meloxicam 15 mg Tablet, 15-count — NDC 68071-1993-5 (Billing 68071-1993-05)

5. WARNINGS AND PRECAUTIONS Serious and potentially fatal cardiovascular (CV) thrombotic events, myocardial infarction, and stroke. Patients with known CV disease/risk factors may be at greater risk.

( 5.1 ) Serious gastrointestinal (GI) adverse events which can be fatal. The risk is greater in patients with a prior history of ulcer disease or GI bleeding, and in patients at higher risk for GI events, especially the elderly. ( 5.2 ) Elevated liver enzymes, and rarely, severe hepatic reactions.

Discontinue use immediately if abnormal liver enzymes persist or worsen. ( 5.3 ) New onset or worsening of hypertension. Blood pressure should be monitored closely during treatment.

( 5.4 ) Fluid retention and edema. Should be used with caution in patients with fluid retention or heart failure. ( 5.5 ) Renal papillary necrosis and other renal injury with long-term use.

Use with caution in the elderly, those with impaired renal function, heart failure, liver dysfunction, and those taking diuretics, ACE-inhibitors, or angiotensin II antagonists. The use of meloxicam in patients with severe renal impairment is not recommended ( 5.6 ) Serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal and can occur without warning. Discontinue meloxicam at first appearance of rash or skin reactions.

( 5.8 )

5.1Cardiovascular Thrombotic Events 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, 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.

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 ( 4.2 ) ]. 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 Warnings and Precautions ( 5.2 ) ].

5.2Gastrointestinal (GI) Effects - Risk of GI Ulceration, Bleeding, and Perforation NSAIDs, including meloxicam, 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 one in five 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 one 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.

Prescribe NSAIDs, including meloxicam, 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…

6. ADVERSE REACTIONS Most common (≥5% and greater than placebo) adverse events in adults are diarrhea, upper respiratory tract infections, dyspepsia, and influenza-like symptoms ( 6.1 ) Adverse events observed in pediatric studies were similar in nature to the adult clinical trial experience ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Unichem Pharmaceuticals (USA), Inc., Pharmacovigilance at 1-866-562-4616 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The following serious adverse reactions are discussed elsewhere in the labeling: Cardiovascular thrombotic events [ see Boxed Warning and Warnings and Precautions ( 5.1 )] Gastrointestinal effects – risk of GI ulceration, bleeding, and perforation [see Boxed Warning and Warnings and Precautions ( 5.2 )] Hepatic effects [see Warnings and Precautions ( 5.3 )] Hypertension [see Warnings and Precautions ( 5.4 )] Congestive heart failure and edema [see Warnings and Precautions ( 5.5 )] Renal effects [see Warnings and Precautions ( 5.6 )] Anaphylactoid reactions [ see Warnings and Precautions ( 5.7 )] Adverse skin reactions [see Warnings and Precautions ( 5.8 )]

6.1Clinical Trials Experience Adults Osteoarthritis and Rheumatoid Arthritis The meloxicam Phase 2/3 clinical trial database includes 10,122 OA patients and 1012 RA patients treated with meloxicam 7.5 mg/day, 3505 OA patients and 1351 RA patients treated with meloxicam 15 mg/day. Meloxicam at these doses was administered to 661 patients for at least 6 months and to 312 patients for at least one year. Approximately 10,500 of these patients were treated in ten placebo- and/or active-controlled osteoarthritis trials and 2363 of these patients were treated in ten placebo- and/or active-controlled rheumatoid arthritis trials.

Gastrointestinal (GI) adverse events were the most frequently reported adverse events in all treatment groups across meloxicam trials. A 12-week multicenter, double-blind, randomized trial was conducted in patients with osteoarthritis of the knee or hip to compare the efficacy and safety of meloxicam with placebo and with an active control. Two 12-week multicenter, double-blind, randomized trials were conducted in patients with rheumatoid arthritis to compare the efficacy and safety of meloxicam with placebo.

Table 1a depicts adverse events that occurred in ≥2% of the meloxicam treatment groups in a 12-week placebo- and active-controlled osteoarthritis trial. Table 1b depicts adverse events that occurred in ≥2% of the meloxicam treatment groups in two 12-week placebo- controlled rheumatoid arthritis trials. Table 1a Adverse Events (%) Occurring in ≥ 2% of Meloxicam Patients in a 12-Week Osteoarthritis Placebo- and Active-Controlled Trial Placebo Meloxicam 7 .

5 mg daily Meloxicam 15 mg daily Diclofenac 100 mg daily No . of Patients 157 154 156 153 Gastrointestinal 17.2 20.1 17.3

28.1Abdominal pain 2.5 1.9 2.6

1.3Diarrhea 3.8 7.8 3.2

9.2Dyspepsia 4.5 4.5 4.5

6.5Flatulence 4.5 3.2 3.2

3.9Nausea 3.2 3.9 3.8

7.2Body as a Whole Accident household 1.9 4.5 3.2

2.6Edema WHO preferred terms edema, edema dependent, edema peripheral, and edema legs combined 2.5 1.9 4.5

3.3Fall 0.6 2.6 0.0

1.3Influenza-like symptoms 5.1 4.5 5.8

2.6Central and Peripheral Nervous System Dizziness 3.2 2.6 3.8

2.0Headache 10.2 7.8 8.3

5.9Respiratory Pharyngitis 1.3 0.6 3.2

1.3Upper respiratory tract infection 1.9 3.2 1.9

3.3Skin Rash WHO preferred terms rash, rash erythematous, and rash maculo-papular combined 2.5 2.6 0.6

2.0Table 1b Adverse Events (%) Occurring in ≥2% of Meloxicam Patients in two 12-Week Rheumatoid Arthritis Placebo- Controlled Trials Placebo Meloxicam 7 . 5 mg daily Meloxicam 15 mg daily No . of Patients 469 481 477 Gastrointestinal D…

7. DRUG INTERACTIONS Concomitant use of meloxicam and warfarin may result in increased risk of bleeding complications ( 7.7 ) Concomitant use of meloxicam and aspirin is not generally recommended because of the potential of increased adverse effect including increased GI bleeding ( 7.2 ) Concomitant use with meloxicam increases lithium plasma levels ( 7.4 ) Concomitant use with NSAIDs may reduce the antihypertensive effect of ACE-inhibitors ( 7.1 ) See also Clinical Pharmacology ( 12.3 ).

7.1ACE-inhibitors NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking meloxicam concomitantly with ACE-inhibitors.

7.2Aspirin When meloxicam is administered with aspirin (1000 mg three times daily) to healthy volunteers, an increase in the AUC (10%) and C max (24%) of meloxicam was noted. The clinical significance of this interaction is not known; however, as with other NSAIDs concomitant administration of meloxicam and aspirin is not generally recommended because of the potential for increased adverse effects. Concomitant administration of low-dose aspirin with meloxicam may result in an increased rate of GI ulceration or other complications, compared to use of meloxicam alone.

Meloxicam is not a substitute for aspirin for cardiovascular prophylaxis.

7.3Diuretics Clinical studies, as well as post marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect.

Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Nevertheless, during concomitant therapy with meloxicam, patients should be observed closely for signs of renal failure [ see Warnings and Precautions ( 5.6 ) ], as well as to ensure diuretic efficacy.

7.4Lithium In a study conducted in healthy subjects, mean pre-dose lithium concentration and AUC were increased by 21% in subjects receiving lithium doses ranging from 804 to 1072 mg twice daily with meloxicam 15 mg every day as compared to subjects receiving lithium alone. These effects have been attributed to inhibition of renal prostaglandin synthesis by meloxicam. Closely monitor patients on lithium treatment for signs of lithium toxicity when meloxicam is introduced, adjusted, or withdrawn.

7.5Methotrexate NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. Therefore, NSAIDs may reduce the elimination of methotrexate , thereby enhancing the toxicity of methotrexate. Use caution when meloxicam is administered concomitantly with methotrexate [ see Clinical Pharmacology ( 12.3 ) ].

7.6Cyclosporine Meloxicam, like other NSAIDs, may affect renal prostaglandins, thereby altering the renal toxicity of certain drugs. Therefore, concomitant therapy with meloxicam may increase cyclosporine's nephrotoxicity. Use caution when meloxicam is administered concomitantly with cyclosporine.

7.7Warfarin 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. Monitor anticoagulant activity, particularly in the first few days after initiating or changing meloxicam therapy in patients receiving warfarin or similar agents, since these patients are at an increased risk of bleeding than with the use of either drug alone. Use caution when administering meloxicam with warfarin since patients on warfarin may experience changes in INR and an increased risk of bleeding complications when a new medication is introduced [ see Clinical Pharmacology ( 12.3 ) ].