Source: FDA, National Drug Code (US) Revision Year: 2020
Nabumetone tablets are contraindicated in patients with known hypersensitivity to nabumetone or product excipients.
Nabumetone tablets should not be given to patients who have experienced asthma, urticaria, or 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 and PRECAUTIONS).
Nabumetone tablets are contraindicated in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).
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, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.
To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the 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, such as Nabumetone, increases the risk of serious GI events (see WARNINGS).
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. NSAIDs are contraindicated in the setting of CABG (see CONTRAINDICATIONS).
Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.
Avoid the use of nabumetone tablets in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If nabumetone tablets are used in patients with a recent MI, monitor patients for signs of cardiac ischemia.
NSAIDs, including nabumetone tablets, can lead to onset of new hypertension or worsening of preexisting 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 nabumetone tablets, 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.
The Coxib and traditional NSAID Trialists' Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.
Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of Nabumetone may blunt the CV effects of several therapeutic agents used to treat these medical conditions [e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers (ARBs)] [see Drug Interactions].
Avoid the use of nabumetone tablets in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If nabumetone tablets are used in patients with severe heart failure, monitor patients for signs of worsening heart failure.
NSAIDs, including nabumetone tablets, 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 1 in 5 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 to 6 months, and in about 2 to 4% of patients treated for 1 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.
In controlled clinical trials involving 1,677 patients treated with nabumetone (1,140 followed for 1 year and 927 for 2 years), the cumulative incidence of peptic ulcers was 0.3% (95% CI; 0%, 0.6%) at 3 to 6 months, 0.5% (95% CI; 0.1%, 0.9%) at 1 year and 0.8% (95% CI; 0.3%, 1.3%) at 2 years. In patients with active peptic ulcer, physicians must weigh the benefits of therapy with nabumetone against possible hazards, institute an appropriate ulcer treatment regimen and monitor the patients' progress carefully.
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 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.
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 an NSAID results in a dose-dependent decrease in prostaglandin synthesis and, secondarily, in a reduction of 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 NSAID therapy is usually followed by recovery to the pretreatment state.
No information is available from controlled clinical studies regarding the use of nabumetone tablets in patients with advanced renal disease. Therefore, treatment with nabumetone tablets is not recommended in these patients with advanced renal disease. If nabumetone tablet therapy must be initiated, close monitoring of the patient’s renal function is advisable.
Because nabumetone undergoes extensive hepatic metabolism, no adjustment of the dosage of nabumetone is generally necessary in patients with mild renal insufficiency; however, as with all NSAIDs, patients with impaired renal function should be monitored more closely than patients with normal renal function (see CLINICAL PHARMACOLOGY). In subjects with moderate renal impairment (creatinine clearance 30 to 49 mL/min) there is a 50% increase in unbound plasma 6MNA and dose adjustment may be warranted. The oxidized and conjugated metabolites of 6MNA are eliminated primarily by the kidneys.
As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to nabumetone tablets. Nabumetone tablets 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 (see CONTRAINDICATIONS and PRECAUTIONS). Emergency help should be sought in cases where an anaphylactoid reaction occurs.
NSAIDs, including nabumetone tablets, 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.
In late pregnancy, as with other NSAIDs, nabumetone tablets should be avoided because it may cause premature closure of the ductus arteriosus.
Adverse reaction information was derived from blinded-controlled and open-labeled clinical trials and from worldwide marketing experience. In the description below, rates of the more common events (greater than 1%) and many of the less common events (less than 1%) represent results of U.S. clinical studies.
Of the 1,677 patients who received nabumetone during U.S. clinical trials, 1,524 were treated for at least 1 month, 1,327 for at least 3 months, 929 for at least a year, and 750 for at least 2 years. More than 300 patients have been treated for 5 years or longer.
The most frequently reported adverse reactions were related to the gastrointestinal tract and included diarrhea, dyspepsia, and abdominal pain.
Gastrointestinal: Diarrhea (14%), dyspepsia (13%), abdominal pain (12%), constipation?footnote?, flatulence1, nausea1, positive stool guaiac1, dry mouth, gastritis, stomatitis, vomiting.
Central Nervous System: Dizziness1, headache1, fatigue, increased sweating, insomnia, nervousness, somnolence.
Dermatologic: Pruritus1, rash1.
Special Senses: Tinnitus1.
Miscellaneous: Edema1.
1 Incidence of reported reaction between 3% and 9%. Reactions occurring in 1% to 3% of the patients are unmarked.
Gastrointestinal: Anorexia, jaundice, duodenal ulcer, dysphagia, gastric ulcer, gastroenteritis, gastrointestinal bleeding, increased appetite, liver function abnormalities, melena, hepatic failure.
Central Nervous System: Asthenia, agitation, anxiety, confusion, depression, malaise, paresthesia, tremor, vertigo.
Dermatologic: Bullous eruptions, photosensitivity, urticaria, pseudoporphyria cutanea tarda, toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome.
Cardiovascular: Vasculitis.
Metabolic: Weight gain.
Respiratory: Dyspnea, eosinophilic pneumonia, hypersensitivity pneumonitis, idiopathic interstitial pneumonitis.
Genitourinary: Albuminuria, azotemia, hyperuricemia, interstitial nephritis, nephrotic syndrome, vaginal bleeding, renal failure.
Special Senses: Abnormal vision.
Hematologic/Lymphatic: Thrombocytopenia.
Hypersensitivity: Anaphylactoid reaction, anaphylaxis, angioneurotic edema.
2 Adverse reactions reported only in worldwide postmarketing experience or in the literature, not seen in clinical trials, are considered rarer and are italicized.
Gastrointestinal: Bilirubinuria, duodenitis, eructation, gallstones, gingivitis, glossitis, pancreatitis, rectal bleeding.
Central Nervous System: Nightmares.
Dermatologic: Acne, alopecia.
Cardiovascular: Angina, arrhythmia, hypertension, myocardial infarction, palpitations, syncope, thrombophlebitis.
Respiratory: Asthma, cough.
Genitourinary: Dysuria, hematuria, impotence, renal stones.
Special Senses: Taste disorder.
Body as a Whole: Fever, chills.
Hematologic/Lymphatic: Anemia, leukopenia, granulocytopenia.
Metabolic/Nutritional: Hyperglycemia, hypokalemia, weight loss.
Call your doctor for medical advice about side effects. You may voluntarily report side effects to FDA at 1-800-FDA-1088.
Borderline elevations of 1 or more liver function tests may occur in up to 15% of patients taking NSAIDs including nabumetone tablets. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately 3 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 nabumetone tablets. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), nabumetone tablets should be discontinued.
Anemia is sometimes seen in patients receiving NSAIDs, including nabumetone tablets. 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 nabumetone tablets, 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 nabumetone tablets who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored (see CLINICAL PHARMACOLOGY).
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other non-steroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, nabumetone tablets should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.
Based on ultraviolet (U.V.) light photosensitivity testing, nabumetone may be associated with more reactions to sun exposure than might be expected based on skin tanning types.
Nabumetone tablets 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 slowly if a decision is made to discontinue corticosteroids.
The pharmacological activity of nabumetone tablets in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
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.
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. 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, nabumetone tablets should be discontinued.
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.
When nabumetone tablets are administered with aspirin, its protein binding is reduced, although the clearance of free nabumetone is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of nabumetone tablets and aspirin is not generally recommended because of the potential of increased adverse effects.
Clinical studies, as well as postmarketing observations, have shown that nabumetone tablets 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), as well as to assure diuretic efficacy.
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.
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.
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 users of either drug alone.
In vitro studies have shown that, because of its affinity for protein, 6MNA may displace other protein-bound drugs from their binding site. Caution should be exercised when administering nabumetone tablets with warfarin since interactions have been seen with other NSAIDs.
Concomitant administration of an aluminum-containing antacid had no significant effect on the bioavailability of 6MNA. When administered with food or milk, there is more rapid absorption; however, the total amount of 6MNA in the plasma is unchanged (see CLINICAL PHARMACOLOGY).
Pregnancy category C.
Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. However, animal reproduction studies are not always predictive of human response. There are no adequate, well-controlled studies in pregnant women. Nabumetone tablets should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.
Because of the known effects of non-steroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.
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 nabumetone tablets on labor and delivery in pregnant women are unknown.
It is not known whether this drug is excreted in human milk, however 6MNA is excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from nabumetone, 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.
Safety and effectiveness in pediatric patients have not been established.
As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older). Of the 1,677 patients in U.S. clinical studies who were treated with nabumetone, 411 patients (24%) were 65 years or older; 22 patients (1%) were 75 years or older. No overall differences in efficacy or safety were observed between these older patients and younger ones. Similar results were observed in a 1 year, non-U.S. postmarketing surveillance study of 10,800 patients treated with nabumetone, of whom 4,577 patients (42%) were 65 years or older.
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