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Lodine®

(etodolac)
Capsules and Tablets


DESCRIPTION
CLINICAL PHARMACOLOGY
INDICATIONS AND USAGE
CONTRAINDICATIONS
WARNINGS
PRECAUTIONS
ADVERSE REACTIONS
OVERDOSAGE
DOSAGE AND ADMINISTRATION
HOW SUPPLIED

DESCRIPTION:<׈4'/a>
Lodine (etodolac) is a pyranocarboxylic acid, chemically designated as () 1,8 diethyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1 -acetic acid. Lodine is a racernic mixture of R- and S-etodolac. The structural formula for etodolac is shown below:

The empirical formula for etodolac is C17H21NO3. 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. Etodolac is a white crystalline compound, insoluble in water but soluble in alcohols, chloroform, dimethyl sulfoxide, and aqueous polyethylene glycol.
The inactive ingredients present in the capsules are cellulose, gelatin, iron oxides, lactose, magnesium stearate, povidone, sodium lauryl sulfate, sodium starch glycolate, and titanium dioxide.
The inactive ingredients present in the tablets are cellulose, FD&C Yellow #10, FD&C Blue #2, FD&C Yellow #6, hydroxypropyl methylcellulose, lactose, magnesium stearate, polyethylene glycol, polysorbate 80, povidone, sodium starch glycolate, and titanium dioxide.
Lodine is available in 200 and 300 mg capsules and 400 mg tablets for oral administration.

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CLINICAL PHARMACOLOGY:
PHAHMACOLOGY
Etodolac is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits antiinflammatory, analgesic, and antipyrefic activities in animal models. The mechanism of action of etodolac, like that of other NSAIDs, is not known but is believed to be associate d with the inhibition of prostaglandin biosynthesis.
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 and the R-form is not. Both enantiomers are stable and there is no R-to-S conversion in vivo.

PHARMACODYNAMICS
Analgesia was demonstrable by 1/2 hour following single doses of 200 to 400 mg Lodine, with the peak effect occurring in 1 to 2 hours. The analgesic effect generally lasts for 4 to 6 hours (with some patients maintaining analgesia up to 8 to 12 hours; see "Analgesia" and "Osteoarthritis" sections under "CLINICAL TRIALS" below).

PHARMACOKINETICS
The pharmacokinetics of etodolac have been evaluated in 267 normal subjects, 44 elderly patients (>65 years old), 19 patients with renal failure (creatinine clearance 37 to 88 mL/min), 9 patients on hemodialysis, and 10 patients with compensated hepatic c irrhosis. Lodine 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 Lodine is at least 80%, and etodolac does not underg o significant first-pass metabolism following oral administration. The dose-proportionality based on AUC (the area under the plasma concentration-time curve) is linear following doses up to 600 mg every 12 hours. Peak concentrations are dose-proportiona l 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. As shown on the graphs below, etodolac plasma concentrations, after mult iple-dose administration, are slightly higher than after single doses, as predicted, indicating no change in pharmacokinetics with multiple-dose use. Etodolac is more than 99% bound to plasma proteins. The free fraction is less than 1% and is independen t of etodolac total concentration over the dose range studied.
Etodolac, when administered orally, exhibits characteristics which are well described by a two-compartment model with first-order absorption. Mean (1 SD) peak plasma concentrations range from approximately 14 4 to 37 9 g/mL after 200 to 600 mg single doses and are reached in 80 30 minutes. The mean plasma clearance of etodolac is 47 (16) mL/h/kg, and terminal disposition half-life is 7.3 ( 4.0) hours (see Table for Summary of Pharmacokinetic Parameters).
As with many drugs which are hepatically metabolized and not dosed on a mg/kg basis, the intersubject variability of etodolac plasma levels, achieved after recommended doses, is substantial. The graph of simulated curves below demonstrates the range of p lasma concentrations that would be expected for 95% of the patients following 200 or 400 mg single doses on the left and on t.i.d. regimens on the right (at steady-state). The crosshatched area represents the overlap in plasma levels following 200 or 400 mg of Lodine orally as single or multiple doses. The area above the upper 95% C.L. lines represents blood levels which would be achieved by larger doses or in individuals with decreased clearance in whom one should anticipate increased adverse reactions . The area below the 95% C.L. lines represents blood levels following lower doses or in individuals with high clearance of etodolac, and one would expect less effectiveness, in such patients. The data used to produce these simulations were derived from tire mean 2 SD of the plasma concentrations at each time point from a total of 267 normal subjects following multiple dosing. As with other drugs, including NSAIDs, greater variability is to be expected in patients, particularly those with GI problems and those taking other drugs affecting the GI tract, protein binding, or hepatic, or renal function.

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LODINE PLASMA CONCENTRATIONS
UPPER AND LOWER 95% CONFIDENCE LIMITS
FOLLOWING SINGLE 200 AND 400 MG ORAL DOSES

LODINE PLASMA CONCENTRATIONS
UPPER AND LOWER 95% CONFIDENCE LIMITS
FOLLOWING SINGLE 200 AND 400 MG T.I.D. ORAL DOSES
Table of Etodolac Steady-State Pharmacokinetic Parameters (n= 267)

Kinetic Parameters     Scientific Notation (units)     Mean  SD

Extent of oral absorption        F (%)                 >80
   (bioavailability)
Peak concentration time          tmax (h)              1.7  1.3
Oral-dose clearance              CL/F (mL/h/kg)         47  16
Central compartment              Vss/F (mL/kg)         132  47
    volume
Steady-state volume              Vss/F (mL/kg)         362  129
Distribution half-life           t1/2,alpha (h)       0.71  0.50
Terminal half-life               t1/2,beta (h)         7.3  4.0

Etodolac is extensively metabolized in the liver, with renal elimination of etodolac and its metabolites being the primary route of excretion. Approximately 72% of the administered d\Uis recovered in the urine as the following, indicated as % of the ad ministered dose:
		-etodolac, unchanged        1%
		-etodolac glucuronide      13%
		-hydroxylated metabolites
		 (6-, 7-, and 8-OH)         5%
		-hydroxylated metabolite
		 glucuronides              20%
		-unidentified metabolites  33%
Fecal excretion accounted for 16% of the dose. Therefore, enterohepatic circulation, if present, is not extensive.
The extent of absorption of etodolac is not affected when Lodine is administered after a meal or with an antacid. Food intake, however, reduces the peak concentration reached by approximately one half and increases the time-to-peak concentration by 1.4 t o 3.8 hours. Coadministration with an antacid decreases the peak concentration reached by about 15 to 20%, with no measurable effect on time-to-peak.
In studies in the elderly, age was found to have no effect on etodolac t1/2 or protein binding, and there was no drug accumulation. Etodolac clearance was reduced by about 15%. Because the reduction in clearance is small, no dosage adjustment is general ly necessary in the elderly on the basis of pharmacokinetics. The elderly may need dosage adjustment, however, on the basis of body size (see "GERIATRIC POPULATION"), and they may be more sensitive to antiprostaglandin effects than younger patients (see "Precautions").
In studies of the effects of mild-to-moderate renal impairment, no significant differences in the disposition of total and free etodoiac were observed. 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. Nevertheless, etodolac is not dialyzable. No dosage adjustment of Lodine is generally required in patie nts with mildto-moderate renal impairment; however, 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 "Precautions").
In patients with compensated hepatic cirrhosis, the disposition of total and free etodolac is not altered. Although no dosage adjustment is generally required in this patient population, etodolac clearance is dependent on hepatic function and could be re duced in patients with severe hepatic failure.

SPECIAL STUDIES
Lodine was compared with other NSAIDs in inducing gastrointestinal (GI) microbleeding. Lodine 1200 mg/day caused less GI blood loss than ibuprofen 2400 mg/day, indomethacin 200 mg/day, or naproxen 750 mg/day. Lodine was also compared with piroxicam 20 m g/day in two studies; piroxicam caused more blood loss than Lodine in one of these studies but not the other.
Lodine was also compared to other NSAIDs in GI endoscopic studies. Encloscopic scores in studies of 12 healthy subjects following 1 week of Lodine 1200 mg/day showed significantly fewer GI mucosal erosions with Lodine than with aspirin 3900 mg/day. In a nother study performed in healthy males 18 to 41 years of age, 12 subjects treated with Lodine 1000 mg/day for one week had lower encloscopic scores than 12 subjects treated with indomethacin 200 mg/day, naproxen 1000 mg/day, or ibuprofen 2400 mg/day. An other encloscopic study comparing effects of Locline 1000 mg/day with piroxicarn 20 mg/day, each administered to 12 normal volunteers for one month, yielded equivocal results, with both treatmefits showing higher scores than the 12-subject placebo treated group. The clinical significance of these findings is unknown.

CLINICAL TRIALS
Analgesia
Controlled clinical trials in analgesia were single-dose, randomized, double-blind, parallel studies in 3 pain models (dental extractions, post-general surgery, and post-episiotomy pain). In these studies, there were patients treated with placebo, 2 or m ore doses of etodolac, and varying combinations of aspirin, acetaminophen with codeine (oral surgery only), or zomepirac. The analgesic effective dose for Lodine established in these acute pain models was 200 to 400 mg. The onset of analgesia occurred a pproximately 30 minutes after oral administration and was comparable for Lodine (200 to 400 mg), aspirin (650 mg), acetaminophen with codeine (600 mg + 60 mg), and zomepirac (100 mg). The peak analgesic effect was between 1 to 2 hours. Duration of relie f 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. However, in some studies there were still statistically significant differences between the d egree of pain relief experienced by patients treated with 200 and 400 mg of Lodine and placebo-treated patients at 8 hours.

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 m g/day, was better than placebo in 2 studies. The clinical trials in osteoarthritis used t.i.d. dosage regimens. The initial dosing recommendation for Lodine in patients with osteoarthritis is t.i.d. administration, due to etodolac's pharmacokinetic prof ile (see "PHARMACOKINETICS" and "INDIVIDUALIZATION OF DOSAGE").

Rheumatoid Arthritis
Lodine is not recommended for the treatment of patients with rheumatoid arthritis because in controlled clinical trials, although Lodine treatment was sometimes better than placebo treatment, it was generally not as effective as treatment with other marke ted NSAIDs.

INDIVIDUALIZATION OF DOSAGE
Lodine, like other NSAIDs, shows considerable interindividual variation in response. Consequently, the recommended strategy for initiating therapy is to use a starting dose likely to be effective for the majority of patients and t adjust dosage thereafte r based on observations of Lodine's beneficial and adverse effects.
The effectiveness of Lodine in otherwise healthy, young to middle-aged adults in acute pain studies showed symptom relief to last approximately 5 to 6 hours following single 400 mg doses and 4 to 5 hours following 200 mg doses as judged by the time by whi ch approximately half of the patients needed remedication. In dental-extraction studies, hourly comparisons were made of the number of placebo-treated patients versus the number of Lodine-treated patients who needed to be remedicated. In these studies, the 200 mg Lodine group had significantly fewer patients who needed remedication up to 6 hours than the placebo group, while the 400 mg Lodine group had significantly fewer patients who required remedication for up to 12 hours.
These results suggest an initial Lodine dose of 400 mg for acute pain followed by doses of 200 to 400 mg every 6 to 8 hours, as needed, not to exceed a maximum total daily dose of 1200 mg. If a patient taking 400 mg doses has adequate pain relief that do es not last 8 hours, then 300 mg every 6 hours (q.i.d.) is a reasonable schedule to try. As with all NSAIDs, if symptoms are still not adequately controlled by recommended doses, another analgesic should be tried.
In osteoarthritis, the recommended starting dose of Lodine is 800 to 1200 mg/day in divided doses: 400 mg t.i.d. or b.i.d. or 300 mg q.i.d. or t.i.d. which is derived from pharmacokinetic and single-dose analgesic trial data. In controlled clinical trial s in patients with osteoarthritis, total daily doses of 600 to 1000 mg of Lodine were successfully given on a b.i.d. schedule. In one study, some patients were apparently adequately treated with as little as 200 mg Lodine b.i.d. The pharmacokinetic profi le of Lodine and the results of single-dose analgesia studies suggest, however, that the drug May provide greater benefit when given on a t.i.d. schedule. As with other NSAIDs, the lowest dose and longest dosing interval should be sough for each patient. Therefore, after observing the response to initial therapy with Lodine, the dose and frequency should be adjusted to suit individual patient's needs. The recommended total daily dose of Lodine is 600 to 1200mg/day given in divided doses: 400 mg t.i.d. or b.i.d.; 300 mg q.i.d., t.i.d., or b.i.d.; 200 mg q.i.d. or t.i.d.
Total daily doses of Lodine above 20 mg/kg/day have not been studied. Therefore, in patients weighing less than 60 kg (1 32 lbs), or where the severity of the disease, concomitant medications, or other diseases warrant, the maximum recommended total dail y dose of 1200 mg should be reduced (see "Precautions").

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INDICATIONS AND USAGE
Lodine is indicated for acute and long-term use in the management of signs and symptoms of osteoarthritis. Lodine is also indicated for the management of pain.

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CONTRAINDICATIONS: Lodine is contraindicated in patients who have previously shown hypersensitivity to it. Lodine should not be given to patients in whom Lodine, asprin, or other NSAIDs induce asthema, rhinitis, urticaria, or other allergic reactions.
Fatal asthmatic reactions have been reported in such patients receiving NSAIDs.

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WARNINGS:
RISK OF GASTROINTESTINAL (GI) ULCERATION, BLEEDING, AND PERFORATION WITH NONSTEROIDAL ANTI-INFLAMMATORY DRUG 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 yea rs' duration, symptomatic upper GI ulcers, gross bleeding, or perforation appear 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 a nd/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 alcoholi sm, 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 car a greater risk of these reactions, although controlled clinical trials showing this do not ex ist 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.

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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 o bserved with increased frequency in treated male rats in a 2-year chronic study. The cause-effect relationship to etodolac has not been established.
A second form of renal toxicity encountered with Lodine, 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 nonstero idal 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 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 wit renal failure has not been studied. As with other drugs whose metabolites are excreted by the kidney, t he possibility that adverse reactions (not listed in "Adverse Reactions") may be attributable to these metabolites should be considered.
Hepatic Effects
As with all NSAIDs, borderline elevations of one or more liver tests may occur in up to 15% of patients. These abnormalities may disappear, remain essentially unchanged, or progress with continued therapy. Meaningful elevations of ALT or AST (approximat ely three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with Lodine. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, shoul d be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with Lodine. Although such reactions are rare, if abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease devel op, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), Locline should be discontinued.
Hematological Effects
Anemia is sometimes seen in patients receiving Locline or other NSAIDs. This may be due to fluid retention, gastrointestinal blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including Lodi ne, should have their hemoglobin or hernatocrit checked if they develop 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. Patie nts receiving Lodine who may be adversely affected by such actions should be carefully observed.
Fluid Retention and Edema
Fluid retention and edema have been observed in some patients taking Lodine. Therefore, as with other NSAIDs, Lodine should be used with caution in patients with fluid retention, hypertension, or heart failure.
Information for Patients Lodine, like other NSAIDs (Nonsteroidal Anti-inflammatory Drugs), is not free of side effects. The side effects of these drugs can cause discomfort and, rarely, there may be serious side effects, such as GI bleeding, that ma result in hospitalization and even fatal outcomes.
NSAIDs are often essential agents in the management of arthritis and have a major role in the treatment of pain, but they also may be commonly employed for conditions that are less serious.
Physicians may wish to discuss with their patients the potential risks (see "Warnings," "Precautions," and "Adverse Reactions" sections) and likely benefits of Lodine treatment, particularly when it may b e used for less serious conditions in which treatment without Lodine may represent an accept able alternative to both the patient and physician.

LABORATORY TESTS
Because serious GI-tract ulceration and bleeding can occur without warning symptoms, physicians should observe chronically treated patients for the signs and symptoms of ulceration and bleeding and should inform the of the importance of this follow-up (se e "RISK OF GI ULCERATION, BLEEDING, AND PERFORATION WITH NSAID THERAPY").

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DRUG INTERACTIONS
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, con cornitant administration of L odine and aspirin is not generally recommended because of the potential of increased adverse effects. Warfarin
Short-term pharniacokinetic studies have demonstrated that concomitant administration of wartarin and Lodine results in reduced protein binding off warfarin, but there was no change in the clearance of free warfarin. There was significant difference in t he 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, following US market introduction of Lodine. there have been a few spontaneous reports of prolonged prothrombin times in Lodine-treated patients receiving concomitant warfarin therapy. Caution should be exercised because interactions have been seen with other NSAIDs.
Phenytoin
Lodine has no apparent pharmacokinetic interaction when administered with phenytoin.
Glyburide
Lodine has no apparent pharmacokinetic or pharmacodynamic interaction when administered with glyburide.
Diuretics
Lodine has no apparent pharmacokinetic interaction when administered with furosemide or hydrochlorothiazide; nor does Lodine attenuate the diuretic response of either of these drugs in normal volunteers. Lodine and other NSAIDs, nevertheless, should be u sed with caution in patients receiving diuretics, who have cardiac, renal, or hepatic failure (see "Renal Effects").
Cyclosporine, Digoxin, Lithium, 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 cligoxin, lithium, and methotrexate and increased toxicity. Nephrotoxicity associated with cyclosp orine 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.
Protein Binding
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, glyburicle, phenytoin, and probenecid. In contrast, phenylbutazone causes an 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 coadminist ration of phenylbutazone, it is not recommended that they be coadministered.

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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 fa lse-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. Locline treatment is associated with a small decrease in se rum 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 one 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 vitro tests p erformed 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 (p = 0.06) in the number of gaps (3.0 to 5.3% un stained regions in the chromatid without dislocation) among the Lodine-treated cultures (50 to 200 g/mL) compared to negative controls (2.0%); no other difference was noted between the controls and drug-treated groups. Etodolac showed no impairment of f ertility 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.

TERATOGENIC EFFECTS: PREGNANCY CATEGORY C
In teratology studies, isolated occurrences of alterations in limb development were found and included polydactyly, oligodactyly, syndactyly, and unossitied 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 distriibution 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.
Lodine 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 arteri osus, 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 Lodine on labor and delivery in pregnant women are un known.

NURSING MOTHERS
Caution should be exercised if Lodine is administered to a nursing woman, because many drugs are excreted in human milk. It is not known whether etodolac is excreted in human milk.

PEDIATRIC USE Safety and effectiveness in pediatric patients have not been established.

GERIATRIC POPULATION
In patients 65 years and older, no substantial differences in the pharmacokinetics or the side-effect profile of Lodine were seen compared with the general population. Therefore, no dosage adjustment is generally necessary in the elderly. As with any NS AID, however, caution should be exercised in treatia^Hhe 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 (see "PHA RMACOKINETICS").

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ADVERSE REACTIONS:
Adverse-reaction information for Lodine was derived from 2,629 arthritic patients treated with Lodine in double-blind and open-label clinical trials of 4 to 320 weeks in duration and worldwide postmarketing surveillance studies in approximately 60,000 pat ients.
In clinical trials, most adverse reactions were mild and transient. The discontinuation rate in controlled clinical trials, because of adverse events, was 9% 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 o Lodine b.i.d. (i.e., 600 to 1000 mg per day).
INCIDENCE GREATER THAN OR EQUAL TO 1%-PROBABLY CAUSALLY RELATED:
Body as a whole-Chills and fever.
Digestive system-Dyspepsia (10%), abdominal pain*, diarrhea*, flatulence*, nausea*, constipation, gastritis, melena, vomiting.
Nervous system-Asthenia/malaise*, dizziness*, depression, nervousness.
Skin and appendages-Pruritus, rash.
Special senses-Blurred vision, tinnitus.
Urogenital system-Dysuria, urinary frequency.
*Drug-related patient complaints occurring in 3 to 9% of patients treated with Lodine. Drug-related patient complaints occurring in fewer 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, anaphylactoid reaction.
Cardiovascular system-Hypertension, congestive heart failure, flushing, palpitations, syncope, vasculitis (including necrotizing and allergic).
Digestive system-Thirst, dry mouth, ulcerative stornatitis, anorexia, eructation, elevated liver enzymes, cholestatic hepatitis, hepatitis, cholestatic jaundice, jaundice, PUB (i.e., peptic ulcer with or without bleeding and/or perforati on), intestinal ulceration, pancreatitis.
Hemic and lymphatic system-Ecchymosis, anemia, thrombocytopenia, bleeding time increased, agranulocytosis, hemolytic anemia, neutropenia, pancytopenia.
Metabolic and nutritional-Edema, serum creatinine increase, hyperglycernia in previously controlled diabetic patients.
Nervous system-insomnia, somnolence.
Respiratory system-Asthma.
Skin and appenclages-Angioedema, sweating, urticaria, vesiculobullous rash, cutaneous vasculitis with purpura, Stevens-Johnson syndrome, 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.
Cardiovascular system-Arrhythmias, myocardial infarction.
Digestive system-Esophagitis with or without stricture or cardiospasm, colitis.
Hemic and lymphatic system-Leukopenia.
Metabolic and nutritional-Change in weight.
Nervous system-Paresthesia, confusion.
Respiratory system-Bronchitis, dyspnea, pharyngitis, rhinitis, sinusitis.
Skin and appenclages-Maculopapular rash, alopecia, skin peeling, photosensitivity.
Special senses-Conjunctivitis, deafness, taste perversion.
Urogenital system-Cystitis, hematuria, leukorrhea, renal calculus, interstitial nephritis, uterine bleeding irregularities.

Drug Abuse and Dependence Lodine is a non-narcotic drug. Several predictive animal studies indicated that Lodine has no addiction potential in humans.

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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 ib uprofen 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 followin an NSAID overdose. There are no specific antidotes. Gut decontamination may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose (5 t o 10 times the usual dose). This should be accomplished via emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) with an osmotic cathartic. Forced diuresis, alkalinization of the urine, hernodialysis, or hernoperfusion would probably not be useful due to etodolac's high protein binding.
There have been infrequent reports of Locline overdose. In one case of intentional etodolac overdosage (Human Toxicol. 1988; 7:203-4), a 53-year-old female ingested from 15 to 46 two-hundred mg etodolac capsules (3 to 8.6 grams). Plasma etodolac concent rations were measured frequently over the next 4 days. At 5 hours after ingestion (3 hours after gastric lavage) the plasma etodolac level was 22 g/mL. These plasma levels and her subsequent recovery with no signs or symptoms of etodolac toxicity were consistent with systemic absorption of 600 to 800 mg. Her laboratory tests on admission showed a prolonged prothrombin time and a false-positive urine bilirubin (attributed to the phenolic etodolac metabolites).

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DOSAGE AND ADMINISTRATION:
ANALGESIA
The recommended dose of Lodine for acute pain is 200 to 400 mg every 6 to 8 hours, as needed, not to exceed a total daily dose of 1200 mg. For patients weighing 60 kg or less, the total daily dose of Lodine should not exceed 20 mg/kg. For more details s ee "INDIVIDUALIZATION OF DOSAGE."
OSTEOARTHRITIS
The recommended dose of Lodine for the management of the signs and symptoms of osteoarthritis is initially 800 to 1200 mg/day in divided doses, followed by dosage adjustment within the range of 600 to 1200 mg/day given in divided doses: 400 mg t.i.d. or b .i.d.; 300 mg q.i.d., t.i.d., or b.i.d.; 200 mg q.i.d. or t.i.d. The total daily dose of Lodine should not exceed 1200 mg. ˞patients weighing 60 kg or less, the total daily dose of Lodine should not exceed 20 mg/kg. For more details see "INDIVIDUALIZ ATION OF DOSAGE."

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HOW SUPPLIED:
Lodine (etodolac) is available as:
Lodine®(etodolac) Capsules
200 mg capsules (light gray with one wide red band with LODINE 200/white with two narrow red bands)
-in bottles of 1 00, NDC 0046-0738-81
-in unit-dose packages of 100, NDC 0046-0738-99
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
-in unit-dose packages of 100, NDC 0046-0739-99

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

Lodine®(etodolac) Tablets
400 mg tablets (yellow-orange, oval, film-coated tablet, debossed LODINE 400 on one side)
-in bottles of 100, NDC 0046-0761-81
-in unit-dose packages of 100, NDC 0046-0761-99

Store at controlled room temperature, 20o-25oC (68o-77oF).

The appearance of these capsules is a registered trademark of Wyeth-Ayerst Laboratories and the appearance of these tablets is a trademark of Wyeth-Ayerst Laboratories.

Caution: Federal law prohibits dispensing without prescription.

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Ayerst Laboratories Inc.

A Wyeth-Ayerst Company
Philadelphia, PA 19101







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