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Nabumetone

Pronunciation

Class: Other Nonsteroidal Anti-inflammatory Agents
Chemical Name: 4-(6-Methoxy-2-naphthyl)-2-butanone
Molecular Formula: C15H16O2
CAS Number: 42924-53-8

Warning(s)

  • Cardiovascular Risk
  • Increased risk of serious (sometimes fatal) cardiovascular thrombotic events (e.g., MI, stroke).1 500 502 508 Risk may occur early in treatment and may increase with duration of use.500 502 505 506 508 (See Cardiovascular Thrombotic Effects under Cautions.)

  • Contraindicated in the setting of CABG surgery.508

  • GI Risk
  • Increased risk of serious (sometimes fatal) GI events (e.g., bleeding, ulceration, perforation of the stomach or intestine).1 Serious GI events can occur at any time and may not be preceded by warning signs and symptoms.1 Geriatric individuals are at greater risk for serious GI events.1 (See GI Effects under Cautions.)

Introduction

Prototypical NSAIA;1 prodrug with little pharmacologic activity until oxidized in the liver to form an active metabolite that is structurally similar to naproxen.1 2 3

Uses for Nabumetone

Consider potential benefits and risks of nabumetone therapy as well as alternative therapies before initiating therapy with the drug.1 Use lowest effective dosage and shortest duration of therapy consistent with the patient’s treatment goals.1

Inflammatory Diseases

Symptomatic treatment of osteoarthritis and rheumatoid arthritis.1

Nabumetone Dosage and Administration

General

  • Consider potential benefits and risks of nabumetone therapy as well as alternative therapies before initiating therapy with the drug.1

Administration

Oral Administration

Administer orally once or twice daily without regard to meals.1

Dosage

To minimize the potential risk of adverse cardiovascular and/or GI events, use lowest effective dosage and shortest duration of therapy consistent with the patient’s treatment goals.1 Adjust dosage based on individual requirements and response; attempt to titrate to the lowest effective dosage.1

Adults

Inflammatory Diseases
Osteoarthritis or Rheumatoid Arthritis
Oral

Initially, 1 g once daily.1 May increase dosage to 1.5–2 g daily, given as a single daily dose or 2 divided doses.1

Patients weighing <50 kg may be less likely to need dosages >1 g daily.1

Prescribing Limits

Adults

Inflammatory Diseases
Osteoarthritis or Rheumatoid Arthritis
Oral

Maximum 2 g daily.1

Special Populations

Renal Impairment

Dosage adjustment not necessary in patients with mild renal impairment (Clcr >50 mL/minute).1

In patients with moderate renal impairment (Clcr 30–49 mL/minute), initiate at ≤750 mg daily (maximum initial dosage is 750 mg daily).1 Monitor renal function; may increase dosage to 1.5 g daily.1

In patients with severe renal impairment (Clcr <30 mL/minute), initiate at ≤500 mg daily (maximum initial dosage is 500 mg daily).1 Monitor renal function; may increase dosage to 1 g daily.1

Cautions for Nabumetone

Contraindications

  • Known hypersensitivity to nabumetone or any ingredient in the formulation.1

  • History of asthma, urticaria, or other sensitivity reaction precipitated by aspirin or other NSAIAs.1 2

  • In the setting of CABG surgery.508

Warnings/Precautions

Warnings

Cardiovascular Thrombotic Effects

NSAIAs (selective COX-2 inhibitors, prototypical NSAIAs) increase the risk of serious adverse cardiovascular thrombotic events (e.g., MI, stroke) in patients with or without cardiovascular disease or risk factors for cardiovascular disease.500 502 508

Findings of FDA review of observational studies, meta-analysis of randomized controlled trials, and other published information500 501 502 indicate that NSAIAs may increase the risk of such events by 10–50% or more, depending on the drugs and dosages studied.500

Relative increase in risk appears to be similar in patients with or without known underlying cardiovascular disease or risk factors for cardiovascular disease, but the absolute incidence of serious NSAIA-associated cardiovascular thrombotic events is higher in those with cardiovascular disease or risk factors for cardiovascular disease because of their elevated baseline risk.500 502 506 508

Increased risk may occur early (within the first weeks) following initiation of therapy and may increase with higher dosages and longer durations of use.500 502 505 506 508

In controlled studies, increased risk of MI and stroke observed in patients receiving a selective COX-2 inhibitor for analgesia in first 10–14 days following CABG surgery.508

In patients receiving NSAIAs following MI, increased risk of reinfarction and death observed beginning in the first week of treatment.505 508

Increased 1-year mortality rate observed in patients receiving NSAIAs following MI;500 508 511 absolute mortality rate declined somewhat after the first post-MI year, but the increased relative risk of death persisted over at least the next 4 years.508 511

Some systematic reviews of controlled observational studies and meta-analyses of randomized studies suggest naproxen may be associated with lower risk of cardiovascular thrombotic events compared with other NSAIAs.4 5 6 500 501 502 503 506 FDA states that limitations of these studies and indirect comparisons preclude definitive conclusions regarding relative risks of NSAIAs.500

Use NSAIAs with caution and careful monitoring (e.g., monitor for development of cardiovascular events throughout therapy, even in those without prior cardiovascular symptoms) and at the lowest effective dosage for the shortest duration necessary.1 500 508

Some clinicians suggest that it may be prudent to avoid NSAIA use, whenever possible, in patients with cardiovascular disease.505 511 512 516 Avoid use in patients with recent MI unless benefits of therapy are expected to outweigh risk of recurrent cardiovascular thrombotic events; if used, monitor for cardiac ischemia.508 Contraindicated in the setting of CABG surgery.508

No consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious adverse cardiovascular events associated with NSAIAs.1 502 508 (See Specific Drugs under Interactions.)

GI Effects

Serious GI toxicity (e.g., bleeding, ulceration, perforation) can occur with or without warning symptoms; increased risk in those with a history of GI bleeding or ulceration, geriatric patients, smokers, those with alcohol dependence, and those in poor general health.1

For patients at high risk for complications from NSAIA-induced GI ulceration (e.g., bleeding, perforation), consider concomitant use of misoprostol; alternatively, consider concomitant use of a proton-pump inhibitor (e.g., omeprazole) or use of an NSAIA that is a selective inhibitor of COX-2 (e.g., celecoxib).

Hypertension

Hypertension and worsening of preexisting hypertension reported; either event may contribute to the increased incidence of cardiovascular events.1 Use with caution in patients with hypertension; monitor BP.1

Impaired response to ACE inhibitors, angiotensin II receptor antagonists, β-blockers, and certain diuretics may occur.1 508 509 (See Specific Drugs under Interactions.)

Heart Failure and Edema

Fluid retention and edema reported.1 508

NSAIAs (selective COX-2 inhibitors, prototypical NSAIAs) may increase morbidity and mortality in patients with heart failure.500 501 504 507 508

NSAIAs may diminish cardiovascular effects of diuretics, ACE inhibitors, or angiotensin II receptor antagonists used to treat heart failure or edema.508 (See Specific Drugs under Interactions.)

Manufacturer recommends avoiding use in patients with severe heart failure unless benefits of therapy are expected to outweigh risk of worsening heart failure; if used, monitor for worsening heart failure.508

Some experts recommend avoiding use, whenever possible, in patients with reduced left ventricular ejection fraction and current or prior symptoms of heart failure.507

Renal Effects

Direct renal injury, including renal papillary necrosis, reported in patients receiving long-term NSAIA therapy.1

Potential for overt renal decompensation.1 Increased risk of renal toxicity in patients with renal or hepatic impairment or heart failure, in patients with volume depletion, in geriatric patients, and in those receiving a diuretic, ACE inhibitor, or angiotensin II receptor antagonist.1 c (See Renal Impairment under Cautions.)

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylactoid reactions reported.1

Immediate medical intervention and discontinuance for anaphylaxis.1

Avoid in patients with aspirin triad (aspirin sensitivity, asthma, nasal polyps); caution in patients with asthma.1

Dermatologic Reactions

Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) reported; can occur without warning.1 Discontinue at first appearance of rash or any other sign of hypersensitivity (e.g., blisters, fever, pruritus).1

Photosensitivity Reactions

Photosensitivity reactions possible.1

General Precautions

Hepatic Effects

Severe reactions including jaundice, fatal fulminant hepatitis, liver necrosis, and hepatic failure (sometimes fatal) reported rarely with NSAIAs.1

Elevations of serum ALT or AST reported.1

Monitor for symptoms and/or signs suggesting liver dysfunction; monitor abnormal liver function test results.1 Discontinue if signs or symptoms of liver disease or systemic manifestations (e.g., eosinophilia, rash) occur or if liver function test abnormalities persist or worsen.1

Hematologic Effects

Anemia reported rarely.1 Determine hemoglobin concentration or hematocrit in patients receiving long-term therapy if signs or symptoms of anemia occur.1

May inhibit platelet aggregation and prolong bleeding time.1

Other Precautions

Not a substitute for corticosteroid therapy; not effective in the management of adrenal insufficiency.1

May mask certain signs of infection.1

Obtain CBC and chemistry profile periodically during long-term use.1

Specific Populations

Pregnancy

Category C.1 Avoid use in third trimester because of possible premature closure of the ductus arteriosus.1

Lactation

Active metabolite is distributed into milk in rats; not known whether nabumetone or its metabolites are distributed into milk in humans.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in children.1

Geriatric Use

Caution advised.1 Safety and efficacy profiles similar to those in younger adults.1 However, fatal adverse GI effects reported more frequently in geriatric patients than in younger adults.1

Hepatic Impairment

Caution advised in patients with severe hepatic impairment, since formation of the active metabolite depends on biotransformation in the liver.1

Renal Impairment

Use with caution in patients with renal disease.1 Use not recommended in patients with advanced renal disease; close monitoring of renal function advised if used.1

Dosage adjustments necessary in patients with moderate or severe renal impairment.1 (See Renal Impairment under Dosage and Administration.)

Oxidized and conjugated metabolites that are excreted in urine may accumulate in patients with renal failure, potentially resulting in adverse effects.1

Common Adverse Effects

Abdominal pain, constipation, diarrhea, dizziness, dyspepsia, edema, flatulence, headache, nausea, positive stool guaiac test, pruritus, rash, tinnitus.1

Interactions for Nabumetone

Protein-bound Drugs

Could be displaced from binding sites by, or could displace from binding sites, other protein-bound drugs.1

Specific Drugs

Drug

Interaction

Comments

ACE inhibitors

Reduced BP response to ACE inhibitor1

Possible deterioration of renal function in individuals with renal impairmentc

Monitor BP1

Angiotensin II receptor antagonists

Reduced BP response to angiotensin II receptor antagonistc

Possible deterioration of renal function in individuals with renal impairmentc

Monitor BPc

Antacids (aluminum-containing)

No effect on 6-methoxy-2-naphthylacetic acid (6MNA) bioavailability1

Aspirin

Increased risk of GI ulceration and other complications1

No consistent evidence that low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs1 502 508

Manufacturer states that concomitant use not recommended1

Diuretics (furosemide, thiazides)

Reduced natriuretic effects possible1

Monitor for diuretic efficacy and renal failure1

Lithium

Increased plasma lithium concentrations1

Monitor for lithium toxicity1

Methotrexate

Possible toxicity associated with increased plasma methotrexate concentrations1

Caution advised1

Warfarin

Possibility of bleeding complications1

Caution advised1

Nabumetone Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration.1 Rapidly biotransformed to active metabolite, 6MNA; peak plasma concentration of 6MNA usually attained within 2.5–4 hours.1 Approximately 35% of a 1-g dose is metabolized to 6MNA.1 Unchanged nabumetone is not detected in plasma.1

Food

Food increases rate of nabumetone absorption; increases rate but not extent of metabolism to 6MNA.1

Special Populations

In geriatric patients, steady-state plasma 6MNA concentrations are higher than in younger individuals.1

Distribution

Plasma Protein Binding

6MNA: >99%.1

Elimination

Metabolism

6MNA is extensively metabolized in the liver to inactive metabolites; 6MNA does not appear to undergo enterohepatic recirculation.1

Elimination Route

Excreted mainly in urine as metabolites of 6MNA and metabolites of nabumetone.1

Half-life

6MNA: about 23–30 hours.1

Special Populations

In patients with moderate renal impairment (Clcr 30–49 mL/minute) and severe renal impairment (Clcr <30 mL/minute), elimination half-life of 6MNA increased.1

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1

Actions

  • Inhibits cyclooxygenase-1 (COX-1) and COX-2.1

  • Pharmacologic actions similar to those of other prototypical NSAIAs; exhibits anti-inflammatory, analgesic, and antipyretic activity.1

Advice to Patients

  • Importance of reading the medication guide for NSAIAs that is provided each time the drug is dispensed.1

  • Risk of serious cardiovascular events (e.g., MI, stroke).1 500 508

  • Risk of GI bleeding and ulceration.1

  • Risk of serious skin reactions.1 Risk of anaphylactoid and other sensitivity reactions.1

  • Risk of hepatotoxicity.1

  • Importance of seeking immediate medical attention if signs and symptoms of a cardiovascular event (chest pain, dyspnea, weakness, slurred speech) occur.1 500 508

  • Importance of notifying clinician if signs and symptoms of GI ulceration or bleeding, unexplained weight gain, or edema develops.1

  • Importance of discontinuing nabumetone and contacting clinician if rash or other signs of hypersensitivity (blisters, fever, pruritus) develop.1 Importance of seeking immediate medical attention if an anaphylactic reaction occurs.1

  • Importance of discontinuing therapy and contacting clinician immediately if signs and symptoms of hepatotoxicity (nausea, fatigue, lethargy, pruritus, jaundice, upper right quadrant tenderness, flu-like symptoms) occur.1

  • Risk of heart failure or edema; importance of reporting dyspnea, unexplained weight gain, or edema.508

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Importance of avoiding nabumetone in late pregnancy (third trimester).1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Nabumetone

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

500 mg*

Nabumetone Tablets

750 mg*

Nabumetone Tablets

AHFS DI Essentials. © Copyright 2017, Selected Revisions August 27, 2015. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. GlaxoSmithKline. Relafen (nabumetone) tablets prescribing information. Research Triangle Park, NC; 2006 Feb.

2. Dahl SL. Nabumetone: a “nonacidic” nonsteroidal antiinflammatory drug. Ann Pharmacother. 1993; 27:456-63. [IDIS 313113] [PubMed 8477124]

3. Friedel HA, Langtry HD, Buckley MM. Nabumetone: a reappraisal of its pharmacology and therapeutic use in rheumatic diseases. Drugs. 1993; 45:131-56. [PubMed 7680981]

4. McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA. 2006; 296: 1633-44. [PubMed 16968831]

5. Kearney PM, Baigent C, Godwin J et al. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ. 2006; 332: 1302-5. [PubMed 16740558]

6. Graham DJ. COX-2 inhibitors, other NSAIDs, and cardiovascular risk; the seduction of common sense. JAMA. 2006; 296:1653-6. [PubMed 16968830]

a. Food and Drug Administration. Analysis and recommendations for Agency action regarding non-steroidal anti-inflammatory drugs and cardiovascular risk. 2005 Apr 6. From FDA web site ().

c. Merck & Co., Inc. Dolobid (diflunisal) tablets prescribing information. Whitehouse Station, NJ; 2006 Feb.

500. Food and Drug Administration. Drug safety communication: FDA strengthens warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes. Silver Spring, MD; 2015 Jul 9. From the FDA web site. Accessed 2016 Mar 22.

501. Coxib and traditional NSAID Trialists' (CNT) Collaboration, Bhala N, Emberson J et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet. 2013; 382:769-79. [PubMed 23726390]

502. Food and Drug Administration. FDA briefing document: Joint meeting of the arthritis advisory committee and the drug safety and risk management advisory committee, February 10-11, 2014. From FDA web site

503. Trelle S, Reichenbach S, Wandel S et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ. 2011; 342:c7086. [PubMed 21224324]

504. Gislason GH, Rasmussen JN, Abildstrom SZ et al. Increased mortality and cardiovascular morbidity associated with use of nonsteroidal anti-inflammatory drugs in chronic heart failure. Arch Intern Med. 2009; 169:141-9. [PubMed 19171810]

505. Schjerning Olsen AM, Fosbøl EL, Lindhardsen J et al. Duration of treatment with nonsteroidal anti-inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: a nationwide cohort study. Circulation. 2011; 123:2226-35. [PubMed 21555710]

506. McGettigan P, Henry D. Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies. PLoS Med. 2011; 8:e1001098. [PubMed 21980265]

507. Yancy CW, Jessup M, Bozkurt B et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013; 62:e147-239. [PubMed 23747642]

508. Sandoz. Nabumetone tablets prescribing information. Princeton, NJ; 2015 Jul.

509. Cumberland Pharmaceuticals Inc. Caldolor (ibuprofen) injection prescribing information. Nashville, TN; 2016 Apr.

511. Olsen AM, Fosbøl EL, Lindhardsen J et al. Long-term cardiovascular risk of nonsteroidal anti-inflammatory drug use according to time passed after first-time myocardial infarction: a nationwide cohort study. Circulation. 2012; 126:1955-63. [PubMed 22965337]

512. Olsen AM, Fosbøl EL, Lindhardsen J et al. Cause-specific cardiovascular risk associated with nonsteroidal anti-inflammatory drugs among myocardial infarction patients--a nationwide study. PLoS One. 2013; 8:e54309. [PubMed 23382889]

516. Bavry AA, Khaliq A, Gong Y et al. Harmful effects of NSAIDs among patients with hypertension and coronary artery disease. Am J Med. 2011; 124:614-20. [PubMed 21596367]

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