Etodolac

Cardiovascular Thrombotic Events • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (see WARNINGS and PRECAUTIONS ). • Etodolac Extended-Release Tablets, 400 mg, 500 mg and 600 mg are contraindicated in the setting of coronary artery bypass graft (CABG) surgery (see CONTRAINDICATIONS and WARNINGS ). Gastrointestinal Risk • NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events. (See WARNINGS ).

WARNINGS Cardiovascular Effects Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as etodolac, increases the risk of serious gastrointestinal (GI) events (see WARNINGS ). Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG (see CONTRAINDICATIONS ). Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of etodolac extended-release tablets in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If etodolac extended-release tablets are used in patients with a recent MI, monitor patients for signs of cardiac ischemia. Hypertension NSAIDs, including etodolac extended-release tablets, can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including etodolac extended-release tablets, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy. Heart Failure and Edema The Coxib and traditional NSAID Trialists' Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of etodolac may blunt the CV effects of several therapeutic agents used to treat these medical conditions [e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers (ARBs)] (see Drug Interactions ). Avoid the use of etodolac extended-release tablets in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If etodolac extended-release tablets are used in patients with severe heart failure, monitor patients for signs of worsening heart failure. Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation NSAIDs, including etodolac extended-release tablets, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3 to 6 months, and in about 2 to 4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population. To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered. Renal Effects Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Advanced Renal Disease No information is available from controlled clinical studies regarding the use of etodolac extended-release tablets in patients with advanced renal disease. Therefore, treatment with etodolac extended-release tablets is not recommended in these patients with advanced renal disease. If etodolac extended-release tablet therapy must be initiated, close monitoring of the patient's renal function is advisable. Anaphylactoid Reactions As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to etodolac extended-release tablets. Etodolac extended-release tablets should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS, Preexisting Asthma ). Emergency help should be sought in cases where an anaphylactoid reaction occurs. Skin Reactions NSAIDs, including etodolac extended-release tablets, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. Pregnancy In late pregnancy, as with other NSAIDs, etodolac extended-release tablets should be avoided because it may cause premature closure of the ductus arteriosus.

ADVERSE REACTIONS A total of 1552 patients were exposed to etodolac extended-release tablets in controlled clinical studies of at least 4 weeks in length and using daily doses in the range of 400 to 1200 mg. In the tabulations below, adverse event rates are generally categorized based on the incidence of events in the first 30 days of treatment with etodolac extended-release tablets. As with other NSAIDs, the cumulative adverse event rates may increase significantly over time with extended therapy. In patients taking NSAIDs, including etodolac extended-release tablets, the most frequently reported adverse experiences occurring in approximately 1 to 10% of patients are: gastrointestinal experiences including: abdominal pain constipation diarrhea dyspepsia flatulence GI ulcers (gastric/duodenal) Adverse events that were observed in < 1% of patients in the first 30 days of treatment with etodolac extended-release tablets in clinical trials. gross bleeding/perforation nausea vomiting other events including: abnormal renal function anemia asthenia dizziness edema elevated liver enzymes headaches hypertension increased bleeding time infection pharyngitis pruritus rashes rhinitis tinnitus Additional NSAID Adverse Experiences Reported Occasionally with NSAIDs or Etodolac Extended-Release Tablets Include Body as a whole - allergic reaction, anaphylactic/anaphylactoid reactions (including shock), chills, fever, sepsis Cardiovascular system - congestive heart failure, flushing, palpitations, tachycardia, syncope, vasculitis (including necrotizing and allergic) Digestive system - anorexia, cholestatic hepatitis, cholestatic jaundice, dry mouth, duodenitis, eructation, esophagitis, gastritis, gastric/peptic ulcers, glossitis, hepatic failure, hepatitis, hematemesis, intestinal ulceration, jaundice, liver necrosis, melena, pancreatitis, rectal bleeding, stomatitis Hemic and lymphatic system - agranulocytosis, ecchymosis, eosinophilia, hemolytic anemia, leukopenia, neutropenia, pancytopenia, purpura, thrombocytopenia Metabolic and nutritional - hyperglycemia in previously controlled diabetic patients Nervous system - anxiety, confusion, depression, dream abnormalities, insomnia, nervousness, paresthesia, somnolence, tremors, vertigo Respiratory system - asthma, dyspnea, pulmonary infiltration with eosinophilia Skin and appendages - angioedema, cutaneous vasculitis with purpura, erythema multiforme, hyperpigmentation, sweating, urticaria, vesiculobullous rash Special senses - blurred vision, photophobia, transient visual disturbances Urogenital system - dysuria, elevated BUN, oliguria/polyuria, proteinuria, renal failure, renal insufficiency, renal papillary necrosis, serum creatinine increase, urinary frequency Other NSAID Adverse Reactions, Which Occur Rarely Are Body as a whole - anaphylactic reactions, appetite changes, death Cardiovascular system - arrhythmia, cerebrovascular accident, hypotension, myocardial infarction Digestive system - colitis, esophagitis with or without stricture or cardiospasm, thirst, ulcerative stomatitis Hemic and lymphatic system - aplastic anemia, lymphadenopathy Metabolic and nutritional - change in weight Nervous system - coma, convulsions, hallucinations, meningitis Respiratory - bronchitis, pneumonia, respiratory depression, sinusitis Skin and appendages - alopecia, exfoliative dermatitis, maculopapular rash, photosensitivity, skin peeling, Stevens-Johnson syndrome, toxic epidermal necrosis Special senses - conjunctivitis, deafness, hearing impairment, taste perversion Urogenital system - cystitis, hematuria, interstitial nephritis, leukorrhea, renal calculus, uterine bleeding irregularities

<table width="80%"> <col width="32%"/> <col width="17%"/> <col width="31%"/> <tbody> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>abdominal pain </paragraph> </td> <td styleCode="Rrule Botrule Toprule " valign="top"> <paragraph>constipation </paragraph> </td> <td styleCode="Rrule Botrule Toprule " valign="top"> <paragraph>diarrhea</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>dyspepsia </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>flatulence </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>GI ulcers (gastric/duodenal)<footnote ID="_Refftx1">Adverse events that were observed in &lt; 1% of patients in the first 30 days of treatment with etodolac extended-release tablets in clinical trials.</footnote> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>gross bleeding/perforation<footnoteRef IDREF="_Refftx1"/> </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>nausea </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>vomiting</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Botrule " valign="top"> <paragraph>other events including:</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>abnormal renal function<footnoteRef IDREF="_Refftx1"/> </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>anemia<footnoteRef IDREF="_Refftx1"/> </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>asthenia</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>dizziness </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>edema<footnoteRef IDREF="_Refftx1"/> </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>elevated liver enzymes<footnoteRef IDREF="_Refftx1"/> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>headaches </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>hypertension </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>increased bleeding time<footnoteRef IDREF="_Refftx1"/> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>infection </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>pharyngitis </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>pruritus</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>rashes </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>rhinitis </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>tinnitus<footnoteRef IDREF="_Refftx1"/> </paragraph> </td> </tr> </tbody> </table>