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Medication News & Update

Aspirin and clopidogrel combination less effective and no safer than warfarin therapy in atrial fibrillation

William E. Dager, Pharm.D., FCSHP

Dr. Wager wrote this article recently it is posted on Clotcare.com and excellent site for keeping up with the latest in anticoagulant and anti-thrombolytic therapies.
December, 2006

Reference: ACTIVE Writing Group on behalf of the ACTIVE Investigators. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet. 2006 Jun 10;367(9526):1903-12.

The ACTIVE trial involved analysis of several adjuncts for preventing complications in atrial fibrillation. In the ACTIVE W portion, patients assigned to receive open treatment oral anticoagulation targeting an INR of 2-3 (n=3371) were compared to clopidogrel 75mg orally daily plus low dose (75-100mg) aspirin (n=3335). Both groups had similar CHADS2 stroke risk scores. Warfarin was well controlled with 64% of INR values between 2-3. Interm analysis for the incidence of primary outcomes for occurrence of stroke, non-CNS systemic embolus, myocardial infarction or vascular related death suggested a significant benefit with the use of warfarin compared to the combined anti-platelet therapies (relative risk reduction of 8.3%/yr vs 6.5%/year favoring oral anticoagulation p = 0.0008). Because of the clear benefit observed with warfarin, the trial was stopped prematurely. The benefit was especially notable in those patients who had already been receiving oral anticoagulation therapy prior to enrolling into the trial (77% had been on oral anticoagulation prior to randomization). The primary area of benefit with oral anticoagulation therapy was a reduction ischemic stroke with a relative risk reduction of 2.4%/yr vs 1.4%/yr p = 0.0001, or an absolute risk reduction of 1%/yr. Significance was achieved despite the relatively low incidence rate. Most of the benefit was seen with a lower incidence of small, non-disabling strokes and non-CNS systemic embolism. The incidence of major hemorrhage was similar between the groups (relative risk 2.4% for clopidogrel/ASA vs 2.2% for warfarin).

For patients who were not receiving oral anticoagulation therapy prior to enrolling in the trial, a benefit of improved outcomes was noted at approximately one year while incurring a higher rate of major bleeding. Those subsequently randomized to receive oral anticoagulation were twice as likely to stop therapy during the trial. In contrast, patients previously receiving an oral anticoagulant at trial entry did not show any benefit in reduced major bleeding until approximately one year out, but a notable benefit in primary outcome was observed from the onset. Overall, the observations of the ACTIVE W trial suggest a benefit with continued well-controlled oral anticoagulation therapy if the individual was already receiving it. It still leaves in question the management of individuals who are not receiving oral anticoagulants or antiplatelet therapy, or have previously stopped such therapy.

Specific Drug Information

Aspirin, ASA
Acuprin® 81 | Ascriptin® Enteric | Aspergum® Orginal | Aspir-Low® | Aspirtab® | Aspir-trin® | Bayer® Adult Low Strength Enteric Coated Aspirin | Bayer® Aspirin | Bayer® Children Aspirin | Bayer® Childrens Aspirin | Bayer® Extra Strength | Bayer® Low Strength | Bayer® Migraine Pain | Bayer® Plus | Bayer® Therapy | Bayer® Womens | Easprin® | Ecotrin® | Ecotrin® Maximum Strength | Empirin® | Entercote® | Extra Strength Bayer® | Genacote® | Gennin® FC | Genprin® | Halfprin® | Litecoat® Aspirin | Minitabs® | Norwich® Aspirin | Ridiprin® | St. Joseph® Aspirin | St. Joseph® Aspirin Adult Chewable | St. Joseph® Aspirin Adult EC | Stanback® Analgesic | Therapy Bayer® | Uni-Tren® | Valomag® | Zero Order™ Aspirin | ZORprin®

Classification:
• Analgesics
    • Salicylates
• Hematological Agents
    • Platelet Inhibitors
        • Salicylates
• Musculoskeletal Agents
    • Antiinflammatory Agents
        • Salicylates

Description, Mechanism of Action, Pharmacokinetics

Description: Aspirin, the salicylic ester of acetic acid, was introduced into medicine in 1899 and 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. Aspirin is used in the treatment of many inflammatory and autoimmune conditions such as juvenile arthritis, rheumatoid arthritis, and osteoarthritis. Because of its antithrombotic effects, aspirin is useful in preventing or reducing the risk of myocardial infarction in patients with a history of myocardial infarction, coronary bypass, angioplasty, angina, stroke [7011], transient ischemic attacks (TIAs), or peripheral vascular disease [1961] and recurring transient ischemic attacks (TIAs). Observational studies have suggested that aspirin reduces the risk of colorectal cancer. However, long-term follow-up of the randomized Physicians' Health Study found no association between aspirin use and colorectal cancer.[4045] In contrast, randomized trials have shown that aspirin reduces the risk of recurrent adenomas in persons with a history of colorectal cancer or adenomas.[4047] [4048] The role of aspirin in the chemoprevention of colorectal cancer, either as primary or secondary prophylaxis, has not been determined. Aspirin was officially approved by the FDA in 1939. A sustained-release aspirin (Asacard) was approved for use in the UK in February 1998 and is under investigation in the US.

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 (PGG2), 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 (PGI2) has opposing effects on hemostasis. Thromboxane A2 is a potent vasoconstrictor and platelet agonist, while PGI2 inhibits platelet aggregation and vasodilation. 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.[3070] 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. 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.[3070] Aspirin may also decrease the progression of atherosclerosis by protecting LDL from oxidative modification and improve endothelial dysfunction in atherosclerotic vessels. More recently, it has been proposed that the beneficial effect of aspirin in MI prophylaxis might be related to its ability to reduce circulating levels of C-reactive protein.[1442] 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.
•Antiinflammatory 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 PGE2, 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.
•Antiproliferative Actions: Even though aspirin acetylates COX-2, acetylated COX-2 retains the ability to metabolize arachidonic acid to produce the monohydroxy fatty acid 15R-hydroxyeicosatetraenoic acid (15R-HETE). Hydroxy fatty acids are thought to have antiproliferative effects.[1625] It is unclear if aspirin's prostaglandin-reducing effect contributes to its antitumor activity.
•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 (see Adverse Reactions).
•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 (> 5 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.
•Uterine Effects: Salicylates produce various effects on the uterus due to inhibition of prostaglandin synthesis. Alleviation of dysmenorrhea may be due to inhibition of prostaglandins of the E and F series. Administration of salicylates late in pregnancy may prolong gestation and labor.
•Other Actions: In the treatment of vernal conjunctivitis, aspirin prevents the formation of prostaglandin D2, a secondary mast cell mediator of allergic conditions. Single doses of aspirin do not exert detrimental effects on exercise metabolism or exercise performance.[1626] Salicylates have complex actions on carbohydrate and cholesterol metabolism. In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. By inhibiting prostaglandin E2 synthesis, salicylates can indirectly increase insulin secretion.

Pharmacokinetics: Aspirin is usually administered orally in adults, but can be given rectally as suppositories in children. Aspirin is absorbed via passive diffusion as unchanged drug and hydrolyzed salicylic acid from the upper intestine and partly from the stomach. Approximately 70% of an aspirin dose reaches the circulation unchanged; the remaining 30% is hydrolyzed to salicylic acid during absorption by esterases in the GI tract, plasma, or liver. The rate of absorption is dependent upon many factors including oral formulation, gastric and intestinal pH, gastric emptying time, and the presence of food. Effervescent and soluble tablets are most rapidly absorbed, followed by un-coated or film-coated tablets, and then enteric coated tablets and extended-release formulations. Food decreases the rate, but not the extent, of absorption. Salicylic acid is more ionized as the pH increases; however, a rise in pH increases the solubility of ionized salicylic acid and increases the dissolution of aspirin tablets. The overall effect of increased pH is an increase in absorption. Time to peak aspirin concentrations is 15—240 minutes depending upon the formulation. Plasma aspirin concentrations decrease as salicylic acid levels increase. Peak plasma salicylate levels occur in approximately 30—60 minutes for effervescent tablets, 45—120 minutes for film-coated tablets, 4—12 hours for extended-release tablets, and 8—14 hours for enteric-coated tablets. Steady-state salicylate serum concentrations are similar after administration of plain, uncoated tablets and enteric-coated tablets.[98] Salicylic acid is widely distributed with high concentrations in the liver and kidney. Salicylic acid crosses the placenta and is excreted in breast milk. During chronic administration, salicylate levels in the fetus may be higher than those in the mother. 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.

Aspirin has a half-life of 15—20 minutes 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 15—30 hours after high doses. 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.

Description, Mechanism of Action, Pharmacokinetics last revised 11/23/2004 9:47:00 AM

Indications

† non-FDA-approved indication

Dosage

For the treatment of rheumatoid arthritis or osteoarthritis in adults:
Oral dosage:
Adults: 2.6—5.4 g/day PO in 4 or more divided doses.

For the treatment of juvenile rheumatoid arthritis (JRA):
Oral or rectal dosage:
Children weighing > 25 kg: 2.4—3.6 g/day in divided doses.
Children weighing <= 25 kg: 60—90 mg/kg/day PO or PR in divided doses.

For the treatment of fever or mild pain, or for the temporary relief of headache, myalgia, back pain, bone pain†, dental pain (e.g., toothache), dysmenorrhea, arthralgia, or minor aches and pains associated with the common cold or flu:
Oral or rectal dosage:
Adults and adolescents: 325—650 mg PO or PR every 4 hours, as needed. Alternatively, 1000 mg PO or PR every 6 hours, as needed. For self-medication, the maximum recommended dose is 4 g/day PO. Do not take aspirin for pain for more than 10 days or for fever for more than 3 days unless directed by a physician.
Children: 10—15 mg/kg PO or PR every 4—6 hours. Maximum daily dose is 4 g/day PO. Do not take aspirin for pain for more than 10 days or for fever for more than 3 days unless directed by a physician.

For the treatment of acute ischemic stroke in patients not eligible for thrombolysis:
Oral dosage:
Adults: The American College of Chest Physicians' (ACCP) recommends early aspirin therapy in doses of 160—325 mg PO once daily for patients in the acute phase of ischemic stroke who are not receiving thrombolysis. ASA should be initiated within 48 hours of stroke onset and may be used in combination with low-dose SC heparin. The use of ASA in this fashion has been shown to reduce stroke recurrence risk and mortality within 14 days of the acute event. Patients who are ASA recipients for up to 4 weeks after the acute event have also showed reductions in these events at 6 months.

For stroke prophylaxis:
•in patients with a history of transient ischemic attack (TIA) or noncardioembolic (atherosthrombotic, lacunar, or crytogenic) stroke:
Oral dosage:
Adults: Some controversy exists regarding the appropriate dose of aspirin in this setting. Aspirin has been effective in doses ranging from 30—1300 mg/day PO. The American College of Chest Physicians (ACCP) recommends aspirin as one of the first-line antiplatelet agents at a dose of 50—325 mg PO once daily; in patients with documented, unexplained TIA, the recommendation is long-term aspirin therapy of 160—325 mg/day PO. Patients intolerant of aspirin may be candidates for alternative antiplatelet therapy.[4037] The Dutch TIA Trial Study Group found that a lower ASA dose was as effective a higher dose (e.g., 30 mg PO once daily vs 283 mg PO once daily).[1258] [1259] In addition, fewer bleeding events occurred with the lower ASA dose. Meta-analyses of multiple studies have shown no important differences in daily doses of aspirin from 30 to 1300 mg PO in the prevention of stroke or related vascular events.
•in patients with atrial fibrillation with moderate risk factors:
Oral dosage:
Adults: The optimal dosage of aspirin in patients with atrial fibrillation has not been clearly established. In patients with one moderate risk factor (e.g., age 65—75 years, diabetes, or CAD with preserved LV systolic function), long-term therapy with aspirin (325 mg PO once daily) or warfarin is appropriate. The American College of Chest Physicians' Consensus Guidelines state that the risk/benefit is unclear for the use of aspirin (325 mg PO once daily) in patients < 65 years and no clinical of echocardiographic evidence of cardiovascular disease.[1275] Aspirin therapy decreases the risk of stroke in patients with atrial fibrillation, but to a much lesser extent than warfarin therapy. The Stroke Prevention in Atrial Fibrillation (SPAF) study found a dose of 325 mg PO enteric-coated aspirin once daily to be effective but a lower dose of 75 mg/day was not beneficial in the Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation (AFASAK) study. This latter study, however, enrolled fewer patients and confidence intervals were wide.

For the treatment of an evolving acute myocardial infarction (AMI):
Oral dosage:
Adults: The American College of Chest Physicians (ACCP) recommends that 75—162.5 mg non-enteric-coated aspirin be chewed and swallowed as soon as possible after the diagnosis of acute MI is made and repeated once daily indefinitely, regardless if thrombolytic therapy will be given. If heparin is to be given, aspirin should be used concomitantly; if warfarin is to be given, aspirin should be withheld until the course of therapy has been completed.[1961] ACC/AHA guidelines recommend aspirin doses of 160—325 mg be given on day 1 of AMI and continue indefinitely.[1483]

For myocardial infarction prophylaxis:
•for primary myocardial infarction prophylaxis:
Oral dosage:
Adults > 50 years: It is recommend aspirin 75—162.5 mg PO once daily may be considered for those who have at least one additional risk factor for coronary artery disease. Men at high-risk for cardiovascular events may be offered warfarin as an alternative to aspirin. In men at very high-risk for cardiovascular events consider low-dose aspirin (75—80 mg/day) with low-intensity warfarin (INR 1.5) as an alternative to either drug alone. Because of the trend towards a higher hemorrhagic stroke rate in patients who received aspirin rather than placebo, the routine use of aspirin in those <= 50 years of age without a history of MI, stroke, or TIA is not recommended by the 2001 ACCP antithrombotic therapy guidelines.[1961]
•for secondary myocardial infarction prophylaxis in patients with a previous history of myocardial infarction (i.e., postmyocardial infarction):
Oral dosage:
Adults: 75—162.5 mg PO once daily. Clinicians may consider low-dose aspirin (75—80 mg PO once daily) with low-intensity warfarin (INR 1.5) in patients with recurrent ischemic episodes following an acute myocardial infarction.[1961]

For the treatment of stable angina and chronic coronary artery disease (CAD):
Oral dosage:
Adults: The American College of Chest Physicians recommends that all patients with stable angina or clinical or laboratory evidence of CAD receive aspirin 75—162.5 mg/day PO indefinitely.[1961]

For the treatment of unstable angina:
Oral dosage:
Adults: As soon as possible after the detection of unstable angina, patients should chew and swallow 162.5 mg of non-enteric coated aspirin. Aspirin 75—162.5 mg PO once daily should continue daily. Hospitalized patients with unstable angina should be treated with heparin or low-molecular weight heparin for at least 48 hours or until the unstable pain pattern resolves, in addition to aspirin.[1595] Patients with continuing ischemia or other high-risk features should receive concomitant tirofiban or epitfiatide with aspirin and heparin, especially if elevations in serum troponin T or I exist.[1961]

For arterial thromboembolism prophylaxis:
•in combination with warfarin in patients with prosthetic heart valves:
Oral dosage:
Adults: The American College of Chest Physicians (ACCP) guidelines recommend warfarin in combination with aspirin 80—100 mg/day PO for patients with caged ball or caged disk valves. An alternative to warfarin alone for patients with tilting disk valves, bileaflet mechanical valves in the mitral position, or bileaflet mechanical valves in the aortic position with atrial fibrillation is warfarin plus aspirin 80—100 mg/day PO. In patients who have mechanical valves and additional risk factors or a history of systemic embolism despite adequate oral anticoagulation, a combination of warfarin and aspirin 81 mg/day PO is recommended. A randomized, double-blind, placebo-controlled study demonstrated that the addition of enteric-coated, slow-release aspirin 100 mg/day PO to warfarin provided better reduction of morbidity and mortality than warfarin alone. The combination of warfarin with aspirin was also associated with an increased risk of bleeding as compared to warfarin alone.[39]
•for chronic extremity arterial insufficiency in patients with intermittent claudication† from arteriosclerosis:
Oral dosage:
Adults: 80—325 mg PO once daily alone or in combination with dipyridamole, unless contraindications present; such patients are at high risk for stroke and acute myocardial infarction. Consider lifelong aspirin therapy in patients with no contraindications.[1218]
•following vascular reconstruction of high-flow, low-resistance arteries > 6 mm in diameter†:
Oral dosage:
Adults: 80—325 mg PO once daily, unless contraindications present; such patients are at high risk for stroke and acute myocardial infarction. Do not offer antithrombotic therapy to maintain patency of reconstruction.[1218]
•following prosthetic femoral-popliteal bypass surgery†:
Oral dosage:
Adults: 80—325 mg PO once daily, unless contraindications present; such patients are at high risk for stroke and acute myocardial infarction; consider addition of dipyridomole.[1218]
•following saphenous vein femoral-popiteal or distal bypass surgery:†
Oral dosage:
Adults: 80—325 mg PO once daily, unless contraindications present; such patients are at high risk for stroke and acute myocardial infarction.[1218]
•for patients who are at high-risk of graft thrombosis following infrainguinal bypass:
Oral dosage:
Adults: 75—80 mg PO once daily in combination with warfarin.[1218]
•following carotid endarterectomy†:
Oral dosage:
Adults: 80—325 mg PO once daily indefinitely, unless contraindications present; such patients are at high risk for stroke and acute myocardial infarction.[1218]
•for patients following saphenous vein or internal mammary artery bypass grafting performed for coronary artery disease (CAD):
NOTE: Aspirin therapy is not recommended when grafting is performed for conditions other than CAD.
Oral dosage:
Adults: 325 mg PO once daily beginning 6 hours after surgery, or if delayed by bleeding, as soon as possible. Aspirin therapy should be continued for at least one year to reduce the frequency of graft closure.[49]

For thrombosis prophylaxis† in patients undergoing percutaneous coronary intervention (PCI)† to reduce the frequency of early ischemic complicatons:
Oral dosage:
Adults: Pretreat with aspirin 80—325 mg PO once daily and continue with long-term treatment for secondary prevention.[1748]

For the treatment of migraine:
Oral dosage:
Adults: 900 mg PO at the onset of the migraine has been recommended.[350] When metoclopramide was administered concomitantly to overcome gastric stasis that occurs during a migraine attack, aspirin 900 mg PO was found as effective as oral sumatriptan and caused fewer adverse reactions.[972]

For the treatment of Kawasaki disease† (mucocutaneous lymph node syndrome):
Oral dosage:
Children: In addition to IV gamma globulin, 80—100 mg/kg/day PO divided in 4 daily doses during the febrile phase (up to 14 days). After patient defervesces for 36 hours, decrease to 3—5 mg/kg/day PO once daily for >= 7 weeks to prevent the formation of coronary aneurysm thrombosis.[1653]

For the treatment of idiopathic or viral pericarditis†:
Oral dosage:
Adults: 325—900 mg PO four times daily.

For colorectal cancer prophylaxis†:
Oral dosage:
Adults: The role of aspirin as primary or secondary chemoprevention for colorectal cancer has yet to be determined. Observational studies have indicated a trend in reducing the risk of developing colorectal cancer. However, results of a long-term study where males participants were randomized to receive aspirin 325 mg PO every other day conflict with these results. Over 12 years of follow-up, random assignment to aspirin was associated with a relative risk of colorectal cancer of 1.03 (95% confidence interval, 0.83 to 1.28).[4045] A cost-effectiveness analysis found that aspirin prophylaxis was generally not cost-effective for persons who follow appropriate colorectal cancer screening programs (NOTE: results of this anaylsis were very sensitive to changes in assumptions regarding aspirin's effects).[4046] In patients with previous colorectal cancer randomized to receive either aspirin 325 mg PO once daily or placebo, one or more adenomas was found in significantly less patients in the aspirin group vs. the placebo group (17% vs. 27%). Aspirin appeared to delay the the development of adenomas; however, the mean size of the adenomas and the proportion of patients with advanced adenomas did not differ between the groups.[4047] In another trial, patients with a recent history of adenomas were randomized to receive placebo, aspirin 81 mg, or aspirin 325 mg PO once daily. After a mean duration of 33 months, the incidence of 1 or more adenomas was 47% in the placebo group, 38% in those given aspirin 81 mg, and 45% in those given aspirin 325 mg. The rate of recurrence was significantly lower in the low-dose aspirin group as compared to placebo, but the higher dose of aspirin did not significantly reduce the recurrance rate.[4048]

For preeclampsia prophylaxis†:
Oral dosage:
Adult females: Data are contradictory regarding the ability of aspirin to prevent preeclampsia. Several small studies showed a protective effect, with no associated risk to the mother or fetus, however several larger placebo-controlled trials revealed no beneficial effects of aspirin. In one study pregnant women at high risk for preeclampsia, aspirin 60 mg PO once daily or placebo was initiated between gestational weeks 13—26. The incidences of preeclampsia, perinatal death, and preterm birth were similar in the aspirin and placebo groups.[2035] In another study of nulliparous women who were 13—25 weeks pregnant, subjects were randomized to aspirin 60 mg PO once daily or placebo until onset of labor. The incidence of preeclampsia was significantly lower in the aspirin group than in the placebo group (4.6% vs. 6.3%); however, the benefit was small and limited to women who had elevated systolic blood pressures at baseline. There were no significant differences in the infants' birth weight or in the incidence of fetal growth retardation, post-partum hemorrhage, or neonatal bleeding problems between the two groups. The incidence of abruptio placentae, however, was greater among the women who received aspirin.[923]

For the treatment of vernal keratoconjunctivitis†:
Oral dosage:
Adults: A dosage of 650 mg PO 3 times daily has been recommended. Doses of 0.5—1.5 g/day have been given to provide symptomatic relief in some patients whose symptoms were not controlled by cromolyn or corticosteroids.[1390]

Therapeutic Drug Monitoring:
Most patients experience salicylate toxicity when the total salicylate level is > 300—350 mcg/ml; however, the elderly may show signs of toxicity at lower levels.

Patients with hepatic impairment:
No dosage adjustment recommendations are available. Patients with hepatic disease are at increased risk of salicylate-induced adverse reactions.

Patients with renal impairment:
CrCl < 10 ml/min: Avoid aspirin in patients with severe renal failure.

Intermittent hemodialysis:
Not applicable; aspirin should be avoided in severe renal failure. Hemodialysis is used to enhance salicylate elimination in aspirin overdosage.

†non-FDA-approved indication

Indications...Dosage last revised 7/28/2003 2:52:00 PM

Administration Guidelines

Oral Administration
•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: 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.
•All preparations: Administer with food or large amounts (240 ml) of water or milk to minimize GI irritation.

Rectal 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 on proper use of suppository (see Patient Information).
•Moisten the suppository with water prior to insertion. If suppository is too soft because of storage in a warm place, chill in the refrigerator for 30 minutes or run cold water over it before removing the wrapper.

Administration last revised 7/1/2002

Contraindications/Precautions

• Absolute contraindications are in italics.

Patients with a tartrazine dye hypersensitivity or salicylate hypersensitivity should avoid aspirin. The risk of cross-sensitivity with other nonsteroidal antiinflammatory drugs is significantly greater with aspirin than other salicylates; avoid use in patients with a known NSAID hypersensitivity. 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.

A patient with acetaminophen hypersensitivity may also be hypersensitive to aspirin. Of 13 patients with acetaminophen hypersensitivity, 3 had aspirin or ibuprofen hypersensitivity.[8423] Of 163 patients with a history of urticaria induced by aspirin but without a history of chronic urticaria, 11% had cross-reactivity to acetaminophen.[8424] The mechanism(s) of hypersensitivity cross-reactivity have not been clearly elucidated. Some cases of cross-reactivity appear to be caused by prostaglandin inhibition, and some cases appear to be caused by an IgE-mediated mechanism. Although unproven, the metabolic breakdown of the parent molecule of some NSAIDs and acetaminophen could yield structurally similar chemical moieties, which could result in IgE production. Patients with a history of aspirin-induced anaphylaxis may be more likely to cross-react to acetaminophen.

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.

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 tobacco smoking patients or in patients with alcoholism. 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. In addition, patients should not self-medicate with aspirin if they consume 3 or more alcoholic beverages per day because of the potential increased risk for GI bleeding. In patients with anemia, this condition may be exacerbated during aspirin therapy due to GI blood loss. Hematocrit should be monitored periodically in patients receiving prolonged or high-dose aspirin therapy since iron deficiency anemia may occur. Traditionally, aspirin has been recommended to be discontinued for a time interval (e.g., 1 week) prior to surgery to minimize postoperative bleeding. However, data presented at the 2003 meeting of the American College of Chest Physicians indicates a risk of increased coronary events with abrupt discontinuation of aspirin in patients with pre-existing coronary artery disease.[4425] Patients with stable coronary disease developed acute coronary events within one week of stopping aspirin therapy; these events included unstable angina and myocardial infarction. Until the results of this trial are published and/or consensus recommendations are available, the decision whether to discontinue aspirin therapy abruptly should include a careful evaluation of the overall risks and benefits given the patient's coexisting conditions and the type of surgery or procedure. The use of aspirin is generally not recommended in patients expected to require CNS surgery due to the increased risk of perioperative bleeding.

Since even low doses of aspirin inhibit platelet aggregation and increases 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 (see Drug Interactions). It should also be avoided 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.[1281]

Intramuscular injections should be administered cautiously to patients receiving aspirin. IM injections may cause bleeding, bruising, or hematomas due to aspirin-induced inhibition of platelet aggregation.

Liver function should be monitored in patients receiving large doses of aspirin (e.g., for treatment of rheumatoid arthritis) or in patients with preexisting hepatic disease 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.

Salicylates should be used with caution in patients with renal impairment and with extreme caution, if at all, in patients with advanced, chronic renal failure since salicylic acid and its metabolites are excreted in the urine. In addition, these patients may be at increased risk of developing salicylate-induced nephrotoxicity. In a case-controlled study of patients with early renal failure, the regular use of aspirin (without acetaminophen) was associated with a risk of chronic renal failure that was 2.5-times as high as that for non-aspirin users.[4064] The risk increased significantly with increasing cumulative lifetime dose and increasing average dose during periods of regular use; duration of therapy was not associated with increased risk. When aspirin was given regularly in analgesic doses (> 500 g per year during periods of regular use) the odds ratio for chronic renal failure was 3.5 (95% confidence interval 1.4 to 8). Low-dose aspirin use for cardiovascular prophylaxis was not significantly associated with the development of renal failure. In this study, it appears that pre-existing renal disease or systemic disease is a required precursor to the development of analgesic-induced renal failure; patients without preexisting renal disease who used analgesics had only a small risk of developing end-stage renal disease. Renal function should be monitored periodically in patients receiving prolonged or high-dose salicylate therapy. Salicylates should be used cautiously in patients with renal disease or systemic lupus erythematosus (SLE) due to the risk of decreased glomerular filtration rate in these patients.

Elderly patients may be at increased risk of salicylate toxicity possibly due to decreased renal function. Elderly patients seem to tolerate GI ulceration or bleeding less well than younger individuals and many spontaneous reports of fatal GI events are in this population. Elderly patients at the highest risk for the development of gastric or duodenal ulcers are those using both NSAIDs and corticosteroids, with a prior history of peptic ulcer disease or NSAID-related GI bleeding, high-dose NSAID therapy, complaints of dyspepsia, and those with concurrent disease states that increase their risk of mortality from a GI bleed or perforation. In addition, elderly patients are more likely to have concomitant disease states, which may exacerbate salicylate-induced renal changes. Care should be taken in dose selection and the lowest effective dose should be used in patients at risk. After initiating salicylate therapy, elderly patients should be monitored for the development of pedal edema, rales, blood pressure elevation, or changes in creatinine or BUN levels. Monitoring of stool for occult blood, serum potassium levels, and a complete blood count should be considered at baseline and periodically during chronic salicylate therapy.

Sodium-restricted patients or patients with hypovolemic states (e.g., ascites, dehydration, heart failure, hypertension, or hypovolemia) may be more susceptible to adverse renal effects of salicylate therapy. Buffered aspirin contains a high sodium content. In patients with carditis, high doses of salicylates may precipitate congestive heart failure or pulmonary edema.

The respiratory effects of salicylates 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. Patients who are unable to compensate for salicylate-induced metabolic acidosis (i.e., respiratory response to CO2 is depressed) may develop respiratory acidosis and increased levels of plasma CO2.

In patients with gout, salicylates may increase serum uric acid levels, resulting in hyperuricemia, and interfere with the efficacy of uricosuric agents.

Aspirin is classified as FDA pregnancy category risk C during the first and second trimesters and should only be used during pregnancy if clearly needed. Because regular use of full-dose aspirin late in pregnancy may result in constriction or premature closure of the fetal ductus arteriosus, aspirin is classified as FDA pregnancy risk category D during the third trimester of pregnancy. Fetal and newborn effects from aspirin exposure in utero may include increased perinatal mortality, intrauterine growth retardation, congenital salicylate intoxication, or depressed albumin-binding capacity. However, a large prospective study involving over 40,000 patients, 64% of whom used aspirin sometime during gestation, failed to show that aspirin was a cause of stillbirths, neonatal deaths, or reduced birth weight.[2036] The lack of adverse effects of aspirin therapy in this study may have been related to the use of relatively low aspirin doses. Several groups have evaluated low-dose aspirin (60—150 mg/day) administered during the second and third trimesters of pregnancy as an agent to prevent preeclampsia. One group found that the efficacy in preventing preeclampsia was only marginal and a higher risk of abruptio placentae was seen.[923] The other group concluded that aspirin appears to be safe for the mother and the fetus.[2037] The safety of higher doses and/or administration during the first trimester, however, is uncertain. Full doses of aspirin administered to pregnant women near term have been associated with toxicities such as hemorrhage, premature closure of the ductus arteriosus, pulmonary hypertension, prolonged gestation, and prolonged labor.

Salicylates are excreted into breast milk and could cause adverse effects in infants. The American Academy of Pediatrics recommends that aspirin be used cautiously during breast-feeding.[4201]

Contraindications last revised 10/31/2005 4:27:00 PM

Drug Interactions

Many prescription and non-prescription medicines contain aspirin, ASA. Based on the pharmacology of aspirin [5717], patients receiving salicylate therapy should avoid non-prescription medications containing salicylates to prevent increased salicylic acid concentrations and toxicity. Repeated or maximum doses of bismuth subsalicylate-containing preparations (e.g., Pepto-Bismol®) could lead to salicylate toxicity in patients receiving concurrent aspirin therapy. Bismuth subsalicylate administration results in significant salicylate serum concentrations in adults.[3166] Avoid concurrent use of aspirin with products that contain aspirin and in patients who are taking aspirin on a regular basis. Advise patients to carefully read the ingredients of any other medicines they are taking with aspirin.[5717]

Prolonged concurrent use of acetaminophen and salicylates is not recommended. High-dose, chronic administration of the combined analgesics significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. In a case-controlled study of patients with early renal failure, the regular use of aspirin and acetaminophen was associated with an odds ratio of 2.2 (95% confidence interval 1.4 to 3.5) when regular aspirin users were the reference group.[4064] The trend toward greater risk with an increasing cumulative life-time dose of acetaminophen was statistically significant with a risk that was 2.4-times as high for subjects who had consumed a total > 500 g of acetaminophen in combination with aspirin than for those who had used aspirin alone. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy.

The coadministration of high-dose aspirin with carbonic anhydrase inhibitors, such as acetazolamide and methazolamide, has resulted in anorexia, tachypnea, lethargy, coma and death. Both acetazolamide and aspirin undergo renal tubular secretion and competition for renal tubular secretion may occur.[6412] Accumulation of the carbonic anhydrase inhibitor may result in increased CNS depression and metabolic acidosis. The acidosis may allow greater CNS penetration of the salicylate. High-dose salicylates should not be prescribed with carbonic anhydrase inhibitors. With normal doses of salicylates, carbonic anhydrase inhibitor-induced urinary alkalinization will result in increased excretion and lowered plasma concentrations of salicylates, which may or may not be clinically significant. Consideration of carbonic anhydrase inhibitor dose reduction and observance for any adverse effects from acetazolamide or methazolamide is warranted.[5717]

Caution should be exercised when aspirin is given in combination with methotrexate. Concomitant administration of salicylates with high-dose methotrexate therapy has been reported to elevate and prolong serum concentrations of methotrexate resulting in deaths from severe hematologic and gastrointestinal toxicity. Although the risk for drug interactions with methotrexate is greatest during high-dose methotrexate therapy, it has been recommended that any salicylate be used cautiously with methotrexate even when lower doses of methotrexate are given for the treatment of rheumatoid arthritis or psoriasis. Elderly patients and patients with renal impairment may be at particular risk. As both methotrexate and salicylates are weak acids, aspirin can impair the renal secretion of methotrexate and increase the risk of methotrexate toxicity. Salicylates can also displace methotrexate from protein-binding sites.[5067] [5232]

Due to the inhibition of renal prostaglandins by salicylates, concurrent use of salicylates and other nephrotoxic agents may lead to additive nephrotoxicity. Also, the plasma salicylic acid concentration is increased by conditions that reduce the glomerular filtration rate or tubular secretion.[7823] Salicylates should be given with caution to patients taking aminoglycosides, amphotericin B, systemic bacitracin, cisplatin, cyclosporine, foscarnet, or parenteral vancomycin. Monitor renal function carefully during concurrent therapy.

Concomitant use of ketorolac and aspirin is contraindicated. Increased adverse gastrointestinal and other effects are possible if ketorolac is used with salicylates. In addition, concomitant administration of salicylates and ketorolac has resulted in a reduction in protein binding and a two-fold increase in unbound plasma concentrations of ketorolac. Also, because ketorolac can cause GI bleeding, inhibit platelet aggregation, and may prolong bleeding time, additive effects may be seen in patients receiving aspirin.[5060]

The concurrent use of aspirin with other nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided because this may increase bleeding or lead to decreased renal function.[5717] The use of aspirin together with nonsalicylate NSAIDs (e.g., indomethacin) can lead to additive GI toxicity.[5232] Due to competition for plasma protein binding sites and/or reduced renal clearance, aspirin may enhance the toxicity of naproxen.[7827] Avoid concurrent use of NSAIDs and aspirin. Concurrent use of chronic ibuprofen therapy (800 mg three times daily) seems to antagonize the inhibition of platelet cyclooxygenase (COX)-1 activity and impairment of platelet aggregation by low-dose aspirin (81 mg once daily) per an ex vivo analysis.[4062] Interestingly in this study, diclofenac or rofecoxib therapy, agents with less activity at COX-1 than ibuprofen, did not affect inhibition of platelet aggregation by aspirin.[4062] An in vitro study has shown that the antagonism of aspirin platelet inhibition probably involves competition at platelet-derived COX-1 and is related to the NSAIDs' ability to inhibit COX-1 mediated thromboxane B2 production in platelets.[4063] However, whether this interference with aspirin's activity leads to adverse clinical consequences or occurs with NSAIDs other than ibuprofen and naproxen (see naproxen monograph) has not been determined.

The concomitant administration of cidofovir and NSAIDs, such as aspirin is contraindicated due to the potential for increased nephrotoxicity. Aspirin should be discontinued 7 days prior to beginning cidofovir.[5118]

The risk of bleeding is increased if aspirin, ASA, is administered to patients already receiving anticoagulants or thrombolytic agents. Aspirin can potentiate the anticoagulant effects and can increase the risk of bleeding because of its effect on platelet aggregation and interaction with heparin and warfarin.[5717] Aspirin can displace warfarin from protein-binding sites leading to increased prothrombin time and bleeding time. Aspirin should be used cautiously in patients receiving warfarin therapy; clinicians should note that dosage adjustment of warfarin therapy may be required.[6412] In addition, large doses of salicylates (>= 3—4 g/day) can cause hypoprothrombinemia,[5170] an additional risk factor for bleeding. Combination therapy with both aspirin and warfarin has been shown to reduce mortality compared to warfarin therapy alone in patients with artificial heart valves.[39] Also use caution in combining aspirin therapy with other platelet inhibitors due to the potential for additive effects; however, some combinations are therapeutic.

Salicylates may have hypoprothrombinemic effects.[5170] Selected cephalosporins (cefoperazone, cefamandole, cefotetan), due to the presence of a methylthiotetrazole (MTT) side chain, have been associated with prolongation of the prothrombin time. Such cephalosporins may also interfere with the synthesis of vitamin K clotting factors and also disturb metabolism of vitamin K by a second, unknown mechanism.[5377] [6654] In selected circumstances such cephalosporins may cause additive effects when given concurrently with salicylates.

Because aspirin, ASA, can cause GI bleeding, inhibit platelet aggregation, and prolong bleeding time, an increased risk of bleeding may be seen in patients receiving agents that cause clinically significant thrombocytopenia. Notable interactions may occur with antithymocyte globulin [6303], strontium-89 chloride [4694], or imatinib, STI-571 [4966].

Due to aspirin's effect on platelet aggregation and GI mucosa, aspirin should be used cautiously in patients with thrombocytopenia following treatment with antineoplastic agents due to an increased risk of bleeding.[5717] In general, because certain antineoplastic agents can cause clinically significant thrombocytopenia, they may increase the risk of aspirin-associated bleeding (i.e. GI bleeding, inhibited platelet aggregation, and prolonged bleeding time). Also, aspirin may mask signs of infection such as fever and pain in patients following treatment with antineoplastic agents or immunosuppressives.[6859] Aspirin, ASA should be used with caution in patients receiving immunosuppressive therapy. Although usually seen with large salicylate doses, aspirin may displace mercaptopurine, 6-MP from secondary binding sites, resulting in bone marrow toxicities and blood dyscrasias.[5232] Special consideration should be given to myelosuppressed patients prior to receiving aspirin.

Ethanol can cause an increased risk of gastric irritation and GI mucosal bleeding when given with aspirin, as both ethanol and aspirin are mucosal irritants and aspirin decreases platelet aggregation. Patients that consume 3 or more alcoholic drinks every day should be counseled about the bleeding risks involved with chronic, heavy alcohol use while taking aspirin.[5717] Administration of aspirin should be limited or avoided altogether in patients with alcoholism or who consume ethanol regularly. Chronic alcoholism is often associated with hypoprothrombinemia, which increases the risk of aspirin-induced bleeding.

Salicylates, by inhibiting prostaglandin E2 synthesis, can indirectly increase insulin secretion. Thus, salicylates can decrease blood sugar and may potentiate the effects of other antidiabetic agents. This mechanism may explain how salicylates can potentiate the clinical effects of sulfonylureas; however, displacement of sulfonylureas from protein binding sites has also been reported.[1310] In large doses, salicylates uncouple oxidative phosphorylation, deplete hepatic and muscle glycogen, and cause hyperglycemia and glycosuria. After acute overdose or use of greater than maximum recommended daily dosages, salicylates can cause either hypoglycemia or hyperglycemia. Due to the potential severity of the interaction, patients who take a sulfonylurea with aspirin should carefully monitor their blood glucose concentrations, especially during the first few hours after aspirin administration. Avoidance of aspirin for patients with hypoglycemia unawareness while receiving sulfonylurea therapy may be desirable. Large doses of aspirin should be used cautiously in patients who receive antidiabetic agents.[5232]

Preclinical data suggest that agents that affect platelet function and inhibit prostaglandin synthesis could decrease the efficacy of photosensitizing agents used during photodynamic therapy.[6359]

Concurrent administration of high doses of antacids (e.g., sodium bicarbonate 4 g or aluminum and magnesium hydroxide 60—120 ml) or other urinary alkalinizing agents [7648] (e.g., sodium bicarbonate) may increase urine pH and decrease serum salicylate levels by decreasing renal tubular reabsorption of salicylic acid. Antacids do not appear to affect the bioavailability of aspirin, but may cause earlier release of aspirin from enteric-coated products.

Aspirin should not be used concurrently with probenecid or sulfinpyrazone when these are used to treat hyperuricemia or gout, because aspirin can decrease the uricosuric effects.[5232] [5035] In addition, sulfinpyrazone can decrease salicylic acid excretion leading to increased plasma concentration.

Corticosteroids enhance the renal clearance of salicylates. Thus, cessation of corticosteroid use may lead to salicylism.[5232] Dose adjustments may be necessary in patients receiving both corticosteroids and aspirin. Also, concomitant administration of corticosteroids with aspirin may increase the GI toxicity of aspirin. Combinations of aspirin with corticosteroids may be just as likely as combinations of nonsalicylate NSAIDs with corticosteroids to cause gastric mucosal injury.[1163]

Due to the high protein binding of salicylic acid, it could be displaced from binding sites, or could displace other highly protein-bound drugs, such as barbiturates (e.g., thiopental) [7823], penicillins, and sulfonamides.[6859] [7109] An enhanced effect of the displaced drug may occur.

Aspirin, ASA may interact with hydantoin anticonvulsants (e.g., phenytoin or fosphenytoin) via several mechanisms. Aspirin and phenytoin are both highly protein bound. Large doses of salicylates (i.e., > 2000 mg/day) can displace phenytoin from plasma protein-binding sites. Although increased serum concentrations of unbound phenytoin may lead to phenytoin toxicity, the liver may also more rapidly clear unbound drug.[5503] Displacement of phenytoin from binding sites can lead to a decrease in the total phenytoin serum concentration.[5717] Close monitoring for excessive toxicity or decreased efficacy is recommended in patients receiving these drugs in combination with aspirin.

Aspirin and valproic acid are both highly protein bound. Displacement of valproic acid from binding sites can lead to an increase in the serum valproic acid concentration.[5717] The displacement of valproic acid can cause an increase in valproic acid free drug concentrations. In such cases, a patient may experience valproic acid toxicity even if the total drug concentration is within the therapeutic range. Careful drug concentration assessment is needed when concomitant aspirin and valproic acid or divalproex sodium is used.

No adverse events associated with the use of salicylates after varicella vaccination have been reported. However, the manufacturer of varicella virus vaccine live recommends the avoidance of salicylates or aspirin, ASA, use for 6 weeks after vaccination.[5065] Reye's syndrome, which exclusively affects children under 15 years old, has been associated with aspirin use following active varicella infection. Vaccination with close clinical monitoring is recommended for children who require therapeutic aspirin therapy; according to the CDC the use of attenuated, live varicella virus vaccine is thought to present less risk than natural varicella disease to such children.

Aspirin should be used with caution in patients who are taking alendronate. Patients taking aspirin, ASA, or aspirin-containing products concurrently with alendronate have an increased incidence of GI adverse events, such as gastric ulceration. In clinical trials, the incidence of upper gastrointestinal adverse events was increased in patients that received aspirin-containing medicines with alendronate 10 mg daily or higher. One patient with a history of peptic ulcer disease and gastrectomy that received alendronate 10 mg daily and aspirin got an anastomotic ulcer with mild hemorrhage. The patient recovered upon alendronate and aspirin discontinuation.[5375]

Concurrent use of mycophenolate mofetil with salicylates can decrease the protein binding of mycophenolic acid (MPA) resulting in an increase in the free fraction of MPA. Mycophenolic acid is more than 98% bound to albumin. Patients should be observed for increased clinical effects from mycophenolate as well as additive adverse effects (i.e., GI effects).[4873]

The efficacy of selected antihypertensive agents needs to be carefully assessed during aspirin usage. During antihypertensive therapy with beta-blockers, high concentrations of vasodilatory prostaglandins are produced in response to reflex-mediated pressor mechanisms (e.g., sympathetic tone). Concurrent use of beta-blockers with aspirin may result in loss of antihypertensive activity due to inhibition of renal prostaglandins and thus, salt and water retention and decreased renal blood flow.[5717] Aspirin can increase the risk of renal insufficiency in patients receiving diuretics, secondary to the effects of aspirin on renal blood flow. Aspirin inhibits renal prostaglandin production, which causes salt and water retention and decreased renal blood flow. Thus, the effectiveness of diuretics in patients with underlying renal or cardiovascular disease may be diminished by the concomitant administration of aspirin.[5717] Aspirin may decrease the hyperuricemic effect of thiazide diuretics (e.g., hydrochlorothiazide) or loop diuretics like furosemide. Concomitant use of aspirin and potassium-sparing diuretics, such as triamterene or spironolactone, may cause hyperkalemia.[5717] The hyponatremic and hypotensive effects of angiotensin-converting enzyme (ACE) inhibitors may be diminished by concurrent use of aspirin; the inhibition of cyclooxygenase by aspirin prevents the formation of vasodilatory prostaglandins.[5717] Furthermore, reduced renal blood flow is expected from the decreased pressure gradient created in the glomeruli when aspirin is used with an ACE inhibitor.[5718] Low-dose aspirin (e.g., 81 mg/day) may be less likely to attenuate the antihypertensive or cardioprotective effects of ACE inhibitors; however, the dose-related effect is controversial.[6439] The established benefits of using low-dose aspirin in combination with an ACE inhibitor in patients with ischemic heart disease and left ventricular dysfunction generally outweigh concerns, especially with appropriate renal function and serum potassium monitoring.[5718] [6060] [6439] Monitor the patient's blood pressure, renal function, and clinical status for the desired responses and adjust therapy accordingly.

The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA may elevate the risk for an upper GI bleed.[4115] SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Clomipramine, a tricyclic antidepressant with serotonergic activity may produce similar results when combined with aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation. A cohort study in >26,000 patients found that SSRI use alone increased the risk for serious GI bleed by 3.6-fold; when an SSRI was combined with aspirin the risk was increased by > 5-fold. Clomipramine was included in the SSRI category in this study. The absolute risk of GI bleed from concomitant therapy with aspirin and a SSRI was low (20/2640 patients) in this cohort study and the clinician may determine that the combined use of these drugs is appropriate.[4115]

Ginkgo, Ginkgo biloba is reported to inhibit platelet aggregation [1900] and several case reports describe bleeding complications with Ginkgo biloba, with or without concomitant drug therapy. Since ginkgo produces clinically-significant antiplatelet effects, it should be used cautiously in patients drugs that inhibit platelet aggregation or pose a risk for bleeding, such as anticoagulants (e.g., warfarin), aspirin, ASA or other platelet inhibitors, or thrombolytic agents.[5200] A patient who had been taking aspirin 325 mg/day PO for 3 years following coronary-artery bypass surgery, developed spontaneous bleeding into his eye after taking a standardized extract of Ginkgo biloba (Ginkoba® commercial product) 40 mg PO twice daily for one week. The patient stopped taking the ginkgo but continued taking the aspirin with no recurrence of bleeding over a 3-month period.[1706] Other clinical data exist [1707] that describe spontaneous subdural hematomas associated with chronic ginkgo biloba ingestion.

Several pungent constituents of ginger, Zingiber officinale are reported to inhibit arachidonic acid (AA) induced platelet activation in human whole blood.[6708] The constituent (8)-paradol is the most potent inhibitor of COX-1 and exhibits the greatest anti-platelet activity versus other gingerol analogues.[6708] The mechanism of ginger-associated platelet inhibition may be related to decreased COX-1/Thomboxane synthase enzymatic activity.[6708] Patients receiving aspirin, ASA, also a potent platelet inhibitor [5717], should use ginger with caution. The risk of bleeding is theoretically increased in patients receiving anticoagulants, platelet inhibitors, or thrombolytic agents, however, no clinical data describing such interactions are available.[5200]

Garlic, Allium sativum may produce clinically-significant antiplatelet effects [2233]; until more data are available, garlic should be used cautiously in patients receiving drugs with a potential risk for bleeding such as platelet inhibitors (e.g., aspirin, ASA).[5200] A case of spontaneous spinal epidural hematoma, attributed to dysfunctional platelets from excessive garlic use in a patient not receiving concomitant anticoagulation, has been reported.[2245] Patients who choose to consume garlic supplements while receiving aspirin should be observed clinically for evidence of adverse effects.

Theoretically feverfew, Tanacetum parthenium may enhance the effects of the platelet inhibitors (including aspirin, ASA) via inhibition of platelet aggregation or via antithrombotic activity.[2913] [2914] [2915] Feverfew also inhibits the secretion of various substances (e.g., arachidonic acid, and serotonin) from the platelet.[1797] Clinical interactions have not yet been reported; however, avoidance of the use of feverfew during antiplatelet therapy seems prudent.[5314] In addition, feverfew appears to inhibit prostaglandin synthesis, reportedly at a different step in the prostaglandin pathway than salicylates.[2911][2912] Theoretically, salicylates might decrease the effectiveness of feverfew, Tanacetum parthenium.[5314]

Drug interactions with fish oil, omega-3 fatty acids are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation [6320], caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events.[3535]

Psyllium can interfere with the absorption of certain oral drugs if administered concomitantly. For example, psyllium fiber can adsorb salicylates [6107]. Per the psyllium manufacturers, administration of other prescribed oral drugs should be separated from the administration of psyllium by at least 2 hours.

Flaxseed fiber can impair the absorption of oral drugs when administered concomitantly.[6099] However, no drug interaction studies have been performed to assess the degree to which the absorption of oral drugs may be altered. Based on interactions of other plant seed fiber (e.g., psyllium) used as a bulk-forming laxative, flaxseed fiber may adsorb salicylates [6107]. Administration of prescribed oral agents should be separated from the administration of flaxseed fiber by at least 2 hours.

Prasterone, dehydroepiandrosterone, DHEA appears to have anti-platelet effects [2459], which may prolong bleeding times. Inhibition of platelet aggregation by DHEA has been demonstrated in vivo in humans; the rate of arachidonate-stimulated platelet aggregation was prolonged or completely inhibited.[2459] In addition, DHEA is converted to androgens and estrogens within the human body and thus, may affect hemostasis via androgenic or estrogenic effects. Estrogens increase the production of clotting factors VII, VIII, IX, and X.[4744] Androgens, such as testosterone, increase the synthesis of several anticoagulant and fibrinolytic proteins. Because of these potential, varied effects on coagulation, patients receiving DHEA concurrently with other platelet inhibitors, including aspirin, ASA should be monitored for side effects or the need for dosage adjustments.

Drug interactions with Horse chestnut, Aesculus hippocastanum are not well documented. Coumarin compounds with the potential for anticoagulant activity have been isolated from the herb.[5279] [5875] It is possible that the use of horse chestnut may increase the risk of bleeding if co-administered with anticoagulants (e.g., enoxaparin, heparin, warfarin), thrombolytic agents, or platelet inhibitors (e.g., aspirin, clopidogrel, and others).[5875] [6504] Reparil® Dragees (Madaus AG, Germany) a drug derived from horse chestnut and containing aescin (escin), is labeled with a precaution that the action of anticoagulants may be potentiated by aescin.[6505] Caution and careful monitoring of clinical and/or laboratory parameters are warranted if horse chestnut is coadministered with any of these agents.

Green tea has demonstrated antiplatelet and fibrinolytic actions in animals.[6434] [6440] It is possible that the use of green tea may increase the risk of bleeding if co-administered with aspirin. Caution and careful monitoring of clinical and/or laboratory parameters are warranted if green tea is coadministered with platelet inhibitors.

Agents that acidify the urine should be avoided in patients receiving high-dose salicylates. Urinary pH changes can have a significant effect on salicylate excretion.[6859] Urine acidifying agents (e.g., ammonium chloride, ascorbic acid, vitamin C, potassium chloride, or phosphate salts) may increase renal tubular reabsorption of salicylic acid and possibly increase salicylic acid levels. However, if the urine is acidic prior to administration of an acidifying agent, the increase in salicylic acid concentrations should be minimal. Increases in salicylic acid levels are more likely in patients receiving acidifying agents with a baseline urinary pH > 6.5.

Interactions last revised 5/13/2005 10:59:00 AM

Adverse Reactions

Symptomatic GI disturbances occur in 2—10% of individuals receiving normal doses of aspirin for analgesia or fever, 10—30% of individuals receiving doses > 3.6 grams/day, and 30—90% of patients with preexisting GI disease. Nausea/vomiting, dyspepsia, abdominal pain, pyrosis (heartburn), and other symptoms of gastric distress can be reduced if aspirin is taken with food or a full glass of water. 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, bleeding, and perforation have been reported rarely. 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.[100] 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.[1036] 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. Patients taking aspirin in large doses (> 15 tablets per week) or regularly (>= 4 days/week) are at increased risk of GI bleeding or gastric ulceration. 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 salicylate therapy. These effects are early manifestations of salicylate toxicity. 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, however, is uncommon and occurs in only 0.3% of the general population. Patients with chronic urticaria have the highest incidence (20%), followed by patients with asthma (4%) and patients with chronic rhinitis (1.5%). 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 may cause reversible hepatotoxicity primarily manifested as mild focal hepatic necrosis and portal hypertension with elevated hepatic enzymes (usually transaminases) and hyperbilirubinemia. 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.

Reye's syndrome, which exclusively affects children under 15 years of age, has been associated with aspirin use following active varicella infection or other viral illnesses. Reye's syndrome is a multisystem disorder evidenced by persistent vomiting, altered sensorium, elevated hepatic enzymes, hypoprothrombinemia, and hyperammonemia.

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 nonfollicular, pustular, erythematous rash starts suddenly, is associated with fever above 38 degrees C, and is distinct from pustular psoriasis, although biopsy results in each reveal spongiform subcorneal pustules. 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. Clinical presentation is diverse with cutaneous lesions beyond erythema and pustules present in half of the cases. For example, bullous lesions, edema, purpura, pruritus, and mucosal erosions are possible. The mean duration of the pustules is 9.7 days followed by an annular desquamation, as long as the causative drug or factor is discontinued. The physiopathological mechanisms of AGEP have not been determined but the pathological criteria of edema, leukocytoclastic vasculitis, eosinophil exocytosis, and keratinocyte focal necrosis are distinctive. Pustule confluence or very small pustules may lead a clinician to make an incorrect diagnosis of TEN, of drug-induced erythroderma, or of staphylococcal scalded skin syndrome.[4446]

Aspirin therapy causes platelet dysfunction by inhibiting platelet aggregation resulting in a prolonged bleeding time. 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.[1281]

With chronic, high-dose 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. Salicylates may cause transient urinary excretion of renal tubular epithelial cells, azotemia, albuminuria, and proteinuria.

Salicylates 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 (> 5 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 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.

During acute or chronic salicylic acid toxicity, moderate-to-severe noncardiogenic pulmonary edema may occur.

Intracranial bleeding may occur in patients at risk who are taking aspirin. One trial reported an incidence of 0.4% in patients treated with 50 mg/day aspirin vs. 0.4% for placebo in patients being evaluated for stroke prophylaxis.[1078]

Overuse of aspirin by headache-prone patients frequently produces drug-induced rebound headache accompanied by dependence on symptomatic medication, tolerance (refractoriness to prophylactic medication), and withdrawal symptoms. In this case, overuse of aspirin has been defined as taking 3 or more doses per day more often than 5 days per week.[4043] The frequency of use may be more important than the dose. Features of a rebound headache include morning headache, end-of-dosing interval headache, or headache improvement with discontinuation of overused medication. Stopping the symptomatic medication may result in a period of increased headache and then headache improvement. Analgesic overuse may be responsible for the transformation of episodic migraine or episodic tension headache into daily headache and may perpetuate the syndrome.[4043]

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 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.

Adverse Reactions last revised 10/24/2005 3:04:00 PM

Monitoring Parameters

Monitoring Parameters
•LFTs: patients at risk
•serum creatinine/BUN: patients at risk
•serum salicylate concentrations: in chronic use or acute toxicity
•stool guaiac: in chronic use

Clopidogrel
Plavix®

Classification:
• Hematological Agents
    • Platelet Inhibitors

Description, Mechanism of Action, Pharmacokinetics

Description: Clopidogrel is an oral antiplatelet agent with a structure and mechanism of action similar to ticlopidine. It is associated with a lower incidence of adverse cutaneous, gastrointestinal, or hematologic adverse reactions than ticlopidine. Unlike ticlopidine, clopidogrel does not require routine hematologic monitoring. Overall tolerability associated with use of clopidogrel appears to be similar to that of aspirin; however, gastrointestinal bleeding may occur less often with clopidogrel. Conversely, clopidogrel appears to possess a slightly higher incidence of neutropenia than aspirin, although severe neutropenia is rare with either drug. Clopidogrel was approved by the FDA for reduction of atherosclerotic events in November 1997. Several of the potential uses of clopidogrel are discussed below.
•Arterial thromboembolism prophylaxis in patients with established cardiovascular disease: Clopidogrel is used to reduce atherosclerotic events (stroke, myocardial infarction, and vascular death) in patients with a history of recent stroke, recent myocardial infarction (MI), or established peripheral vascular disease. The CAPRIE study shows that it is more effective than aspirin in reducing atherosclerotic events in high risk patients.[1637] The CAPRIE study included three types of patients, those with recent MI, recent stroke, or symptomatic peripheral arterial disease. In these populations clopidogrel has been shown to reduce atherosclerotic events. In the CHARISMA trial, patients with a history of or at risk for cardiovascular disease (n > 15,000) were randomized to clopidogrel plus low-dose aspirin or low-dose aspirin alone. The findings from this trial indicate that combination antiplatelet therapy does not reduce the risk of MI, stroke, or cardiovascular death compared with aspirin alone (rate of 6.8% in the combination group vs. 7.3% in the aspirin only group, p=0.22); furthermore, combination therapy is associated with an increased risk of moderate bleeding (rate of 2.1% in the combination therapy group vs. 1.3% in the placebo group, p<0.001), but not an increased risk of severe bleeding. Data from a sub-group analysis should be interpreted with caution; the data indicate that combination antiplatelet therapy in patients with established cardiovascular disease reduces the risk of recurrent MI, stroke, or cardiovascular death (rate of 6.9% in the combination therapy group vs. 7.9% in the aspirin only group; RR 0.88, 95% CI 0.77—0.998, p=0.046). However, in patients without established cardiovascular disease but who have risk factors including diabetes mellitus, hypertension, or hypercholesterolemia, combination antiplatelet therapy is not associated with a difference in clinical outcomes and may be associated with an increased risk of cardiovascular death. More data are needed to determine the role of combination antiplatelet therapy in patients with established cardiovascular disease; however, it may be prudent to avoid combination therapy in patients without established cardiovascular disease.[8833] [9091]
•Acute coronary syndrome (ACS): In the acute coronary syndrome (ACS) population, clopidogrel has been shown to decrease cardiovascular events.[686] [687] The CURE study evaluated the efficacy and safety of the combination of clopidogrel plus aspirin in patients with ACS without ST-segment elevation (unstable angina or non-Q-wave acute myocardial infarction); clopidogrel plus aspirin reduced cardiovascular events (combined endpoint: cardiovascular death, non-fatal MI, or stroke).[686] Several additional studies have demonstrated a benefit of long-term combination clopidogrel/aspirin therapy in reducing cardiovascular events in patients with ACS undergoing percutaneous coronary intervention (PCI).[687] [4335] Accordingly, the 2006 AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease recommend that in patients with ACS, including patients undergoing PCI with stent placement, clopidogrel should be used with aspirin for up to 12 months.[9219] Clopidogrel is preferred to ticlopidine for ACS due to its improved safety profile and shorter onset of action.[2998] Although the risk of major bleeding is increased with clopidogrel in ACS, the risk of hemorrhagic stroke or life-threatening bleeding is not increased.[686]
•ST-segment elevation myocardial infarction (STEMI): In patients with ST-segment elevation MI (STEMI), clopidogrel added to standard therapy (e.g., aspirin and fibrinolytic therapy) has been shown to improve rates of patency of the related infarcted artery and reduce recurrent MI, ischemia, stroke, and death, without increasing the risk of minor or major bleeding. These outcomes have been demonstrated in patients regardless of whether or not they undergo angioplasty or percutaneous coronary intervention (PCI).[9236] [9237] The FDA approved clopidogrel for the treatment of acute ST segment elevation myocardial infarction (STEMI) on August 16, 2006.
•Stroke prophylaxis in patients with noncardioembolic TIA or stroke: For patients with a history of noncardioembolic TIA or stroke, the American College of Chest Physicians (ACCP) recommends clopidogrel as one of several first-line antiplatelet regimens; other first-line regimens include low-dose aspirin or aspirin; dipyridamole combination therapy (Grade 1A recommendation).[7011] [7012]
•Cardioembolic stroke prophylaxis in patients with atrial fibrillation: Although warfarin remains the treatment of choice for stroke prophylaxis in patients with atrial fibrillation, clopidogrel has been investigated for use in this population. The Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE) has been initiated to determine the benefits of clopidogrel with aspirin for the prevention of cardioembolic stroke in patients with atrial fibrillation. One arm of the trial, ACTIVE W, which randomized patients that were eligible and willing to take warfarin to either aspirin (75—100 mg/day) plus clopidogrel (75 mg/day) or warfarin (goal INR 2—3), was stopped early (after a median of 1.28 years) as aspirin plus clopidogrel was found to be inferior to warfarin; in addition, minor but not major bleeding was more common in patients receiving combination antiplatelet therapy.[9199] A second arm of the study, ACTIVE A is ongoing and has randomized patients ineligible or unwilling to take warfarin to either aspirin or aspirin plus clopidogrel. The role of combination antiplatelet therapy in patients ineligible or unwilling to take warfarin therapy is not yet known.

Mechanism of Action: Clopidogrel is a thienopyridine compound which acts to antagonize adenosine diphosphate (ADP). Clopidogrel is inactive in vitro and requires hepatic activation to exert its antiplatelet effect. The active metabolite selectively and irreversibly inhibits ADP-induced platelet aggregation. It prevents binding of adenosine diphosphate (ADP) to its platelet receptor. Thus, ADP-mediated activation of the glycoprotein GPIIb/IIIa complex is impaired. Because the glycoprotein GPIIb/IIIa complex is the major receptor for fibrinogen, impaired activation of the GPIIb/IIIa complex prevents fibrinogen binding to platelets which ultimately inhibits platelet aggregation. Because the active metabolite of clopidogrel irreversibly modifies the platelet ADP receptor; platelets exposed to the drug are affected for the remainder of their lifespan. In platelet aggregation studies, clopidogrel 75 mg once daily produced inhibition of ADP-induced platelet aggregation equivalent to that of ticlopidine 250 mg twice daily. The active metabolite of clopidogrel also inhibits platelet aggregation induced by agonists other than ADP by blocking the amplification of platelet activation by released ADP; the active metabolite does not inhibit phosphodiesterase.

Pharmacokinetics: Clopidogrel is administered orally; it is inactive in vitro and requires hepatic biotransformation to an active metabolite. Previously, hepatic activation was thought to be mediated by the CYP P450 1A subfamily [5476]; however, more recent in vivo [5477] and in vitro [5163] evidence indicate that hepatic activation is mediated by the CYP 3A subfamily. The uncharacterized active metabolite is labile and highly reactive. The pharmacokinetic profile of clopidogrel is described using the pharmacologically inactive primary metabolite, a carboxylic-acid derivative. The carboxylic-acid derivative represents roughly 85% of the circulating metabolites in plasma.

Following oral administration, clopidogrel is rapidly absorbed and undergoes extensive first-pass metabolism in the liver. Absorption is at least 50% and is not significantly affected by food. Peak plasma concentrations (roughly 3 mg/L) of the primary circulating metabolite occur at about one hour following multiple dosing of 75 mg/day. Plasma concentrations of the parent drug are undetectable 2 hours after an oral dose. Plasma concentrations of the main circulating metabolite increase proportionally with clopidogrel doses in the range of 50—150 mg. Clopidogrel and the main circulating metabolite bind reversibly in vitro to human plasma proteins (98% and 94%, respectively). Approximately 50% of radiolabeled clopidogrel is eliminated in urine and about 46% via the feces over a period of 5 days. The half-life of the carboxylic acid derivative is roughly 8 hours.

Dose dependent inhibition of platelet aggregation can be seen two hours after a single oral dose. With repeated doses of 75 mg/day, maximum inhibition of platelet aggregation is achieved within 3—7 days. At steady state, platelet aggregation is inhibited by 40—60%. Bleeding time prolongation is not significantly affected by age, renal impairment, or gender. Platelet aggregation and bleeding time gradually return to baseline about 5 days after discontinuation of clopidogrel.

Description, Mechanism of Action, Pharmacokinetics last revised 8/18/2006 5:19:00 PM

Indications

Dosage

For arterial thromboembolism prophylaxis (i.e., myocardial infarction prophylaxis, stroke prophylaxis, thrombosis prophylaxis):
•for patients with stable coronary artery disease, congestive heart failure, or atherosclerosis as documented by recent stroke, transient ischemic attack (TIA), recent myocardial infarction, or established peripheral arterial disease:
NOTE: For patients with a history of noncardioembolic TIA or stroke, the American College of Chest Physicians (ACCP) recommends clopidogrel, low-dose aspirin, or aspirin; dipyridamole combination therapy as first-line treatments (Grade 1A recommendation).[7011] [7012] In patients who can not tolerate aspirin or have an aspirin allergy, clopidogrel should be used. The use of aspirin plus clopidogrel is not recommended as the combination is not associated with an added benefit, but is associated with an increased risk of bleeding.[9239]
NOTE: Results of the large CHARISMA study indicate that in patients at risk for cardiovascular disease, combination therapy of clopidogrel plus low-dose aspirin versus aspirin alone does not reduce the risk of recurrent myocardial infarction, stroke, or cardiovascular death. Furthermore, combination therapy is associated with an increase in moderate bleeding.[8833] [9091]
Oral dosage:
Adults: 75 mg PO once daily. Per the American College of Chest Physicians (ACCP), in those patients with stable coronary artery disease or congestive heart failure who are considered to be at high-risk for a myocardial infarction, clopidogrel 75 mg PO once daily should be administered in combination with aspirin.[9241]
Elderly: See adult dosage.
Children: Safe and effective use has not been established.
•for patients with acute coronary syndrome (unstable angina or non-Q-wave acute myocardial infarction), including patients who are to be managed medically, and for those undergoing percutaneous coronary intervention (PCI) or CABG:
NOTE: In the CURE study, most patients with acute coronary syndrome (ACS) also received heparin acutely, and the use of GPIIb/IIIa inhibitors were not permitted for 3 days prior to study randomization. Although the risk of major bleeding is increased with clopidogrel in ACS, the risk of hemorrhagic stroke or life-threatening bleeding is not increased.[686]
Oral dosage:
Adults: The FDA-approved regimen is a 300 mg PO loading dose, then 75 mg PO once daily in combination with aspirin.[2998] Per the 2006 AHA/ACC guidelines for secondary prevention in patients with coronary or other atherosclerotic vascular disease, clopidogrel should be given to all patients with ACS for up to 12 months; aspirin (75—162 mg/day PO) should be continued indefinitely.[9219] In patients with an aspirin allergy, clopidogrel monotherapy can be used.[9242] In patients undergoing PCI, the clopidogrel 300 mg loading dose should be administered at least 6 hours before the procedure. A 600 mg loading dose has also been used; however the safety and efficacy compared to 300 mg is less established. A higher loading dose will more rapidly achieve a higher level of antiplatelet activity.[4464] [4465] [9238] In patients that have had a bare metal stent placed after PCI, clopidogrel should be given for at least 1 month, with aspirin initially given at a higher dose (325 mg/day PO) for 1 month; in patients that have had a sirolimus-eluting stent placed, clopidogrel should be given for at least 3 months, with aspirin given at a higher dose for 3 months; for patients that have had a paclitaxel-eluting stent placed, clopidogrel should be given for at least 6 months, with aspirin given at a higher dose for 6 months.[9219] If CABG is planned, withhold clopidogrel for at least 5—7 days prior to the procedure to minimize potential for bleeding.[2998] A loading dose of clopidogrel 300 mg PO can be administered 6 hours after CABG followed by 75 mg PO once daily for 9—12 months. Clopidogrel should be administered in combination with aspirin.[9241]
Elderly: See adult dosage.
Children: Safe and effective use have not been established.
•for patients with ST-segment elevation MI (STEMI):
Oral dosage:
Adults: 75 mg PO once daily in combination with aspirin, with or without a 300 mg PO loading dose, is the recommended dose. Clopidogrel can be administered with or without thrombolytics. Additionally, per the American College of Chest Physicians (ACCP), clopidogrel 300 mg PO followed by 75 mg PO once daily is recommended for patients that can not tolerate or have an allergy to aspirin.[9242] In patients with ST-segment elevation MI (STEMI), 75 mg PO once daily in addition to aspirin 75—162 mg PO per day and either a fibrinolytic agent or anticoagulant (or both) has been shown to improve rates of patency of the related infarcted artery and reduce recurrent MI, ischemia, stroke, and death, without increasing the risk of minor or major bleeding. This benefit is not known to pertain to patients who receive primary angioplasty.[9236] [9238] In the CLARITY-TIMI 28 trial, approximately 3500 patients < 75 years were randomized to receive a clopidogrel 300mg PO loading dose followed by 75 mg PO daily or placebo in addition to a fibrinolytic agent, aspirin, and an anticoagulant (if indicated). Approximately 94% of the patients underwent angiography; in these patients, clopidogrel or placebo was continued through the day of angiography. In patients not undergoing angiography, clopidogrel or placebo was continued for 8 days or until hospital discharge, whichever occurred first. The median number of doses of study drug administered was four. PCI, which occurred from days 2—8 (median 3.5 days) after enrollment, was performed in approximately 57% of patients. The primary efficacy endpoint (occluded infarct-related artery at angiography plus death or recurrent infarction prior to angiography; or death or reinfarction by day 8 or hospital discharge in those patients not undergoing angiography) occurred in 15% of patients receiving clopidogrel vs. 21.7% of patients receiving placebo (36% relative reduction; P<0.001). All patients were offered open-label clopidogrel after angiography or PCI. The odds of cardiovascular death, recurrent MI, or recurrent ischemia occurring at 30 days was reduced by 20% in patients treated with clopidogrel (from 14.1 to 11.6%, P=0.03).[9236] In a second study, aspirin plus clopidogrel or placebo was administered to patients until hospital discharge or for 4 weeks, whichever occurred first; a loading dose of clopidogrel was not administered. Approximately 54% of the patients received a fibrinolytic agent and 75% received an anticoagulant. Approximately 3% of the patients in this study underwent an elective PCI. The mean duration of clopidogrel or placebo in survivors was 14.9 days. Death, reinfarction, and stroke were reduced in patients that received clopidogrel (9.2% for clopidogrel vs. 10.1% for placebo, P=0.002); additionally, death from any cause was reduced in patients receiving clopidogrel (7.5% for clopidogrel vs. 8.1% for placebo, P=0.03). It should be noted that in this study, the rates of efficacy or bleeding were not different in patients > 70 years of age versus those <= 70 years of age.[9237]
Elderly: See adult dosage. NOTE: The safety and efficacy of a 300 mg loading dose in combination with aspirin and fibrinolytics in elderly patients >= 75 years of age is not known.[9236]
Children: Safe and effective use have not been established.

Maximum Dosage Limits:
•Adults: 75 mg/day PO chronic treatment (up to 600 mg PO for single loading dose).
•Elderly: 75 mg/day PO chronic treatment (up to 600 mg PO for single loading dose).
•Adolescents: Safe and effective use has not been established.
•Children: Safe and effective use has not been established.

Patients with hepatic impairment:
No specific guidelines are available. Clopidogrel is extensively metabolized by the liver and dosage reductions may be needed in moderate to severe hepatic disease. Use caution in patients with severe hepatic disease, who may have bleeding diatheses.

Patients with renal impairment:
Although no dosage adjustment is recommended, the manufacturer warns that clopidogrel should be used with caution in patients with severe renal impairment. Experience is limited in this patient population.

Indications...Dosage last revised 8/18/2006 5:19:00 PM

Administration Guidelines

Oral Administration
•Clopidogrel is administered with or without food.

Administration last revised 7/10/2006 10:14:00 AM

Contraindications/Precautions

• Absolute contraindications are in italics.

Clopidogrel is contraindicated in any patient with active pathological bleeding such as GI bleeding, retinal bleeding, retroperitoneal bleeding, or intracranial bleeding. As with other antiplatelet agents, clopidogrel should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery, or other pathological conditions (especially gastrointestinal or intraocular). If a patient is to undergo elective surgery and an antiplatelet effect is not desired, clopidogrel should be discontinued 7 days prior to the surgery. Clopidogrel prolongs bleeding time and is associated with a 2% incidence of GI bleeding. Thus, this drug should be used with caution in individuals who have lesions with a propensity to bleed, such as patients with peptic ulcer disease. In addition, drugs that might induce such lesions (such as aspirin or other NSAIDs) should be used with caution in patients taking clopidogrel (see Drug Interactions). If symptoms of bleeding occur during clopidogrel therapy, blood cell counts and/or other appropriate testing should be promptly considered.

Clopidogrel should be used with caution in patients with hepatic disease. A bleeding diathesis may exist in these patients, especially in those with severe liver disease, which may increase the risk of bleeding associated with clopidogrel. In addition, severe hepatic disease may impair the conversion of clopidogrel, the prodrug, to its active form.

Although no dosage adjustment is recommended in patients with renal impairment, the manufacturer warns that clopidogrel should be used with caution in patients with severe renal impairment. Experience is limited in patients with severe renal disease or renal failure.

Clopidogrel is classified as FDA pregnancy risk category B. Reproduction studies performed in rats and rabbits at doses up to 500 and 300 mg/kg/day (respectively, 65 and 78 times the recommended daily human dose on a mg/m2 basis), revealed no evidence of impaired fertility or fetotoxicity due to clopidogrel. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of a human response, clopidogrel should be used during pregnancy only if clearly needed.

It is not known whether clopidogrel or its metabolites are excreted in human milk. However, studies have shown that clopidogrel and/or its metabolites are excreted in rat milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue breast-feeding or to discontinue the drug, taking into account the importance of the drug to the mother.

Of the total number of subjects in controlled clinical studies, approximately 50% of patients treated with clopidogrel were elderly (i.e., 65 years of age and over). Approximately 16% of patients treated with clopidogrel were 75 years of age and over. In the CURE trial, the percent of patients experiencing thrombotic events increased with age regardless of treatment group. The percent of patients experiencing thrombotic events in patients < 65 years of age was 5.2% for the clopidogrel plus aspirin group vs. 7.6% for the aspirin plus placebo group. In patients aged 65—74 years, the percent of patients experiencing thrombotic events was 10.2 % for the clopidogrel plus aspirin group vs. 12.4% for the aspirin plus placebo group; in patients >= 75 years of age, 17.8% of patients in the clopidogrel plus aspirin group vs. 19.2% of patients in the aspirin plus placebo group experienced thrombotic events. In addition, the incidence of major bleeding increased with age in both treatment groups; however, the incidence of bleeding was higher in patients treated with combination clopidogrel and aspirin. In patients < 65 years of age, the incidence of major bleeding events was 2.5% in the clopidogrel plus aspirin group vs. 2.1% in the aspirin plus placebo group. In patients aged 65—74 years, the incidence of major bleeding rose to 4.1% in the clopidogrel plus aspirin group vs. 3.1% in the aspirin plus placebo group; in patients >= 75 years of age, the incidence of bleeding was 5.9% in the clopidogrel plus aspirin group vs. 3.6% in the aspirin plus placebo group. If bleeding is a potential concern and combination therapy is desired, elderly patients should be encouraged to use a low dose of aspirin with clopidogrel.

Safe and effective use of clopidogrel has not been established in children.

Contraindications last revised 2/11/2005 2:54:00 PM

Drug Interactions

NOTE: At high concentrations in vitro, clopidogrel inhibits the activity of cytochrome P450 2C9. Clopidogrel requires hepatic biotransformation to an active metabolite; the activation is thought to be mediated by the CYP3A4 isoenzyme (see Pharmacokinetics).[5163]

Because clopidogrel inhibits platelet aggregation, a potential additive risk for bleeding exists if clopidogrel is given in combination with other drugs that affect hemostasis such as platelet inhibitors.[5164] Ticlopidine and clopidogrel inhibit platelets via the same mechanism [5165] [5166]; combination therapy would therefore be illogical. Because clopidogrel and cilostazol cause platelet inhibition through different mechanisms [5165] [5167], clinical evaluation may reveal that the combined use of these two drugs is both safe and effective; currently such evidence is lacking and combination therapy should be used with caution, if at all, as the magnitude of increased risk of bleeding is unknown. The manufacturers of cilostazol have indicated that studies are planned to determine the pharmacodynamic effects of clopidogrel and cilostazol combination therapy. Dipyridamole and clopidogrel also cause platelet inhibition via different mechanisms [5168]; however, their combined use has not been formally evaluated in clinical trials. The increased risk of bleeding is not known at this time and combined use should be avoided until data supporting safety and efficacy are known.

Concomitant administration of clopidogrel and aspirin (500 mg twice daily for 1 day) did not significantly increase bleeding time prolongation induced by clopidogrel. However, clopidogrel does potentiate the effect of aspirin on collagen-induced platelet aggregation.[5165] In patients with recent TIA or stroke who are at high risk for recurrent ischemic events, the combination of aspirin and clopidogrel has not been shown to be more effective than clopidogrel alone; however, the incidence of major bleeding (i.e., bleeding that was substantially disabling, intraocular, or required >= 2 units of transfused blood) is more common with combination therapy. In addition, large doses of salicylates (>= 3—4 g/day) can cause hypoprothrombinemia [5170], an additional risk factor for bleeding. The CHARISMA trial, a study that enrolled > 15,000 patients with established or at risk for cardiovascular disease, randomized patients to either clopidogrel plus low-dose aspirin or low-dose aspirin alone. The findings from this trial indicate that combination antiplatelet therapy does not reduce the risk of MI, stroke, or CV death; furthermore, combination therapy is associated with an increased risk of moderate bleeding (rate of 2.1% in the combination therapy group vs. 1.3% in the placebo group, p<0.001), but not severe bleeding. Data from a subgroup analysis of patients with established cardiovascular disease, which should be interpreted with caution, indicate that combination antiplatelet therapy reduces the relative risk of recurrent myocardial infarction, stroke, or cardiovascular death by 12.5% when compared to aspirin therapy alone (n=12,153; p=0.046). However, in patients without established cardiovascular disease, but who have risk factors for cardiovascular disease including diabetes mellitus, hypertension, or hypercholesterolemia, combination antiplatelet therapy is not associated with a difference in clinical outcomes and may be associated with an increase in cardiovascular death.[8833] More data are needed to determine the role of combination antiplatelet therapy in patients with established cardiovascular disease; however, it may be prudent to avoid using clopidogrel and aspirin combination therapy in patients that do not have established cardiovascular disease. Regardless of the indication, patients receiving both aspirin and clopidogrel should be monitored for an increased risk of bleeding.

In healthy volunteers, an increase in occult GI blood loss occurred when clopidogrel was administered concomitantly with naproxen.[5165] Thus, if combination therapy with NSAIDs and clopidogrel is deemed necessary, caution is advised.[5165]

Because clopidogrel inhibits platelet aggregation, a potential additive risk for bleeding exists if clopidogrel is given in combination with other agents that affect hemostasis such as thrombolytic agents, rheologic agents (i.e., pentoxifylline [6316]), or anticoagulants.[5164] Although the risk of bleeding is increased when clopidogrel is used concomitantly with thrombolytic agents [5171], it is common to see patients receive these drugs simultaneously. In healthy volunteers receiving heparin, clopidogrel does not alter the effect of heparin on coagulation parameters or require adjustment of the heparin dose. In addition, heparin has no effect on inhibition of platelet aggregation induced by clopidogrel.[5165] Nevertheless, the safety of this combination has not been established and concomitant administration of clopidogrel with heparin should be undertaken with caution. Because of increased bleeding risk, coadministration of clopidogrel with warfarin should be undertaken with caution.[5165]

Clopidogrel requires hepatic biotransformation to an active metabolite; the activation is thought to be mediated by the CYP3A4 isoenzyme.[5163] As a result, drugs that inhibit CYP3A4 theoretically may decrease the hepatic metabolism of clopidogrel to its active metabolite. CYP3A4 inhibitors may include: amiodarone [5629], anti-retroviral protease inhibitors [4718], aprepitant [7438], systemic azole antifungals [4718], clarithromycin [4718], conivaptan [8569], dalfopristin; quinupristin [4718], danazol [4718], delavirdine [4718], diltiazem [4718], efavirenz (inducer or inhibitor) [5172], erythromycin [4718], fluoxetine [4718], fluvoxamine [4718], imatinib, STI-571 [4718], mifepristone, RU-486 [4718], nefazodone [4718], troleandomycin [4718], verapamil [4718], and zafirlukast [4718]. This list is not inclusive of all CYP3A4 inhibitors.

Clopidogrel requires hepatic biotransformation to an active metabolite; the activation is thought to be mediated by the CYP3A4 isoenzyme (see Pharmacokinetics).[5163] Bosentan may induce the CYP3A4 metabolism of clopidogrel to its active metabolite. Patients should be monitored for potential increased antiplatelet effects when clopidogrel is used in combination with CYP3A4 inducers such as bosentan. In addition, clopidogrel may inhibit CYP2C9 metabolism of bosentan. At high concentrations in vitro, clopidogrel inhibits the activity of CYP2C9.[5163] It is prudent to monitor for potential adverse effects of bosentan during coadministration with clopidogrel. Excessive bosentan dosage may result in hypotension or elevated hepatic enzymes. It is important to review all the medications taken concurrently with bosentan. According to the manufacturer, coadministration of bosentan with a potent CYP2C9 inhibitor plus a CYP3A4 inhibitor is not recommended; large increases in bosentan plasma concentrations are expected with such combinations.[5226]

Rifampin, rifabutin, rifapentine, bosentan, carbamazepine or barbiturates (e.g., phenobarbital or primidone) may induce the CYP3A4 metabolism of clopidogrel to its active metabolite.[4718] Patients should be monitored for potential increased antiplatelet effects when clopidogrel is used in combination with CYP3A4 inducers.

At high concentrations in vitro, clopidogrel inhibits the activity of cytochrome P450 2C9.[5165] Thus, clopidogrel could increase plasma concentrations of drugs metabolized by this isoenzyme, such as alosetron [5112], ethotoin, fluvastatin [4718], many NSAIDs [4718], tamoxifen [4718], tolbutamide [4718], torsemide [4718], and warfarin [4718]. Although there are no in vivo data with which to predict the magnitude or clinical significance of these potential interactions, caution should be used when any of these agents is coadministered with clopidogrel.

Because phenytoin and fosphenytoin are metabolized by cytochrome P450 2C9 [4718], concomitant therapy with clopidogrel at high concentrations could increase their plasma concentrations and cause symptoms of toxicity. Phenytoin concentrations should be monitored more closely when initiating clopidogrel therapy. In addition, clopidogrel is metabolized by CYP 3A; phenytoin and fosphenytoin induce cytochrome P450 3A4 isozymes.[4718] Therefore, the therapeutic effectiveness of clopidogrel should be monitored when used concomitantly with phenytoin or fosphenytoin.

No clinically significant pharmacodynamic interactions were observed when clopidogrel was coadministered with atenolol or nifedipine.[5165] The pharmacodynamic activity of clopidogrel was not significantly affected by the coadministration of estrogen, or by coadministration with a hepatic enzyme inducer (phenobarbital) or inhibitor (cimetidine).[5165] The pharmacokinetics of digoxin or theophylline were not modified by concomitant administration of clopidogrel.[5165]

Ginkgo biloba can produce clinically-significant antiplatelet effects.[1900] Therefore, Ginkgo biloba should be used cautiously in patients taking platelet inhibitors such as clopidogrel [5165] to minimize the potential for additive risk of bleeding. A compound found in Ginkgo biloba, ginkgolide-B, may act as a selective antagonist of platelet activating factor (PAF). Although a review of Ginkgo biloba in 1992 stated that no known drug interactions exist,[1705] spontaneous hyphema has been reported in an elderly male who began taking ginkgo while stabilized on daily aspirin. After ginkgo was stopped, no further bleeding was noted despite continuing the aspirin therapy.[1706] Other clinical data exist[1707] that describe spontaneous subdural hematomas associated with chronic Ginkgo biloba ingestion.

Additive platelet effects may occur if clopidogrel is given in combination with ginger, Zingiber officinale, or garlic, Allium sativum. Ginger inhibits thromboxane synthetase (platelet aggregation inducer) and is a prostacyclin agonist.[5200] Garlic produces clinically significant antiplatelet effects.[2223]

Because clopidogrel inhibits platelet aggregation, a potential additive risk for bleeding exists if clopidogrel is given in combination with other drugs that affect hemostasis.[5164] Clopidogrel should be used cautiously in patients with thrombocytopenia following the administration of myelosuppressive antineoplastic agents, antithymocyte globulin [6303], strontium-89 chloride [4694], or other drugs that cause significant thrombocytopenia due to the increased risk of bleeding.

Aspirin, and other agents that affect platelet activity including platelet inhibitors, could decrease the efficacy of photosensitizing agents used in photodynamic therapy.[6359] [6625]

Drug interactions with Horse chestnut, Aesculus hippocastanum are not well documented. Coumarin compounds with the potential for anticoagulant activity have been isolated from the herb.[5279] [5875] It is possible that the use of horse chestnut may increase the risk of bleeding if co-administered with anticoagulants (e.g., enoxaparin, heparin, warfarin), thrombolytic agents, or platelet inhibitors (e.g., aspirin, clopidogrel, and others).[5875] [6504] Reparil® Dragees (Madaus AG, Germany) a drug derived from horse chestnut and containing aescin (escin), is labeled with a precaution that the action of anticoagulants may be potentiated by aescin.[6505] Caution and careful monitoring of clinical and/or laboratory parameters are warranted if horse chestnut is coadministered with any of these agents.

Theoretically feverfew, Tanacetum parthenium may enhance the effects of the platelet inhibitors (including aspirin, ASA) via inhibition of platelet aggregation or via antithrombotic activity.[2913] [2914] [2915] Feverfew also inhibits the secretion of various substances (e.g., arachidonic acid, and serotonin) from the platelet.[1797] In theory, concurrent use may increase the risk of bleeding. Clinical interactions have not yet been reported; however, avoidance of the use of feverfew during antiplatelet therapy seems prudent.[5314]

Green tea has demonstrated antiplatelet and fibrinolytic actions in animals.[6434] [6440] It is possible that the use of green tea may increase the risk of bleeding if coadministered with clopidogrel. Caution and careful monitoring of clinical and/or laboratory parameters are warranted if green tea is coadministered with platelet inhibitors.

Prasterone, dehydroepiandrosterone, DHEA appears to have anti-platelet effects,[2459] which may prolong bleeding times and increase the risk of bleeding in patients taking platelet inhibitors including clopidogrel. In addition, DHEA is converted to androgens and estrogens within the human body and thus may affect hemostasis via androgenic or estrogenic effects. Estrogens increase the production of clotting factors VII, VIII, IX, and X.[4744] Androgens, such as testosterone, increase the synthesis of several anticoagulant and fibrinolytic proteins. Because of these potential and varied effects on coagulation, patients receiving DHEA concurrently with other platelet inhibitors should be monitored for side effects or the need for dosage adjustments.

Fish oil, omega-3 fatty acids have platelet aggregation inhibition properties.[6320] Caution is advised in combining fish oil, omega-3 fatty acids with platelet inhibitors due to a theoretical risk of bleeding. However, clinically significant bleeding events have not yet been reported in study patients.

Atorvastatin has been reported to attenuate the antiplatelet activity of clopidogrel potentially by inhibiting CYP3A4 metabolism to its active metabolite;[5163] [5477] however, conflicting data exists.[5398] The clinical significance of this theoretical interaction is not known. Patients should be monitored for therapeutic effectiveness when clopidogrel is administered with atorvastatin or other HMG Co-A reductase inhibitors metabolized by the CYP 3A4 isozyme (i.e., lovastatin, simvastatin, and cerivastatin).

Ramelteon should be administered with caution in patients taking CYP2C9 inhibitors, such as clopidogrel.[8143] [4718] The AUC and Cmax of ramelteon has been elevated > 150% when administered with other CYP2C9 inhibitors. The patient should be monitored closely for toxicity even though ramelteon has a wide therapeutic index.

Doxercalciferol is converted in the liver to 1,25-dihydroxyergocalciferol, the major active metabolite, and 1-alpha, 24-dihydroxyvitamin D2, a minor metabolite. Although not specifically studied, cytochrome P450 enzyme inhibitors including clopidogrel may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy. Patients should be monitored for a decrease in efficacy if clopidogrel is coadministered with doxercalciferol.[7566] [6904]

Clopidogrel is metabolized by CYP3A4. The effects of echinacea on CYP3A4 are complex. In vitro data suggest that echinacea can inhibit the CYP3A4 isoenzyme; however, the clinical significance of these data are not yet known, as some authors have reported the in vivo activity in humans to be minor. Other limited in vivo data indicate that echinacea inhibits intestinal CYP3A4, but induces hepatic CYP3A4. In 6 subjects administered echinacea plus intravenous midazolam a probe for CYP3A4), the systemic clearance of midazolam increased by 34% and the AUC decreased to 75%. However, when oral midazolam was administered, the oral availability increased leading to no change in the overall clearance of oral midazolam. The overall effects on orally administered drugs metabolized by CYP3A4 are unknown and may be negligible. It may be prudent to closely monitor for changes in efficacy or toxicity when echinacea is coadministered with drugs that are metabolized by CYP3A4, including clopidogrel, until more data are available.[7213] [7566] [8894]

Interactions last revised 7/26/2006 12:14:00 PM

Adverse Reactions

Clopidogrel has been evaluated for safety in over 11,300 patients, including over 7,000 patients treated for >= 1 year. In the CAPRIE study, 9599 patients received clopidogrel and 9586 patients received aspirin for an average of 1.6 years.[1637] Overall tolerability of clopidogrel was similar to that of aspirin; 13% of patients in both groups withdrew early from the treatment regimen due to adverse events. Adverse events that were reported with a higher incidence in clopidogrel-treated patients than in aspirin-treated patients were diarrhea (3.3% vs. 1.6%), purpura (5.3% vs. 3.7%), maculopapular rash (4.2% vs. 3.5%), and pruritus (3.3% vs. 1.6%). The frequency of severe rash (unspecified) and severe diarrhea among patients receiving clopidogrel (0.23% and 0.26%, respectively) was twice as high as that reported among aspirin-treated patients, although these events were uncommon. Adverse events reported in >= 2.5% of the study population, but at a higher incidence with aspirin compared with clopidogrel, included abdominal pain (7.1% vs. 5.6%) and dyspepsia (6.1% vs. 5.2%). Most of these adverse effects were mild and transient.

Due to drug-induced platelet dysfunction, bleeding may occur at any site. In the CAPRIE study,[1637] clopidogrel was associated with a lower incidence of severe GI bleeding than aspirin (0.49% vs. 0.71%), including fewer hospitalizations for GI bleeding (0.7% vs. 1.1%) and fewer GI ulcers (0.7% vs. 1.2%). The incidence of severe intracranial bleeding was not significantly different between clopidogrel and aspirin (0.31% vs. 0.43%). Bleeding events reported during worldwide marketing or post-marketing experience with clopidogrel have also included ocular hemorrhage, prolonged bleeding time, retinal hemorrhage and retroperitoneal bleeding. In the CURE study, the incidence of major bleeding increased with age; however, the incidence of bleeding was higher in patients treated with combination clopidogrel and aspirin than in patients treated with aspirin alone. In patients < 65 years of age, the incidence of major bleeding events was 2.5% in the clopidogrel plus aspirin group vs. 2.1% in the aspirin plus placebo group. In elderly patients aged 65—74 years, the incidence of major bleeding rose to 4.1% in the clopidogrel plus aspirin group vs. 3.1% in the aspirin plus placebo group; in patients >= 75 years of age, the incidence of bleeding was 5.9% in the clopidogrel plus aspirin group vs. 3.6% in the aspirin plus placebo group. If bleeding is a potential concern and combination therapy is desired, elderly patients should be encouraged to use a low dose of aspirin with clopidogrel.

Severe neutropenia (absolute neutrophil count < 450/mm3) was reported in 0.04% of clopidogrel-treated patients and 0.02% of aspirin-treated patients. Ticlopidine, an antiplatelet agent similar to clopidogrel, has been associated with a 0.8—1% incidence of severe neutropenia. Although use of clopidogrel does not require routine hematologic monitoring, the possibility of myelotoxicity should be considered in a patient who demonstrates fever or other signs of infection while receiving the drug. Other hematological effects that have been reported during clopidogrel therapy include: agranulocytosis, aplastic anemia and pancytopenia. Fever has been reported during post-marketing experience with clopidogrel.

Although not reported during clinical trials, thrombotic thrombocytopenic purpura (TTP) has been reported rarely in patients receiving clopidogrel, sometimes after short exposure (< 2 weeks). Eleven cases of TTP were reported between March 1998 and March 2000; in all but one case, TTP developed within 14 days of beginning clopidogrel therapy. One patient died, eight had complete resolution of TTP after discontinuing clopidogrel and treatment with plasma exchange, and two had relapses up to seven months after the onset of TTP, with recovery after plasma exchange. It should be noted that almost half the patients with clopidogrel-induced TTP had received cholesterol-lowering drugs. In one of the patients, TTP appeared to be induced by atorvastatin, and one patient had a recurrence during treatment with atorvastatin that responded quickly to plasma exchange. In this series of patients, clopidogrel-induced TTP differed from ticlopidine-induced TTP in that it occurred sooner, was prone to recurrence, and required up to 30 plasma exchanges before clinical improvement occurred.[2754] TTP is a serious condition that can be fatal and requires urgent treatment including plasmapheresis (plasma exchange). Thrombocytopenia, microangiopathic hemolytic anemia (schistocytes seen on peripheral smear), neurological findings, renal dysfunction, and fever characterize TTP. In world-wide post-marketing experience, TTP has been reported at a rate of about four cases per million patients exposed or about 11 cases per million patient-years. The rate in the general population is approximately four cases per million person-years.

Other adverse effects that have been reported during worldwide marketing or post-marketing experience include acute hepatic failure, anaphylactoid reactions, angioedema, bronchospasm, colitis, confusion, elevated hepatic enzymes, erythema multiforme, fever, glomerulonephritis, hallucinations, hepatitis, hypersensitivity reactions, hypotension, interstitial pneumonitis, lichen planus, myalgia, pancreatitis, serum sickness, Stevens-Johnson syndrome, stomatitis, toxic epidermal necrolysis, and vasculitis.

Adverse Reactions last revised 8/15/2006 10:47:00 AM

Monitoring Parameters

Monitoring Parameters
•CBC: baseline
•LFTs: baseline

Warfarin
Coumadin® | Jantoven™

Classification:
• Hematological Agents
    • Anticoagulants

Description, Mechanism of Action, Pharmacokinetics

Description: Warfarin is an oral coumarin anticoagulant. In 1939, it was discovered that spoiled sweet clover possessed anticoagulant properties due to the presence of a compound identified as bishydroxycoumarin. In 1948, a potent congener was introduced as an effective rodenticide; this compound was named warfarin. Warfarin is a racemic mixture of two active isomers; the S-isomer is 3—5 times as potent as the R-isomer. Clinically, warfarin is used to prevent and treat thromboembolic disease in patients with various clinical conditions. By adopting the International Normalized Ratio (INR) method of monitoring warfarin therapy and decreasing the intensity of anticoagulation for most indications, the major hemorrhagic risks of warfarin therapy have decreased substantially. The FDA originally approved warfarin in 1954. Several of the major uses of warfarin are discussed below.
•Treatment of deep venous thrombosis (DVT) or pulmonary embolism (PE): In patients with idiopathic deep vein thrombosis or pulmonary embolism, treatment with moderate-intensity warfarin therapy (INR 2—3) for 3—6 months following initial therapy with heparin or low-molecular weight heparin is considered conventional therapy to prevent recurrent thrombosis.[1963] However, a prospective, randomized trial has shown a decreased incidence of recurrent thromboembolism when warfarin therapy is continued for 2 years after initial DVT occurrence versus treatment for only 3 months (1.3% vs. 27.4%, respectively).[2686] The optimal intensity and duration of anticoagulation following treatment of idiopathic DVT has not been definitively established. Newer trials have evaluated long-term anticoagulation (e.g., > 2 years) following idiopathic DVT to reduce the recurrence rates for thromboembolism.[4320] [4321] One recent trial (PREVENT) of low-intensity anticoagulation (INR 1.5—2), when given long-term (followed up to 4.5 years) following DVT, has resulted in significantly lower recurrence rates compared to placebo.[4320] However, the safety and efficacy of low-intensity, long-term anticoagulation has not been directly compared to the ACCP recommended moderate-intensity, short-term guidelines. A more recent trial (ELATE) has shown that conventional-intensity warfarin therapy is more effective and is not associated with a higher risk of important bleeding compared to low-intensity warfarin therapy for the long-term (average duration 2.4 years) prevention of recurrent venous thromboembolism.[4321]
•Deep venous thrombosis (DVT) prophylaxis: The use of warfarin to prevent venous thrombosis after orthopedic or major gynecologic surgery is effective.[4371] Moderate-intensity anticoagulation (INR 2—3) is generally effective for DVT prophylaxis. Since warfarin therapy is complicated and carries a small risk of clinically significant bleeding, it is generally reserved for high-risk patients. Low molecular weight heparin started postoperatively or the night before surgery has been shown to be more effective than warfarin therapy in preventing venous thrombosis in patients undergoing elective hip replacement or major knee surgery.
•Arterial thromboembolism prophylaxis in patients with mechanical prosthetic heart valves: In patients with mechanical prosthetic heart valves, permanent warfarin therapy offers the most consistent protection against thromboembolism.[1965] The 2001 ACCP antithrombotic guidelines recommend an INR range of 2.5—3.5 for most patients with mechanical prosthetic valves.[1965] An INR of 2 to 3 is advised for patients with bioprosthetic valves with bileaflet mechanical valves (e.g., St. Jude Medical device) in the aortic position.[1965]
•Cardioembolic stroke prophylaxis in patients with atrial fibrillation: In patients with AF and additional risk factors, warfarin therapy is generally associated with a 65—70% reduction in embolic stroke as compared to untreated control subjects. Warfarin is considerably more effective than aspirin for the prevention of cardioembolism and ischemic stroke in patients with atrial fibrillation (AF).[2687] The European Atrial Fibrillation Trial (EAFT) has previously demonstrated a lower risk of recurrent stroke in patients with atrial fibrillation receiving warfarin compared to aspirin (68% vs, 16% stroke risk reduction).[4372] The ACTIVE-W study, which compared warfarin (INR 2—3) to clopidogrel (75 mg/day) plus aspirin (70—100 mg/day) in patients with atrial fibrillation and a high risk of stroke, confirms these findings. As compared to oral anticoagulants, treatment with clopidogrel plus aspirin results in an absolute annual risk increase of 1.67% in the composite endpoint of stroke, non-CNS systemic embolism, myocardial infarction, or vascular death (RR 1.44, 95% CI 1.18—1.76, P=0.0003). The beneficial effects of oral anticoagulants found in this study were even more pronounced in those patients taking oral anticoagulants before study entry. Minor bleeding was more common in patients taking clopidogrel plus aspirin; however, the risk of major bleeding was not different between the 2 groups.[9199]
•Stroke prophylaxis in patients with a history of non-cardioembolic ischemic stroke: In contrast to the superiority of warfarin for cardioembolic stroke prophylaxis, aspirin or aspirin in combination with another antiplatelet drug (e.g., dipyridamole or clopidogrel) is recommended for patients with a history of non-cardioembolic cerebral ischemic events.[2040] Some investigators advocate the use of warfarin as a therapeutic alternative to aspirin for non-cardioembolic ischemic stroke based on the WARSS trial. The WARSS (2-year trial) has reported no difference in the rate of recurrent ischemic stroke or major bleeding between warfarin (INR 1.4—2.8) and aspirin (325 mg/day) in patients with a history of non-cardioembolic ischemic stroke.[4373] However, since warfarin therapy requires monitoring and higher costs relative to aspirin, warfarin may be justified in patients requiring oral anticoagulants for a coexisting indication. High-intensity warfarin (INR 3—4.5) is not recommended due to the risk of intracranial hemorrhage based on the findings of the SPIRIT study.[4375] [2040]
•Coronary artery thrombosis prophylaxis following acute myocardial infarction: After myocardial infarction, warfarin may be used to reduce the risk of systemic or pulmonary embolism in high-risk patients such as those with anterior Q-wave infarction, AF, severe LV dysfunction, or congestive heart failure.[1961] The optimal antithrombotic regimen for long-term management in patients postmyocardial infarction has not been established. A recent guide to warfarin therapy provides three potential strategies: 1) aspirin alone, 2) aspirin plus moderate-intensity warfarin (INR 2—3), or 3) high-intensity warfarin (INR 3—4) alone.[4371] The warfarin regimens are associated with a higher risk of bleeding, and require more intensive monitoring, whereas aspirin monotherapy is less effective. The ASPECT-2 study has reported reduced cardiovascular events and deaths with high-intensity (INR 3—4) warfarin or moderate-intensity (INR 2—2.5) warfarin plus aspirin 80 mg/day compared to aspirin alone (80 mg/day).[4376] In a similar trial, WARIS II has compared warfarin (INR 2.8—4.2), aspirin 75 mg/day, or aspirin 75 mg/day plus warfarin (INR 2—2.5), initiated at discharge postmyocardial infarction.[4377] Consistent with the ASPECT-2 trial, the WARIS II warfarin regimens are more effective in reducing composite events (death, MI, stroke) vs. aspirin alone, but have a higher rate of bleeding and require greater monitoring. Further study is needed to evaluate other strategies such as aspirin plus low-intensity warfarin (INR < 2) or monotherapy with moderate intensity warfarin (INR 2—3).

Mechanism of Action: Warfarin inhibits the synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X and anticoagulant proteins C and S. Specifically, warfarin interferes with the cyclic interconversion of vitamin K and its 2,3 epoxide (vitamin K epoxide). Vitamin K is a cofactor for the carboxylation of glutamate residues to gamma-carboxyglutamates on the N-terminal regions of vitamin K-dependent proteins. Carboxylation allows the coagulation proteins to undergo a conformational change which is necessary for their activation. Warfarin exerts its anticoagulant effect by inhibiting vitamin K epoxide reductase and possibly vitamin K reductase. This results in depletion of the reduced form of vitamin K (vitamin KH2) and limits the gamma-carboxylation of the vitamin K-dependent coagulant proteins. The degree of effect on the vitamin K-dependent proteins is dependent upon the dose of warfarin. The anticoagulant effects of warfarin are stereoselective; the S-isomer of warfarin is 3—5 times more potent than the R-isomer. Therapeutic doses of warfarin decrease the total amount of active vitamin K-dependent clotting factors produced by the liver by 30—50%.

Since warfarin does not affect the activity of synthesized coagulation factors, depletion of these mature factors through normal catabolism and replacement by newly synthesized dysfunctional vitamin K-dependent clotting factors must occur before therapeutic effects of warfarin are seen. Each factor differs in its degradation half-life; factor II 60 hours, factor VII 4—6 hours, factor IX 24 hours, and factor X 48—72 hours. The half-lives of proteins C and S are approximately 8 and 30 hours, respectively. As a result, 3—4 days of therapy may be required before a complete clinical response to any one dosage is seen. Since warfarin reduces the activity of anticoagulant proteins C and S, a hypercoagulable state may be induced for a short period of time after treatment with warfarin is started. The rapid loss of protein C temporarily shifts the balance in favor of clotting until sufficient time has passed for warfarin to decrease the activity of coagulant factors.

Warfarin prolongs the prothrombin time (PT), which is responsive to depression of three of the four vitamin K-dependent coagulation factors (factors II, VII, and X). These factors are reduced by warfarin at a rate proportionate to their respective half-lives. During the first 2—5 days of warfarin therapy, the PT primarily reflects the depression of factor VII. With subsequent warfarin treatment, the PT is prolonged by depression of factors II and X. Prothrombin time ratio results can be affected by the responsiveness of the thromboplastin to warfarin. The International Normalized Ratio (INR) has been developed and adopted as a method to standardize monitoring of oral anticoagulant therapy. The PT and INR are related based upon the ISI value (International Sensitivity Index value). The ISI is a measure of the responsiveness of a given thromboplastin to reduction of the vitamin K-dependent coagulation factors compared to the first World Health Organization international reference preparation (IRP). At an ISI value of 0.1, the PT ratio is identical to the INR. As the ISI value of the thromboplastin increases, the INR for a given PT ratio also increases. Therefore, a lower ISI is associated with a more responsive reagent. The INR is less reliable as a measure of anticoagulation in the early course of warfarin therapy; however, it is more reliable than the PT or PT ratio for clinical management.

Warfarin does not affect established thrombus and does not reverse ischemic tissue damage. Warfarin therapy prevents further extension of the clot and prevents secondary thromboembolic complications. The antithrombotic effect of warfarin is generally thought to reflect its anticoagulant effects, mediated through its ability to inhibit thrombin generation by reducing levels of vitamin K-dependent coagulation factors. However, there is evidence that the reduction of prothrombin (factor II), and possibly factor X, is more important than the reduction of factors VII and IX for the antithrombotic effect of warfarin. Reduction in prothrombin levels may results in a decrease in the amount of thrombin that can be generated and bound to fibrin, thereby reducing the thrombogenicity of the clot. If the antithrombotic effect of warfarin is reflected by its ability to lower prothrombin levels, this provides a rationale for overlapping heparin with warfarin in the treatment of patients with thrombotic disease until the prothrombin level is lowered into the therapeutic range. In contrast to heparin, warfarin has no anticoagulant effect in vitro. Warfarin does not affect prostaglandin-mediated platelet aggregation.

The action of warfarin may be overcome by the administration of vitamin K or by transfusion of plasma proteins that contain clotting factors. Hereditary resistance to warfarin has been described. Affected patients may require doses that are 5- to 20-fold higher than average to achieve an anticoagulant effect. This is thought to be due to altered affinity of the receptor for warfarin. There are also anecdotal reports of acquired resistance to warfarin. Acquired resistance to warfarin could be due to poor patient compliance, drug interactions that alter the response to warfarin, exogenous consumption of vitamin K, decreased absorption of warfarin, or increased clearance of warfarin.

Effects of warfarin on bone metabolism: Gamma-carboxyglutamate (Gla) proteins synthesized in bone include osteocalcin, protein S, and matrix Gla protein. Warfarin interferes with the carboxylation of these proteins and inhibits the action of vitamin K in osteoblasts. These effects may be responsible for bone abnormalities that can occur in neonates when women are treated with warfarin during pregnancy. There is no evidence, however, that warfarin adversely affects bone metabolism when administered to children or adults, including post-menopausal women.

Pharmacokinetics: Warfarin is primarily administered via the oral route, although an injectable preparation is available in the US. Orally administered warfarin is well absorbed from the GI tract, but individual brands of warfarin can exhibit different rates or degrees of absorption. Administration with food may delay the rate but not the extent of absorption. Warfarin is also readily absorbed through the skin, and systemic manifestations are possible with significant exposure to rodenticides. The administration of intravenous warfarin provides serum concentrations similar to equivalent oral doses, but the Tmax will be shorter. There is no increased biological effect or earlier onset of anticoagulant action with the intravenous formulation. Although warfarin plasma concentrations are detectable within 1 hour of oral or intravenous administration, anticoagulation effects are dependent on the gradual catabolism of circulating activated clotting; requiring up to 4 days for complete clinical effect. Therefore, loading doses (7.5—10 mg) do not provide more rapid complete anticoagulation and may be associated with development of a hypercoagulable state. It takes roughly 4 days to return to normal blood coagulation parameters following discontinuation of the drug.

Warfarin is highly bound (about 97%) to plasma protein, mainly albumin. The high degree of protein binding is one of several mechanisms whereby other drugs interact with warfarin. Warfarin is distributed to the liver, lungs, spleen, and kidneys but does not appear to be distributed into breast milk in significant amounts. It crosses the placenta and is a known teratogen.

Warfarin is stereoselectively metabolized by hepatic cytochrome P-450 (CYP) isoenzymes to inactive hydroxylated metabolites (predominant route) and by reductases to reduced metabolites (warfarin alcohols). Warfarin alcohols have minimal anticoagulant activity. The CYP isoenzymes involved in the metabolism of warfarin include 2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. CYP2C9 is the principle enzyme that metabolizes S-warfarin and modulates the in vivo activity of warfarin. CYP1A2 and CYP3A4 metabolize the R-isomer. Genetic polymorphism of CYP2C9 may play a role in the interpatient variability of response to warfarin and predisposition to drug interactions. Polymorphism of CYP2C9 exists in roughly 25% of Caucasians. Mutations of CYP2C9 may decrease the clearance of S-warfarin and necessitate lower warfarin dosages. Poor CYP2C9 metabolizers are more dependent on the metabolism of S-warfarin via the CYP3A4 pathway.[2688] Drugs that affect any of these enzymes may alter the anticoagulation response to warfarin. As a result, drugs that preferentially induce the metabolism of S-warfarin impair coagulation to a greater extent than those that induce R-warfarin metabolism. The terminal half-life of warfarin after a single dose is 7 days; however the clinically effective half-life ranges from 20—60 hours (mean 40 hours) depending upon the rate of catabolism of activated clotting factors. The clearance of R-warfarin is generally half that of S-warfarin, and thus, the half-life of R-warfarin is longer than that of S-warfarin. The half-life of R-warfarin ranges from 37—89 hours, while that of S-warfarin ranges from 21—43 hours.

Warfarin metabolism may be altered in the presence of hepatic dysfunction or advanced age but is not affected by renal impairment. Patients with hepatic impairment may have increased half-lives of warfarin; dosage adjustment may be necessary. Inactive metabolites of warfarin are excreted in the urine and to a lesser extent in the bile. Up to 92% of the orally administered warfarin is recovered in the urine, primarily as metabolites. Since renal clearance is considered to be a minor component of warfarin clearance, no dosage adjustment is necessary in patients with renal impairment. In elderly patients, racemic warfarin clearance may be unchanged or reduced with increasing age. Limited information suggests no difference in the clearance of S-warfarin in elderly versus young patients. However, there may be a slight decrease in the clearance of R-warfarin in elderly patients as opposed to younger patients. Therefore, as a patient age increases, a lower dose of warfarin is usually required to produce a therapeutic effect.

Description, Mechanism of Action, Pharmacokinetics last revised 6/30/2006 2:56:00 PM

Indications

† non-FDA-approved indication

Dosage

General dosing guidelines:
NOTE: The response to warfarin is influenced by pharmacokinetic factors (e.g., differences in absorption or metabolism) and pharmacodynamic factors (e.g., differences in hemostatic response to given concentrations of warfarin). Due to individual variations in dose-response during the course of anticoagulant therapy, warfarin dosage must be monitored closely to prevent over- or under-dosing. Dosing should be based on the degree of change from baseline of each patient's individual International Normalized Ratio (INR). An INR > 4.0 appears to provide no additional therapeutic benefit in most patients and is associated with a higher risk of bleeding.
Oral or Intravenous dosage:
Adults: Initially, 5 mg PO or IV once daily, with dosage adjustments made according to INR results. Loading doses do not provide more rapid complete anticoagulation and are not recommended. In a study comparing 5 mg and 10 mg loading doses, the 5 mg dose produces less excess anticoagulation (INR > 3) than the 10 mg dose.[2689] If a rapid anticoagulant effect is required, an initial dose of heparin should be used and overlapped with warfarin for at least 4 days.[2023] The maintenance dosage of warfarin should be based on INR determinations and is usually 2—10 mg PO or IV once daily. The INR should be monitored daily until the therapeutic range has been achieved for at least 2 consecutive days, then 2—3 times a week for 1—2 weeks, then less often depending upon the stability of the INR results. If the INR remains stable, monitoring may be reduced to every 4 weeks. If dosage adjustments are required, then more frequent monitoring is needed until a stable response is obtained.
Elderly and debilitated patients: Lower initial doses (e.g., 2—4 mg) may be appropriate in the elderly and in patients at high risk of bleeding.
Patients with hereditary warfarin resistance: 5 to 20-fold higher doses of warfarin may be required in these patients to achieve a therapeutic effect.
Children and infants: Initially, 0.2 mg/kg PO or IV once daily for 2 days (0.1 mg/kg in patients with liver dysfunction); with a maximum dose of 10 mg/day. Adjust dose until desired INR is achieved. Usual maintenance doses are approximately 0.1 mg/kg PO once daily, with a range of 0.05—0.34 mg/kg PO. NOTE: Consistent anticoagulation may be hard to achieve in children < 5 years.

For the treatment and further prevention of deep venous thrombosis (DVT) or pulmonary embolism after the initial, acute phase has been treated with heparin, LMWH, or thrombolytic therapy:
NOTE: The optimal intensity and duration of anticoagulation following treatment of idiopathic DVT has not been definitively established. In patients with idiopathic deep vein thrombosis (DVT) or pulmonary embolism (PE), treatment with moderate-intensity warfarin therapy (INR 2—3) for 3—6 months following initial therapy with heparin or low-molecular weight heparin is considered conventional therapy to prevent recurrent venous thromboembolism (VT).[1963] Newer trials have evaluated long-term anticoagulation (e.g., > 2 years) to reduce the VT recurrence rates.[4320] [4321] One recent trial (PREVENT) of low-intensity anticoagulation (INR 1.5—2), when given long-term (followed up to 4.5 years) following DVT, has resulted in significantly lower VT recurrence rates compared to placebo.[4320] However, the safety and efficacy of low-intensity, long-term anticoagulation has not been directly compared to the ACCP recommended moderate-intensity, short-term guidelines. Both strategies are provided below. A more recent trial (ELATE) has shown that conventional-intensity warfarin therapy is more effective than low-intensity warfarin therapy for the long-term (average duration 2.4 years) prevention of recurrent VT in patients who previously received >= 3 months of warfarin therapy. In addition, this trial failed to show a reduced risk of clinically important bleeding with a low-intensity warfarin.[4321]
•conventional, moderate-intensity (INR 2—3), short-term anticoagulation (ACCP guidelines):
Oral dosage:
Adults: A target INR of 2.5 (range: 2—3) for warfarin therapy for 3—12 months depending on thromboembolic condition and coexisting risk factors is recommended by the American College of Chest Physicians (ACCP) guidelines for antithrombotic therapy.[1963] [9315] However, longer-term treatment regimens (e.g., > 2 years) have also been evaluated due to the high recurrence rate of DVT during conventional short-term regimens.[2686] [4321] Treatment with heparin or low molecular weight heparin (LMWH) and warfarin may be started together and treatment with heparin (or LMWH) discontinued on day 5 or 6 if the INR has been therapeutic for 2 consecutive days. According to ACCP guidelines, warfarin should be continued for >= 3 months in most patients; specifically, for first time event with a reversible or limited-time risk factor (e.g., surgery, trauma, immobilization, estrogen use), treat for >= 3 months; for first episode of idiopathic DVT, treat for >= 6 months; or for recurrent idiopathic DVT, or a continuing risk factor (e.g., cancer, antithrombin deficiency, or anticardiolipin antibody syndrome), treat for >= 12 months.[1963] For those with symptomatic isolated calf vein thrombosis, ACCP recommends treatment with warfarin for >= 6 to 12 weeks.[1963] Several studies have found that the recurrence rate of DVT is significantly higher with treatment of shorter duration. Recurrence rates are lower at 6 months versus 6 weeks (9.5% vs. 18.1%, respectively)[1084] and 2 years versus 3 months (1.3% vs. 27.4%, respectively).[2686] A recent trial (ELATE) has shown that conventional-intensity warfarin therapy is more effective than low-intensity warfarin therapy for long-term (average duration 2.4 years) prevention of recurrent VT in patients who previously received >= 3 months of warfarin therapy. In addition, this trial failed to show a reduced risk of clinically important bleeding with a low-intensity warfarin.[4321] Patients with activated protein C resistance should probably receive indefinite treatment if they have recurrent disease, are homozygous for the gene, or have multiple thrombophilic conditions.[1963]
•low-intensity† (INR 1.5—1.9), long-term† anticoagulation:
Oral dosage:
Adults: The American College of Chest Physicians (ACCP) guidelines for antithrombotic therapy recommends against the use of low-intensity anticoagulation with warfarin (INR 1.5—1.9).[9315] During an early investigative trial (PREVENT), a target lower-intensity INR range of 1.5—2 has been evaluated long-term vs. placebo in patients previously treated for about 6 months following DVT.[4320] The average duration of warfarin therapy was 2.1 years (maximum 4.3 years). This study was stopped early due to statistically reduced rate of VT in the low-intensity anticoagulation group. However, the safety and efficacy of low-intensity, long-term anticoagulation has not been directly compared to the ACCP recommended moderate-intensity, short-term guidelines (see above indication). A more recent trial (ELATE) has shown that conventional-intensity (INR 2—3) warfarin therapy is more effective than low-intensity (INR 1.5—1.9) warfarin therapy for the long-term prevention of recurrent VT in patients previously treated with >= 3 months of warfarin therapy. In addition, the ELATE trial did not show a reduced risk of clinically important bleeding that was expected with the low-intensity warfarin regimen.[4321]

For deep venous thrombosis (DVT) prophylaxis:
•for deep venous thrombosis (DVT) prophylaxis in patients undergoing total hip replacement surgery, knee replacement surgery, or hip fracture surgery:
Oral or intravenous dosage:
Adults: A target INR of 2—3 is recommended by the American College of Chest Physicians (ACCP). Randomized studies have shown that warfarin 1 mg PO once daily is ineffective in preventing post-operative venous thrombosis in patients having major orthopedic surgery. Warfarin should be started preoperatively or immediately after the operation. In patients undergoing total hip replacement surgery, adjuvant prophylaxis with elastic stockings or intermittent pneumatic compression may provide additional efficacy. The optimal duration of therapy is unknown; however, at least 7—10 days of postoperative therapy has been recommended in patients undergoing total hip replacement or total knee replacement surgery.[1960]
•for deep venous thrombosis (DVT) prophylaxis in patients with long-term indwelling central venous catheters to prevent axillary-subclavian venous thrombosis†:
Oral dosage:
Adults: 1 mg (INR 1.3—1.9) PO once daily has been demonstrated to decrease the incidence of catheter-related thrombosis.[1695] In patients with breast cancer, warfarin 1 mg PO once daily has demonstrated efficacy for thromboembolism prevention during chemotherapy (relative-risk reduction 85%).[3317]

For thrombosis prophylaxis (i.e., arterial thromboembolism prophylaxis, stroke prophylaxis or coronary artery thrombosis prophylaxis):
NOTE: For information regarding prophylaxis in orthopedic surgery or with central venous catheters, see 'deep venous thrombosis (DVT) prophylaxis'.
•for thrombosis prophylaxis in patients with atrial fibrillation:
Oral or intravenous dosage:
Adults: A target INR of 2.5 (range: 2—3) is recommended.[9219] A case-control study found that INR levels > 2 added little efficacy, while the risk of stroke increased at INR levels < 2. The odds of stroke increased even more dramatically if the INR was < 1.5.[2176] Long-term warfarin therapy should be considered for all patients with atrial fibrillation with a high risk factor (e.g., previous TIA, stroke or systemic embolism; those with poor left ventricular function; rheumatic mitral valve disease; prosthetic heart valve; age >= 75 years; or those with hypertension. A target INR of 3 (range: 2.5—3.5) is recommended for atrial fibrillation patients with tilting disk valves or bileaflet mechanical valves in the mitral or aortic position. Patients with one moderate risk factor (e.g., age 65—75 years, diabetes mellitus, or coronary artery disease with preserved LV function) should be treated with warfarin or aspirin therapy long-term. Patients with no high-risk or moderate-risk factors and no clinical or echocardiographic evidence of cardiovascular disease should be treated with aspirin.[1275]
•for thrombosis prophylaxis in patients with atrial fibrillation or atrial flutter who are undergoing cardioversion:
Oral dosage:
Adults: Warfarin with a target INR of 2.5 (range 2—3) 3 weeks before and >= 4 weeks after the procedure. Warfarin should be continued until normal sinus rhythm has been maintained for >= 4 weeks. Patients who have had AF for < 48 hours should be offered anticoagulation during the peri cardioversion period.[1275]
•for thrombosis prophylaxis in patients with prosthetic heart valves:
Oral or intravenous dosage:
Adults with bioprosthetic heart valves: A target INR of 2.5 (range: 2—3) is recommended.[9244] Patients with bioprosthetic valves in the mitral position or aortic position may be treated with warfarin for the first 3 months after valve insertion, although the evidence for patients with aortic valves is less compelling.[1965] [9244] For this subgroup, favorable results have also been reported with low dose aspirin 100 mg/day PO for the first 3 months following aortic valve insertion.[9244] Patients who also have atrial fibrillation should be treated long-term (target INR 2—3).[9244] In patients with bioprosthetic valves who have evidence of left atrial thrombus at surgery, long-term treatment with warfarin, targeting an INR of 2.5 (range; 2—3) has been recommended.[1965] [9244] Patients with bioprosthetic valves who have a history of systemic embolism should be treated with oral anticoagulants for 3—12 months at a goal INR of 2.5 (range: 2—3).[1965] [9244]
Adults with mechanical prosthetic heart valves: A target INR of 2.5 (range: 2—3) is recommended for patients with a bileaflet mechanical valve in the aortic position, provided the left atrium is of normal size, the patient is in sinus rhythm, and the ejection fraction is normal. A goal INR of 3 (range: 2.5—3.5) is recommended for patients with tilting disk valves and bileaflet mechanical valves in the mitral position; or in patients with bileaflet mechanical aortic valves who have atrial fibrillation (AF). An alternative recommendation for patients with tilting disk valves, bileaflet mechanical valves in the mitral position, or bileaflet mechanical valves in the aortic position plus AF is a target INR of 2.5 (range: 2—3) in combination with aspirin (80—100 mg/day). A goal INR of 3 (range: 2.5—3.5) in combination with aspirin is recommended for patients with caged ball or caged disk valves. In patients who have mechanical valves and additional risk factors or who suffer systemic embolism despite adequate therapy with oral anticoagulants, aspirin (80—100 mg/day) in addition to warfarin (target INR 3; range: 2.5—3.5) is recommended.[1965]
Pregnant females: As an alternative to heparin or LMWH throughout the pregnancy, after the 13th week of pregnancy change to appropriate warfarin dosage (see adult dose) until the middle of the third trimester, then switch back to heparin or LMWH until delivery. Long-term anticoagulation should be resumed postpartum.[2038]
Adults and children with mechanical prosthetic heart valves and infective endocarditis: Continue long-term warfarin therapy unless a specific contraindication exists. The risk of intracranial hemorrhage is substantial; when making therapeutic decision, consider the presence of comorbid risk factors and the success of antibiotic therapy.[2039]
Children with mechanical prosthetic heart valves: Based on adult data, the recommended target INR is 3 (range 2.5—3.5). If systemic embolism occurs despite adequate anticoagulation, add aspirin (6—20 mg/day) or dipyridamole (2—5 mg/kg/day). When full-dose anticoagulation therapy is contraindicated, long-term therapy with warfarin to a target INR of 2.5 (range 2—3) in combination with aspirin (6—20 mg/day) and dipyridamole (2—5 mg/kg/day) may be used.
•for thrombosis prophylaxis in patients with mechanical prosthetic heart valves and a history of bleeding while receiving warfarin therapy:
Oral dosage:
Adults: Every effort should be made to maintain the INR at the lower limit of the therapeutic range (See standard dosage guidelines for prosthetic heart valve patients). For patients with a mechanical prosthetic heart valve and a persistent risk of increased bleeding, the anticoagulant intensity can be reduced to an INR of 2—2.5.
•for stroke prophylaxis in patients with cerebral venous sinus thrombosis (CVST) after primary treatment with heparin or LMWH:
Oral dosage:
Adults: A target INR of 2.5 (range 2—3) for 3—6 months has been recommended.[2040] [7011]
•for thrombosis prophylaxis in patients with valvular heart disease:
Oral dosage:
Adults with rheumatic mitral valve disease: A target INR of 2.5 (range 2—3) is recommended in patients with a history of systemic embolism or presence of paroxysmal or chronic atrial fibrillation.[9244] For patients in normal sinus rhythm and left atrial diameter > 5.5 cm, consider long-term warfarin (target INR 2.5, range 2—3) based on risk factors for thromboembolism. For patients with recurrent systemic embolism despite adequate warfarin therapy, increase INR goal to 3 (range 2.5—3.5), or add aspirin (80—100 mg/day): for patients unable to take aspirin add dipyridamole (400 mg/day), ticlopidine (250 mg PO twice daily), or clopidogrel (75 mg/day PO).[2039]
Adults with mitral valve prolapse and documented systemic embolism, recurrent TIA, chronic or paroxysmal atrial fibrillation despite aspirin: Long-term warfarin therapy (INR target 2.5, range 2—3) is recommended.[2039]
Adults with mitral annular calcification and systemic embolism not calcified or atrial fibrillation: Long-term warfarin therapy (INR target 2.5, range 2—3) is recommended.[2039]
Adults with non-rheumatic mitral regurgitation and atrial fibrillation or history of systemic embolism: Long-term warfarin therapy (INR target 2.5, range 2—3) is recommended.[2039]
Adults with aortic valve and aortic arch disorders: Only in patients with mobile aortic atheroma and aortic plaque > 4 mm (by TEE) is long-term warfarin therapy (INR target 2.5, range 2—3) recommended.[2039]
Adults with patent foramen ovale (PFO)or atrial septal aneurysm with unexplained systemic embolism or TIA or documented DVT or PE: Long term warfarin therapy (INR target 2.5, range 2—3) is recommended unless venous interruption or PFO closure is considered preferable therapy. In selecting therapy, consider the possibility of paradoxic embolism and systemic embolism from the arterial side of the aneurysm.[2039]
•for stroke prophylaxis in patients with dilated cardiomyopathy (DCM), particularly in the subgroup of patients with concomitant atrial fibrillation or with a prior history of systemic embolization:
Oral dosage:
Adults: The use of anticoagulation in patients with dilated cardiomyopathy (DCM) is controversial. In patients with concomitant atrial fibrillation or with a prior history of systemic embolization, a target INR of 2—3 has been recommended. Not recommended for patients with DCM and no coexisting risk factors.[942]
•for secondary myocardial infarction prophylaxis (i.e., prevention of a subsequent myocardial infarction or coronary artery thrombosis prophylaxis) or for stroke prophylaxis in high-risk postmyocardial infarction patients (e.g., patients with acute MI complicated by severe LV dysfunction, CHF, atrial fibrillation, previous emboli, or 2D echocardiograph evidence of mural thrombosis):
Oral dosage:
Adults: The use of warfarin following myocardial infarction is controversial. After myocardial infarction (MI), warfarin may be used to reduce the risk of systemic or pulmonary embolism in high-risk patients such as those with anterior Q-wave infarction, AF, severe LV dysfunction, or congestive heart failure.[1961] The optimal antithrombotic regimen for long-term management in patients post-MI has not been established. A recent guide to warfarin therapy provides three potential strategies for antithrombotic therapy following MI: 1) aspirin alone, 2) aspirin plus moderate-intensity (INR 2—3) warfarin, or 3) high-intensity (INR 3—4) warfarin alone.[4371] The ASPECT-2 study has reported reduced cardiovascular events and deaths with high-intensity (INR 3—4) warfarin or moderate-intensity (INR 2—2.5) warfarin plus aspirin 80 mg/day compared to aspirin alone (80 mg/day).[4376] In a similar trial, WARIS II has compared warfarin (INR 2.8—4.2), aspirin 75 mg/day, or aspirin 75 mg/day plus warfarin (INR 2—2.5), initiated at discharge post-MI.[4377] Consistent with the ASPECT-2 trial, the WARIS II warfarin regimens are more effective in reducing composite events (death, MI, stroke) vs. aspirin alone, but have a higher rate of bleeding and require greater monitoring. Further study is needed to evaluate other strategies such as aspirin plus low-intensity warfarin (INR < 2) or monotherapy with moderate intensity warfarin (INR 2—3). Previously, in the ASPECT-1 study comparing oral anticoagulation to placebo, patients given anticoagulants were less likely to suffer a recurrent MI; however, since the benefits were not better than studies of aspirin and since the risk of bleeding complications is greater with oral anticoagulants, many clinicians traditionally prescribed aspirin in this setting.[232] [711] According to previous guidelines in 2001 by the American College of Chest Physicians (ACCP), aspirin has been recommended over warfarin for long-term therapy in patients with a low risk of embolism. Warfarin therapy (target INR of 2.5 (range: 2—3) for <= 3 months) has been recommended in the clinical setting of increased embolic risk or if aspirin or when other anti-platelet therapy is contraindicated.[1961] Warfarin should be continued indefinitely in patients with atrial fibrillation. Some patients with recurrent ischemic episodes following acute MI may benefit from a combination of warfarin and aspirin. Treatment with low-dose aspirin and low-intensity warfarin (target INR of 1.5) has been suggested.[1961]
•for coronary artery thrombosis prophylaxis in high or very high-risk patients with stable angina† or chronic coronary artery disease†:
Oral dosage:
Adult males at high-risk for cardiovascular events: Low-intensity warfarin (target INR 1.5) has been recommended in men at high risk of cardiovascular events in the prevention of those events and for reduction of overall mortality.[1961]
Adult males at very high-risk for cardiovascular events: The combination of low-dose aspirin (75—80 mg/day) and low-intensity warfarin (target INR 1.5) may be considered over either agent alone for the prevention of cardiovascular events and reduction in mortality for men at very high-risk for such events.
•for the coronary artery thrombosis prophylaxis in patients with unstable angina†:
Oral dosage:
Adults: Patients who have contraindications to aspirin, ticlopidine, and clopidogrel should receive heparin, followed by warfarin (INR 2—3) for a period of several months.[1961] Aspirin in combination with therapeutic anticoagulation (heparin for the first 3—4 days after the onset of acute unstable angina followed by warfarin for up to 12 weeks) was found to be superior to aspirin alone in 214 patients with unstable angina.[656] In this study, therapy was initiated within a mean of 9.5 hours of qualifying pain and warfarin was dosed to achieve an INR of 2—3.

For the prophylaxis of arterial and/or venous thromboembolism in patients with the antiphospholipid antibody syndrome:
Oral dosage:
Adults: A target INR >= 2 to 3 has been recommended for some patients.[2023] Some authors suggest that an INR of >= 3 is more effective in preventing thromboembolism, than no treatment.[1016]

For the treatment of cardioembolic ischemic stroke†:
Oral or Intravenous dosage:
Adults: A target INR of 2—3 has been recommended following heparin therapy in non-hypertensive patients with small to moderate-sized embolic strokes in whom a CT scan done 48 hours or more after stroke onset documents the absence of spontaneous hemorrhagic transformation.[1695] Warfarin therapy should be postponed 5—14 days in patients with large embolic strokes or uncontrolled hypertension because of the increased chance of hemorrhagic transformation.[1695]

Therapeutic Drug Monitoring:
The response to warfarin is influenced by pharmacokinetic factors (e.g., differences in absorption or metabolism) and pharmacodynamic factors (e.g., differences in hemostatic response to given concentrations of warfarin). Warfarin dosing should be based on the degree of change from baseline of each patient's individual International Normalized Ratio (INR). The target INR goals are specific to each indication based on the most recent American College of Chest Physicians (ACCP) antithrombotic guidelines.[7012]

Maximum Dosage Limits:
Warfarin has a narrow therapeutic index. The maximum dosage is individualized based on INR monitoring and assessment of efficacy and safety parameters (see specific indications for target INR goals).

Patients with hepatic impairment:
Although specific guidelines for dosage adjustment are not available, patients with hepatic impairment may require a lower dosage of warfarin due to decreased warfarin metabolism and decreased production of coagulation factors.

Patients with renal impairment:
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

†non-FDA-approved indication

Indications...Dosage last revised 7/27/2006 1:39:00 PM

Administration Guidelines

Oral Administration
•Administration with food decreases the rate but not the extent of absorption.
•The bioavailability of warfarin tablets may vary slightly from manufacturer to manufacturer. Patients should not be switched to another brand of warfarin once stabilized without close monitoring of the INR during the transition.

Intravenous Administration
•Equivalent intravenous and oral doses of warfarin produce similar plasma concentrations.
•The administration of intravenous warfarin does not provide any increased biological effect or earlier onset of action compared to oral dosing, therefore IV therapy is usually reserved for those patients who cannot absorb warfarin via the oral route.

Reconstitution:
•Reconstitute 5 mg vial with 2.7 ml of sterile water for injection to yield a final concentration of warfarin 2 mg/ml.
•Following reconstitution, the solution is stable for 4 hours at room temperature. However, the solution does not contain a preservative; any unused portion should be discarded.

Intravenous injection:
•Inject slowly over 1—2 minutes into a peripheral vein.
•Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

Administration last revised 2/19/2004 10:24:00 AM

Contraindications/Precautions

• Absolute contraindications are in italics.

Warfarin is contraindicated during pregnancy and is classified as FDA pregnancy risk category X. It crosses the placenta and has been shown to cause abnormalities in the fetus, especially when taken during the first trimester after the 6th week of gestation, and may cause fatal hemorrhage in the fetus in utero. The teratogenic effects are known as the Fetal Warfarin Syndrome (FWS) and include chondrodysplasia punctata and CNS abnormalities. Women who become pregnant while taking the drug should be advised of the potential hazards (see Adverse Reactions) and the possibility of termination of the pregnancy in light of the risks to the fetus. Warfarin should be replaced by heparin, especially during the first trimester. In some cases, however, a decision to continue warfarin therapy during pregnancy could be justified (e.g., a patient with a mechanical heart valve, where there is a high risk of embolism and full-dose heparin cannot be used, or where a temporary loss of therapeutic control would be life-threatening). Warfarin should not be used during labor or immediately after obstetric delivery because of the possibility of hemorrhage.

Warfarin should not be used in any condition in which there may be blood loss or in which uncontrolled bleeding could be a hazard. Examples include surgery, especially involving the eye, brain, or spinal cord; peptic ulcer disease, especially if GI bleeding is involved; blood dyscrasias such as hemophilia, polycythemia vera, idiopathic thrombocytopenic purpura (ITP), or leukemia; eclampsia or preeclampsia; diagnostic or therapeutic procedures with potential for uncontrolled bleeding including lumbar puncture, epidural anesthesia, or spinal anesthesia; head trauma; pericarditis; pericardial effusion; infective endocarditis; or thrombocytopenia. Usually, warfarin therapy is stopped 4—5 days prior to surgery. In patients with an intermediate- or high-risk for thromboembolism, give either heparin or low molecular weight heparin (LMWH) as the INR falls. Administration of vitamin K 24—48 hours prior to surgery will shorten the duration of heparin or LMWH prior to surgery; however, it may make it more difficult to reinstitute warfarin anticoagulation. In situations with a low risk of bleeding, another option is to lower the dose of warfarin and operate at an INR of 1.3—1.5. This INR level has shown to be safe in randomized trials of gynecologic and orthopedic surgery patients.[2023] A severe elevation (> 50 seconds) in activated partial thromboplastin time (aPTT) with a PT/INR in the desired range has been identified as a risk factor for postoperative hemorrhage. Warfarin should not be used in patients with active bleeding, especially in those with intracranial bleeding or retinal bleeding. Warfarin also should be used cautiously in the following conditions because bleeding, should it occur, would be extremely serious during warfarin therapy: vasculitis; polyarthritis; moderate to severe hypertension; cerebral or abdominal aneurysm; or indwelling catheters. The risk of major bleeding with warfarin therapy is increased in patients with a history of stroke or GI bleeding, atrial fibrillation, or in the presence of serious comorbid conditions such as renal disease or anemia. An INR > 4 appears to provide no additional therapeutic benefit in most patients and is associated with a higher risk of bleeding. High-intensity oral anticoagulation (INR 3—4.5) is associated with an unacceptable incidence of intracranial hemorrhage when used in patients with cerebral ischemia of presumed arterial origin (e.g., patients with recent TIA or minor ischemic stroke).[4375] Warfarin therapy must be individualized for the patient. Warfarin has a narrow therapeutic range and may be affected by factors such as other drugs, dietary vitamin K (see Drug Interactions), and other disease states. Warfarin dosage should be controlled by periodic monitoring of the INR or other suitable coagulation tests. Determination of whole blood cloning or bleeding times are not effective measures to monitor warfarin therapy.

In patients at high-risk of bleeding, warfarin should be discontinued prior to dental work. However, patients not at high-risk may continue warfarin therapy in most cases. During dental procedures that require local bleeding control, administer a mouthwash acid or aminocaproic acid mouthwash, without interrupting anticoagulant therapy.

Caution should be observed when warfarin is administered to patients at risk for tissue necrosis and/or gangrene (e.g. patients with diabetes mellitus). Anticoagulation therapy with warfarin may enhance the release of atheromatous plaque emboli, increasing the risk of complication from cholesterol microembolization. Discontinuation of warfarin recommended when this occurs.

Warfarin should be used with caution in patients with heparin-induced thrombocytopenia (HIT) and deep venous thrombosis. The prothrombotic effects of HIT combined with the procoagulant effects of early warfarin therapy (reduced protein C activity) can result in complications including warfarin-induced skin necrosis and limb gangrene.[4530] [4531] Cases of venous limb ischemia, necrosis, and gangrene have occurred in these patients when heparin treatment was discontinued and warfarin therapy was started or continued. In some patients, amputation of the involved area and/or death occurred. Patients who develop limb gangrene while receiving warfarin often have a high INR (usually > 4) after starting warfarin therapy. The pathogenesis of warfarin-associated limb gangrene in patients with HIT appears to be insufficient protein C activity (has natural anticoagulant properties) to control the increased thrombin generation seen in these patients. Warfarin can be given safely if thrombin generation is adequately controlled with the use of danaparoid, hirudin, or argatroban, or if warfarin is initiated following resolution of the HIT. Warfarin should not be given alone or in combination with ancrod in patients with acute HIT.[1966]

Patients with congestive heart failure may exhibit greater than expected responses to warfarin. These patients require more frequent monitoring and, possibly, reduced doses of warfarin.

Hepatic disease, including infectious hepatitis and cholestasis with symptoms of jaundice, potentiates the response to warfarin therapy by impairing the synthesis of coagulation factors or altering the metabolism of warfarin. Because chronic alcohol consumption may result in alcoholic liver disease (including cirrhosis), patients who chronically ingest large amounts of ethanol may have an enhanced response to warfarin therapy. In these patients, small doses of warfarin may cause a pronounced hypoprothrombinemic effect; thus, caution is required.

Intramuscular injections of other drugs should be avoided if possible in patients receiving warfarin. IM injections may cause bleeding, bruising, or hematomas due to the anticoagulant effect of warfarin therapy. If required and appropriate for the administered drug, IM injections should be given to the upper extremities, which permits easy access for manual compression, inspection for bleeding, and use of pressure bandages.

Patients with protein C deficiency or protein S deficiency can become transiently hypercoagulable when warfarin is initiated and may result in necrosis of the skin and underlying tissue. The risk associated with these conditions, both for recurrent thrombosis and for adverse reactions, is difficult to evaluate since it does not appear to be consistent for all patients. The initial symptom may be an intense burning in the affected area. Warfarin therapy should be immediately stopped because skin necrosis can be permanently disfiguring. If warfarin therapy is indicated in patients with protein C deficiency, anticoagulation should begin with heparin for 5—7 days to decrease the risk of tissue necrosis.

Vitamin C deficiency causes increased capillary fragility. Administration of warfarin can increase the risk of localized bleeding in patients with vitamin C deficiency.

Vitamin K deficiency enhances the response to warfarin and may lead to an increased risk of bleeding. The effects of warfarin can be potentiated in patients with poor nutritional status and decreased vitamin K intake (especially if they are treated with antibiotics and IV fluids without vitamin K supplementation) or in states of fat malabsorption. In addition, patients with eating disorders such as anorexia nervosa or bulimia nervosa may have poor or fluctuating vitamin K intake.

Because safe use of warfarin in the outpatient setting depends on good patient compliance, therapy should be carefully evaluated for patients with senility, alcoholism, or psychosis.

Warfarin is considered compatible with breast-feeding by the American Academy of Pediatrics. Warfarin is not excreted into breast milk, and several clinical studies have not noted the induction of an anticoagulant effect in the breast-fed infant when warfarin is administered to the nursing mother. The use of warfarin in the post-partum mother who requires anticoagulation is not contraindicated, and these women should be encouraged to breast-feed their infants.

Hypermetabolic states produced by fever or hyperthyroidism can increase the responsiveness to warfarin, probably by increasing the catabolism of vitamin K-dependent coagulation factors. Infection or disturbances of intestinal flora due to sprue or antibiotic therapy may alter responses to warfarin. Thus, warfarin therapy should be monitored closely in these situations.

Numerous factors alone or in combination, including travel or changes in diet, environment, physical state, and medication may influence the response to warfarin. It is considered good practice to monitor the patient's response with additional PT/INR determinations in the period immediately after discharge from the hospital and whenever other medications are initiated, discontinued, or taken irregularly. The following conditions, alone or in combination, may be responsible for increased INR responses to warfarin: collagen vascular disease, diarrhea or steatorrhea, and neoplastic disease. Peripheral edema, hereditary coumarin resistance, hyperlipidemia, hypothyroidism and nephrotic syndrome, alone or in combination, have been associated with decreased responses to warfarin.

Tobacco smoke contains hydrocarbons that induce hepatic CYP450 microsomal enzymes. Because the effect on hepatic microsomal enzymes is not related to the nicotine component of tobacco, sudden tobacco smoking cessation may reduce the clearance and increase the therapeutic effects of warfarin despite the initiation of a nicotine replacement product. However, the decreased warfarin clearance may not always result in a clinically significant change in the PT or INR. Monitor to assess the need for warfarin dosage adjustment when changes in smoking status occur.

Elderly patients are more susceptible to the effects of anticoagulants, possibly due to a decrease in the clearance of warfarin with age. Limited data suggests no difference in S-warfarin clearance and slightly decreased clearance of R-warfarin with increasing age. Therefore, lower doses of warfarin are usually required to produce a therapeutic level of anticoagulation. In addition, in a retrospective cohort of Medicare beneficiaries (mean age 79.4 years) receiving warfarin for atrial fibrillation, the use of long-term warfarin (>= 365 days) was associated with an increased risk of osteoporotic fracture (OR 1.25, 95% CI 1.06—1.48), especially vertebral fracture. However, when analyzed separately by gender, the increased risk of fracture was significant in men (odds ratio 1.63, 95% CI 1.26—2.10), but not women (OR 1.05, 95% CI 0.88—1.26). Furthermore, the risk of fracture was not increased in patients taking warfarin for < 1 year. Other independent predictors of fracture in this cohort of patients (regardless of length of warfarin therapy) were increasing age, high risk of falls, hyperthyroidism, neuropsychiatric disease, and alcoholism. Factors that were associated with a protective risk of fracture include African-American race, male gender, and the use of b-adrenergic antagonists. Because the available alternative therapies (e.g., heparin, low molecular weight heparin) have also been associated with an increased risk of fracture, the authors of this study recommend that when prescribing warfarin to patients at risk of falling, patients should be encouraged to wear stable shoes, consume adequate amounts of calcium and vitamin D, exercise regularly, and use walking aids when necessary. In addition, unnecessary drugs should be discontinued.[8971]

Contraindications last revised 5/3/2006 9:59:00 AM

Drug Interactions

Green tea has demonstrated antiplatelet and fibrinolytic actions in animals.[6434] [6440] It is possible that the use of green tea may increase the risk of bleeding if coadministered with warfarin. Caution and careful monitoring of clinical and/or laboratory parameters are warranted if green tea is coadministered with warfarin. In addition, because exogenous administration or occult sources of vitamin K may decrease or reverse the activity of warfarin, stability of the diet including consumption of green tea can be an important factor in maintaining anticoagulation goals.[367] In general, the amount of green tea in a single cup of brewed tea is 0.03 mcg/100g;[6529] however, the amount varies depending on the amount of tea leaves used, the length of time the tea bags are allowed to brew, and the volume of tea consumed. Additionally, if a patient drinks multiple cups of tea per day, the amount of vitamin K could reach significance. Published data are limited in regard to this interaction. A patient with previous INRs of 3.2. and 3.79 on a dose of 7.5mg daily of warfarin (goal INR 2.5—3.5) had an INR of 1.37. One month later, the patient's INR was 1.14. The patient admitted that he had started consuming 0.5—1 gallon of green tea daily approximately one week prior to the INR of 1.37. The patient denied noncompliance and other changes in diet, medications, or health. The patient discontinued green tea and one week later his INR was 2.55.[6581] Patients should be advised to maintain a stable intake of green tea.

Phytonadione, vitamin K1, is a pharmacologic antagonist of warfarin; it is often administered to reverse elevated INR from warfarin overdose.[5907] Exogenous administration or occult sources of vitamin K may decrease or reverse the activity of warfarin. Response to warfarin usually returns after stopping the vitamin K-containing product. Occult sources of vitamin K include enteral feedings [367] [5497], certain multivitamins, and many food products [367]. Foods that contain large amounts of vitamin K include green tea, brussel sprouts, and kale. Other foods that contain moderate-high quantities of vitamin K include asparagus, avocado, broccoli, cabbage, cauliflower, collard greens, lettuce, liver, soy products (including soy milk, soybeans or soybean oil), lentils, peas, mustard greens, turnip greens, parsley, green scallions, and spinach. Medical products that contain soybean oil such as intravenous lipid emulsions or propofol, may decrease warfarin anticoagulation.[2648] Intravenous lipids may interfere with warfarin anticoagulation in many ways including enhancing the production of clotting factors, facilitating platelet aggregation, supplying vitamin K, and enhancing warfarin binding to albumin. In general, it is recommended that patients avoid large servings or frequent intake of foods that contain substantial amounts of vitamin K. Case reports have been received by the British MHRA Committee on Safety of Medicines (CSM) that have suggested the effect of warfarin is enhanced by the ingestion of cranberry juice (cranberry, Vaccinium macrocarpon Ait.); the proposed mechanism is the inhibition of warfarin metabolism via CYP2C9 by the cranberry juice; the details of the case reports of these interactions are limited. No controlled data are available, and it is not clear if warfarin would interact with cranberry supplements (e.g., dried extracts); caution is advised until further data are available; the CSM recommends that patients limit or avoid cranberry juice intake if on warfarin therapy.[4456] There are a lack of controlled data to support an interaction of warfarin with grapefruit juice. In one small open-label study, the ingestion of grapefruit juice (8 oz. three times per day) did not affect the PT or INR values in 10 patients stabilized on warfarin therapy.[3803] However, in a case report, a previously stabilized patient who drank a large amount (i.e., 1.5 L) of grapefruit juice daily for 10 days had an increased INR to 6.29 (baseline 2—3).[3804] Grapefruit juice is known to inhibit cytochrome P450 (CYP) isoenzymes 3A4 and 1A2, which are responsible for the metabolism of R-warfarin to inactive metabolites. However, it appears grapefruit juice only inhibits these cytochromes in the gut wall, thus affecting drugs that undergo significant first-pass metabolism. Warfarin does not undergo significant first pass metabolism, which decreases the likelihood of a significant reaction with grapefruit juice. A case report noted an enhanced effect of warfarin, resulting in an elevated INR and associated bleeding, when a patient increased her ingestion of chamomile tea (chamomile, Matricaria recutita); this is the first noted report of an interaction.[9310] Various chamomile species are known to contain coumarin related compounds that are postulated to have an additive effect with warfarin, but mechanisms have not been precisely determined. The authors recommend that patients limit or avoid chamomile use if on warfarin therapy.[9310] Clearly, dietary influences and dietary supplements may greatly affect the response to warfarin therapy. Educate patients on the potential risks of dietary extremes and the ingestion of nutritional supplements, and the importance of dietary balance. Monitor the patient clinically for adverese events and via appropriate and regular monitoring of the INR.

Tobacco smoke contains polycyclic aromatic hydrocarbons that induce hepatic CYP450 microsomal enzymes (e.g., CYP1A1, CYP1A2, CYP2E1).[5056] R-warfarin is partially metabolized by CYP1A2.[5279] Because the effect on hepatic microsomal enzymes is not related to the nicotine component of tobacco, the sudden cessation of tobacco smoking may result in a reduced clearance of warfarin, despite the initiation of a nicotine replacement product. However, the decreased warfarin clearance may not always result in a clinically significant change in the PT or INR; monitor the patient's INR to assess the need for warfarin dosage adjustment when changes in smoking status occur. No interaction is expected to directly occur from the use of nicotine replacement products with warfarin.

Salicylates may displace warfarin from protein binding sites leading to increased anticoagulation effects.[367] Large doses (>= 3—4 g/day) of salicylates can cause hypoprothrombinemia, an additional risk factor for bleeding.[5170] Non-acetylated salicylates do not appear to affect platelet aggregation in the same manner as aspirin and are associated with a lower risk of bleeding when given currently with warfarin. Topical application of methylsalicylate ointment has been associated with systemic absorption and increased warfarin effects. The platelet inhibitory effects of aspirin probably contribute more to its interaction with warfarin than displacement of warfarin from protein binding sites. Although minor and intermediate (but not major) bleeding episodes increase when aspirin and warfarin are administered concomitantly, the combination warfarin with low-dose aspirin has been shown to reduce mortality in patients with heart-valve replacement.[39] Because platelet inhibitors affect hemostasis, they may potentiate the anticoagulant actions of warfarin without increasing the prothrombin time, resulting in an increased risk of bleeding during concurrent use.[5907] It has been reported that the concomitant use of warfarin and ticlopidine may be associated with cholestatic hepatitis. Also, anagrelide has been shown to inhibit CYP1A2. In theory, coadministration of anagrelide with warfarin, a substrate of CYP1A2, could lead to an increase in the INR and an increase in the risk of bleeding.[6912]

Based on the pharmacology of warfarin [5279], other oral anticoagulants and thrombolytic agents could cause additive risk of bleeding when given concurrently with warfarin. Pre-treatment with oral anticoagulants is reported to be an independent risk factor for intracranial hemorrhage in thrombolytic-treated patients.[5171] Concomitant use of warfarin and streptokinase or urokinase is not recommended and may be hazardous. Heparin, especially in high concentrations, can increase INR values.[5279] While concomitant therapy with heparin and warfarin makes accurate interpretation of the prothrombin time difficult, brief periods of overlapping therapy with heparin and warfarin routinely occur in clinical practice. Prothrombin times stabilized during coadministration of heparin and warfarin will change slightly when heparin is discontinued.

Agents that can decrease the anticoagulation effects of warfarin include chlorthalidone [5279], chlordiazepoxide [5874], ethchlorvynol [5279], haloperidol [5279], meprobamate [5279], spironolactone [5279], and trazodone [5874]. Monitor coagulation parameters and adjust warfarin doses as needed.

Retinoids reported to decrease the anticoagulation effects of warfarin include etretinate [367] [7574] and isotretinoin.[7575] Monitor coagulation parameters and adjust warfarin doses as needed.

Amiodarone and its metabolites inhibit the metabolism of both R- and S-warfarin, but the metabolism of S-warfarin is more strongly inhibited. A doubling of the INR is seen in the majority of patients receiving this drug combination. This effect can occur as early as 4—6 days following the initial administration of the combination but can be delayed for weeks in some cases. The interaction may persist for weeks or months after discontinuing amiodarone, due to its long half-life. A 50% reduction in the dosage of warfarin is recommended when amiodarone therapy is initiated. Intensive clinical observation and frequent determination of INR values should be performed to guide further adjustments in therapy.[367]

Various NSAIDs may exhibit pharmacokinetic and/or pharmacodynamic interactions with warfarin.[367] NSAIDs may be problematic if administered to a patient receiving warfarin due to their effects on platelet aggregation and their potential for causing gastritis. In addition, NSAIDs may affect the protein binding of warfarin, which may be clinically significant in patients receiving large doses of NSAIDs. Phenylbutazone is also known to inhibit the metabolism of warfarin.[367] NSAIDs should be used cautiously in patients receiving warfarin.

Agents that have been associated with an increase in activity of warfarin include chenodiol [5279], diazoxide [5279], disulfiram [367], enflurane, glucagon [5279], halothane [5279], influenza virus vaccine [367], megestrol [7873], methylphenidate [5279], pentoxifylline [5279] [6316], propranolol [367], terbinafine, and troglitazone. See the individual monographs for more specific information.

Azathioprine may inhibit the anticoagulant effect of warfarin.[4710] Several case reports have documented an interaction of azathioprine with warfarin [367]; azathioprine decreases warfarin serum concentrations and the INR and thus increases warfarin dosage requirements.[367] [4712] The mechanism of the interaction is not known. Conversely, if azathioprine is discontinued in a patient stabilized on warfarin, an increased risk of bleeding may occur. It is prudent to monitor the INR and response to warfarin prior to azathioprine initiation, frequently following initiation of azathioprine therapy and again on azathioprine cessation. Adjust warfarin dosage based on INR and clinical response.[4712]

In a limited number of patients, the hypoprothrombinemic response to warfarin was increased following large doses of vitamin A. The use of large doses of vitamin A in patients receiving warfarin should be carefully monitored until further clarification of this interaction can be made.

Vitamin E should be used cautiously in patients receiving warfarin. While the mechanism is unclear, it is believed that concomitant administration of large doses of vitamin E (e.g., > 400 units per day) with warfarin potentiates hypoprothrombinemia due to the vitamin K antagonistic activity of vitamin E.[5875]

In a case report, a male rheumatoid arthritis patient developed gross hematuria and an elevated INR (11) following the addition of leflunomide to a stable warfarin regimen. Following resolution of his hematuria and fall of his INR into the normal range the patient was restarted on maintenance warfarin therapy at lower dose.[4044] Although the manufacturer reports rare cases of increased INR during concurrent warfarin therapy, the British Committee on Safety of Medicines has received over 300 reports of increased INR in patients receiving leflunomide and warfarin.[4044] In vitro studies of protein binding have indicated that warfarin does not displace the M1 metabolite from binding sites. Leflunomide is metabolized to a metabolite A771726 which inhibits CYP2C9, and could potentially inhibit CYP2C9 metabolism of the S-isomer of warfarin. It is prudent to monitor INR baseline prior to leflunomide initiation, and frequently following initiation of leflunomide therapy and subsequent dosage changes. Adjust warfarin dosage based on INR and clinical response. Once a stable INR is documented, INR can be monitored at the intervals otherwise recommended based on the indication for anticoagulation and co-existing conditions.

Many antiretroviral agents may interact with warfarin. Agents that inhibit cytochrome P450 (CYP) isoenzymes 3A4, 1A2, or 2C9 may decrease the metabolism of warfarin leading to increased anticoagulation effects. Interactions may occur when warfarin is given with anti-retroviral protease inhibitors [4718], delavirdine [4718], or efavirenz [5172]. (NOTE: This list is not inclusive of all agents that may inhibit CYP 3A4, 1A2, or 2C9) Ritonavir [5044] and efavirenz may have induction or inhibition affects on warfarin metabolism.[1800] When warfarin (single dose of 5 mg) is administered with ritonavir (400 mg every 12 hours) a 9% increase in warfarin AUC and a 9% decrease in warfarin Cmax is seen. In contrast, nevirapine induces cytochrome P450 3A4 and may decrease the therapeutic response to warfarin.[3209] The high vitamin E content in amprenavir formulations may exacerbate the effects of warfarin.[5074] Patients should be carefully monitored for changes in INR, with the potential need for warfarin dosage adjustments, if warfarin and antiretroviral agents are coadministered.

Concomitant use of propafenone and warfarin results in a significant increase in warfarin plasma levels by 39%, with an increase in prothrombin time of about 25%. Warfarin dosages should be adjusted as needed.[5014]

Omeprazole (CYP2C19 inhibitor) can prolong the elimination of warfarin, particularly R-warfarin which is a CYP2C19 substrate.[6305] Although R-warfarin is less potent than S-warfarin in anticoagulant activity, combined use of omeprazole and warfarin has been associated with reports of increased INR and prothrombin time (PT). In addition, post-marketing reports of the combination of esomeprazole and warfarin have indicated elevations in PT. There have been reports of increased International Normalized Ratio (INR) and prothrombin time in patients receiving other proton pump inhibitors (PPIs) (including esomeprazole [6265], lansoprazole [5142], rabeprazole [5515], and pantoprazole [6226]) and warfarin concomitantly. It is prudent to monitor the INR more closely if these agents are combined with warfarin.[5279]

Concomitant administration of zileuton and warfarin resulted in a 15% decrease in the clearance of R-warfarin but no change in the clearance of the more potent S-isomer. These pharmacokinetic changes were accompanied by a significant prolongation of prothrombin time. Prothrombin times or INRs should be monitored very carefully if zileuton is either added or discontinued during warfarin therapy.[5415]

Agents that inhibit cytochrome P450 (CYP) isoenzymes 3A4, 1A2, or 2C9 may decrease the metabolism of warfarin leading to increased anticoagulation effects. Interactions may occur when warfarin is given with leflunomide [4718], modafinil [4718], omeprazole [367], propafenone [367], propoxyphene [5279], and zafirlukast [4948]. (NOTE: This list is not inclusive of all agents that may inhibit CYP 3A4, 1A2, or 2C9).

Sorafenib is a competative inhibitor of CYP450 isoenzyme 3A4 and therefore may decrease the metabolism of warfarin leading to increased anticoagulant effects.[8637] Addiitonnaly, since both sorafenib and warfarin are highly protein bound (99.5% and 99%, respectively), displacement from plasma proteins may also occur. The manufacturer of sorafenib recommends that patients who require anticoagulation while receiving sorafenib be monitored closely for changes in prothrombin time, INR values, or clinical signs or symptoms of bleeding. Infrequent bleeding events or INR elevations have occurred during coadministration with sorafenib.

Although tolcapone is highly protein bound, in vitro studies have shown that tolcapone at a concentration of 50 mcg/ml did not displace other highly protein-bound drugs from their binding sites at therapeutic concentrations. The in vitro studies included warfarin.[5578] However, clinical information regarding the combination of warfarin and tolcapone in vivo is limited, therefore, the INR should be monitored when tolcapone and warfarin are administered together.

Concurrent administration of highly protein-bound agents may displace warfarin from its binding sites leading to increased anticoagulation. In an in-vitro study valproic acid, divalproex sodium (valproate) increased the unbound fraction of warfarin by 33%. The therapeutic relevance of this interaction is uncertain; however, it would be prudent to monitor coagulation tests more closely when valproate therapy is introduced or stopped.[6620]

The interaction between warfarin and phenytoin is very complex. An immediate interaction may occur as phenytoin can displace warfarin from protein binding sites causing rapid increases in the INR.[367] After prolonged administration, phenytoin may reduce the effectiveness of warfarin by inducing the metabolism of warfarin. Competitive inhibition may also occur since phenytoin and warfarin are both substrates for cytochrome P450 2C9. In addition, phenytoin has been reported to inhibit the production of vitamin K-dependent clotting factors in newborns. Warfarin dosage adjustments (either increases or decreases) may be necessary if phenytoin is added or after phenytoin is discontinued. Warfarin may alter phenytoin serum concentrations as well.[2564] Similar interactions with warfarin would be expected with ethotoin (a hydantoin [4741]) and fosphenytoin (which is metabolized to phenytoin [5265]).

Nilutamide inhibits the activity of hepatic cytochrome P450 isoenzymes and may reduce the metabolism of drugs metabolized by these enzymes. Drugs with a low therapeutic margin (e.g., phenytoin, theophylline, warfarin) could have a delayed elimination and corresponding increases in their serum half-life. The dosage of these drugs or others with similar metabolism may need to be modified if they are administered concomitantly with nilutamide.[7755]

Concurrent administration of highly protein-bound agents such as nifedipine can theoretically displace warfarin from its binding sites, with potential for increased anticoagulation effects. The manufacturer of nifedipine reports rare cases of increased prothrombin time when nifedipine was administered to patients taking warfarin; the relationship to nifedipine is uncertain.[5803]

Bicalutamide has been shown in vitro to displace coumarin anticoagulants such as warfarin from protein-binding sites. Prothrombin times should be closely monitored in patients receiving warfarin and subsequently started on bicalutamide.[7874]

Concurrent administration of highly protein-bound agents may displace warfarin from its binding sites leading to increased anticoagulation. In addition, warfarin may displace other extensively protein-bound agents when added to established regimens. Alterations in protein binding of warfarin and the coadministered drug may occur with concomitant administration of warfarin and clozapine, flutamide [7875], or nicardipine.

Moricizine may increase the hypoprothrombinemic effect of warfarin. Increased INR may occur and the risk of bleeding may be potentiated. The mechanism of this interaction is not known but may involve decreased warfarin clearance.[5908] A review of warfarin drug interactions, however, concluded that no clinically significant drug interaction existed between warfarin and moricizine.[367] In a single dose warfarin study in 12 healthy volunteers, chronic moricizine administration had no effect on warfarin oral clearance, volume of distribution, peak concentrations, or protein binding.[7062] In addition, no significant effect on the prothrombin time profile was observed during this study.

Cholestyramine can decrease warfarin absorption.[367] Staggering the doses of cholestyramine and warfarin is recommended but this may not completely avoid a drug interaction. Cholestyramine has also been shown to enhance the clearance of IV warfarin. Thus, it is theoretically possible that cholestyramine may interfere with the actions of warfarin after warfarin has been absorbed. Colestipol may be an acceptable alternative to cholestyramine in patients receiving warfarin, although, both cholestyramine and colestipol can decrease vitamin K absorption from the gut, which may indirectly affect the clinical response to warfarin.[5876] Colesevelam may also decrease vitamin K absorption from the gut and interfere with the clinical effects of warfarin.[7576]

Sucralfate has been reported to interfere with warfarin absorption.[367] While isolated reports have shown that sucralfate can inhibit warfarin oral absorption, other studies have shown no clinical effect.

Pharmacokinetic studies of concomitant sevelamer and warfarin have not demonstrated an interaction.[5909] However, sevelamer may interfere with the absorption of many drugs including warfarin. Per the manufacturer of sevelamer, administering warfarin at least 1 hour before or 3 hours after sevelamer doses can minimize the potential for a drug interaction.[4827]

Closely monitor patients receiving azole antifungals concomitantly with warfarin.[367] In post-marketing experience, bleeding events have been reported in association with increases in prothrombin time in patients receiving azole antifungals concurrently with warfarin.[5405] At low doses, fluconazole minimally decreases warfarin metabolism, although when fluconazole is administered at higher doses, a significant prolongation of the INR may be seen.[199] Increased INR values have been reported with the concurrent use of warfarin and fluconazole or itraconazole.[4700] [7742] Ketoconazole may have similar effects and should also be used cautiously in patients receiving warfarin.[4699] Due to CYP2C9, CYP2C19 or CYP3A4 inhibition, voriconazole may lead to enhanced effects of coumarin anticoagulants. When single 30 mg doses of warfarin were combined with voriconazole, the protime was doubled.[4882] Miconazole may inhibit the clearance of the S-isomer of warfarin,[5916] and several reports describe potentiation of the anticoagulant effects of warfarin by miconazole oral, topical, and vaginal products.

Using cimetidine and warfarin together has lead to an increase in INR and moderate to severe bleeding in some patients. It is recommended to avoid this combination if possible and use alternative agents.[367] Ranitidine appears to have less of an effect on hepatic metabolism of warfarin, but it has been associated with both increased and decreased responses to warfarin. Famotidine and nizatidine are not expected to interact with warfarin.

Allopurinol may interfere with the metabolism of warfarin.[7607] [7608] [7609] [7610] Allopurinol has affected the hypoprothrombinemic response to dicumarol, which resulted in bleeding episodes in some patients.[4770] [7606] [7609] The INR should be monitored carefully in patients receiving oral anticoagulants when allopurinol therapy is added.

Quinine and quinidine may potentiate the anticoagulation effects of warfarin; bleeding has been reported.[367] This interaction is probably due to additive hypoprothrombinemia associated with concomitant administration of warfarin and quinine or quinidine. Close monitoring of the INR is required when either of these agents is added to warfarin therapy.

Mefloquine has been reported to increase the effects of warfarin in patients stabilized on warfarin therapy. Two case reports indicate that after starting mefloquine therapy for malaria prophylaxis in 2 elderly men there were episodes of significant bleeding and prolongation of prothrombin times.[9127] For patients who are stabilized on warfarin therapy and require mefloquine malaria prophylaxis, it is recommended that steady state mefloquine concentrations be achieved prior to leaving for malarial areas. This allows for prothrombin time monitoring and warfarin dosage adjustments.

The INR values of patients stabilized on warfarin has been reported to increase following the addition of amitriptyline. Similarly, increased dicumarol plasma concentrations have been observed to increase when amitriptyline or nortriptyline were added. The mechanism is not understood, but it may be due to anticholinergic effects decreasing gastrointestinal motility, leading to increased bioavailability of the oral anticoagulant.

Although data are limited, SSRIs may exhibit pharmacodynamic interactions with warfarin.[5279] Fluoxetine, fluvoxamine, paroxetine, and sertraline may potentiate the hypoprothrombinemic effects of warfarin.[5279] Fluvoxamine inhibits several CYP isoenzymes, including CYP2C9, and appears to have the greatest potential to decrease warfarin metabolism in vivo. According to a manufacturer-based study, fluvoxamine co-therapy increased warfarin serum concentrations by 98%, resulting in a prolonged INR, which could increase the risk of bleeding and bruising.[5635] Other SSRIs generally do not affect the enzymes associated with the metabolism of the potent S-isomer of warfarin (CYP2C9 substrate); however, the other SSRIs may affect the metabolism of R-warfarin, (substrate for CYP3A4, CYP2C19, and CYP1A2 isozymes). Citalopram and escitalopram appear the least likely to interact by inhibiting CYP isozymes, but still may have some propensity to interact with warfarin.[4996] The coadministration of citalopram with warfarin did not significantly affect the pharmacokinetics of either citalopram or warfarin.[4996] The combination of warfarin and citalopram did result in a small increase in prothrombin time that was felt to be clinically unimportant.[1861] Any SSRI treatment may result in impaired platelet aggregation, which may result from platelet serotonin depletion and may contribute to abnormal bleeding. It would be prudent for clinicians to monitor the INR and patient's clinical status closely if a SSRI is added to or deleted from the regimen of a patient stabilized on warfarin.

Although data are limited, venlafaxine may exhibit pharmacodynamic interactions with warfarin. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy.[5002] The potential severity of warfarin toxicity mandates that clinicians monitor the INR and patient's clinical status closely if venlafaxine is added to or deleted from the regimen of a patient stabilized on warfarin.

Griseofulvin can decrease the hypoprothrombinemic response to warfarin via increased hepatic metabolism of warfarin.[367] The interaction between warfarin and griseofulvin may require up to 12 weeks to fully manifest. This interaction may be more significant with the ultramicrocrystalline formulation of griseofulvin. Clinicians should reassess the INR several weeks after griseofulvin is added to or discontinued from warfarin therapy.

Rifampin increases the metabolism of both R- and S-warfarin.[367] Although the effects of rifampin on S-warfarin are less than on R-warfarin, the clinical impact on the INR is significant. A 2- to 3-fold increase in the daily dose of warfarin may be needed within a week of starting rifampin to maintain appropriate anticoagulation. Once rifampin is discontinued, the dose of warfarin will need to be decreased by at least 50% over the next few weeks. Rifapentine or rifabutin may have similar effects on warfarin anticoagulation.[2564] St. John's wort, Hypericum perforatum, is also an inducer of warfarin metabolism.[2717]

As a class, barbiturates may induce the metabolism of warfarin by cytochrome P450 3A enzymes, although the extent of enzyme induction may differ among agents.[367] Phenobarbital is a hepatic enzyme inducer and the clinical effects of warfarin can be compromised if this drug combination is added.[367] Dosage adjustments of warfarin may be necessary within 2 weeks of beginning barbiturate treatment, but the effect of the barbiturate on warfarin metabolism may persist for more than a month after discontinuing the barbiturate. Importantly, discontinuation of a barbiturate during warfarin therapy can lead to fatal bleeding episodes when the hepatic enzyme-inducing properties of the barbiturate subside. Clinicians should note that warfarin doses would require readjustment if a barbiturate is added or discontinued during warfarin therapy.[5326]

Carbamazepine may induce the metabolism of warfarin requiring the dosage of warfarin to be increased, even doubled, over several weeks after initiating carbamazepine therapy. If carbamazepine is discontinued dosage reductions of warfarin may be necessary. Patients should be monitored closely.[367]

A dose-dependent interaction between warfarin and aminoglutethimide may occur. Warfarin clearance may increase 3- to 5-fold within 2 weeks of initiating or increasing aminoglutethimide therapy. The mechanism of this interaction appears to be due to hepatic enzyme induction. Warfarin clearance will return to normal within 2—3 weeks of discontinuing aminoglutethimide therapy.[2564]

Chloral hydrate may enhance the anticoagulation effects of warfarin.[367] Trichloroacetic acid, a metabolite of chloral hydrate displaces warfarin from its binding sites. The effect on warfarin anticoagulation is usually small and transient.

According to the manufacturer, the use of warfarin in patients with blood dyscrasias is contraindicated. Therefore, to minimize the bleeding risk, warfarin should be used cautiously in patients receiving antineoplastic agents that cause myelosuppression or blood dyscrasias.[5279] In addition, effects of antineoplastic agents on protein synthesis as well as protein binding may lead to transient changes in a patient's INR while receiving warfarin. The INR may increase and/or decrease throughout the chemotherapy cycle leading to supra- or sub-therapeutic values; monitor warfarin therapy closely. Capecitabine, gefitinib [5012], etoposide [5992] [5993], 5-fluorouracil [6470], gemcitabine [2679], ifosfamide[6077], mitotane [4790], oxaliplatin [7085], and trastuzumab [4785] have been associated with increases in INR when given concurrently with warfarin. Mercaptopurine has been associated with decreased responses to warfarin. Cyclophosphamide has been associated with both increases and decreases in warfarin responses. Although only limited data are available, it appears that levamisole can dramatically potentiate warfarin-induced hypoprothrombinemia. Because the metabolism of warfarin via cytochrome P450 2C9 may be inhibited by imatinib, STI-571, patients who require anticoagulation while receiving imatinib should receive low-molecular weight heparin or standard heparin.[4966] The manufacturer labeling for capecitabine includes a black box warning regarding concomitant use with warfarin.[4717] Administration of capecitabine concomitantly with coumarin-derivative anticoagulants has resulted in prolonged coagulation parameters and/or bleeding; deaths have been reported (see Capecitabine monograph for more information).

Drugs that can cause thrombocytopenia may lead to an increased risk of bleeding when given concurrently with warfarin. Examples of drugs that cause clinically significant thrombocytopenia include myelosuppressive cancer chemotherapy agents, antithymocyte globulin [6303], and strontium-89 chloride [4694].

Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion.[1628] Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses (>1.3 g/day) for longer than 10—14 days.

Although data are very limited, there have been reports of increased hypoprothrombinemia when ethacrynic acid was administered to patients receiving warfarin. According to the manufacturer for ethacrynic acid, ethacrynic acid has been shown to displace warfarin from plasma protein; a reduction in the usual anticoagulant dosage may be required in patients receiving both drugs.[5138] Since other loop diuretics have been used safely in patients receiving warfarin, it would be prudent to use a loop diuretic other than ethacrynic acid in these patients.

Various antibiotics can affect warfarin's anticoagulant effect. Some antibiotics are known to destroy intestinal flora that synthesize vitamin K and a decrease in the activity level of vitamin K can enhance warfarin's anticoagulant effect. Interactions with antibiotics may be further complicated by concurrent fever, which may increase the effect of warfarin, changes in nutritional intake, and underlying disease states. The manufacturer of warfarin states that concurrent use of warfarin and the following antibiotics has been associated with increased INR in some patients: cefamandole [5279], cefazolin [5279], cefoperazone [5279], cefotetan [5279], cefoxitin [5279], ceftriaxone [5279], chloramphenicol [5279] [5859], loracarbef [6816], metronidazole [367], neomycin [5279], and tetracyclines [5279]. Increased prothrombin time, with or without clinical bleeding, has also been reported with coadministration of cefixime with warfarin.[6507]

Clarithromycin, erythromycin, and troleandomycin potentiate warfarin effects by inhibiting its metabolism by hepatic isozyme CYP3A4.[367] [1631] Unlike other macrolides, dirithromycin and azithromycin have less of an effect on cytochrome P450 isoenzymes. Although drug interaction studies have not shown a significant interaction with dirithromycin or azithromycin and warfarin, there have been numerous reports of increased INR with the combination of azithromycin and warfarin. Close monitoring of the INR in patients who receive warfarin and macrolides is recommended. This interaction may be severe in critically ill patients.

Concomitant use of warfarin and a quinolone antibiotic, especially ciprofloxacin [367] [2025], nalidixic acid [5877] [6817]norfloxacin [367], or ofloxacin [367], may result in an increased INR. Patients should be closely monitored for adverse effects following the addition of quinolones to stabilized warfarin therapy. An interaction may occur 2—16 days following the addition of quinolone therapy to a patient receiving warfarin anticoagulation. Several case reports discuss increased INR values in patients receiving the combination of warfarin and ciprofloxacin, levofloxacin [5151], norfloxacin, ofloxacin, and sparfloxacin. Other patient specific factors, such as fever, other disease states (i.e., cancer), or other concurrent medication, may play an important role in precipitating this interaction.

The concurrent use of warfarin and high doses of intravenous carbenicillin [6644] [6645], piperacillin [6749], or ticarcillin [5182] has resulted in increased INR values in some patients. In contrast, the addition of high-dose nafcillin to established warfarin therapy may decrease the response to warfarin.[2564] [7855] [7857] [7858] [7859] A 2- to 5-fold increase in warfarin dosage may be required within 2 weeks of starting therapy. The dosage of warfarin may be reduced to pretreatment levels within 4 weeks of discontinuing nafcillin therapy. In addition, dicloxacillin has been associated with increases in warfarin metabolism but the interaction is variable.[2564] [7860]

Sulfonamides, including sulfamethizole, sulfamethoxazole, and sulfisoxazole, may potentiate the anticoagulant effect of warfarin.[367] [5273] Sulfonamides are known to inhibit the hepatic metabolism of the S-warfarin and have, in some cases, doubled the hypoprothrombinemic effect of warfarin. A protein-binding interaction also may be possible, with sulfonamides displacing warfarin from protein binding sites. Most of the reported cases of an interaction between warfarin and a sulfonamide drug involved the combination of sulfamethoxazole and trimethoprim, which may be due to the additive effects of trimethoprim mediated CYP2C8 inhibition of warfarin metabolism.[5910] However, due to the potential severity of excessive anticoagulation, sulfonamides should be administered cautiously to a patient already stabilized on warfarin. Warfarin doses may need to be adjusted when sulfonamide therapy is discontinued.

A small study in 16 healthy subjects evaluated the interaction of daptomycin (6 mg/kg IV once daily for 5 days) followed by a single 25 mg PO dose of warfarin.[6011] There was no significant effect on the pharmacokinetics of either drug and the INR was not significantly altered. Daptomycin does not induce or inhibit the following CYP 450 enzymes: 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4; it is unlikely that daptomycin would exhibit pharmacokinetic interactions with warfarin or other drugs metabolized by CYP450 isozymes.[6011] However, since the study of an interaction of daptomycin and warfarin is limited to volunteer single-dose studies, the manufacturer recommends that anticoagulant activity be monitored for the first few days in patients receiving daptomycin and warfarin.[6011]

Androgens are associated with potentiation of the hypoprothrombinemic effect of warfarin.[367] These interactions have resulted in bleeding episodes in some patients receiving coumarin derivatives along with danazol, esthylestrenol, oxandrolone, oxymetholone, or methyltestosterone. A multidose study of oxandrolone in 15 healthy individuals concurrently treated with warfarin resulted in significant increases in warfarin half-life and AUC; a 5.5-fold decrease in the mean warfarin dosage from 6.13 mg/day to 1.13 mg/day (approximately 80—85% dose reduction) was necessary to maintain a target INR of 1.5. When oxandrolone is prescribed to patients being treated with warfarin, doses of warfarin may need to be decreased significantly to maintain a desirable INR level and diminish the risk of potentially serious bleeding. A case report describes an increased INR in a woman receiving topical testosterone propionate ointment and anticoagulation with warfarin. In addition, danazol and stanozolol (androgen-related compounds), are associated with potentiation of the hypoprothrombinemic effect of warfarin. Danazol may inhibit warfarin metabolism and/or may potentiate the anticoagulant effects by affecting the coagulation system, and has been associated with reports of serious bleeding events.[3946] When androgen therapy is initiated in a patient already receiving warfarin, the patient should be closely monitored with frequent evaluation of the INR and clinical parameters; the dosage of warfarin should be adjusted as necessary until a stable target INR is achieved. Careful monitoring of the INR and necessary adjustment of the warfarin dosage are also recommended when the androgen or androgen-related (danazol, stanozolol) therapy is changed or discontinued.

The interaction between thioamine antithyroid agents and warfarin is variable. The effects of warfarin can be enhanced due to the vitamin K antagonistic properties of methimazole [5176] or propylthiouracil, PTU [7879]. Isolated cases have reported hypoprothrombinemia due to methimazole or propylthiouracil, which may be additive with warfarin. In addition, as hyperthyroidism is corrected, the anticoagulant effect of warfarin can diminish due to a change in the clearance rate of endogenous clotting factors. Thus, administration of antithyroid agents such as methimazole or PTU can also reduce the effectiveness of warfarin. INRs should be monitored closely whenever methimazole is added or discontinued during warfarin therapy or when the thyroid status of a patient is expected to change. Warfarin dosage should be adjusted accordingly based on the INR and the clinical goals for the patient.

The concurrent use of thyroid hormones and warfarin potentiates anticoagulation effects of warfarin.[5874] The mechanism of this interaction may be the increased catabolism of vitamin K clotting factors as the hypothyroid state is corrected. As a result, the hypoprothrombinemic response to warfarin occurs earlier and to a greater degree. Dextrothyroxine has been shown to potentiate the effects of warfarin. Dextrothyroxine may increase the affinity of warfarin for its receptor sites in addition to increasing the catabolism of vitamin K dependent clotting factors. A reduction in the dosage of warfarin is recommended with concomitant therapy.[5935]

Estrogens increase the hepatic synthesis of prothrombin and factors VII, VIII, IX, and X and decrease antithrombin III; estrogens also increase norepinephrine-induced platelet aggregability.[4744] A positive relationship between combination oral contraceptives (OCs) and thromboembolic disease has been demonstrated; the US FDA has suggested class labeling of combined OCs in accordance with this data.[7622] OC products containing >= 50-mcg ethinyl estradiol are associated with the greatest risk of thromboembolic complications. Combined oral contraceptive agents are contraindicated in patients with a current or past history of stroke, cerebrovascular disease, coronary artery disease, coronary thrombosis, thrombophlebitis, thromboembolic disease or valvular heart disease with complications.[7622] Because of these contraindications and the potential for pharmacodynamic interaction, concurrent use of estrogens or OCs in female patients receiving anticoagulation therapy with warfarin is generally avoided, even though the dose of ethinyl estradiol is < 50 mcg/day in many modern combined hormonal oral contraceptives. Isolated case reports have noted an augmented response to warfarin in a patient receiving an OC [130] and a patient receiving a levonorgestrel-containing emergency contraceptive [3014]; however, such interactions have not been substantiated with other reports. If concurrent use of an estrogen or OC cannot be avoided in a patient taking warfarin, the patient should be carefully monitored for alterations in anticoagulant effectiveness and signs and symptoms of thromboembolic complications or bleeding. Dosage adjustment of warfarin should be based on the prothrombin time or INR value.

A 10% decrease in prothrombin time was observed in a single-dose study of raloxifene with warfarin. If raloxifene is given concurrently with warfarin or other coumarin derivatives, the INR should be carefully monitored when starting or stopping therapy with raloxifene. No clinically relevant effects of warfarin on plasma concentrations or therapeutic activity of raloxifene have been noted.[6344]

Tamoxifen and toremifene can significantly increase INR values in patients receiving warfarin. Abnormal bleeding and hemorrhage have been reported during concomitant administration of these agents and warfarin. The effect of these agents on stable warfarin therapy may not be realized for several weeks after the initiation of therapy. Tamoxifen or toremifene should be administered cautiously with warfarin and the dosage of warfarin adjusted accordingly.[4782][5555]

When used concomitantly, testolactone may increase the effects of warfarin. The patient should be monitored for signs and symptoms of bleeding and the INR should be monitored closely with the dose of warfarin adjusted as necessary.[4846]

Since vitamin K absorption may be theoretically decreased by the use of mineral oil, patients on chronic stable doses of warfarin should be monitored closely for changes in coagulation parameters when mineral oil is prescribed for regular use. This interaction is more theoretical than of practical concern, as evidence of this interaction is lacking, particularly since administration of mineral oil is likely to be on an 'as needed' intermittent basis.[6100]

Factor IX and VIIa, recombinant may reverse the anticoagulant effects of warfarin. Factor IX complex contains therapeutic levels of other vitamin K clotting factors including factors II, VII, and X. Factor IX complex administration has been shown to lower the INR in patients with warfarin-related intracranial hemorrhages.[5880] Administration of factor VIIa, recombinant, has also been used therapeutically to reverse the INR during warfarin-related bleeding.[5881]

Two reports are noted of a severe interaction between cyclosporine and warfarin.[37] [6799] In the first case, a 65-year-old female had a decrease of her INR by about 40% after oral cyclosporine 300 mg twice daily initiation. She had been receiving 18.75 mg of warfarin weekly for venous thromboembolism. Her warfarin requirement increased to 27.5 mg/week. After the increase in warfarin dose, cyclosporine blood concentrations remained within the therapeutic range, and the INR values became stable with the same warfarin dose. When warfarin was discontinued, cyclosporine blood concentrations remained unchanged.[6799] In the second case, cyclosporine concentrations fell after warfarin therapy was begun, but the patient was also receiving phenobarbital.[37] Until more information is available, patients should have their INR monitored closely during and after concomitant cyclosporine usage.

Clofibrate is known to enhance the hypoprothrombinemic actions of warfarin.[367] While clofibrate does displace warfarin from protein binding sites, the magnitude is slight. Fenofibrate [6131] and gemfibrozil [4975] can also potentiate the anticoagulant effect of warfarin. All fibrates should be used cautiously in any patient receiving warfarin.

Fluvastatin [5045], lovastatin [5335], rosuvastatin [4705], and simvastatin [5336] have been associated with potentiation of warfarin's clinical effect. In general, it is prudent to monitor INR at baseline, at initiation of these HMG Co-A reductase inhibitors, and after subsequent dosage changes. Adjust warfarin dosage based on INR and clinical response. Once a stable INR is documented, the INR can be monitored at the intervals otherwise recommended based on the indication for anticoagulation and co-existing conditions. Alternatively, another HMG-CoA reductase inhibitor may be considered. It appears that pravastatin [5334] and atorvastatin may be less likely to significantly interact with warfarin based on drug interaction studies. Atorvastatin has been reported to slightly and transiently decrease the anticoagulant activity of warfarin; these effects were not considered clinically significant.[4279] Since compounds in red yeast rice claim to have HMG-CoA reductase inhibitor activity, red yeast rice should not be used in combination with warfarin.[5911]

In controlled studies of patients or healthy subjects anticoagulated with warfarin, small to moderate amounts of wine (e.g., 2 drinks per day or less) do not alter INR values or warfarin levels.[2026] However, acute intoxication resulting from large amounts of ethanol may enhance the hypoprothrombinemic response to oral anticoagulants due to inhibition of warfarin's metabolism.[367] Although chronic consumption of ethanol may increase warfarin clearance, studies have not demonstrated a reduction in anticoagulant effect.[367] However, chronic consumption of alcohol may lead to hepatic disease, resulting in potentiation of hypoprothrombinemia due to impaired hepatic synthesis of clotting factors.

Isoniazid, INH, can inhibit the hepatic oxidative metabolism of warfarin. Alterations in the effects of warfarin may occur if isoniazid is added or discontinued. This interaction may be dose-dependent; a significant interaction with warfarin occurs at INH doses of 600 mg/day but not necessarily at INH doses of 300 mg/day.[6241]

Sulfinpyrazone, when used as a uricosuric agent, should be avoided when possible with concurrent anticoagulants, due to potential for increased bleeding risk.[6482] If possible, select alternative anti-gout treatments, particularly if the patient is on warfarin therapy. Sulfinpyrazone markedly potentiates the anticoagulation effects of warfarin.[367] [5125] Sulfinpyrazone may inhibit CYP2C9 [4718], leading to a decrease in the clearance of S-warfarin; sulfinpyrazone also inhibits platelet aggregation. If concurrent therapy is warranted and cannot be avoided, significant initial dosage reductions (e.g., 50%) of warfarin may be necessary, with further dosage adjusted based on INR values. The INR and the patients clinical status should be closely monitored during concurrent therapy, particularly during the initiation or termination phases of sulfinpyrazone treatment.

Data indicate that administration of cisapride to patients receiving oral anticoagulants (e.g., warfarin) may cause a prolongation in the prothrombin time and increase the INR.[5137] When using cisapride with warfarin, monitor the coagulation time during the initiation and discontinuation of cisapride. Warfarin dose adjustment may be necessary.

The effect of corticosteroids on oral anticoagulants (e.g., warfarin) is variable. There are reports of enhanced as well as diminished effects of anticoagulants when given concurrently with corticosteroids;[6524] however, limited published data exist, and the mechanism of the interaction is not well described. High-dose corticosteroids appear to pose a greater risk for increased anticoagulant effect.[6525] [6526] In addition, corticosteroids have been associated with a risk of peptic ulcer and gastrointestinal bleeding.[6524] [6527] Thus corticosteroids should be used cautiously and with appropriate clinical monitoring in patients receiving oral anticoagulants; coagulation indices (e.g., INR, etc.) should be monitored to maintain the desired anticoagulant effect. During high-dose corticosteroid administration, daily laboratory monitoring may be desirable.[6525]

There are reports that high doses (e.g., > 5—10 g/day) of ascorbic acid, vitamin C may decrease the anticoagulation effects of warfarin.[5449] No clinical intervention appears to be necessary unless large doses of ascorbic acid are being consumed.

The interaction between oral anticoagulants and oral sulfonylureas is complex; both enhancement or reduction of hypoprothrombinemic response to oral anticoagulants has been reported in various literature accounts along with a potential for altered hypoglycemic response to the sulfonylurea.[5279] [6141] [8159] One proposed mechanism may be related to displacement of the drugs from plasma protein binding sites.[5279] [8159] Dicumarol has been reported to inhibit the metabolism of chlorpropamide and tolbutamide, however, warfarin did not exhibit a similar effect on tolbutamide kinetics.[8160] Glyburide has been reported to augment the hypoprothrombinemic response to warfarin, although other reports have showed no interaction.[6158] Warfarin appears less likely to interact with sulfonylureas than dicumarol. In clinical trials, glimepiride therapy resulted in a slight, but statistically significant decrease in pharmacodynamic response to warfarin. The reductions in effect are unlikely to be clinically important in most cases.[6143] Nevertheless, it would be wise for clinicians to use warfarin and sulfonylureas together cautiously until the combined effects of the drugs are known. Monitor the INR as indicated and be alert for altered blood sugar control when either of these drugs is added or discontinued.

Increased INRs have been reported in patients previously stabilized on warfarin who start taking tramadol.[5882] Closely monitor patients for changes in INRs and bleeding, or use another analgesic agent in place of tramadol in patients receiving warfarin.

One case report of an interaction between warfarin and acarbose has been published.[2499] The mechanism or incidence of the interaction has not been established. INRs should be closely observed during the first month of acarbose or miglitol therapy.

Increased INR values have been reported with concurrent use of warfarin and tolterodine. In two case reports, patients stabilized on warfarin experienced elevated INR values 10—14 days after beginning tolterodine treatment.[2677] Careful monitoring of the INR should be considered.

Niacin (nicotinic acid) is occasionally associated with small but statistically significant increases (mean 4%) in prothrombin time.[5932] While rare, there is a possibility that an interaction would occur in some patients stabilized on warfarin. It appears prudent to monitor the INR periodically.

Agents that decrease clotting, such as anticoagulants, could decrease the efficacy of photosensitizing agents used in photodynamic therapy.[6625]

Because mifepriston, RU-486 is a CYP 3A4 inhibitor [4718], it may inhibit the metabolism of warfarin. When mifepristone, RU-486 is used for the termination of pregnancy, concurrent use of anticoagulants is contraindicated due to the increased risk of serious bleeding and the potential for increased serum levels of R-warfarin.[4720] Due to the slow elimination of mifepristone from the body, such interactions may be prolonged.

Co-enzyme Q10, ubiquinone is structurally similar to vitamin K; a decreased response to warfarin has been noted if this dietary supplement is taken.[5875] Avoid concurrent use when possible. If co-enzyme Q10 is taken concurrently with warfarin, monitor INR and adjust warfarin dosage to attain clinical and anticoagulant endpoints.

Methylphenidate may decrease the metabolism of warfarin and other coumarin anticoagulants (e.g., dicumarol). Downward dosage adjustments of the anticoagulant may be required when methylphenidate is used concomitantly. Close monitoring of the INR is recommended.[5248] Although data are unavailable for dexmethylphenidate, a similar interaction may occur.[5249]

Coadministration of bosentan 500 mg twice daily for 6 days decreases the plasma concentrations of both S-warfarin (a CYP2C9 substrate) and R-warfarin (a CYP3A4 substrate) by 29 and 38%, respectively.[5226] Clinical experience with concomitant administration of bosentan and warfarin in patients with pulmonary arterial hypertension did not show clinically relevant changes in INR or warfarin dosage compared to baseline values. In addition, the need to change the warfarin dosage during clinical trials due to changes in INR or adverse events has been reported to be similar for patients receiving bosentan or placebo. One case report has documented a reduction in INR and increased warfarin dosage requirement (by 64%) when bosentan was coadministered with warfarin.[4498] Monitor INR closely when bosentan is initiated or discontinued in patients who are stabilized on warfarin therapy.

Tibolone has been reported to augment the anticoagulant effect of warfarin due to tibolone's ability to increase fibrinolytic activity; in addition, increased INRs have been reported in warfarin-treated patients after initiation of tibolone. Monitor for an increased INR and symptoms of bleeding as needed during concomitant therapy.[5878]

Drug interactions with fish oil, omega-3 fatty acids are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation [6320] [7299], caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3—6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy.[3535] However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day.[5879] The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.[5879] [7299]

Coadministration of warfarin with aprepitant may result in a clinically significant decrease in warfarin serum concentrations and in the International Normalized Ratio (INR). Aprepitant is an inducer of isoenzyme CYP2C9, an enzyme involved in warfarin metabolism. In patients receiving chronic warfarin, the INR should be closely monitored during the 2 week period (particularly at 7—10 days) following initiation of the aprepitant dosage regimen (3 days) with each chemotherapy cycle. Studies have noted a 34% decrease in S-warfarin trough concentrations, accompanied by a 14% decrease in the INR at five days following completion of the aprepitant regimen.[7438]

A possible drug interaction between ropinirole and warfarin has been reported clinically, with a resultant increase in the INR. While no signs of bleeding occurred in the reported case, the increase in INR necessitated a warfarin dosage adjustment during concurrent treatment. After ropinirole was discontinued, the warfarin dosage had to be adjusted upward. Closely monitor the INR when starting or stopping ropinirole therapy in a patient stabilized on warfarin.[3500]

Warfarin therapy can be affected by changes in dietary intake of vitamin K.[5279] Orlistat doses of 120 mg three times per day administered orally for 16 days in 12 normal-weight subjects did not appear to alter undercarboxylated osteocalcin, a marker of vitamin K nutritional status. No changes in the pharmacokinetics or pharmacodynamics (PT and serum Factor VII) of warfarin were noted following a single 30 mg dose of Coumadin® in a placebo-controlled, randomized, third-party blind, two-way crossover study.[2263] However, vitamin K levels tended to decrease in patients taking orlistat. Since vitamin K1 (phytonadione, vitamin K1) absorption may be affected by orlistat, patients on chronic stable doses of warfarin should be monitored closely for changes in coagulation parameters when orlistat is prescribed; some experts recommend that the INR be monitored weekly during the first month of orlistat therapy.

Albendazole induces cytochrome P450 1A (CYP1A) [4768] and although not studied, may induce the metabolism of R-warfarin. Patients receiving albendazole in combination should be closely monitored when albendazole is prescribed. Conversely, the discontinuation of albendazole therapy may result in a reduced clearance of R-warfarin, leading to an increase in anticoagulant effect. The patient's clinical status and INR should be monitored carefully when albendazole is prescribed and on discontinuation of albendazole therapy.

Psyllium can interfere with the absorption of certain oral drugs if administered concomitantly. For example, psyllium fiber is theorized to adsorb oral anticoagulants (e.g., warfarin); although, response to a single dose of warfarin was not affected by repeated administration (every 2 hours) of psyllium in a group (n=6) of healthy subjects.[6100] Per the psyllium manufacturers, administration of other prescribed oral drugs should be separated from the administration of psyllium by at least 2 hours.

Flaxseed fiber can impair the absorption of oral drugs when administered concomitantly.[6099] However, no drug interaction studies have been performed to assess the degree to which the absorption of oral drugs may be altered. Based on interactions of other plant seed fiber (e.g., psyllium) used as a bulk-forming laxative, flaxseed fiber may adsorb oral anticoagulants (e.g., warfarin) [6100]. Administration of prescribed oral agents should be separated from the administration of flaxseed fiber by at least 2 hours.

Interactions have been reported clinically between ginseng and warfarin. With regard to warfarin, one case report is noted of a decreased INR (reduced anticoagulant effect) after the addition of ginseng (Ginsana™) in a patient stabilized on warfarin, followed by a return to the desired INR after ginseng was discontinued.[1816] [5200] In another report, ginseng was implicated in a life-threatening case of valve thrombosis in a patient with an inability to maintain a therapeutic INR on warfarin after he began using a commercial ginseng product.[5203] The effect of ginseng on warfarin has been evaluated in a double-blind, placebo-controlled trial of 4 weeks duration in healthy volunteers.[6018] The subjects (n= 20) received warfarin (5 mg/day PO x 3 days/week). Beginning in week two, 12 of the subjects took ginseng powder (2 g/day PO in capsules); 8 subjects took placebo capsules. Compared with the placebo group, the ginseng group had significantly reduced INR values, warfarin AUCs, and peak plasma warfarin concentrations after 2 weeks.[6018] Concurrent use of ginseng and warfarin is not recommended; clinicians should discuss ginseng use with patients.[5200] [6018] Ginseng (Panax ginseng) also exerts antiplatelet activity [5202] and theoretically may interact with other drugs that exhibit antiplatelet effects or anticoagulant activity; however, data are not available to confirm or deny clinical interactions.

Theoretically feverfew, Tanacetum parthenium may enhance the effects of the anticoagulants via inhibition of platelet aggregation or via antithrombotic activity.[2913] [2914] [2915] Feverfew also inhibits the secretion of various substances (e.g., arachidonic acid, and serotonin) from the platelet.[1797] In theory, concurrent use may increase the risk of bleeding. Clinical interactions have not yet been reported; however, avoidance of the use of feverfew during anticoagulant therapy seems prudent.[5314] [5875]

Ginkgo, Ginkgo biloba is reported to inhibit platelet aggregation [1900] and several case reports describe bleeding complications with Ginkgo biloba, with or without concomitant drug therapy. Since ginkgo produces clinically-significant antiplatelet effects, it should be used cautiously in patients drugs that inhibit platelet aggregation or pose a risk for bleeding, such as anticoagulants (e.g., warfarin), aspirin, ASA or other platelet inhibitors, or thrombolytic agents.[5200] A patient who had been taking aspirin 325 mg/day PO for 3 years following coronary-artery bypass surgery, developed spontaneous bleeding into his eye after taking a standardized extract of Ginkgo biloba (Ginkoba® commercial product) 40 mg PO twice daily for one week. The patient stopped taking the ginkgo but continued taking the aspirin with no recurrence of bleeding over a 3-month period.[1706]

Garlic, Allium sativum may produce clinically-significant antiplatelet effects [2233]; until more data are available, garlic should be used cautiously in patients receiving drugs with a potential risk for bleeding such as warfarin. In regard to warfarin, no substantial clinical data are available to support or deny a potential for interaction; the data are limited to a random case report.[5200] A case of spontaneous spinal epidural hematoma, attributed to dysfunctional platelets from excessive garlic use in a patient not receiving concomitant anticoagulation, has been reported.[2245] Avoid concurrent use of herbs which interact with warfarin when possible. If these herbal products are taken concurrently with warfarin, monitor INR and adjust warfarin dosage to attain clinical and anticoagulant endpoints.

Drug interactions with Horse chestnut, Aesculus hippocastanum are not well documented. Coumarin compounds with the potential for anticoagulant activity have been isolated from the herb.[5279] [5875] It is possible that the use of horse chestnut may increase the risk of bleeding if coadministered with anticoagulants (e.g., enoxaparin, heparin, warfarin), thrombolytic agents, or platelet inhibitors (e.g., aspirin, clopidogrel, and others).[5875] [6504] Reparil® Dragees (Madaus AG, Germany) a drug derived from horse chestnut and containing aescin (escin), is labeled with a precaution that the action of anticoagulants may be potentiated by aescin.[6505] Caution and careful monitoring of clinical and/or laboratory parameters are warranted if horse chestnut is coadministered with any of these agents.

Certain herbs inhibit platelet function which may increase bleeding risks in patients on warfarin. Such herbs include ginger, Zingiber officinale [5200]. Other herbal medications may also increase the effect of warfarin. Dong quai, Angelica sinensis contains natural coumarin derivatives that may increase INR values.[5875] Kava kava, Piper methysticum exhibits antithrombotic activity [5570] and also inhibits CYP isozymes important in warfarin clearance such as CYP2C9, 2C19, 1A2 and 3A4.[5569] Several case reports describe clinically significant increases in PT/INR and severe bleeding in patients taking the combination of danshen and warfarin.[5875] Avoid concurrent use of herbs which interact with warfarin when possible. If these herbal products are taken concurrently with warfarin, monitor INR and adjust warfarin dosage to attain clinical and anticoagulant endpoints.

Case reports have reported a possible interaction between chondroitin; glucosamine and warfarin [6164] or other coumarin anticoagulants, resulting in an increase in INR and a need for warfarin dosage adjustment. In one case report, the patient was taking twice the recommended dosage of a popular chondroitin; glucosamine supplement (Cosamin DS).[6164] Controlled clinical trials of chondroitin; glucosamine for the treatment of osteoarthritis have not reported drug interactions with oral anticoagulants at typical dosages of up to 1500 mg glucosamine; 1200 mg chondroitin/day PO. However, drug interactions with these supplements have not been specifically studied. Until more is known regarding the potential for chondroitin or glucosamine to interact with warfarin, it may be prudent to closely monitor patients stabilized on warfarin if these dietary supplements are added to their therapy regimen.[6164]

Coadministration with ezetimibe has not demonstrated significant effects on the bioavailability or the anticoagulant effects of warfarin when studied in 12 healthy adult males.[4704] However, the manufacturer recommends that if ezetimibe is added to warfarin, the INR should be appropriately monitored.[4704]

Telithromycin did not alter the pharmacokinetics or pharmacodynamics of warfarin when the drugs were administered concurrently in healthy volunteers.[3224] However, spontaneous post-marketing reports suggest that administration of telithromycin and oral anticoagulants concomitantly may potentiate the effects of the oral anticoagulants such as warfarin. Consideration should be given to monitoring prothrombin times/INR while patients are receiving telithromycin and oral anticoagulants simultaneously.

The effect of intravenous conivaptan, a potent CYP3A4 inhibitor, on warfarin pharmacokinetics or pharmacodynamics has not been evaluated. Warfarin undergoes major metabolism by CYP2C9 and minor metabolism by CYP3A4. The effects of oral conivaptan 40 mg twice daily on the prothrombin time has been assessed in patients receiving stable oral warfarin therapy.[8569] After 10 days of oral conivaptan administration, the S- and R-warfarin concentrations are approximately 90% and 98% of those prior to conivaptan administration. The corresponding prothrombin time values after 10 days of oral conivaptan administration are 95% of baseline. No effect of oral conivaptan on the pharmacokinetics or pharmacodynamics of warfarin has been observed during pre-marketing trials.

Warfarin is metabolized by both CYP1A2 and CYP3A4. In vivo data indicate that echinacea may inhibit hepatic CYP1A2, induce hepatic CYP3A4, and inhibit intestinal CYP3A4. The efficacy and safety of warfarin if used in combination with echinacea are unknown; however, close monitoring of patients for changes in efficacy or toxicity may be prudent if warfarin is used in combination with echinacea, until more data are available.[7566] [8894]

In vitro, flavocoxid demonstrated a 23% inhibition of CYP1A2 isoenzymes.[8954] This inhibition could potentially be clinically relevant, especially when flavocoxid is coadministered with CYP1A2 substrates that have a narrow therapeutic index such as warfarin.[8993] Until more data are available, it may be prudent to monitor for potential adverse effects of warfarin when coadministered with flavocoxid.

Interactions last revised 8/24/2006 3:23:00 PM

Adverse Reactions

Bleeding is the primary adverse effect of warfarin therapy and is related to the intensity of anticoagulation, length of therapy, the patient's underlying clinical disorder, and the use of concomitant drugs that may affect hemostasis or interfere with warfarin's metabolism. Fatal or non-fatal hemorrhage may occur from any tissue or organ. Bleeding complications may be minor (e.g., ecchymosis, epistaxis, or petechiae) or major (e.g., intracranial bleeding or retroperitoneal bleeding). Bleeding that occurs when the INR is < 3.0 is often associated with an obvious underlying cause or an occult GI or renal lesion. Massive hemorrhage most frequently involves the GI tract (i.e., GI bleeding) or genitourinary sites (e.g., hematuria), but may involve the spinal cord or cerebral, pericardial, pulmonary, adrenal, or hepatic sites. Other manifestations of bleeding may include excessive uterine or vaginal bleeding or bleeding from the gums or other mucous membranes. Although rare, massive ocular hemorrhage has been reported in patients with pre-existing disciform macular degeneration. In the Stroke Prevention in Reversible Ischemia Trial (SPIRIT), patients who received warfarin therapy at a targeted INR of 3.0—4.5 had a significant increase in major bleeding as compared to aspirin (8.1% vs. 0.9%, respectively).[4375] The bleeding incidence increased by a factor of 1.4 for each 0.5 unit increase of the INR. In five randomized trials in patients with non-valvular atrial fibrillation, the annual incidence of major bleeding was 1.3% in patients assigned to less intense warfarin therapy (target INR generally 2.0—3.0), compared with 1.0% in patients assigned to placebo. Although intracranial bleeding was more frequent in patients treated with warfarin in these trials (0.3% per year vs. 0.1% per year in patients not treated with warfarin or aspirin), the absolute difference was small. The intensity of anticoagulant effect is the most important risk factor for intracranial hemorrhage, with the risk increasing dramatically with an INR > 4.0 In making decisions regarding use of warfarin, the potential decrease in thromboembolism must be balanced against the potential increased bleeding risk. All patients should have prothrombin time (PT)/INR evaluations made before and following initiation of therapy (see Dosage). Patients should be monitored closely for signs or symptoms of bleeding. Hemorrhagic complications may be manifested by signs or symptoms that do not indicate obvious bleeding, such as dizziness, weakness, shortness or breath, headache, or pain in the chest, abdomen, or other areas. If a patient has an elevated INR and is not bleeding or does not require surgery, it is reasonable to reduce the INR to a safe range either by omitting a dose of warfarin or by administering vitamin K1. If the patient has serious bleeding, the INR should be reduced to 1.0 as soon as possible (see Vitamin K1 dosage). In some cases of serious bleeding, transfusion of whole blood, fresh frozen plasma, or Factor IX complex may be required.

Anticoagulation therapy with warfarin may enhance the release of atheromatous plaque emboli leading to systemic cholesterol microembolization. Sequelae may include livedo reticularis; rash; gangrene; abrupt and intense pain in the leg, foot or toes; foot ulcers; myalgia; penile gangrene; abdominal pain; flank or back pain; hematuria; renal insufficiency; hypertension; cerebral ischemia; spinal cord infarction; pancreatitis; symptoms similar to polyarteritis; or any other symptoms of vascular compromise due to embolic occlusion. The most commonly involved visceral organs are kidneys, pancreas, spleen, and liver. Some symptoms have progressed to organ necrosis or death. Purple-toe syndrome is a consequence of cholesterol microembolization and usually occurs between 3—10 weeks or later after the initiation of warfarin therapy. It is characterized by a dark purplish or mottled color of the toes or plantar surfaces that blanches on moderate pressure and fades with elevation of the legs; pain and tenderness of the toes; waxing and waning of color over time. While purple-toe syndrome is thought to be reversible, some cases may progress to gangrene or tissue necrosis, which may require debridement or may lead to amputation. Discontinuation of warfarin is recommended when any of these conditions occur.

Skin necrosis is a relatively uncommon adverse reaction to warfarin therapy that is usually observed between the third to eighth day of therapy. Skin necrosis is associated with local thrombosis and usually appears within a few days of the start of warfarin therapy. When it occurs it can be extremely severe and disfiguring and may require treatment through debridement or amputation of the affected tissue, limb, breast or penis. It occurs more frequently in women and in patients with preexisting protein C deficiency and, less commonly, with protein S deficiency. Patients initially become hypercoagulable because warfarin depresses anticoagulant proteins C and S more quickly than coagulant proteins II, VII, IX, and X. Extensive thrombosis of the venules and capillaries occurs within the subcutaneous fat. Women will note an intense, painful burning in places such as the thigh, buttocks, waist, and/or breast several days after beginning warfarin; skin necrosis and permanent scarring may follow. Immediate withdrawal of warfarin therapy is indicated. Heparin can be safely substituted in place of warfarin; however, the treatment of patients who require long-term anticoagulant therapy remains problematic. It may be reasonable to restart warfarin therapy at a low dose (e.g., 2 mg) while therapeutic heparin is used to prevent an abrupt fall in protein C levels before there is a reduction in the levels of factors II, IX, and X. The dosage of warfarin can be increased gradually over several weeks.[2027]

Warfarin crosses the placenta during pregnancy, and has the potential to cause both teratogenesis and bleeding in the fetus. Warfarin and other coumarin derivatives cause an embryopathy commonly termed Fetal Warfarin Syndrome (FWS). During the first trimester exposure, particularly during the 6th—12th weeks of gestation, embryopathy characterized by nasal hypoplasia with or without stippled epiphyses (chondrodysplasia punctata) may occur. CNS abnormalities, including dorsal midline dysplasia characterized by agenesis of the corpus collosum, Dandy-Walker malformation, and midline cerebellar atrophy have been reported. Ventral midline dysplasia, characterized by optic atrophy, and eye abnormalities have been observed. Seizures, deafness, blindness, and mental retardation can occur in any trimester. Spontaneous fetal abortion and still birth are known to occur and a higher risk of fetal mortality is associated with use of warfarin. Although rare, other teratogenic reports following in utero exposure to warfarin include urinary tract abnormalities such as single kidney, asplenia, anencephaly, spina bifida, cranial nerve palsy, hydrocephalus, cardiac defects and congenital heart disease, polydactyly, deformities of toes, diaphragmatic hernia, corneal leukoma, cleft palate, cleft lip, schizencephaly, and microcephaly. The effects of anticoagulation on the fetus are a particular concern during the time of labor, when the combination of the trauma of delivery and anticoagulation could lead to bleeding in the neonate. There are a few small studies that have used warfarin in pregnancy after the 12th week of gestation, but these studies are insufficient to recommend the use of warfarin in the pregnant patient. Thus, warfarin should not be given during pregnancy (see Contraindications).

Other adverse reactions that occur infrequently with warfarin include agranulocytosis, alopecia, anaphylactoid reactions, anorexia, cold intolerance, diarrhea, dizziness, elevated hepatic enzymes, exfoliative dermatitis, headache, hepatitis, jaundice, leukopenia, nausea/vomiting, pruritus, and urticaria.

In a retrospective cohort of Medicare beneficiaries (mean age 79.4 years) receiving warfarin for atrial fibrillation, the use of long-term warfarin (>= 365 days) was associated with an increased risk of osteoporotic bone fractures (OR 1.25, 95% CI 1.06—1.48), especially vertebral fracture. However, when analyzed separately by gender, the increased risk of fracture was significant in men (odds ratio 1.63, 95% CI 1.26—2.10), but not women (OR 1.05, 95% CI 0.88—1.26). Furthermore, the risk of fracture was not increased in patients taking warfarin for < 1 year. Other independent predictors of fracture in this cohort of patients (regardless of length of warfarin therapy) were increasing age, high risk of falls, hyperthyroidism, neuropsychiatric disease, and alcoholism. Factors that were associated with a protective risk of fracture include African-American race, male gender, and the use of b-adrenergic antagonists. Because the available alternative therapies (e.g., heparin, low molecular weight heparin) have also been associated with an increased risk of fracture, the authors of this study recommend that when prescribing warfarin to patients at risk of falling, patients should be encouraged to wear stable shoes, consume adequate amounts of calcium and vitamin D, exercise regularly, and use walking aids when necessary. In addition, unnecessary drugs should be discontinued.[8971]

Rare events of tracheal or tracheobronchial calcification have been reported in association with long-term warfarin therapy. The clinical significance is not known. Priapism has been associated with anticoagulant administration; however, a causal relationship with warfarin has not been established.

Adverse Reactions last revised 5/3/2006 9:59:00 AM

Monitoring Parameters

Monitoring Parameters
•INR
•prothrombin time (PT)
•stool guaiac