WARNINGS
Risk of Gastrointestinal (GI) Ulceration, Bleeding, and Perforation with Nonsteroidal Anti-Inflammatory Drug (NSAID) Therapy
Serious GI toxicity, such as bleeding, ulceration, and perforation, can occur at any time, with or without warning symptoms, in patients treated chronically with NSAIDs. Although minor upper GI problems, such as dyspepsia, are common, usually developing early in therapy, physicians should remain alert for ulceration and bleeding in patients treated chronically with NSAIDs, even in the absence of previous GI-tract symptoms. In patients observed in clinical trials of such agents for several months’ to 2 years’ duration, symptomatic upper GI ulcers, gross bleeding, or perforation appears to occur in approximately 1% of patients treated for 3 to 6 months and in about 2% to 4% of patients treated for 1 year. Physicians should inform patients about the signs and/or symptoms of serious GI toxicity and what steps to take if they occur.
Studies to date have not identified any subset of patients not at risk of developing peptic ulceration and bleeding. Except for a prior history of serious GI events and other risk factors known to be associated with peptic ulcer disease, such as alcoholism, smoking, etc., no risk factors (e.g., age, sex) have been associated with increased risk. Elderly or debilitated patients seem to tolerate ulceration or bleeding less well than other individuals, and most spontaneous reports of fatal GI events are in this population. Studies to date are inconclusive concerning the relative risk of various NSAIDs in causing such reactions. High doses of any NSAID probably carry a greater risk of these reactions, although controlled clinical trials showing this do not exist in most cases. In considering the use of relatively large doses (within the recommended dosage range), sufficient benefit should be anticipated to offset the potential increased risk of GI toxicity.
Anaphylactoid Reactions
Anaphylactoid reactions may occur in patients without prior exposure to etodolac. Etodolac should not be given to patients with aspirin triad. The triad 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 nonsteroidal anti-inflammatory drugs. Fatal reactions have been reported in such patients (see CONTRAINDICATIONS and PRECAUTIONS – Pre-existing Asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs.
Advanced Renal Disease
In cases with advanced kidney disease, as with other NSAIDs, treatment with etodolac should only be initiated with close monitoring of the patient’s kidney function (see PRECAUTIONS – Renal Effects).
Pregnancy
In late pregnancy, as with other NSAIDs, etodolac should be avoided because it may cause premature closure of the ductus arteriosus (see PRECAUTIONS – Teratogenic Effects – Pregnancy Category C).
PRECAUTIONS
General Precautions
Renal Effects
As with other NSAIDs, long-term administration of etodolac to rats has resulted in renal papillary necrosis and other renal medullary changes. Renal pelvic transitional epithelial hyperplasia, a spontaneous change occurring with variable frequency, was observed with increased frequency in treated male rats in a 2-year chronic study.
A second form of renal toxicity encountered with etodolac, as with other NSAIDs, is seen in patients with conditions in which renal prostaglandins have a supportive 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 decomposition. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, or liver dysfunction; those taking diuretics; and the elderly. Discontinuation of nonsteroidal anti-inflammatory drug therapy is usually followed by recovery to the pretreatment state.
Etodolac metabolites are eliminated primarily by the kidneys. The extent to which the inactive glucuronide metabolites may accumulate in patients with renal failure has not been studied. As with other drugs whose metabolites are excreted by the kidney, the possibility that adverse reactions (not listed in ADVERSE REACTIONS) may be attributable to these metabolites should be considered.
Hepatic Effects
Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs, including etodolac. These abnormalities may disappear, remain essentially unchanged, or progress with continued therapy. Meaningful elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with etodolac. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with etodolac. Rare cases of liver necrosis and hepatic failure, some of them with fatal outcomes have been reported. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), etodolac should be discontinued.
Hematological Effects
Anemia is sometimes seen in patients receiving NSAIDs including etodolac. This may be due to fluid retention, GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including etodolac, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.
All drugs which inhibit the biosynthesis of prostaglandins may interfere to some extent with platelet function and vascular responses to bleeding.
Fluid Retention and Edema
Fluid retention and edema have been observed in some patients taking NSAIDs, including etodolac. Therefore, etodolac should be used with caution in patients with fluid retention, hypertension, or heart failure.
Pre-existing Asthma
About 10% of patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthmas has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, etodolac should not be administered to patients with this form of aspirin sensitivity and should be used with caution in all patients with pre-existing asthma.
Information for Patients
Etodolac, like other drugs of its class, can cause discomfort and, rarely, more serious side effects, such as gastrointestinal bleeding, which may result in hospitalization and even fatal outcomes.
Physicians may wish to discuss with their patients the potential risks (see WARNINGS, PRECAUTIONS, ADVERSE REACTIONS) and likely benefits of nonsteroidal anti-inflammatory drug treatment.
Patients on etodolac should report to their physicians signs or symptoms of gastrointestinal ulceration or bleeding, blurred vision or other eye symptoms, skin rash, weight gain, or edema.
Because serious gastrointestinal tract ulcerations and bleeding can occur without warning symptoms, physicians should follow chronically treated patients for the signs and symptoms of ulcerations and bleeding and should inform them of the importance of this follow-up (see WARNINGS – Risk of GI Ulceration, Bleeding and Perforation with Nonsteroidal Anti-inflammatory Therapy).
Patients should also be instructed to seek medical emergency help in case of an occurrence of anaphylactoid reactions (see WARNINGS).
Laboratory Tests
Patients on long-term treatment with etodolac, as with other NSAIDs, should have their hemoglobin or hematocrit checked periodically for signs or symptoms of anemia. Appropriate measures should be taken in case such signs of anemia occur.
If clinical signs and symptoms consistent with liver disease develop or if systemic manifestations occur (e.g., eosinophilia, rash, etc.) and if abnormal liver tests are detected, persist or worsen, etodolac should be discontinued.
Drug Interactions
Antacids
The concomitant administration of antacids has no apparent effect on the extent of absorption of etodolac. However, antacids can decrease the peak concentration reached by 15% to 20% but have no detectable effect on the time-to-peak.
Aspirin
When etodolac is administered with aspirin, its protein binding is reduced, although the clearance of free etodolac is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of etodolac and aspirin is not generally recommended because of the potential of increased adverse effects.
Warfarin
Short-term pharmacokinetic studies have demonstrated that concomitant administration of warfarin and etodolac results in reduced protein binding of warfarin, but there was no change in the clearance of free warfarin. There was no significant difference in the pharmacodynamic effect of warfarin administered alone and warfarin administered with etodolac as measured by prothrombin time. Thus, concomitant therapy with warfarin and etodolac should not require dosage adjustment of either drug. However, there have been a few spontaneous reports of prolonged prothrombin times in etodolac-treated patients receiving concomitant warfarin therapy. Caution should be exercised because interactions have been seen with other NSAIDs.
Cyclosporine, Digoxin, Lithium, Methotrexate
Etodolac, like other NSAIDs, through effects on renal prostaglandins, may cause changes in the elimination of these drugs leading to elevated serum levels of digoxin, lithium, and methotrexate and increased toxicity. Nephrotoxicity associated with cyclosporine may also be enhanced. Patients receiving these drugs who are given etodolac, or any other NSAID, and particularly those patients with altered renal function, should be observed for the development of the specific toxicities of these drugs.
Phenylbutazone
Phenylbutazone causes increase (by about 80%) in the free fraction of etodolac. Although in vivo studies have not been done to see if etodolac clearance is changed by coadministration of phenylbutazone, it is not recommended that they be coadministered.
Drug/Laboratory Test Interactions
The urine of patients who take etodolac can give a false-positive reaction for urinary bilirubin (urobilin) due to the presence of phenolic metabolites of etodolac. Diagnostic dip-stick methodology, used to detect ketone bodies in urine, has resulted in false-positive findings in some patients treated with etodolac. Generally, this phenomenon has not been associated with other clinically significant events. No dose-relationship has been observed.
Etodolac treatment is associated with a small decrease in serum uric acid levels. In clinical trials, mean decreases of 1 to 2 mg/dL were observed in arthritic patients receiving etodolac (600 mg to 100 mg/day) after 4 weeks of therapy. These levels then remained stable for up to 1 year of therapy.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
No carcinogenic effect of etodolac was observed in mice or rats receiving oral doses of 15 mg/kg/day (45 to 89 mg/m2, respectively) or less for periods of 2 years or 18 months, respectively. Etodolac was not mutagenic in in vitro tests performed with S. typhimurium and mouse lymphoma cells as well as in an in vivo mouse micronucleus test. However, data from the in vitro human peripheral lymphocyte test showed an increase in the number of gaps (3.0 to 5.3% unstained regions in the chromatid without dislocation) among the etodolac-treated cultures (50 to 200 µg/mL) compared to negative controls (2.0%); no other difference was noted between the controls and drug-treated groups. Etodolac showed no impairment of fertility in male and female rats up to oral doses of 16 mg/kg (94 mg/m2). However, reduced implantation of fertilized eggs occurred in the 8 mg/kg group.
Pregnancy
Teratogenic Effects – Pregnancy Category C
In teratology studies, isolated occurrences of alterations in limb development were found and included polydactyly, oligodactyly, syndactyly, and unossified phalanges in rats and oligodactyly and synostosis of metatarsals in rabbits. These were observed at dose levels (2 to 14 mg/kg/day) close to human clinical doses. However, the frequency and the dosage group distribution of these findings in initial or repeated studies did not establish a clear drug or dose-response relationship.
There are no adequate or well-controlled studies in pregnant women. Etodolac should be used during pregnancy only if the potential benefits justify the potential risk to the fetus. Because of the known effects of NSAIDs on parturition and on the human fetal cardiovascular system with respect to closure of the ductus arteriosus, use during late pregnancy should be avoided.
Labor and Delivery
In rat studies with etodolac, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of etodolac on labor and delivery in pregnant women are unknown.
Nursing Mothers
It is not known whether etodolac is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from etodolac, a decision should be made whether to discontinue nursing or to discontinue the drug taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Population
As with any NSAID, however, caution should be exercised in treating the elderly, and when individualizing their dosage, extra care should be taken when increasing the dose because the elderly seem to tolerate NSAID side effects less well than younger patients. In patients 65 years and older, no substantial differences in the side effect profile of etodolac were seen compared with the general population (see CLINICAL PHARMACOLOGY – Pharmacokinetics).
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