nabumetone 750 MG Oral Tablet

Generic Name: NABUMETONE
Brand Name: Nabumetone
  • Substance Name(s):
  • NABUMETONE

WARNINGS

Cardiovascular Effects Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to 3 years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal.

All NSAIDs, both COX-2 selective and nonselective, may have a similar risk.

Patients with known CV disease or risk factors for CV disease may be at greater risk.

To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible.

Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms.

Patients should be informed about the signs and/or 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 does increase the risk of serious GI events (see , Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation ).

Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS ).

Hypertension 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.

Congestive Heart Failure and Edema Fluid retention and edema have been observed in some patients taking NSAIDs.

Nabumetone tablets should be used with caution in patients with fluid retention or heart failure.

Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation 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.

Renal Effects 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.

Advanced Renal Disease 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, Pharmacokinetics, Renal Insufficiency ).

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.

Anaphylactoid Reactions 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, General, Preexisting Asthma ).

Emergency help should be sought in cases where an anaphylactoid reaction occurs.

Skin Reactions 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.

Pregnancy In late pregnancy, as with other NSAIDs, nabumetone tablets should be avoided because it may cause premature closure of the ductus arteriosus.

DRUG INTERACTIONS

Drug Interactions ACE-Inhibitors 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.

Aspirin 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.

Diuretics 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, Renal Effects ), as well as to assure diuretic efficacy.

Lithium 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.

Methotrexate 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.

Warfarin 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, Pharmacokinetics ).

OVERDOSAGE

Symptoms following acute NSAIDs overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care.

Gastrointestinal bleeding can occur.

Hypertension, acute renal failure, respiratory depression, and coma may occur, but are rare.

Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose.

Patients should be managed by symptomatic and supportive care following a NSAIDs overdose.

There are no specific antidotes.

Emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 g/kg in children), and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose (5 to 10 times the usual dose).

Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

There have been overdoses of up to 25 grams of nabumetone reported with no long-term sequelae following standard emergency treatment (i.e., activated charcoal, gastric lavage, IV H2-blockers, etc.).

DESCRIPTION

Nabumetone is a naphthylalkanone designated chemically as 4-(6-methoxy-2-naphthalenyl)-2-butanone.

It has the following structure: Nabumetone is a white to off-white crystalline substance.

It is nonacidic and practically insoluble in water, but soluble in alcohol and most organic solvents.

It has an n-octanol: phosphate buffer partition coefficient of 2,400 at pH 7.4.

Each tablet, for oral administration, contains either 500 mg or 750 mg of nabumetone.

In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, corn starch, hypromellose, magnesium stearate, povidone, sodium lauryl sulfate, sodium starch glycolate, titanium dioxide and triacetin.

The 500 mg tablets also contain talc and the 750 mg tablets also contain iron oxide red.

Structure

CLINICAL STUDIES

CLINICAL TRIALS Osteoarthritis The use of nabumetone in relieving the signs and symptoms of osteoarthritis (OA) was assessed in double-blind, controlled trials in which 1,047 patients were treated for 6 weeks to 6 months.

In these trials, nabumetone in a dose of 1,000 mg/day administered at night was comparable to naproxen 500 mg/day and to aspirin 3,600 mg/day.

Rheumatoid Arthritis The use of nabumetone in relieving the signs and symptoms of rheumatoid arthritis (RA) was assessed in double-blind, randomized, controlled trials in which 770 patients were treated for 3 weeks to 6 months.

Nabumetone, in a dose of 1,000 mg/day administered at night, was comparable to naproxen 500 mg/day and to aspirin 3,600 mg/day.

In controlled clinical trials of rheumatoid arthritis patients, nabumetone has been used in combination with gold, d-penicillamine, and corticosteroids.

Patient Exposure in Clinical Trials of Osteoarthritis and Rheumatoid Arthritis In clinical trials with osteoarthritis and rheumatoid arthritis patients, most patients responded to nabumetone in doses of 1,000 mg/day administered nightly; total daily dosages up to 2,000 mg were used.

In open-labeled studies, 1,490 patients were permitted dosage increases and were followed for approximately 1 year (mode).

Twenty percent of patients (n = 294) were withdrawn for lack of effectiveness during the first year of these open-labeled studies.

The following table provides patient-exposure to doses used in the U.S.

clinical trials: Table 2: Clinical Double-Blinded and Open-Labeled Trials of Nabumetone in Osteoarthritis and Rheumatoid Arthritis Dose of Nabumetone Number of Patients Mean/Mode Duration of Treatment (yr) OA RA OA RA 500 mg 17 6 0.4/– 0.2/– 1,000 mg 917 701 1.2/1 1.4/1 1,500 mg 645 224 2.3/1 1.7/1 2,000 mg 15 100 0.6/1 1.3/1 As with other NSAIDs, the lowest dose should be sought for each patient.

Patients weighing under 50 kg may be less likely to require dosages beyond 1,000 mg; therefore, after observing the response to initial therapy, the dose should be adjusted to meet individual patients’ requirements.

HOW SUPPLIED

Nabumetone tablets USP, 750 mg are pink, oval-shaped, film-coated, biconvex tablets debossed with “3671” on one side of the tablet and plain on the other side.

They are available in bottles of 100, 500 and 1000.

NDC 63187-307-30………………………….bottles of 30 Store at 20° – 25°C (68° – 77°F) [See USP Controlled Room Temperature].

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

Manufactured By: Watson Pharma Private Ltd.

Verna, Salcette Goa 403 722 INDIA Distributed by: Watson Pharma, Inc.

Corona, CA 92880 USA Repackaged by: Proficient Rx LP Thousand Oaks, CA 91320 Rev.

date: 12/10 195702

GERIATRIC USE

Geriatric Use 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.

INDICATIONS AND USAGE

Carefully consider the potential benefits and risks of nabumetone tablets and other treatment options before deciding to use nabumetone tablets.

Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS ).

Nabumetone tablets are indicated for relief of signs and symptoms of osteoarthritis and rheumatoid arthritis.

PEDIATRIC USE

Pediatric Use Safety and effectiveness in pediatric patients have not been established.

PREGNANCY

Pregnancy In late pregnancy, as with other NSAIDs, nabumetone tablets should be avoided because it may cause premature closure of the ductus arteriosus.

NUSRING MOTHERS

Nursing Mothers 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.

BOXED WARNING

Cardiovascular Risk • NSAIDs1 may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal.

This risk may increase with duration of use.

Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see WARNINGS).

• Nabumetone tablets are contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

Gastrointestinal Risk • NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal.

These events can occur at any time during use and without warning symptoms.

Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS).

1 Throughout this package insert, the term NSAID refers to a non-aspirin non-steroidal anti-inflammatory drug.

INFORMATION FOR PATIENTS

Information for Patients 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.

•Nabumetone tablets, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death.

Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative signs or symptoms.

Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects ).

•Nabumetone tablets, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death.

Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative signs or symptoms including epigastric pain, dyspepsia, melena, and hematemesis.

Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation ).

•Nabumetone tablets, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalization and even death.

Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms.

Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.

•Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.

•Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms).

If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.

•Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat).

If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS ).

•In late pregnancy, as with other NSAIDs, nabumetone tablets should be avoided because they may cause premature closure of the ductus arteriosus.

DOSAGE AND ADMINISTRATION

Carefully consider the potential benefits and risks of nabumetone tablets and other treatment options before deciding to use nabumetone tablets.

Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS ).

After observing the response to initial therapy with nabumetone tablets, the dose and frequency should be adjusted to suit an individual patient’s needs.

Osteoarthritis and Rheumatoid Arthritis The recommended starting dose is 1,000 mg taken as a single dose with or without food.

Some patients may obtain more symptomatic relief from 1,500 mg to 2,000 mg per day.

Nabumetone tablets can be given in either a single or twice-daily dose.

Dosages greater than 2,000 mg per day have not been studied.

The lowest effective dose should be used for chronic treatment (see WARNINGS, Renal Effects ).

Patients weighing under 50 kg may be less likely to require dosages beyond 1,000 mg; therefore, after observing the response to initial therapy, the dose should be adjusted to meet individual patients’ requirements.