actions: The antiinflammatory action of aspirin is believed to be a result of peripheral inhibition of COX-1 and COX-2, but aspirin may also inhibit the action and synthesis of other mediators of inflammation. It is thought that COX-2 is the more important pathway for the inflammatory response since COX-2 is inducible in settings of inflammation by cytokines. Inhibition of COX-2 by aspirin suppresses the production of prostaglandins of the E and F series. These prostaglandins induce vasodilation and increase tissue permeability, which, in turn, promote the influx of fluids and leukocytes. Ultimately, the classic symptoms of inflammation result: swelling, redness, warmth, and pain. Aspirin does not only decrease capillary permeability (which reduces swelling and the influx of inflammatory mediators), but it can also reduce the release of destructive enzymes from lysozymes.
-Analgesic Actions: Salicylates are effective in cases where inflammation has caused sensitivity of pain receptors (hyperalgesia). It appears prostaglandins, specifically prostaglandins E and F, are responsible for sensitizing the pain receptors; therefore, salicylates have an indirect analgesic effect by inhibiting the production of further prostaglandins and do not directly affect hyperalgesia or the pain threshold. Salicylates may also interfere with pain perception centrally by activity within the hypothalamus. The total serum salicylate levels associated with analgesic activity are 30-100 mcg/ml.
-Antipyretic Actions: Salicylates promote a return to a normal body temperature set point in the hypothalamus by suppressing the synthesis of prostaglandins, specifically PGE-2, in circumventricular organs in and near the hypothalamus. Salicylates rarely decrease body temperature in afebrile patients. Paradoxically, toxic doses of salicylates may increase body temperature by increasing oxygen consumption and metabolic rate. The total serum salicylate levels associated with antipyretic activity are 30-100 mcg/ml.
-Gastrointestinal Effects: Adverse gastrointestinal effects from salicylates may be mediated through decreased prostaglandin synthesis due to inhibition of COX-1. A direct irritant effect on gastric mucosa may also be involved. Salicylates increase the permeability of the gastric mucosa to cations, thus increasing the entry of acid into the mucosa. Salicylates are also known to stimulate the chemoreceptor trigger zone, resulting in nausea and vomiting.
-Respiratory Effects: The respiratory effects of salicylates lead to acid/base changes and alterations in electrolyte and water balance. Salicylates stimulate respiration directly and indirectly resulting in respiratory alkalosis. This is caused by a salicylate-induced increase in oxygen consumption, primarily in skeletal muscle, leading to increased carbon dioxide production and respiratory stimulation. Increased alveolar ventilation balances the increased carbon dioxide production; therefore, plasma carbon dioxide (PaCO2) does not change. Salicylate-induced respiratory alkalosis is compensated for by increasing renal excretion of bicarbonate, which is accompanied by increased sodium and potassium excretion. The serum bicarbonate level is then lowered and the serum pH returns to normal (i.e., compensated respiratory alkalosis). However, if the respiratory response to hypercapnia has been depressed (e.g., administration of a barbiturate or opiate agonist), salicylates will cause a significant increase in PaCO2 and respiratory acidosis. Hyperventilation also occurs due to direct stimulation of the respiratory center in the medulla. At high salicylate plasma concentrations (>= 350 mcg/ml), marked hyperventilation will occur, and at serum concentrations of about 500 mcg/ml, hyperpnea will be seen. Finally, at high-therapeutic and at toxic doses, aspirin can affect oxidative phosphorylation, however, this action is insignificant at lower doses. Other changes in acid-base status (e.g., metabolic and respiratory acidosis) and electrolyte and water balance (hypokalemia, hypernatremia, dehydration) may be seen during salicylate intoxication.
-Renal Effects: In addition to changes in sodium and fluid status secondary to acid/base changes, salicylates may decrease renal blood flow and glomerular filtration rate, which may be accompanied by water and potassium retention, in sodium-restricted patients and patients with impaired renal function or hypovolemic states. Changes in renal function are due to inhibition of renal prostaglandin synthesis, which increase renal blood flow and maintain normal renal function. Salicylate-induced renal effects are uncommon in patients with normal renal function.
-Uricosuric Effects: Salicylates act on the renal tubules to affect uric acid excretion. Lower doses (e.g., 1-2 g/day) of salicylates inhibit the active secretion of uric acid into the urine via the proximal tubules. However, high doses (> 3 g/day) of salicylates inhibit the tubular reabsorption of uric acid, resulting in a uricosuric effect. Uric acid secretion is not changed at intermediate dosages. While once used for their uricosuric properties, other agents have replaced salicylates for this purpose.
Pharmacokinetics: Aspirin is administered orally or rectally. Salicylic acid is widely distributed with high concentrations in the liver and kidney. Aspirin is poorly protein bound as compared to salicylic acid. However, aspirin may acetylate albumin, resulting in changes the ability of albumin to bind other drugs. Protein binding of salicylic acid to albumin varies with serum salicylate and albumin concentrations. At salicylate levels of <= 100 mcg/ml, salicylic acid is 90-95% protein bound; approximately 70-85% protein bound at 100-400 mcg/ml; and only 20-60% protein bound at serum concentrations of > 400 mcg/ml. Patients with low serum albumin have higher free salicylate concentrations.
Aspirin has a half-life of 15-20 minutes in adults as it is rapidly hydrolyzed by the liver to salicylic acid. Salicylic acid is primarily metabolized in the liver. Metabolites include salicyluric acid (glycine conjugate), the ether or phenolic glucuronide, and the ester or acyl glucuronide. In addition, a small amount is metabolized to gentisic acid (2,5-dihydroxybenzoic acid) and 2,3-dihydroxybenzoic and 2,3,5-dihydroxybenzoic acids. Salicyluric acid and salicyl phenolic glucuronide are formed via saturable enzyme pathways, and therefore, exhibit non-linear pharmacokinetics. The elimination half-life of salicylic acid varies with dosage. After a single low dose, the serum half-life of salicylic acid is 2-3 hours, but can increase to 12 hours with anti-inflammatory doses and up to 15-30 hours after overdoses. Because of decreased serum protein binding, the effect of increasing doses is more pronounced on free salicylate levels than total salicylate levels. Approximately 80-100% of the salicylic acid from a single salicylate dose is excreted within 24-72 hours in the urine as free salicylic acid (10%), salicyluric acid (75%), salicylic phenolic (10%) and acyl (5%) glucuronides, and gentisic acid (< 1%). The excretion of free salicylic acid is variable and depends upon the dose and the urinary pH. In alkaline urine, > 30% of the dose may be eliminated as free salicylic acid, but in acidic urine only about 2% is eliminated as free salicylic acid.
Affected cytochrome P450 isoenzymes: none
Aspirin is rapidly absorbed following oral administration and bioavailability of regular aspirin in adults is approximately 40-50%. However, the absorption from enteric-coated tablets and sustained-release preparations is delayed and bioavailability is significantly lower compared with regular aspirin. Platelet function inhibition is seen within 1 hour in adults. Peak concentrations are achieved approximately 2 hours after administration in children.
The bioavailability of aspirin after rectal administration in adults has been reported to be 20-40%. Peak concentrations are reached approximately 4 hours after rectal administration in adults. Limited pharmacokinetic data in 8 children (5-9 years) revealed that the absorption of aspirin was very slow after rectal administration and was highly dependent on retention time. In children that retained the suppository for <= 5 hours, urinary recovery was 54-64%. Therefore, aspirin given rectally may not attain effective serum levels.
Pharmacokinetic data are unavailable in neonates. Aspirin is primarily metabolized in the liver. Neonates would be expected to have a slower clearance of aspirin due to their immature hepatic function.
Pharmacokinetic data are very limited in children. Data from 10 children (2-7 years) who received aspirin revealed a mean elimination half-life for salicylic acid of 3.4 hours. This is similar to what has been reported in adults.
Pharmacokinetic data are unavailable in patients with hepatic impairment; however, aspirin is extensively metabolized in the liver and patients with hepatic impairment may have decreased elimination.
Pharmacokinetic data are unavailable in patients with renal impairment. Aspirin is renally excreted and patients with renal impairment may have decreased elimination. Aspirin is 50-100% hemodialyzable.
The pharmacokinetics of aspirin are altered in children with Kawasaki disease. These patients have been shown to achieve lower salicylate concentrations compared with healthy children receiving the same aspirin dose due to a combination of impaired bioavailability and/or increased clearance.