Nabumetone

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, USP are indicated: For relief of the signs and symptoms of rheumatoid arthritis. For relief of the signs and symptoms of osteoarthritis.

Dosage and Administration Section DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of nabumetone tablets and other treatment options before deciding to use nabumetone. 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.

CONTRAINDICATIONS 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, Anaphylactoid Reactions and PRECAUTIONS, General, Preexisting Asthma ). Nabumetone tablets are contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS ).

ADVERSE REACTIONS 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. Incidence ≥ 1% - Probably Causally Related Gastrointestinal Diarrhea (14%), dyspepsia (13%), abdominal pain (12%), constipation *2 , flatulence *2 , nausea *2 , positive stool guaiac *2 , dry mouth, gastritis, stomatitis, vomiting. Central Nervous System Dizziness *2 , headache *2 , fatigue, increased sweating, insomnia, nervousness, somnolence. Dermatologic Pruritus *2 , rash *2 . Special Senses Tinnitus *2 . Miscellaneous Edema *2 . * 2 Incidence of reported reaction between 3% and 9%. Reactions occurring in 1% to 3% of the patients are unmarked. Incidence < 1% - Probably Causally Related †3 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, exfoliative dermatitis , toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome, and fixed drug eruption (FDE) 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. 3 † Adverse reactions reported only in worldwide postmarketing experience or in the literature, not seen in clinical trials, are considered rarer and are italicized. Incidence < 1% - Causal Relationship Unknown 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. To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch for voluntary reporting of adverse reactions.

Drug Interactions ACE-inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE­inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors. Aspirin When nabumetone is 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 and aspirin is not generally recommended because of the potential of increased adverse effects. Diuretics Clinical studies, as well as post-marketing observations, have shown that nabumetone 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 Gl bleeding are synergistic, such that users of both drugs together have a risk of serious Gl 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 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 ). Carcinogenesis, Mutagenesis In two-year studies conducted in mice and rats, nabumetone had no statistically significant tumorigenic effect. Nabumetone did not show mutagenic potential in the Ames test and mouse micronucleus test in vivo. However, nabumetone- and 6MNA- treated lymphocytes in culture showed chromosomal aberrations at 80 mcg/mL and higher concentrations (equal to the average human exposure to nabumetone at the maximum recommended dose). Impairment of Fertility Nabumetone did not impair fertility of male or female rats treated orally at doses of 320 mg/kg/day (1888 mg/m 2 ) before mating. Pregnancy Risk Summary Use of NSAIDs, including nabumetone tablets, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of nabumetone tablets use between about 20 and 30 weeks of gestation and avoid nabumetone tablets use at about 30 weeks of gestation and later in pregnancy [see WARNINGS ; Fetal Toxicity ]. Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including nabumetone tablets, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in s …

DESCRIPTION Nabumetone, USP is a naphthylalkanone designated chemically as 4-(6-methoxy-2- naphthalenyl)-2-butanone. 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 2400 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: microcrystalline cellulose, sodium starch glycolate, hydroxy propyl methyl cellulose, sodium lauryl sulphate, colloidal silicon dioxide and magnesium stearate. The 500 mg tablets also contain opadry white (Titanium dioxide, Hypromellose 3cP, Hypromellose 6cP, Macrogol and Polysorbate 80) and the 750 mg tablets contain opadry beige (Hypromellose 6cP, titanium dioxide, iron oxide yellow, iron oxide red and Macrogol). Structural Formula

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 grams to 100 grams in adults; 1 g/kg 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 long­term sequelae following standard emergency treatment (i.e., activated charcoal, gastric lavage, IV H 2 -blockers, etc.).

HOW SUPPLIED Nabumetone Tablets USP, 500 mg are available as white to off white, oval shaped, biconvex, film-coated tablets, debossed with "LU" on one side and "V01" on the other side. They are supplied as follows: NDC 68180-141-01 Bottles of 100's NDC 68180-141-03 Bottles of 1000's Nabumetone Tablets USP, 750 mg are available as white to off white, oval shaped, biconvex, film-coated tablets, debossed with "LU" on one side and "V02" on the other side. They are supplied as follows: NDC 68180-142-01 Bottles of 100's NDC 68180-142-03 Bottles of 1000's Store at 25°C (77°F); excursions permitted to 15°-30°C (59°- 86°F) [see USP Controlled Room Temperature]. Preserve in well-closed containers. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). _____________________________________________________________________________________________________ 1 Throughout this package insert, the term NSAID refers to a non-aspirin non- steroidal anti-inflammatory drug. 2 Incidence of reported reaction between 3% and 9%. Reactions occurring in 1% to 3% of the patients are unmarked. 3 † Adverse reactions reported only in worldwide postmarketing experience or in the literature, not seen in clinical trials, are considered rarer and are italicized. Manufactured for: Lupin Pharmaceuticals, Inc. Baltimore, Maryland 21202 United States Manufactured by: Lupin Limited Goa 403722 INDIA August 7, 2015 ID#: 242328