Nabumetone

Pronunciation

(na BYOO me tone)

U.S. Brand Names

Relafen®

Generic Available

Yes

Canadian Brand Names

Apo-Nabumetone®; Gen-Nabumetone; Relafen™; Rhoxal-nabumetone

Use

Management of osteoarthritis and rheumatoid arthritis

Use - Unlabeled/Investigational

Sunburn, mild to moderate pain

Pregnancy Risk Factor

C/D (3rd trimester)

Lactation

Enters breast milk/not recommended

Contraindications

Hypersensitivity to NSAIDs including aspirin, or any component of the formulation; should not be administered to patients with active peptic ulceration and those with severe hepatic impairment or in patients in whom nabumetone, aspirin, or other NSAIDs have induced asthma, urticaria, or other allergic-type reactions; fatal asthmatic reactions have occurred following NSAID administration; 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.

Adverse Reactions

>10%:

Central nervous system: Dizziness

Dermatologic: Rash

Gastrointestinal: Abdominal cramps, abdominal pain (12%), diarrhea (14%), dyspepsia (13%), heartburn, indigestion, nausea

1% to 10%:

Central nervous system: Headache, nervousness

Dermatologic: Itching

Endocrine & metabolic: Fluid retention

Gastrointestinal: Vomiting

Otic: Tinnitus

<1%: Abnormal vision, acne, agitation, albuminuria, alopecia, anemia, angina, angioneurotic edema, anorexia, anxiety, arrhythmia, asthma, azotemia, bullous eruptions, cholestatic jaundice, confusion, depression, duodenal ulcer, dysphagia, dyspnea, fever, gallstones, gastric ulcer, gastroenteritis, gingivitis, GI bleeding, granulocytopenia, hyperglycemia, hypertension, hyperuricemia, hypokalemia, impotence, leukopenia, liver function abnormalities, malaise, melena, MI, nephrolithiasis, nightmares, pancreatitis, paresthesia, photosensitivity, pseudoporphyria cutanea tarda, syncope, thrombocytopenia, thrombophlebitis, tremor, urticaria, vasculitis, vertigo, weakness

Postmarketing and/or case reports: Anaphylactoid reaction, anaphylaxis, CHF, eosinophilic pneumonia, erythema multiforme, hepatic failure, hepatitis, hypersensitivity pneumonitis, interstitial nephritis, interstitial pneumonitis, nephrotic syndrome, renal failure, Stevens-Johnson syndrome, toxic epidermal necrolysis

Overdosage/Toxicology

Symptoms of overdose include apnea, metabolic acidosis, coma, nystagmus, leukocytosis, and renal failure. 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 drugs (ticlopidine, clopidogrel, aspirin, abciximab, dipyridamole, eptifibatide, tirofiban) can cause an increased risk of bleeding.

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.

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.

Warfarin's INRs may be increased by nabumetone. 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: Nabumetone peak serum concentrations may be increased if taken with food or dairy products.

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).

Mechanism of Action

Nabumetone is a nonacidic NSAID that is rapidly metabolized after absorption to a major active metabolite, 6-methoxy-2-naphthylacetic acid. As found with previous NSAIDs, nabumetone's active metabolite inhibits the cyclooxygenase enzyme which is indirectly responsible for the production of inflammation and pain during arthritis by way of enhancing the production of endoperoxides and prostaglandins E2 and I2 (prostacyclin). The active metabolite of nabumetone is felt to be the compound primarily responsible for therapeutic effect. Comparatively, the parent drug is a poor inhibitor of prostaglandin synthesis.

Pharmacodynamics/Kinetics

Onset of action: Several days

Distribution: Diffusion occurs readily into synovial fluid

Protein binding: >99%

Metabolism: Prodrug, rapidly metabolized to an active metabolite (6-methoxy-2-naphthylacetic acid); extensive first-pass effect

Half-life elimination: Major metabolite: 24 hours

Time to peak, serum: Metabolite: Oral: 3-6 hours; Synovial fluid: 4-12 hours

Excretion: Urine (80%) and feces (10%) with little as unchanged drug

Dosage

Adults: Oral: 1000 mg/day; an additional 500-1000 mg may be needed in some patients to obtain more symptomatic relief; may be administered once or twice daily

Monitoring Parameters

Patients with renal insufficiency: Baseline renal function followed by repeat test within weeks (to determine if renal function has deteriorated)

Patient Education

Take this medication exactly as directed; do not increase dose without consulting prescriber. Do not crush tablets. 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 healthcare prescriber. You may experience drowsiness, dizziness, nervousness, or headache (use caution when driving or engaging in tasks requiring alertness until response to drug is known); anorexia, nausea, vomiting, or heartburn (small, frequent meals, frequent oral care, sucking lozenges, or chewing gum may help); 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 pregnant. Breast-feeding is not recommended.

Nursing Implications

Advise patient to inform physician if stomach disturbances, blurred vision, or other eye symptoms, rash, weight gain, edema, or passing of dark-colored or tarry stools occurs; concomitant use of ethanol should be avoided if possible since it may add to the irritant action of nabumetone in the stomach; aspirin should be avoided

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

Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation). 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; may rarely cause insomnia, confusion, depression, or hallucinations

Mental Health: Effects on Psychiatric Treatment

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

Dosage Forms

Tablet: 500 mg, 750 mg

References

Bernhard GC, "Worldwide Safety Experience With Nabumetone," J Rheumatol , 1992, 19(Suppl 36):48-57.

Brier ME, Sloan RS, and Aronoff GR, "Population Pharmacokinetics of the Active Metabolite of Nabumetone in Renal Dysfunction," Clin Pharmacol Ther , 1995, 57(6):622-7.

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.

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 Misoprostrol 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.

Hyneck ML, "An Overview of the Clinical Pharmacokinetics of Nabumetone," J Rheumatol , 1992, 19(Suppl 36):20-4.

Jackson RE, Mitchell FN, and Brindley DA, "Safety Evaluation of Nabumetone in United States Clinical Trials," Am J Med , 1987, 83(4B):115-20.

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.

Jenner PN, "A 12-Month Postmarketing Surveillance Study of Nabumetone: A Preliminary Report," Drugs , 1990, 40(Suppl 5):80-6.

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

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.

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.

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

Aflex® (TH); Apo-Nabumetone® (CA); Artaxan® (IT); Balmox® (CH, PT); Bumetone® (TH); Coxalgan® (PL); Coxeton® (PL); Elitar® (PT); Flambate® (AR); Gen-Nabumetone (CA); Goflex® (ID); Idam® (AR); Listran® (ES); Mebutan® (NL); Nabone® (TH); Nabonet® (TH); Nabuco® (IL); Nabucox® (FR); Nabugesic® (HK, JO, KW, LB, MT, MY, RO); Nabumetone® (GB); Naburen® (CO, DO, GT, HN, PA, SV); Nabuser® (IT); Nabuton® (PL); Nadorex® (CO); Naflex® (TH); Nametone® (TH); No-Ton® (TH); Recox® (PL); Relafen™ (CA); Relifen® (JP, ZA); Relif® (ES); Relifex® (BR, CR, DK, DO, FI, GB, GT, HK, HN, HU, IE, IL, KW, MX, NO, PA, PL, RO, SE, SV, TH, TR); Religer® (IE); Relisan® (ZA); Relitone® (ZA); Rhoxal-nabumetone (CA); Rodanol® (RU, SI); Rodanol S® (HU, PL)

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