Etodolac

Pronunciation

(ee toe DOE lak)

U.S. Brand Names

Lodine®; Lodine® XL

Synonyms

Etodolic Acid

Generic Available

Yes

Canadian Brand Names

Apo-Etodolac®; Lodine®; Utradol™

Use

Acute and long-term use in the management of signs and symptoms of osteoarthritis and management of pain; rheumatoid arthritis; juvenile rheumatoid arthritis

Use - Dental

Management of postoperative pain

Pregnancy Risk Factor

C/D (3rd trimester)

Lactation

Excretion in breast milk unknown/contraindicated

Contraindications

Hypersensitivity to etodolac, aspirin, other NSAIDs, or any component of the formulation; active gastric/duodenal ulcer disease; patients with "aspirin triad" (bronchial asthma, aspirin intolerance, rhinitis); pregnancy (3rd trimester)

Warnings/Precautions

Fatal asthmatic and anaphylactoid reactions have occurred in patients with "aspirin triad." Use with caution in patients with CHF, hypertension, dehydration, decreased renal or hepatic function, history of GI disease (bleeding, ulcers, or previous GI symptoms with NSAID use), or those receiving anticoagulants and/or corticosteroids. Use lowest effective dose for shortest period possible; bleeding risk has been correlated to dose and duration of therapy. Gastrointestinal bleeding may occur without prior symptoms of gastrointestinal irritation. Elderly are at a high risk for adverse effects from NSAIDs. As many as 60% of elderly can develop peptic ulceration and/or hemorrhage asymptomatically.

Use of NSAIDs can compromise existing renal function especially when Clcr<30 mL/minute. CNS adverse effects such as confusion, agitation, and hallucination are generally seen in overdose or high-dose situations; however, elderly may demonstrate these adverse effects at lower doses than younger adults. Withhold for at least 4-6 half-lives prior to surgical or dental procedures.

The extended release formulation consists of drug within a nondeformable matrix; following drug release/absorption, the matrix/shell is expelled in the stool. The use of nondeformable products in patients with known stricture/narrowing of the GI tract has been associated with symptoms of obstruction.

Adverse Reactions

1% to 10%:

Central nervous system: Depression (1% to 3%)

Dermatologic: Rash (1% to 3%), pruritus (1% to 3%)

Gastrointestinal: Abdominal cramps (3% to 9%), nausea (3% to 9%), vomiting (1% to 3%), dyspepsia (10%), diarrhea (3% to 9%), constipation (1% to 3%), flatulence (3% to 9%), melena (1% to 3%), gastritis (1% to 3%)

Genitourinary: Polyuria (1% to 3%)

Neuromuscular & skeletal: Weakness (3% to 9%)

Ocular: Blurred vision (1% to 3%)

Otic: Tinnitus (1% to 3%)

<1%: CHF, hypertension, arrhythmia, tachycardia, confusion, hallucinations, aseptic meningitis, mental depression, drowsiness, insomnia, urticaria, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, angioedema, polydipsia, hot flashes, GI ulceration, cystitis, agranulocytosis, anemia, hemolytic anemia, bone marrow suppression, leukopenia, thrombocytopenia, hepatitis, peripheral neuropathy, toxic amblyopia, blurred vision, conjunctivitis, dry eyes, decreased hearing, acute renal failure, allergic rhinitis, dyspnea, epistaxis, anorexia, stomatitis

Overdosage/Toxicology

Symptoms of overdose include acute renal failure, vomiting, drowsiness, leukocytosis. Management of NSAID intoxication is supportive and symptomatic.

Drug Interactions

ACE inhibitors: Antihypertensive effects may be decreased by concurrent therapy with NSAIDs; monitor blood pressure.

Angiotensin II antagonists: Antihypertensive effects may be decreased by concurrent therapy with NSAIDs; monitor blood pressure.

Anticoagulants (warfarin, heparin, LMWHs) in combination with NSAIDs can cause increased risk of bleeding.

Antiplatelet agents (ticlopidine, clopidogrel, aspirin, abciximab, dipyridamole, eptifibatide, tirofiban) can cause an increased risk of bleeding.

Cholestyramine and colestipol reduce the bioavailability of some NSAIDs; separate administration times.

Corticosteroids may increase the risk of GI ulceration; avoid concurrent use.

Cyclosporine: NSAIDs may increase serum creatinine, potassium, blood pressure, and cyclosporine levels; monitor cyclosporine levels and renal function carefully.

Hydralazine's antihypertensive effect is decreased; avoid concurrent use.

Lithium levels can be increased; avoid concurrent use if possible or monitor lithium levels and adjust dose. Sulindac may have the least effect. When NSAID is stopped, lithium will need adjustment again.

Loop diuretics efficacy (diuretic and antihypertensive effect) is reduced. Indomethacin reduces this efficacy, however, it may be anticipated with any NSAID.

Methotrexate: Severe bone marrow suppression, aplastic anemia, and GI toxicity have been reported with concomitant NSAID therapy. Avoid use during moderate or high-dose methotrexate (increased and prolonged methotrexate levels). NSAID use during low-dose treatment of rheumatoid arthritis has not been fully evaluated; extreme caution is warranted.

Thiazides antihypertensive effects are decreased; avoid concurrent use.

Verapamil plasma concentration is decreased by some NSAIDs; avoid concurrent use.

Warfarin's INRs may be increased by piroxicam. Other NSAIDs may have the same effect depending on dose and duration. Monitor INR closely. Use the lowest dose of NSAIDs possible and for the briefest duration.

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may enhance gastric mucosal irritation).

Food: Etodolac peak serum levels may be decreased if taken with food.

Herb/Nutraceutical: Avoid cat's claw, dong quai, evening primrose, feverfew, garlic, ginger, ginkgo, red clover, horse chestnut, green tea, ginseng (all have additional antiplatelet activity)

Stability

Protect from moisture

Mechanism of Action

Inhibits prostaglandin synthesis by decreasing the activity of the enzyme, cyclooxygenase, which results in decreased formation of prostaglandin precursors

Pharmacodynamics/Kinetics

Onset of action: Analgesic: 2-4 hours; Maximum anti-inflammatory effect: A few days

Absorption: Well absorbed

Distribution: Vd: 0.4 L/kg

Protein binding: High

Metabolism: Hepatic

Half-life elimination: 7 hours

Time to peak, serum: 1 hour

Excretion: Urine

Dosage

Single dose of 76-100 mg is comparable to the analgesic effect of aspirin 650 mg; in patients

65 years, no substantial differences in the pharmacokinetics or side-effects profile were seen compared with the general population

Children 6-16 years: Oral: Juvenile rheumatoid arthritis (Lodine® XL):

20-30 kg: 400 mg once daily

31-45 kg: 600 mg once daily

46-60 kg: 800 mg once daily

>60 kg: 1000 mg once daily

Adults: Oral:

Acute pain: 200-400 mg every 6-8 hours, as needed, not to exceed total daily doses of 1200 mg; for patients weighing <60 kg, total daily dose should not exceed 20 mg/kg/day

Rheumatoid arthritis, osteoarthritis: Initial: 600-1200 mg/day given in divided doses: 400 mg 2 times/day; 300 mg 2 or 3 times/day; 500 mg 2 times/day; total daily dose should not exceed 1200 mg; for patients weighing <60 kg, total daily dose should not exceed 20 mg/kg/day

Lodine® XL: 400-1000 mg once daily

Elderly: Refer to adult dosing; in patients 65 years, no dosage adjustment required based on pharmacokinetics. The elderly are more sensitive to antiprostaglandin effects and may need dosage adjustments.

Monitoring Parameters

Monitor CBC, liver enzymes; in patients receiving diuretics, monitor urine output and BUN/serum creatinine

Test Interactions

False-positive for urinary bilirubin and ketone increase bleeding time

Dietary Considerations

May be taken with food to decrease GI distress.

Patient Education

Take this medication exactly as directed; do not increase dose without consulting prescriber. Do not crush tablets or break capsules. Take with food or milk to reduce GI distress. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. Do not use alcohol, aspirin or aspirin-containing medication, or any other anti-inflammatory medications without consulting prescriber. You may experience anorexia, nausea, vomiting, or heartburn (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help); drowsiness, dizziness, nervousness, or headache (use caution when driving or engaging in tasks requiring alertness until response to drug is known); or fluid retention (weigh yourself weekly and report unusual (3-5 lb/week) weight gain). GI bleeding, ulceration, or perforation can occur with or without pain; discontinue medication and contact prescriber if persistent abdominal pain or cramping, or blood in stool occurs. Report breathlessness, respiratory difficulty, or unusual cough; chest pain, rapid heartbeat, palpitations; unusual bruising/bleeding; blood in urine, stool, mouth, or vomitus; swollen extremities; skin rash or itching; acute fatigue; or hearing changes (ringing in ears). Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. This drug should not be used in the 3rd trimester of pregnancy. Do not breast-feed.

Anesthesia and Critical Care Concerns/Other Considerations

The 2002 ACCM/SCCM guidelines for analgesia (critically-ill adult) suggest that NSAIDs may be used in combination with opioids in select patients for pain management. Concern about adverse events (increased risk of renal dysfunction, altered platelet function and gastrointestinal irritation) limits its use in patients who have other underlying risks for these events.

In short-term use, NSAIDs vary considerably in their effect on blood pressure. When NSAIDs are used in patients with hypertension, appropriate monitoring of blood pressure responses should be completed and the duration of therapy, when possible, kept short. The use of NSAIDs in the treatment of patients with congestive heart failure may be associated with an increased risk for fluid accumulation and edema. May precipitate renal failure in dehydrated patients.

Cardiovascular Considerations

In short-term use, NSAIDs vary considerably in their effect on blood pressure. A recent meta-analysis (see References) showed that indomethacin and naproxen had the largest effect on blood pressure. Other NSAIDs, including piroxicam, ibuprofen, and sulindac had less of an effect. Ibuprofen combined with captopril or losartan may attenuate the antihypertensive effects of ACE inhibition or receptor blockade on sitting or 24-hour ambulatory diastolic blood pressure. When NSAIDs are used in patients with hypertension, appropriate monitoring of blood pressure responses should be completed and the duration of therapy, when possible, kept short. The use of NSAIDs in the treatment of patients with congestive heart failure may be associated with an increased risk for fluid accumulation and edema. One study showed that NSAID use in elderly patients had an increased risk of hospitalization for heart failure. This study gives compelling reasons to avoid or limit the use of NSAIDs in patients with congestive heart failure, particularly in the elderly population.

Dental Health: Effects on Dental Treatment

NSAID formulations are known to reversibly decrease platelet aggregation via mechanisms different than observed with aspirin. The dentist should be aware of the potential of abnormal coagulation. Caution should also be exercised in the use of NSAIDs in patients already on anticoagulant therapy with drugs such as warfarin (Coumadin®).

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

Dizziness is common; may cause nervousness; rarely produces confusion, depression, insomnia, or hallucinations

Mental Health: Effects on Psychiatric Treatment

May rarely cause agranulocytosis; use caution with clozapine and carbamazepine; may decrease the clearance of lithium resulting in elevated serum levels and potential toxicity; monitor serum lithium levels

Dosage Forms

[DSC] = Discontinued product

Capsule (Lodine®): 200 mg, 300 mg

Tablet: 400 mg, 500 mg

Lodine®: 400 mg, 500 mg [DSC]

Tablet, extended release (Lodine® XL): 400 mg, 500 mg, 600 mg

References

Boldy DA, Hale KA, and Vale JA, "Etodolac Overdose," Hum Toxicol , 1988, 7(2):203-4.

Brooks PM and Day RO, "Nonsteroidal Anti-inflammatory Drugs - Differences and Similarities," N Engl J Med , 1991, 324(24):1716-25.

Clinch D, Banerjee AK, and Ostick G, "Absence of Abdominal Pain in Elderly Patients With Peptic Ulcer," Age Ageing , 1984, 13(2):120-3.

Clive DM and Stoff JS, "Renal Syndromes Associated With Nonsteroidal Anti-inflammatory Drugs," N Engl J Med , 1984, 310(9):563-72.

Conlin P, Moore T, Swartz S, et al, "Effect of Indomethacin on Blood Pressure Lowering by Captopril and Losartan in Hypertensive Patients," Hypertension , 2000, 36(3):461-5.

Court H and Volans GN, "Poisoning After Overdose With Nonsteroidal Anti-inflammatory Drugs," Adverse Drug React Acute Poisoning Rev , 1984, 3(1):1-21.

"Drugs for Pain," Med Lett Drugs Ther , 2000, 42(1085):73-8.

Graham DY, "Prevention of Gastroduodenal Injury Induced by Chronic Nonsteroidal Anti-inflammatory Drug Therapy," Gastroenterology , 1989, 96(2 Pt 2 Suppl):675-81.

Gurwitz JH, Avorn J, Ross-Degnan D, et al, "Nonsteroidal Anti-Inflammatory Drug-Associated Azotemia in the Very Old," JAMA , 1990, 264(4):471-5.

Hawkey CJ, Karrasch JA, Szczepañski L, et al, "Omeprazole Compared With Misoprostol for Ulcers Associated With Nonsteroidal Anti-inflammatory Drugs," N Engl J Med , 1998, 338(11):727-34.

Heerdink ER, Leufkens HG, Herings RM, et al, "NSAIDs Associated With Increased Risk of Congestive Heart Failure in Elderly Patients Taking Diuretics," Arch Intern Med , 1998, 158(10):1108-12.

Hoppmann RA, Peden JG, and Ober SK, "Central Nervous System Side Effects of Nonsteroidal Anti-inflammatory Drugs. Aseptic Meningitis, Psychosis, and Cognitive Dysfunction," Arch Intern Med , 1991, 151(7):1309-13.

Jacobi J, Fraser GL, Coursin DB, et al, "Clinical Practice Guidelines for the Sustained Use of Sedatives and Analgesics in the Critically Ill Adult," Crit Care Med , 2002, 30(1):119-41. Available at: http://www.sccm.org/pdf/sedatives.pdf. Accessed August 2, 2003.

Knodel LC, "Preventing NSAID-induced Ulcers: The Role of Misoprostol," Consult Pharm , 1989, 4:37-41.

Mabee CL, Mabee SW, Baker PB, et al, "Fulminant Hepatic Failure Associated With Etodolac Use," Am J Gastroenterol , 1995, 90(4):659-61.

Morgan TO, Anderson A, and Bertram D, "Effect of Indomethacin on Blood Pressure in Elderly People With Essential Hypertension Well Controlled on Amlodipine or Enalapril," Am J Hypertens , 2000, 13(11):1161-7.

Page J and Henry D, "Consumption of NSAIDs and the Development of Congestive Heart Failure in Elderly Patients: An Underrecognized Public Health Problem," Arch Intern Med , 2000, 160(6):777-84.

Pope JE, Anderson JJ, and Felson DT, "A Meta-analysis of the Effects of Nonsteroidal Anti-inflammatory Drugs on Blood Pressure," Arch Intern Med , 1993, 153(4):477-84.

Pounder R, "Silent Peptic Ulceration: Deadly Silence or Golden Silence?" Gastroenterology , 1989, 96(2 Pt 2 Suppl):626-31.

Schnitzer TJ and Constantine G, "Etodolac (Lodine®) in the Treatment of Osteoarthritis: Recent Studies," J Rheumatol Suppl , 1997, 47:23-31.

Smolinske SC, Hall AH, Vandenberg SA, et al, "Toxic Effects of Nonsteroid Anti-inflammatory Drugs in Overdose. An Overview of Recent Evidence on Clinical Effects and Dose-Response Relationships," Drug Saf , 1990, 5(4):252-74.

Spencer-Green G, "Low Dose Etodolac in Rheumatoid Arthritis: A Review of Early Studies," J Rheumatol Suppl , 1997, 47:3-9.

Tucker PW, Smith JR, and Adams DF, "A Comparison of 2 Analgesic Regimens for the Control of Postoperative Periodontal Discomfort," J Periodontol , 1996, 67(2):125-9.

Vale JA and Meredith TJ, "Acute Poisoning Due to Nonsteroidal Anti-inflammatory Drugs," Med Toxicol , 1986, 1(1):12-31.

Verbeeck RK, "Pharmacokinetic Drug Interactions With Nonsteroidal Anti-inflammatory Drugs," Clin Pharmacokinet , 1990, 19(1):44-66.

Yeomans ND, Tulassay Z, Juhasz L, et al, "A Comparison of Omeprazole With Ranitidine for Ulcers Associated With Nonsteroidal Anti-inflammatory Drugs," N Engl J Med , 1998, 338(11):719-26.

International Brand Names

Apo-Etodolac® (CA); Articulan® (PT); Dualgan® (PT); Eccoxolac® (GB); Elderin® (HK, RU, SI); Etodin® (TR); Etol® (TR); Etonox® (TH); Etopan® (IL); Hypen® (JP); Lodine® (AT, CA, CH, CY, EG, FI, FR, GB, HK, IT, JO, KW, LB, LU, MT, TR); Lodot® (PT); Lonene® (ID); Metazin® (PT); Sodolac® (PT); Tadolak® (TR); Todolac® (DK); Utradol™ (CA)

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