lodine (Etodolac)  capsule 
lodine (Etodolac)  tablet, film coated 
[Wyeth Pharmaceuticals Inc.]

Rx only

DESCRIPTION

Lodine® (etodolac) is a member of the pyranocarboxylic acid group of nonsteroidal anti-inflammatory drugs (NSAIDs). Each tablet and capsule contains etodolac for oral administration. Etodolac is a racemic mixture of [+]S and [-]R-enantiomers. Etodolac is a white crystalline compound, insoluble in water but soluble in alcohols, chloroform, dimethyl sulfoxide, and aqueous polyethylene glycol.

The chemical name is (±) 1,8-diethyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetic acid. The molecular weight of the base is 287.37. It has a pKa of 4.65 and an n-octanol:water partition coefficient of 11.4 at pH 7.4. The molecular formula for etodolac is C17H21NO3, and it has the following structural formula:

The inactive ingredients in Lodine include:

—in capsules: cellulose, gelatin, iron oxides, lactose, magnesium stearate,povidone, sodium lauryl sulfate, sodium starch glycolate, and titanium dioxide.

—in tablets: cellulose, hypromellose, lactose, magnesium stearate, polyethylene glycol, polysorbate 80, povidone, sodium starch glycolate, and titanium dioxide. The 400 mg tablets contain D&C Yellow #10, FD&C Blue #2, and FD&C Yellow #6 as color additives. The 500 mg tablets contain FD&C Blue #2 only.

CLINICAL PHARMACOLOGY

Pharmacodynamics

Lodine is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of Lodine, like that of other NSAIDs, is not completely understood, but may be related to prostaglandin synthetase inhibition.

Lodine is a racemic mixture of [-]R- and [+]S-etodolac. As with other NSAIDs, it has been demonstrated in animals that the [+]S-form is biologically active. Both enantiomers are stable and there is no [-]R to [+]S conversion in vivo.

Pharmacokinetics

Absorption

The systemic bioavailability of etodolac from Lodine is 100% as compared to solution and at least 80% as determined from mass balance studies. Etodolac is well absorbed and had a relative bioavailability of 100% when 200 mg capsules were compared with a solution of etodolac. Based on mass balance studies, the systemic availability of etodolac from either the tablet or capsule formulation is at least 80%. Etodolac does not undergo significant first-pass metabolism following oral administration. Mean (± 1 SD) peak plasma concentrations (Cmax) range from approximately 14 ± 4 to 37 ± 9 μg/mL after 200 to 600 mg single doses and are reached in 80 ± 30 minutes (see Table 1 for summary of pharmacokinetic parameters). The dose-proportionality based on the area under the plasma concentration-time curve (AUC) is linear following doses up to 600 mg every 12 hours. Peak concentrations are dose proportional for both total and free etodolac following doses up to 400 mg every 12 hours, but following a 600 mg dose, the peak is about 20% higher than predicted on the basis of lower doses. The extent of absorption of etodolac is not affected when Lodine is administered after a meal. Food intake, however, reduces the peak concentration reached by approximately one-half and increases the time to peak concentration by 1.4 to 3.8 hours.

Table 1. Mean (CV%)† Pharmacokinetic Parameters of Lodine in Normal Healthy Adults and Various Special Populations

†% Coefficient of variation
*Age Range (years)
NA = not available
PK Parameters	Normal Healthy Adults (18-65)* (n=179)	Healthy Males (18-65) (n=176)	Healthy Females (27-65) (n=3)	Elderly (>65) (70-84)	Hemodialysis (24-65) (n=9)		Renal Impairment (46-73) (n=10)	Hepatic Impairment (34-60) (n=9)
					Dialysis On	Dialysis Off
Tmax, h	1.4 (61%)†	1.4 (60%)	1.7 (60%)	1.2 (43%)	1.7 (88%)	0.9 (67%)	2.1 (46%)	1.1 (15%)
Oral Clearance, mL/h/kg (CL/F)	49.1 (33%)	49.4 (33%)	35.7 (28%)	45.7 (27%)	NA	NA	58.3 (19%)	42.0 (43%)
Apparent Volume of Distribution, mL/kg (Vd/F)	393 (29%)	394 (29%)	300 (8%)	414 (38%)	NA	NA	NA	NA
Terminal Half-Life, h	6.4 (22%)	6.4 (22%)	7.9 (35%)	6.5 (24%)	5.1 (22%)	7.5 (34%)	NA	5.7 (24%)

Distribution

The mean apparent volume of distribution (Vd/F) of etodolac is approximately 390 mL/kg. Etodolac is more than 99% bound to plasma proteins, primarily to albumin. The free fraction is less than 1% and is independent of etodolac total concentration over the dose range studied. It is not known whether etodolac is excreted in human milk; however, based on its physical-chemical properties, excretion into breast milk is expected. Data from in vitro studies, using peak serum concentrations at reported therapeutic doses in humans, show that the etodolac free fraction is not significantly altered by acetaminophen, ibuprofen, indomethacin, naproxen, piroxicam, chlorpropamide, glipizide, glyburide, phenytoin, and probenecid.

Metabolism

Etodolac is extensively metabolized in the liver. The role, if any, of a specific cytochrome P450 system in the metabolism of etodolac is unknown. Several etodolac metabolites have been identified in human plasma and urine. Other metabolites remain to be identified. The metabolites include 6-, 7-, and 8-hydroxylated-etodolac and etodolac glucuronide. After a single dose of 14C-etodolac, hydroxylated metabolites accounted for less than 10% of total drug in serum. On chronic dosing, hydroxylated-etodolac metabolite does not accumulate in the plasma of patients with normal renal function. The extent of accumulation of hydroxylated-etodolac metabolites in patients with renal dysfunction has not been studied. The hydroxylated-etodolac metabolites undergo further glucuronidation followed by renal excretion and partial elimination in the feces.

Excretion

The mean oral clearance of etodolac following oral dosing is 49 (± 16) mL/h/kg. Approximately 1% of a Lodine dose is excreted unchanged in the urine with 72% of the dose excreted into urine as parent drug plus metabolite:

— etodolac, unchanged	1%
— etodolac glucuronide	13%
— hydroxylated metabolites (6-, 7-, and 8-OH)	5%
— hydroxylated metabolite glucuronides	20%
— unidentified metabolites	33%

Although renal elimination is a significant pathway of excretion for etodolac metabolites, no dosing adjustment in patients with mild to moderate renal dysfunction is generally necessary. The terminal half-life (t1/2) of etodolac is 6.4 hours (22% CV). In patients with severe renal dysfunction or undergoing hemodialysis, dosing adjustment is not generally necessary.

Fecal excretion accounted for 16% of the dose.

Special Populations

Geriatric

In Lodine clinical studies, no overall differences in safety or effectiveness were observed between these patients and younger patients. In pharmacokinetic studies, age was shown not to have any effect on etodolac half-life or protein binding, and there was no change in expected drug accumulation. Therefore, no dosage adjustment is generally necessary in the elderly on the basis of pharmacokinetics (see PRECAUTIONS, Geriatric Use).

Etodolac is eliminated primarily by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see WARNINGS, Renal Effects).

Pediatric

Safety and effectiveness in pediatric patients below the age of 18 years have not been established.

Race

Pharmacokinetic differences due to race have not been identified. Clinical studies included patients of many races, all of whom responded in a similar fashion.

Hepatic Insufficiency

Etodolac is predominantly metabolized by the liver. In patients with compensated hepatic cirrhosis, the disposition of total and free etodolac is not altered. Patients with acute and chronic hepatic diseases do not generally require reduced doses of etodolac compared to patients with normal hepatic function. However, etodolac clearance is dependent on liver function and could be reduced in patients with severe hepatic failure. Etodolac plasma protein binding did not change in patients with compensated hepatic cirrhosis given Lodine.

Renal Insufficiency

Lodine pharmacokinetics have been investigated in subjects with renal insufficiency. Etodolac renal clearance was unchanged in the presence of mild-to-moderate renal failure (creatinine clearance 37 to 88 mL/min). Furthermore, there were no significant differences in the disposition of total and free etodolac in these patients. However, etodolac should be used with caution in such patients because, as with other NSAIDs, it may further decrease renal function in some patients. In patients undergoing hemodialysis, there was a 50% greater apparent clearance of total etodolac, due to a 50% greater unbound fraction. Free etodolac clearance was not altered, indicating the importance of protein binding in etodolac's disposition. Etodolac is not significantly removed from the blood in patients undergoing hemodialysis.

CLINICAL TRIALS

Analgesia

Controlled clinical trials in analgesia were single-dose, randomized, double-blind, parallel studies in three pain models, including dental extractions. The analgesic effective dose for Lodine established in these acute pain models was 200 to 400 mg. The onset of analgesia occurred approximately 30 minutes after oral administration. Lodine 200 mg provided efficacy comparable to that obtained with aspirin (650 mg). Lodine 400 mg provided efficacy comparable to that obtained with acetaminophen with codeine (600 mg + 60 mg). The peak analgesic effect was between 1 to 2 hours. Duration of relief averaged 4 to 5 hours for 200 mg of Lodine and 5 to 6 hours for 400 mg of Lodine as measured by when approximately half of the patients required remedication.

Osteoarthritis

The use of Lodine in managing the signs and symptoms of osteoarthritis of the hip or knee was assessed in double-blind, randomized, controlled clinical trials in 341 patients. In patients with osteoarthritis of the knee, Lodine, in doses of 600 to 1000 mg/day, was better than placebo in two studies. The clinical trials in osteoarthritis used b.i.d. dosage regimens.

Rheumatoid Arthritis

In a 3-month study with 426 patients, Lodine 300 mg b.i.d. was effective in management of rheumatoid arthritis and comparable in efficacy to piroxicam 20 mg/day. In a long-term study with 1,446 patients in which 60% of patients completed 6 months of therapy and 20% completed 3 years of therapy, Lodine in a dose of 500 mg b.i.d. provided efficacy comparable to that obtained with ibuprofen 600 mg q.i.d. In clinical trials of rheumatoid arthritis patients, Lodine has been used in combination with gold, d-penicillamine, chloroquine, corticosteroids, and methotrexate.

INDICATIONS AND USAGE

Carefully consider the potential benefits and risks of Lodine and other treatment options before deciding to use Lodine. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).

Lodine (etodolac capsules and tablets) is indicated:

• For acute and long-term use in the management of signs and symptoms of the following:
  1. Osteoarthritis
  2. Rheumatoid arthritis
• For the management of acute pain

CONTRAINDICATIONS

Lodine is contraindicated in patients with known hypersensitivity to etodolac.

Lodine should not be given to patients who have experienced asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS, Anaphylactoid Reactions and PRECAUTIONS, Pre-existing Asthma).

Lodine is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (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, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or 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 does increase the risk of serious GI events (see WARNINGS, Gastrointestinal Effects—Risk of Ulceration, Bleeding, and Perforation).

Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS).

Hypertension

NSAIDs, including Lodine, can lead to onset of new hypertension or worsening of pre-existing 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 Lodine, 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.

Congestive Heart Failure and Edema

Fluid retention and edema have been observed in some patients taking NSAIDs. Lodine should be used with caution in patients with fluid retention or heart failure.

Gastrointestinal Effects—Risk of Ulceration, Bleeding, and Perforation

NSAIDs, including Lodine, 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 3-6 months, and in about 2-4% 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. Physicians should inform patients about the signs and/or symptoms of serious GI toxicity and what steps to take if they occur.

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, and 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 greater 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.

Caution should be used when initiating treatment with Lodine in patients with considerable dehydration. It is advisable to rehydrate patients first and then start therapy with Lodine.

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.

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.

Advanced Renal Disease

No information is available from controlled clinical studies regarding the use of Lodine in patients with advanced renal disease. Therefore, treatment with Lodine is not recommended in these patients with advanced renal disease. If Lodine 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 prior exposure to Lodine. Lodine 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. Fatal reactions have been reported in such patients (see CONTRAINDICATIONS and PRECAUTIONS, General, Pre-existing Asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs.

Skin Reactions

NSAIDs, including Lodine, 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, the third trimester, as with other NSAIDs, Lodine should be avoided because it may cause premature closure of the ductus arteriosus (see PRECAUTIONS, Pregnancy, Nonteratogenic Effects).

PRECAUTIONS

General

Lodine cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered solely if a decision is made to discontinue corticosteroids.

The pharmacological activity of Lodine in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.

Hepatic Effects

Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including Lodine. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable 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 NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis, and hepatic failure, some of them with fatal outcomes, have been reported.

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 Lodine. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), Lodine should be discontinued.

Hematological Effects

Anemia is sometimes seen in patients receiving NSAIDs including Lodine. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including Lodine, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.

NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving Lodine who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.

Pre-existing Asthma

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, Lodine 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

Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.

1. Lodine, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects).
2. Lodine, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects—Risk of Ulceration, Bleeding, and Perforation).
3. Lodine, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.
4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.
5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
6. Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS).
7. In late pregnancy, the third trimester, as with other NSAIDs, Lodine should be avoided because it may cause premature closure of the ductus arteriosus.

Laboratory Tests

Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile 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 or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, Lodine should be discontinued.

Drug Interactions

ACE-inhibitors

Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors (see WARNINGS).

Antacids

The concomitant administration of antacids has no apparent effect on the extent of absorption of Lodine. However, antacids can decrease the peak concentration reached by 15% to 20% but have no detectable effect on the time-to-peak.

Aspirin

When Lodine 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.

Cyclosporine, Digoxin, Methotrexate

Lodine, like other NSAIDs, through effects on renal prostaglandins, may cause changes in the elimination of these drugs leading to elevated serum levels of cyclosporine, digoxin, methotrexate, and increased toxicity. Nephrotoxicity associated with cyclosporine may also be enhanced. Patients receiving these drugs who are given Lodine, 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. NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate.

Diuretics

Etodolac has no apparent pharmacokinetic interaction when administered with furosemide or hydrochlorothiazide. Nevertheless, clinical studies, as well as postmarketing observations have shown that Lodine can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS, Renal Effects), as well as to assure diuretic efficacy.

Glyburide

Etodolac has no apparent pharmacokinetic interaction when administered with glyburide.

Lithium

NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.

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.

Phenytoin

Etodolac has no apparent pharmacokinetic interaction when administered with phenytoin.

Warfarin

The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than that of users of either drug alone. Short-term pharmacokinetic studies have demonstrated that concomitant administration of warfarin and Lodine® (etodolac capsules and tablets) 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 Lodine as measured by prothrombin time. Thus, concomitant therapy with warfarin and Lodine should not require dosage adjustment of either drug. However, caution should be exercised because there have been a few spontaneous reports of prolonged prothrombin times, with or without bleeding, in etodolac-treated patients receiving concomitant warfarin therapy.

Drug/Laboratory Test Interactions

The urine of patients who take Lodine 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 Lodine. Generally, this phenomenon has not been associated with other clinically significant events. No dose relationship has been observed.

Lodine 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 1000 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 Lodine-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. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women.

Nonteratogenic Effects

Lodine should be used during pregnancy only if the potential benefits justify the potential risk to the fetus. Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of the ductus arteriosus), use during pregnancy (particularly during the third trimester) should be avoided.

Labor and Delivery

In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of Lodine 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 Lodine, 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 below the age of 18 years have not been established.

Geriatric Use

As with any NSAID, caution should be exercised in treating the elderly (65 years and older) and when increasing the dose (see WARNINGS).

In Lodine clinical studies, no overall differences in safety or effectiveness were observed between these patients and younger patients. In pharmacokinetic studies, age was shown not to have any effect on etodolac half-life or protein binding, and there was no change in expected drug accumulation. Therefore, no dosage adjustment is generally necessary in the elderly on the basis of pharmacokinetics (see CLINICAL PHARMACOLOGY, Special Populations).

Elderly patients may be more sensitive to the antiprostaglandin effects of NSAIDs (on the gastrointestinal tract and kidneys) than younger patients (see WARNINGS). In particular, elderly or debilitated patients who receive NSAID therapy seem to tolerate gastrointestinal ulceration or bleeding less well than other individuals, and most spontaneous reports of fatal GI events are in this population.

Etodolac is eliminated primarily by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see WARNINGS, Renal Effects).

ADVERSE REACTIONS

In patients taking Lodine or other NSAIDs, the most frequently reported adverse experiences occurring in approximately 1-10% of patients are:

Gastrointestinal experiences including: abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gross bleeding/perforation, heartburn, nausea, GI ulcers (gastric/duodenal), vomiting.

Other events including: abnormal renal function, anemia, dizziness, edema, elevated liver enzymes, headaches, increased bleeding time, pruritis, rashes, tinnitus.

Adverse-reaction information for Lodine was derived from 2,629 arthritic patients treated with Lodine (etodolac capsules and tablets) in double-blind and open-label clinical trials of 4 to 320 weeks in duration and worldwide postmarketing surveillance studies. In clinical trials, most adverse reactions were mild and transient. The discontinuation rate in controlled clinical trials, because of adverse events, was up to 10% for patients treated with Lodine.

New patient complaints (with an incidence greater than or equal to 1%) are listed below by body system. The incidences were determined from clinical trials involving 465 patients with osteoarthritis treated with 300 to 500 mg of Lodine b.i.d. (i.e., 600 to 1000 mg/day).

Incidence Greater Than Or Equal To 1%—Probably Causally Related

Body as a whole—Chills and fever.

Digestive system—Dyspepsia (10%), abdominal pain1, diarrhea1, flatulence1, nausea1, constipation, gastritis, melena, vomiting.

Nervous system—Asthenia/malaise1, dizziness1, depression, nervousness.

Skin and appendages—Pruritus, rash.

Special senses—Blurred vision, tinnitus.

Urogenital system—Dysuria, urinary frequency.

---

1

Drug-related patient complaints occurring in 3 to 9% of patients with Lodine.
Drug-related patient-complaints occurring in few than 3%, but more than 1%, are unmarked.

Incidence Less Than 1%—Probably Causally Related

(Adverse reactions reported only in worldwide postmarketing experience, not seen in clinical trials, are considered rarer and are italicized.)

Body as a whole—Allergic reaction, anaphylactic/anaphylactoid reactions (including shock).

Cardiovascular system—Hypertension, congestive heart failure, flushing, palpitations, syncope, vasculitis (including necrotizing and allergic).

Digestive system—Thirst, dry mouth, ulcerative stomatitis, anorexia, eructation, elevated liver enzymes, cholestatic hepatitis, hepatitis, cholestatic jaundice, duodenitis, jaundice, hepatic failure, liver necrosis, peptic ulcer with or without bleeding and/or perforation, intestinal ulceration, pancreatitis.

Hemic and lymphatic system—Ecchymosis, anemia, thrombocytopenia, bleeding time increased, agranulocytosis, hemolytic anemia, leukopenia, neutropenia, pancytopenia.

Metabolic and nutritional—Edema, serum creatinine increase, hyperglycemia in previously controlled diabetic patients.

Nervous system—Insomnia, somnolence.

Respiratory system—Asthma, pulmonary infiltration with eosinophilia.

Skin and appendages—Angioedema, sweating, urticaria, vesiculobullous rash, cutaneous vasculitis with purpura, Stevens-Johnson Syndrome, toxic epidermal necrolysis, hyperpigmentation, erythema multiforme.

Special senses—Photophobia, transient visual disturbances.

Urogenital system—Elevated BUN, renal failure, renal insufficiency, renal papillary necrosis.

Incidence Less Than 1%—Causal Relationship Unknown

(Medical events occurring under circumstances where causal relationship to Lodine is uncertain. These reactions are listed as alerting information for physicians.)

Body as a whole—Infection, headache.

Cardiovascular system—Arrhythmias, myocardial infarction, cerebrovascular accident.

Digestive system—Esophagitis with or without stricture or cardiospasm, colitis.

Metabolic and nutritional—Change in weight.

Nervous system—Paresthesia, confusion.

Respiratory system— Bronchitis, dyspnea, pharyngitis, rhinitis, sinusitis.

Skin and appendages—Alopecia, maculopapular rash, photosensitivity, skin peeling.

Special senses—Conjunctivitis, deafness, taste perversion.

Urogenital system—Cystitis, hematuria, leukorrhea, renal calculus, interstitial nephritis, uterine bleeding irregularities.

Additional Adverse Reactions Reported with NSAIDS

Body as a whole—Sepsis, death

Cardiovascular system—Tachycardia

Digestive system—Gastric ulcers, gastritis, gastrointestinal bleeding, glossitis, hematemesis

Hemic and lymphatic system—Lymphadenopathy

Nervous system—Anxiety, dream abnormalities, convulsions, coma, hallucinations, meningitis, tremors, vertigo

Respiratory system—Respiratory depression, pneumonia

Urogenital system—Oliguria/polyuria, proteinuria

OVERDOSAGE

Symptoms following acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur and coma has occurred following massive ibuprofen or mefenamic-acid overdose. Hypertension, acute renal failure, and respiratory depression may occur but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following overdose.

Patients should be managed by symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose (5 to 10 times the usual dose). Forced diuresis, alkalinization of the urine, hemodialysis, or hemoperfusion would probably not be useful due to etodolac's high protein binding.

DOSAGE AND ADMINISTRATION

Carefully consider the potential benefits and risks of Lodine and other treatment options before deciding to use Lodine. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).

After observing the response to initial therapy with Lodine, the dose and frequency should be adjusted to suit an individual patient's needs. As with other NSAIDs, the lowest dose and longest dosing interval should be sought for each patient. Therefore, after observing the response to initial therapy with Lodine, the dose and frequency should be adjusted to suit an individual patient's needs.

Dosage adjustment of Lodine is generally not required in patients with mild to moderate renal impairment. Etodolac should be used with caution in such patients, because, as with other NSAIDs, it may further decrease renal function in some patients with impaired renal function (see WARNINGS, Renal Effects).

Analgesia

The recommended total daily dose of Lodine for acute pain is up to 1000 mg, given as 200-400 mg every 6 to 8 hours. Doses of etodolac greater than 1000 mg/day have not been adequately evaluated in well-controlled clinical trials.

Osteoarthritis and Rheumatoid Arthritis

The recommended starting dose of Lodine for the management of the signs and symptoms of osteoarthritis or rheumatoid arthritis is: 300 mg b.i.d., t.i.d., or 400 mg b.i.d., or 500 mg b.i.d. A lower dose of 600 mg/day may suffice for long-term administration. Physicians should be aware that doses above 1000 mg/day have not been adequately evaluated in well-controlled clinical trials.

In chronic conditions, a therapeutic response to therapy with Lodine is sometimes seen within one week of therapy, but most often is observed by two weeks. After a satisfactory response has been achieved, the patient's dose should be reviewed and adjusted as required.

HOW SUPPLIED

Lodine (etodolac capsules and tablets) is available as:

Lodine® (etodolac capsules) Capsules

200 mg capsules (light gray with one wide red band with LODINE 200/white with two narrow red bands)

—in bottles of 100, NDC 0046-0738-81

300 mg capsules (light gray with one wide red band with LODINE 300/light gray with two narrow red bands)

—in bottles of 100, NDC 0046-0739-81

Store at controlled room temperature 20°-25°C (68°-77°F), protected from moisture.

Lodine® (etodolac tablets) Tablets

400 mg tablets (yellow-orange, oval, film-coated tablet, debossed LODINE 400 on one side)

—in bottles of 100, NDC 0046-0761-81

Store at controlled room temperature 20°-25°C(68°-77°F).

Store tablets in original container until ready to use.

Dispense in light-resistant container.

500 mg tablets (blue, oval, film-coated tablet, branded LODINE 500 on one side)

—in bottles of 100, NDC 0046-0787-81

Store at controlled room temperature 20°-25°C(68°-77°F).

Store tablets in original container until ready to use.

Dispense in a light-resistant container.

The appearance of these capsules is a registered trademark of Wyeth Pharmaceuticals and the appearance of these tablets is a trademark of Wyeth Pharmaceuticals.

Wyeth®

Wyeth Pharmaceuticals Inc.
Philadelphia, PA 19101

W10484C004
ET01
Rev 07/05

Lodine (Etodolac)

PRODUCT INFO Product Code 0046-0738 Dosage Form CAPSULE Route Of Administration ORAL DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength etodolac (etodolac) Active 200 MILLIGRAM  In 1 CAPSULE Cellulose Inactive   Gelatin Inactive   Iron Oxides Inactive   Lactose Inactive   Magnesium Stearate Inactive   Povidone Inactive   Sodium Lauryl Sulfate Inactive   Sodium Starch Glycolate Inactive   Titanium Dioxide Inactive

IMPRINT INFORMATION Characteristic Appearance Characteristic Appearance Color GRAY (gray ) , WHITE (white ) Score 1 Shape CAPSULE (capsule) Symbol true Imprint Code LODINE;200 Coating false Size 22mm

PACKAGING # NDC Package Description Multilevel Packaging 1 0046-0738-81 100 CAPSULE In 1 BOTTLE None

Lodine (Etodolac)

PRODUCT INFO Product Code 0046-0739 Dosage Form CAPSULE Route Of Administration ORAL DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength etodolac (etodolac) Active 300 MILLIGRAM  In 1 CAPSULE Cellulose Inactive   Gelatin Inactive   Iron Oxides Inactive   Lactose Inactive   Magnesium Stearate Inactive   Povidone Inactive   Sodium Lauryl Sulfate Inactive   Sodium Starch Glycolate Inactive   Titanium Dioxide Inactive

IMPRINT INFORMATION Characteristic Appearance Characteristic Appearance Color GRAY (gray ) Score 1 Shape CAPSULE (capsule ) Symbol true Imprint Code LODINE;300 Coating false Size 22mm

PACKAGING # NDC Package Description Multilevel Packaging 1 0046-0739-81 100 CAPSULE In 1 BOTTLE None

Lodine (Etodolac)

PRODUCT INFO Product Code 0046-0761 Dosage Form TABLET, FILM COATED Route Of Administration ORAL DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength etodolac (etodolac) Active 400 MILLIGRAM  In 1 TABLET Cellulose Inactive   Hypromellose Inactive   Lactose Inactive   Magnesium Stearate Inactive   polyethylene glycol Inactive   polysorbate 80 Inactive   povidone Inactive   sodium starch glycolate Inactive   titanium dioxide Inactive   D&C Yellow 10 Inactive   FD&C Blue 2 Inactive   FD&C Yellow 6 Inactive

IMPRINT INFORMATION Characteristic Appearance Characteristic Appearance Color YELLOW (yellow ) , ORANGE (orange ) Score 1 Shape OVAL (oval ) Symbol false Imprint Code LODINE;400 Coating true Size 19mm

PACKAGING # NDC Package Description Multilevel Packaging 1 0046-0761-81 100 TABLET In 1 BOTTLE None

Lodine (Etodolac)

PRODUCT INFO Product Code 0046-0787 Dosage Form TABLET, FILM COATED Route Of Administration ORAL DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength etodolac (etodolac) Active 500 MILLIGRAM  In 1 TABLET Cellulose Inactive   Hypromellose Inactive   Lactose Inactive   Magnesium Stearate Inactive   polyethylene glycol Inactive   polysorbate 80 Inactive   povidone Inactive   sodium starch glycolate Inactive   titanium dioxide Inactive   FD&C Blue 2 Inactive

IMPRINT INFORMATION Characteristic Appearance Characteristic Appearance Color BLUE (Blue) Score 1 Shape OVAL (oval ) Symbol false Imprint Code LODINE;500 Coating true Size 19mm

PACKAGING # NDC Package Description Multilevel Packaging 1 0046-0787-81 100 TABLET In 1 BOTTLE None

Revised: 03/2006Wyeth Pharmaceuticals Inc.