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WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [ see Warnings and Precautions ( 5.1 ) ]. Meloxicam is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [ see Contraindications (4) and Warnings and Precautions ( 5.1 ) ]. Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs cause an increased risk of serious gastrointestinal (GI) 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 and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [ see Warnings and Precautions ( 5.2 ) ]. WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning . Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use ( 5.1 ) Meloxicam is contraindicated in the setting of coronary artery bypass graft (CABG) surgery ( 4, 5.1 ) NSAIDs cause an increased risk of serious gastrointestinal (GI) 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 and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events ( 5.2 )

1 INDICATIONS AND USAGE Meloxicam is a non-steroidal anti-inflammatory drug indicated for: Osteoarthritis (OA) (1.1) Rheumatoid Arthritis (RA) (1.2) Juvenile Rheumatoid Arthritis (JRA) in patients who weigh ≥60 kg (1.3) 1.1 Osteoarthritis (OA) Meloxicam is indicated for relief of the signs and symptoms of osteoarthritis [ see Clinical Studies (14.1)]. 1.2 Rheumatoid Arthritis (RA) Meloxicam is indicated for relief of the signs and symptoms of rheumatoid arthritis [ see Clinical Studies (14.1) ]. 1.3 Juvenile Rheumatoid Arthritis (JRA) Pauciarticular and Polyarticular Course Meloxicam is indicated for relief of the signs and symptoms of pauciarticular or polyarticular course Juvenile Rheumatoid Arthritis in patients who weigh ≥ 60 kg [ see Dosage and Administration ( 2.4 ) and Clinical Studies (14.2) ].

2 DOSAGE AND ADMINISTRATION Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals ( 2.1 ) OA (2.2) and RA (2.3) : Starting dose: 7.5 mg once daily Dose may be increased to 15 mg once daily JRA (2.4) : 7.5 mg once daily in children ≥60 kg Meloxicam tablets are not interchangeable with approved formulations of oral meloxicam even if the total milligram strength is the same ( 2.6 ) 2.1 General Dosing Instructions Carefully consider the potential benefits and risks of meloxicam and other treatment options before deciding to use meloxicam. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [ see Warnings and Precautions ( 5 ) ]. After observing the response to initial therapy with meloxicam, adjust the dose to suit an individual patient's needs. In adults, the maximum recommended daily oral dose of meloxicam is 15 mg regardless of formulation. In patients with hemodialysis, a maximum daily dosage of 7.5 mg is recommended [ see Use in Specific Populations ( 8.7 ) and Clinical Pharmacology ( 12.3 ) ]. Meloxicam may be taken without regard to timing of meals. 2.2 Osteoarthritis For the relief of the signs and symptoms of osteoarthritis the recommended starting and maintenance oral dose of meloxicam is 7.5 mg once daily. Some patients may receive additional benefit by increasing the dose to 15 mg once daily. 2.3 Rheumatoid Arthritis For the relief of the signs and symptoms of rheumatoid arthritis, the recommended starting and maintenance oral dose of meloxicam is 7.5 mg once daily. Some patients may receive additional benefit by increasing the dose to 15 mg once daily. 2.4 Juvenile Rheumatoid Arthritis (JRA) Pauciarticular and Polyarticular Course For the treatment of juvenile rheumatoid arthritis, the recommended oral dose of meloxicam is 7.5 mg once daily in children who weigh ≥ 60 kg. There was no additional benefit demonstrated by increasing the dose above 7.5 mg in clinical trials. Meloxicam tablets should not be used in children who weigh <60 kg. 2.5 Renal Impairment The use of meloxicam in subjects with severe renal impairment is not recommended. In patients on hemodialysis, the maximum dosage of meloxicam is 7.5 mg per day [ see Clinical Pharmacology ( 12.3 ) ]. 2.6 Non-Interchangeability with Other Formulations of Meloxicam Meloxicam tablets have not shown equivalent systemic exposure to other approved formulations of oral meloxicam. Therefore, meloxicam tablets are not interchangeable with other formulations of oral meloxicam product even if the total milligram strength is the same. Do not substitute similar dose strengths of meloxicam tablets with other formulations of oral meloxicam product.

3 DOSAGE FORMS AND STRENGTHS Meloxicam tablets: 7.5 mg and 15 mg ( 3 ) Meloxicam tablets, USP: 15 mg: yellow coloured, round, flat bevelled tablets, debossed with "CIPLA" on one side and "159" on the other.

4 CONTRAINDICATIONS Meloxicam is contraindicated in the following patients: Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to meloxicam or any components of the drug product [ see Warnings and Precautions ( 5.7 , 5.9 ) ] History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [ see Warnings and Precautions ( 5.7 , 5.8 ) ] In the setting of coronary artery bypass graft (CABG) surgery [ see Warnings and Precautions ( 5.1 ) ] Known hypersensitivity to meloxicam or any components of the drug product ( 4 ) History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs ( 4) In the setting of CABG surgery ( 4 )

5 WARNINGS AND PRECAUTIONS Hepatotoxicity : Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop ( 5.3 ) Hypertension : Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure ( 5.4 , 7 ) Heart Failure and Edema : Avoid use of meloxicam in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure ( 5.5) Renal Toxicity : Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of meloxicam in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function ( 5.6 ) Anaphylactic Reactions : Seek emergency help if an anaphylactic reaction occurs ( 5.7 ) Exacerbation of Asthma Related to Aspirin Sensitivity : Meloxicam is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) ( 5.8 ) Serious Skin Reactions : Discontinue meloxicam at first appearance of skin rash or other signs of hypersensitivity ( 5.9 ) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue meloxicam and evaluate clinically ( 5.10 ) Fetal Toxicity: Limit use of NSAIDs, including meloxicam, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus ( 5.11 , 8.1 ) Hematologic Toxicity : Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia ( 5.12 , 7 ) 5.1 Cardiovascular 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, 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.

e 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 meloxicam, increases the risk of serious gastrointestinal (GI) events [ see Warnings and Precautions( 5.2 ) ]. Status Post Coronary Artery Bypass Graft (CABG) Surgery 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 ( 4 )]. Post-MI Patients 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 meloxicam in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If meloxicam is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including meloxicam, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, 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 occurred in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients: Use the lowest effective dosage for the shortest possible duration. Avoid administration of more than one NSAID at a time. Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.

ID at a time. Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue meloxicam until a serious GI adverse event is ruled out. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [ see Drug Interactions ( 7 ) ]. 5.3 Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including meloxicam. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue meloxicam immediately, and perform a clinical evaluation of the patient [ see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology( 12.3 ) ]. 5.4 Hypertension NSAIDs, including meloxicam, can lead to new onset or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [ see Drug Interactions ( 7 ) ]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.5 Heart Failure and Edema 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 meloxicam 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 ( 7 ) ]. Avoid the use of meloxicam in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If meloxicam is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs, including meloxicam, has resulted in renal papillary necrosis, renal insufficiency, acute renal failure, 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 may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation.

s 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 may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. The renal effects of meloxicam may hasten the progression of renal dysfunction in patients with preexisting renal disease. Because some meloxicam metabolites are excreted by the kidney, monitor patients for signs of worsening renal function. Correct volume status in dehydrated or hypovolemic patients prior to initiating meloxicam. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of meloxicam [ see Drug Interactions ( 7 ) ]. No information is available from controlled clinical studies regarding the use of meloxicam in patients with advanced renal disease. Avoid the use of meloxicam in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If meloxicam is used in patients with advanced renal disease, monitor patients for signs of worsening renal function [ see Clinical Pharmacology ( 12.3 ) ]. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. 5.7 Anaphylactic Reactions Meloxicam has been associated with anaphylactic reactions in patients with and without known hypersensitivity to meloxicam and in patients with aspirin-sensitive asthma [ see Contraindications ( 4 ) and Warnings and Precautions ( 5.8 ) ]. Seek emergency help if an anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, meloxicam is contraindicated in patients with this form of aspirin sensitivity [ see Contraindications ( 4 ) ]. When meloxicam is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.9 Serious Skin Reactions NSAIDs, including meloxicam, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal.NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of meloxicam tablets at the first appearance of skin rash or any other sign of hypersensitivity. Meloxicam tablets is contraindicated in patients with previous serious skin reactions to NSAIDs [ see Contraindications ( 4 ) ]. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as meloxicam.

Meloxicam tablets is contraindicated in patients with previous serious skin reactions to NSAIDs [ see Contraindications ( 4 ) ]. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as meloxicam. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue meloxicam and evaluate the patient immediately. 5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including meloxicam, in pregnant women at about 30 weeks gestation and later. NSAIDs, including meloxicam, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including meloxicam, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit meloxicam use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if meloxicam treatment extends beyond 48 hours. Discontinue meloxicam if oligohydramnios occurs and follow up according to clinical practice [ see Use in Specific Populations ( 8.1 ) ]. 5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with meloxicam has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including meloxicam, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [ see Drug Interactions ( 7 ) ]. 5.13 Masking of Inflammation and Fever The pharmacological activity of meloxicam in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.14 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [ see Warnings and Precautions ( 5.2 , 5.3 , 5.6 ) ].

5.9 Serious Skin Reactions NSAIDs, including meloxicam, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal.NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of meloxicam tablets at the first appearance of skin rash or any other sign of hypersensitivity. Meloxicam tablets is contraindicated in patients with previous serious skin reactions to NSAIDs [ see Contraindications ( 4 ) ].

rm patients about the signs and symptoms of serious skin reactions, and to discontinue the use of meloxicam tablets at the first appearance of skin rash or any other sign of hypersensitivity. Meloxicam tablets is contraindicated in patients with previous serious skin reactions to NSAIDs [ see Contraindications ( 4 ) ]. 8.1 Pregnancy Risk Summary Use of NSAIDs, including meloxicam, 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 meloxicam use between about 20 and 30 weeks of gestation, and avoid meloxicam use at about 30 weeks of gestation and later in pregnancy ( see Clinical Considerations, Data ). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including meloxicam, 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 some cases, neonatal renal impairment. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, embryofetal death was observed in rats and rabbits treated during the period of organogenesis with meloxicam at oral doses equivalent to 0.65- and 6.5-times the maximum recommended human dose (MRHD) of meloxicam. Increased incidence of septal heart defects were observed in rabbits treated throughout embryogenesis with meloxicam at an oral dose equivalent to 78-times the MRHD. In pre- and post-natal reproduction studies, there was an increased incidence of dystocia, delayed parturition, and decreased offspring survival at 0.08-times MRHD of meloxicam. No teratogenic effects were observed in rats and rabbits treated with meloxicam during organogenesis at an oral dose equivalent to 2.6 and 26-times the MRHD [see Data] . Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as meloxicam, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including meloxicam, can cause premature closure of the fetal ductus arteriosus ( see Data ). Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If meloxicam treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue meloxicam and follow up according to clinical practice ( see Data ).

gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If meloxicam treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue meloxicam and follow up according to clinical practice ( see Data ). Labor or Delivery There are no studies on the effects of meloxicam during labor or delivery. In animal studies, NSAIDs, including meloxicam, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal Data Meloxicam was not teratogenic when administered to pregnant rats during fetal organogenesis at oral doses up to 4 mg/kg/day (2.6-fold greater than the MRHD of 15 mg of meloxicam based on BSA comparison). Administration of meloxicam to pregnant rabbits throughout embryogenesis produced an increased incidence of septal defects of the heart at an oral dose of 60 mg/kg/day (78-fold greater than the MRHD based on BSA comparison). The no effect level was 20 mg/kg/day (26-fold greater than the MRHD based on BSA conversion). In rats and rabbits, embryolethality occurred at oral meloxicam doses of 1 mg/kg/day and 5 mg/kg/day, respectively (0.65- and 6.5-fold greater, respectively, than the MRHD based on BSA comparison) when administered throughout organogenesis. Oral administration of meloxicam to pregnant rats during late gestation through lactation increased the incidence of dystocia, delayed parturition, and decreased offspring survival at meloxicam doses of 0.125 mg/kg/day or greater (0.08-times MRHD based on BSA comparison).

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Cardiovascular Thrombotic Events [ see Boxed Warning and Warnings and Precautions ( 5.1 ) ] GI Bleeding, Ulceration, and Perforation [ see Boxed Warning and Warnings and Precautions ( 5.2 ) ] Hepatotoxicity [ see Warnings and Precautions ( 5.3 ) ] Hypertension [ see Warnings and Precautions ( 5.4 ) ] Heart Failure and Edema [ see Warnings and Precautions ( 5.5 ) ] Renal Toxicity and Hyperkalemia [ see Warnings and Precautions ( 5.6 ) ] Anaphylactic Reactions [ see Warnings and Precautions ( 5.7 ) ] Serious Skin Reactions [ see Warnings and Precautions ( 5.9 ) ] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [ see Warnings and Precautions ( 5.10 ) ] Fetal Toxicity [ see Warnings and Precautions ( 5.11 ) ] Hematologic Toxicity [ see Warnings and Precautions ( 5.12 ) ] 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 Cipla Limited, India at 1-866-604-3268 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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. 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 1 WHO preferred terms edema, edema dependent, edema peripheral, and edema legs combined 2 WHO preferred terms rash, rash erythematous, and rash maculo-papular combined Placebo Meloxicam 7.5 mg daily Meloxicam 15 mg daily Diclofenac 100 mg daily No.

tients in a 12-Week Osteoarthritis Placebo- and Active-Controlled Trial 1 WHO preferred terms edema, edema dependent, edema peripheral, and edema legs combined 2 WHO preferred terms rash, rash erythematous, and rash maculo-papular combined 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 28.1 Abdominal pain 2.5 1.9 2.6 1.3 Diarrhea 3.8 7.8 3.2 9.2 Dyspepsia 4.5 4.5 4.5 6.5 Flatulence 4.5 3.2 3.2 3.9 Nausea 3.2 3.9 3.8 7.2 Body as a Whole Accident household 1.9 4.5 3.2 2.6 Edema 1 2.5 1.9 4.5 3.3 Fall 0.6 2.6 0.0 1.3 Influenza-like symptoms 5.1 4.5 5.8 2.6 Central and Peripheral Nervous System Dizziness 3.2 2.6 3.8 2.0 Headache 10.2 7.8 8.3 5.9 Respiratory Pharyngitis 1.3 0.6 3.2 1.3 Upper respiratory tract infection 1.9 3.2 1.9 3.3 Skin Rash 2 2.5 2.6 0.6 2.0 Table 1b Adverse Events (%) Occurring in ≥2% of Meloxicam Patients in two 12-Week Rheumatoid Arthritis Placebo-Controlled Trials 1 MedDRA high level term (preferred terms): dyspeptic signs and symptoms (dyspepsia, dyspepsia aggravated, eructation, gastrointestinal irritation), upper respiratory tract infections-pathogen unspecified (laryngitis NOS, pharyngitis NOS, sinusitis NOS), joint related signs and symptoms (arthralgia, arthralgia aggravated, joint crepitation, joint effusion, joint swelling) 2 MedDRA preferred term: nausea, abdominal pain NOS, influenza-like illness, headaches NOS, and rash NOS Placebo Meloxicam Meloxicam 7.5 mg daily 15 mg daily No. of Patients 469 481 477 Gastrointestinal Disorders 14.1 18.9 16.8 Abdominal pain NOS 2 0.6 2.9 2.3 Dyspeptic signs and symptoms 1 3.8 5.8 4.0 Nausea 2 2.6 3.3 3.8 General Disorders and Administration Site Conditions Influenza-like illness 2 2.1 2.9 2.3 Infection and Infestations Upper respiratory tract infections-pathogen class unspecified 1 4.1 7.0 6.5 Musculoskeletal and Connective Tissue Disorders Joint related signs and symptoms 1 1.9 1.5 2.3 Nervous System Disorders Headaches NOS 2 6.4 6.4 5.5 Skin and Subcutaneous Tissue Disorders Rash NOS 2 1.7 1.0 2.1 The adverse events that occurred with meloxicam in ≥2% of patients treated short-term (4 to 6 weeks) and long-term (6 months) in active-controlled osteoarthritis trials are presented in Table 2. Table 2 Adverse Events (%) Occurring in ≥2% of Meloxicam Patients in 4 to 6 Weeks and 6 Month Active-Controlled Osteoarthritis Trials 1 WHO preferred terms edema, edema dependent, edema peripheral, and edema legs combined 2 WHO preferred terms rash, rash erythematous, and rash maculo-papular combined 4 to 6 Weeks Controlled Trials 6 Month Controlled Trials Meloxicam 7.5 mg daily Meloxicam 15 mg daily Meloxicam 7.5 mg daily Meloxicam 15 mg daily No. of Patients 8955 256 169 306 Gastrointestinal 11.8 18.0 26.6 24.2 Abdominal pain 2.7 2.3 4.7 2.9 Constipation 0.8 1.2 1.8 2.6 Diarrhea 1.9 2.7 5.9 2.6 Dyspepsia 3.8 7.4 8.9 9.5 Flatulence 0.5 0.4 3.0 2.6 Nausea 2.4 4.7 4.7 7.2 Vomiting 0.6 0.8 1.8 2.6 Body as a Whole Accident household 0.0 0.0 0.6 2.9 Edema 1 0.6 2.0 2.4 1.6 Pain 0.9 2.0 3.6 5.2 Central and Peripheral Nervous System Dizziness 1.1 1.6 2.4 2.6 Headache 2.4 2.7 3.6 2.6 Hematologic Anemia 0.1 0.0 4.1 2.9 Musculoskeletal Arthralgia 0.5 0.0 5.3 1.3 Back pain 0.5 0.4 3.0 0.7 Psychiatric Insomnia 0.4 0.0 3.6 1.6 Respiratory Coughing 0.2 0.8 2.4 1.0 Upper respiratory tract infection 0.2 0.0 8.3 7.5 Skin Pruritus 0.4 1.2 2.4 0.0 Rash 2 0.3 1.2 3.0 1.3 Urinary Micturition frequency 0.1 0.4 2.4 1.3 Urinary tract infection 0.3 0.4 4.7 6.9 Higher doses of meloxicam (22.5 mg and greater) have been associated with an increased risk of serious GI events; therefore, the daily dose of meloxicam should not exceed 15 mg.

7.5 Skin Pruritus 0.4 1.2 2.4 0.0 Rash 2 0.3 1.2 3.0 1.3 Urinary Micturition frequency 0.1 0.4 2.4 1.3 Urinary tract infection 0.3 0.4 4.7 6.9 Higher doses of meloxicam (22.5 mg and greater) have been associated with an increased risk of serious GI events; therefore, the daily dose of meloxicam should not exceed 15 mg. Pediatrics Pauciarticular and Polyarticular Course Juvenile Rheumatoid Arthritis (JRA) Three hundred and eighty-seven patients with pauciarticular and polyarticular course JRA were exposed to meloxicam with doses ranging from 0.125 to 0.375 mg/kg per day in three clinical trials. These studies consisted of two 12-week multicenter, double-blind, randomized trials (one with a 12-week open-label extension and one with a 40-week extension) and one 1-year open-label PK study. The adverse events observed in these pediatric studies with meloxicam were similar in nature to the adult clinical trial experience, although there were differences in frequency. In particular, the following most common adverse events, abdominal pain, vomiting, diarrhea, headache, and pyrexia, were more common in the pediatric than in the adult trials. Rash was reported in seven (<2%) patients receiving meloxicam. No unexpected adverse events were identified during the course of the trials. The adverse events did not demonstrate an age or gender-specific subgroup effect. The following is a list of adverse drug reactions occurring in <2% of patients receiving meloxicam in clinical trials involving approximately 16,200 patients. Body as a Whole allergic reaction, face edema, fatigue, fever, hot flushes, malaise, syncope, weight decrease, weight increase Cardiovascular angina pectoris, cardiac failure, hypertension, hypotension, myocardial infarction, vasculitis Central and Peripheral Nervous System convulsions, paresthesia, tremor, vertigo Gastrointestinal colitis, dry mouth, duodenal ulcer, eructation, esophagitis, gastric ulcer, gastritis, gastroesophageal reflux, gastrointestinal hemorrhage, hematemesis, hemorrhagic duodenal ulcer, hemorrhagic gastric ulcer, intestinal perforation, melena, pancreatitis, perforated duodenal ulcer, perforated gastric ulcer, stomatitis ulcerative Heart Rate and Rhythm arrhythmia, palpitation, tachycardia Hematologic leukopenia, purpura, thrombocytopenia Liver and Biliary System ALT increased, AST increased, bilirubinemia, GGT increased, hepatitis Metabolic and Nutritional dehydration Psychiatric abnormal dreaming, anxiety, appetite increased, confusion, depression, nervousness, somnolence Respiratory asthma, bronchospasm, dyspnea Skin and Appendages alopecia, angioedema, bullous eruption, photosensitivity reaction, pruritus, sweating increased, urticaria Special Senses abnormal vision, conjunctivitis, taste perversion, tinnitus Urinary System albuminuria, BUN increased, creatinine increased, hematuria, renal failure 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of meloxicam. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions about whether to include an adverse event from spontaneous reports in labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2) number of reports, or (3) strength of causal relationship to the drug.

ir frequency or establish a causal relationship to drug exposure. Decisions about whether to include an adverse event from spontaneous reports in labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2) number of reports, or (3) strength of causal relationship to the drug. Adverse reactions reported in worldwide postmarketing experience or the literature include: acute urinary retention; agranulocytosis; alterations in mood (such as mood elevation); anaphylactoid reactions including shock; erythema multiforme; exfoliative dermatitis; interstitial nephritis; jaundice; liver failure; Stevens-Johnson syndrome; fixed drug eruption (FDE); toxic epidermal necrolysis, and infertility female.

<table ID="ID275" width="598" styleCode="Noautorules"><col width="163"/><col width="102"/><col width="114"/><col width="114"/><col width="105"/><tfoot><tr><td align="left" colspan="5"><paragraph styleCode="Footnote">¹WHO preferred terms edema, edema dependent, edema peripheral, and edema legs combined </paragraph></td></tr><tr><td align="left" colspan="5"><paragraph styleCode="Footnote">²WHO preferred terms rash, rash erythematous, and rash maculo-papular combined </paragraph></td></tr></tfoot><tbody><tr><td styleCode=" Toprule Botrule"/><td align="left" styleCode=" Toprule Botrule"><content styleCode="bold">Placebo</content> </td><td align="left" styleCode=" Toprule Botrule"><content styleCode="bold">Meloxicam</content> <content styleCode="bold">7.5 mg daily</content> </td><td align="left" styleCode=" Toprule Botrule"><content styleCode="bold">Meloxicam</content> <content styleCode="bold">15 mg daily</content> </td><td align="left" styleCode=" Toprule Botrule"><content styleCode="bold">Diclofenac</content> <content styleCode="bold">100 mg daily</content> </td></tr><tr><td align="left" styleCode=" Botrule"><content styleCode="bold">No.

ontent styleCode="bold">Meloxicam</content> <content styleCode="bold">15 mg daily</content> </td><td align="left" styleCode=" Toprule Botrule"><content styleCode="bold">Diclofenac</content> <content styleCode="bold">100 mg daily</content> </td></tr><tr><td align="left" styleCode=" Botrule"><content styleCode="bold">No. of Patients</content> </td><td align="left" styleCode=" Botrule"><content styleCode="bold">157</content> </td><td align="left" styleCode=" Botrule"><content styleCode="bold">154</content> </td><td align="left" styleCode=" Botrule"><content styleCode="bold">156</content> </td><td align="left" styleCode=" Botrule"><content styleCode="bold">153</content> </td></tr><tr><td align="left"><content styleCode="bold">Gastrointestinal</content> </td><td align="left">17.2 </td><td align="left">20.1 </td><td align="left">17.3 </td><td align="left">28.1 </td></tr><tr><td align="left">Abdominal pain </td><td align="left">2.5 </td><td align="left">1.9 </td><td align="left">2.6 </td><td align="left">1.3 </td></tr><tr><td align="left">Diarrhea </td><td align="left">3.8 </td><td align="left">7.8 </td><td align="left">3.2 </td><td align="left">9.2 </td></tr><tr><td align="left">Dyspepsia </td><td align="left">4.5 </td><td align="left">4.5 </td><td align="left">4.5 </td><td align="left">6.5 </td></tr><tr><td align="left">Flatulence </td><td align="left">4.5 </td><td align="left">3.2 </td><td align="left">3.2 </td><td align="left">3.9 </td></tr><tr><td align="left" styleCode=" Botrule">Nausea </td><td align="left" styleCode=" Botrule">3.2 </td><td align="left" styleCode=" Botrule">3.9 </td><td align="left" styleCode=" Botrule">3.8 </td><td align="left" styleCode=" Botrule">7.2 </td></tr><tr><td colspan="5" align="left"><content styleCode="bold">Body as a Whole</content> </td></tr><tr><td align="left">Accident household </td><td align="left">1.9 </td><td align="left">4.5 </td><td align="left">3.2 </td><td align="left">2.6 </td></tr><tr><td align="left">Edema ¹ </td><td align="left">2.5 </td><td align="left">1.9 </td><td align="left">4.5 </td><td align="left">3.3 </td></tr><tr><td align="left">Fall </td><td align="left">0.6 </td><td align="left">2.6 </td><td align="left">0.0 </td><td align="left">1.3 </td></tr><tr><td align="left" styleCode=" Botrule">Influenza-like symptoms </td><td align="left" styleCode=" Botrule">5.1 </td><td align="left" styleCode=" Botrule">4.5 </td><td align="left" styleCode=" Botrule">5.8 </td><td align="left" styleCode=" Botrule">2.6 </td></tr><tr><td colspan="5" align="left"><content styleCode="bold">Central and Peripheral</content> <content styleCode="bold">Nervous System</content> </td></tr><tr><td align="left">Dizziness </td><td align="left">3.2 </td><td align="left">2.6 </td><td align="left">3.8 </td><td align="left">2.0 </td></tr><tr><td align="left" styleCode=" Botrule">Headache </td><td align="left" styleCode=" Botrule">10.2 </td><td align="left" styleCode=" Botrule">7.8 </td><td align="left" styleCode=" Botrule">8.3 </td><td align="left" styleCode=" Botrule">5.9 </td></tr><tr><td align="left"><content styleCode="bold">Respiratory</content> </td><td/><td/><td/><td/></tr><tr><td align="left">Pharyngitis </td><td align="left">1.3 </td><td align="left">0.6 </td><td align="left">3.2 </td><td align="left">1.3 </td></tr><tr><td align="left" styleCode=" Botrule">Upper respiratory tract infection </td><td align="left" styleCode=" Botrule">1.9 </td><td align="left" styleCode=" Botrule">3.2 </td><td align="left" styleCode=" Botrule">1.9 </td><td align="left" styleCode=" Botrule">3.3 </td></tr><tr><td colspan="5" align="left"><content styleCode="bold">Skin</content> </td></tr><tr><td align="left" styleCode=" Botrule">Rash ² </td><td align="left" styleCode=" Botrule">2.5 </td><td align="left" styleCode=" Botrule">2.6

styleCode=" Botrule">1.9 </td><td align="left" styleCode=" Botrule">3.3 </td></tr><tr><td colspan="5" align="left"><content styleCode="bold">Skin</content> </td></tr><tr><td align="left" styleCode=" Botrule">Rash ² </td><td align="left" styleCode=" Botrule">2.5 </td><td align="left" styleCode=" Botrule">2.6 </td><td align="left" styleCode=" Botrule">0.6 </td><td align="left" styleCode=" Botrule">2.0 </td></tr></tbody></table> <table ID="ID277" width="614" styleCode="Noautorules"><col width="348"/><col width="78"/><col width="96"/><col width="92"/><tfoot><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">¹MedDRA high level term (preferred terms): dyspeptic signs and symptoms (dyspepsia, dyspepsia aggravated, eructation, gastrointestinal irritation), upper respiratory tract infections-pathogen unspecified (laryngitis NOS, pharyngitis NOS, sinusitis NOS), joint related signs and symptoms (arthralgia, arthralgia aggravated, joint crepitation, joint effusion, joint swelling) </paragraph></td></tr><tr><td align="left" colspan="4"><paragraph styleCode="Footnote">²MedDRA preferred term: nausea, abdominal pain NOS, influenza-like illness, headaches NOS, and rash NOS </paragraph></td></tr></tfoot><tbody><tr><td styleCode=" Toprule"/><td align="left" styleCode=" Toprule"><content styleCode="bold">Placebo</content> </td><td align="left" styleCode=" Toprule"><content styleCode="bold">Meloxicam</content> </td><td align="left" styleCode=" Toprule"><content styleCode="bold">Meloxicam</content> </td></tr><tr><td styleCode=" Botrule"/><td styleCode=" Botrule"/><td align="left" styleCode=" Botrule"><content styleCode="bold">7.5 mg daily</content> </td><td align="left" styleCode=" Botrule"><content styleCode="bold">15 mg daily</content> </td></tr><tr><td align="left" styleCode=" Botrule"><content styleCode="bold">No.

</tr><tr><td styleCode=" Botrule"/><td styleCode=" Botrule"/><td align="left" styleCode=" Botrule"><content styleCode="bold">7.5 mg daily</content> </td><td align="left" styleCode=" Botrule"><content styleCode="bold">15 mg daily</content> </td></tr><tr><td align="left" styleCode=" Botrule"><content styleCode="bold">No. of Patients</content> </td><td align="left" styleCode=" Botrule">469 </td><td align="left" styleCode=" Botrule">481 </td><td align="left" styleCode=" Botrule">477 </td></tr><tr><td align="left" styleCode=" Botrule"><content styleCode="bold">Gastrointestinal Disorders</content> </td><td align="left" styleCode=" Botrule">14.1 </td><td align="left" styleCode=" Botrule">18.9 </td><td align="left" styleCode=" Botrule">16.8 </td></tr><tr><td align="left" styleCode=" Botrule">Abdominal pain NOS ² </td><td align="left" styleCode=" Botrule">0.6 </td><td align="left" styleCode=" Botrule">2.9 </td><td align="left" styleCode=" Botrule">2.3 </td></tr><tr><td align="left" styleCode=" Botrule">Dyspeptic signs and symptoms ¹ </td><td align="left" styleCode=" Botrule">3.8 </td><td align="left" styleCode=" Botrule">5.8 </td><td align="left" styleCode=" Botrule">4.0 </td></tr><tr><td align="left" styleCode=" Botrule">Nausea ² </td><td align="left" styleCode=" Botrule">2.6 </td><td align="left" styleCode=" Botrule">3.3 </td><td align="left" styleCode=" Botrule">3.8 </td></tr><tr><td colspan="4" align="left"><content styleCode="bold">General Disorders and Administration Site Conditions</content> </td></tr><tr><td align="left" styleCode=" Botrule">Influenza-like illness ² </td><td align="left" styleCode=" Botrule">2.1 </td><td align="left" styleCode=" Botrule">2.9 </td><td align="left" styleCode=" Botrule">2.3 </td></tr><tr><td align="left"><content styleCode="bold">Infection and Infestations</content> </td><td/><td/><td/></tr><tr><td align="left" styleCode=" Botrule">Upper respiratory tract infections-pathogen class unspecified ¹ </td><td align="left" styleCode=" Botrule">4.1 </td><td align="left" styleCode=" Botrule">7.0 </td><td align="left" styleCode=" Botrule">6.5 </td></tr><tr><td align="left"><content styleCode="bold">Musculoskeletal and Connective Tissue Disorders</content> </td><td/><td/><td/></tr><tr><td align="left" styleCode=" Botrule">Joint related signs and symptoms ¹ </td><td align="left" styleCode=" Botrule">1.9 </td><td align="left" styleCode=" Botrule">1.5 </td><td align="left" styleCode=" Botrule">2.3 </td></tr><tr><td align="left"><content styleCode="bold">Nervous System Disorders</content> </td><td/><td/><td/></tr><tr><td align="left" styleCode=" Botrule">Headaches NOS ² </td><td align="left" styleCode=" Botrule">6.4 </td><td align="left" styleCode=" Botrule">6.4 </td><td align="left" styleCode=" Botrule">5.5 </td></tr><tr><td align="left"><content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content> </td><td/><td/><td/></tr><tr><td align="left">Rash NOS ² </td><td align="left">1.7 </td><td align="left">1.0 </td><td align="left">2.1 </td></tr></tbody></table>

<td align="left" styleCode=" Botrule">5.5 </td></tr><tr><td align="left"><content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content> </td><td/><td/><td/></tr><tr><td align="left">Rash NOS ² </td><td align="left">1.7 </td><td align="left">1.0 </td><td align="left">2.1 </td></tr></tbody></table> <table ID="ID394" width="613" styleCode="Noautorules"><col width="168"/><col width="117"/><col width="117"/><col width="114"/><col width="97"/><tfoot><tr><td align="left" colspan="5"><paragraph styleCode="Footnote">¹WHO preferred terms edema, edema dependent, edema peripheral, and edema legs combined </paragraph></td></tr><tr><td align="left" colspan="5"><paragraph styleCode="Footnote">²WHO preferred terms rash, rash erythematous, and rash maculo-papular combined </paragraph></td></tr></tfoot><tbody><tr><td styleCode="Lrule Toprule Rrule"/><td align="right" styleCode=" Toprule Botrule"><content styleCode="bold">4 to 6 Weeks</content> </td><td align="left" styleCode=" Toprule Botrule Rrule"><content styleCode="bold">Controlled Trials</content> </td><td align="right" styleCode=" Toprule Botrule"><content styleCode="bold">6 Month</content> </td><td align="left" styleCode=" Toprule Botrule Rrule"><content styleCode="bold">Controlled Trials</content> </td></tr><tr><td styleCode="Lrule Botrule Rrule"/><td align="left" styleCode=" Botrule Rrule"><content styleCode="bold">Meloxicam</content> <content styleCode="bold">7.5 mg daily</content> </td><td align="left" styleCode=" Botrule Rrule"><content styleCode="bold">Meloxicam</content> <content styleCode="bold">15 mg daily</content> </td><td align="left" styleCode=" Botrule Rrule"><content styleCode="bold">Meloxicam</content> <content styleCode="bold">7.5 mg daily</content> </td><td align="left" styleCode=" Botrule Rrule"><content styleCode="bold">Meloxicam</content> <content styleCode="bold">15 mg daily</content> </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule"><content styleCode="bold">No.

tyleCode="bold">Meloxicam</content> <content styleCode="bold">7.5 mg daily</content> </td><td align="left" styleCode=" Botrule Rrule"><content styleCode="bold">Meloxicam</content> <content styleCode="bold">15 mg daily</content> </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule"><content styleCode="bold">No. of Patients</content> </td><td align="left" styleCode=" Botrule Rrule"><content styleCode="bold">8955</content> </td><td align="left" styleCode=" Botrule Rrule"><content styleCode="bold">256</content> </td><td align="left" styleCode=" Botrule Rrule"><content styleCode="bold">169</content> </td><td align="left" styleCode=" Botrule Rrule"><content styleCode="bold">306</content> </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule"><content styleCode="bold">Gastrointestinal</content> </td><td align="left" styleCode=" Botrule Rrule">11.8 </td><td align="left" styleCode=" Botrule Rrule">18.0 </td><td align="left" styleCode=" Botrule Rrule">26.6 </td><td align="left" styleCode=" Botrule Rrule">24.2 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Abdominal pain </td><td align="left" styleCode=" Botrule Rrule">2.7 </td><td align="left" styleCode=" Botrule Rrule">2.3 </td><td align="left" styleCode=" Botrule Rrule">4.7 </td><td align="left" styleCode=" Botrule Rrule">2.9 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Constipation </td><td align="left" styleCode=" Botrule Rrule">0.8 </td><td align="left" styleCode=" Botrule Rrule">1.2 </td><td align="left" styleCode=" Botrule Rrule">1.8 </td><td align="left" styleCode=" Botrule Rrule">2.6 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Diarrhea </td><td align="left" styleCode=" Botrule Rrule">1.9 </td><td align="left" styleCode=" Botrule Rrule">2.7 </td><td align="left" styleCode=" Botrule Rrule">5.9 </td><td align="left" styleCode=" Botrule Rrule">2.6 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Dyspepsia </td><td align="left" styleCode=" Botrule Rrule">3.8 </td><td align="left" styleCode=" Botrule Rrule">7.4 </td><td align="left" styleCode=" Botrule Rrule">8.9 </td><td align="left" styleCode=" Botrule Rrule">9.5 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Flatulence </td><td align="left" styleCode=" Botrule Rrule">0.5 </td><td align="left" styleCode=" Botrule Rrule">0.4 </td><td align="left" styleCode=" Botrule Rrule">3.0 </td><td align="left" styleCode=" Botrule Rrule">2.6 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Nausea </td><td align="left" styleCode=" Botrule Rrule">2.4 </td><td align="left" styleCode=" Botrule Rrule">4.7 </td><td align="left" styleCode=" Botrule Rrule">4.7 </td><td align="left" styleCode=" Botrule Rrule">7.2 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Vomiting </td><td align="left" styleCode=" Botrule Rrule">0.6 </td><td align="left" styleCode=" Botrule Rrule">0.8 </td><td align="left" styleCode=" Botrule Rrule">1.8 </td><td align="left" styleCode=" Botrule Rrule">2.6 </td></tr><tr><td align="left" styleCode=" Lrule Botrule"><content styleCode="bold">Body as a Whole</content> </td><td styleCode=" Botrule"/><td styleCode=" Botrule"/><td styleCode=" Botrule"/><td styleCode=" Botrule Rrule"/></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Accident household </td><td align="left" styleCode=" Botrule Rrule">0.0 </td><td align="left" styleCode=" Botrule Rrule">0.0 </td><td align="left" styleCode=" Botrule Rrule">0.6 </td><td align="left" styleCode=" Botrule Rrule">2.9 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Edema ¹ </td><td align="left" styleCode=" Botrule Rrule">0.6 </td><td align="left" styleCode=" Botrule Rrule">2.0 </td><td align="left" styleCode=" Botrule Rrule">2.4 </td><td align="left" styleCode=" B

align="left" styleCode=" Botrule Rrule">2.9 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Edema ¹ </td><td align="left" styleCode=" Botrule Rrule">0.6 </td><td align="left" styleCode=" Botrule Rrule">2.0 </td><td align="left" styleCode=" Botrule Rrule">2.4 </td><td align="left" styleCode=" B otrule Rrule">1.6 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Pain </td><td align="left" styleCode=" Botrule Rrule">0.9 </td><td align="left" styleCode=" Botrule Rrule">2.0 </td><td align="left" styleCode=" Botrule Rrule">3.6 </td><td align="left" styleCode=" Botrule Rrule">5.2 </td></tr><tr><td align="left" styleCode=" Lrule Botrule"><content styleCode="bold">Central and Peripheral Nervous System</content> </td><td styleCode=" Botrule"/><td styleCode=" Botrule"/><td styleCode=" Botrule"/><td styleCode=" Botrule Rrule"/></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Dizziness </td><td align="left" styleCode=" Botrule Rrule">1.1 </td><td align="left" styleCode=" Botrule Rrule">1.6 </td><td align="left" styleCode=" Botrule Rrule">2.4 </td><td align="left" styleCode=" Botrule Rrule">2.6 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Headache </td><td align="left" styleCode=" Botrule Rrule">2.4 </td><td align="left" styleCode=" Botrule Rrule">2.7 </td><td align="left" styleCode=" Botrule Rrule">3.6 </td><td align="left" styleCode=" Botrule Rrule">2.6 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule"><content styleCode="bold">Hematologic</content> </td><td styleCode=" Botrule Rrule"/><td styleCode=" Botrule Rrule"/><td styleCode=" Botrule Rrule"/><td styleCode=" Botrule Rrule"/></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Anemia </td><td align="left" styleCode=" Botrule Rrule">0.1 </td><td align="left" styleCode=" Botrule Rrule">0.0 </td><td align="left" styleCode=" Botrule Rrule">4.1 </td><td align="left" styleCode=" Botrule Rrule">2.9 </td></tr><tr><td align="left" styleCode=" Lrule Botrule"><content styleCode="bold">Musculoskeletal</content> </td><td styleCode=" Botrule"/><td styleCode=" Botrule"/><td styleCode=" Botrule"/><td styleCode=" Botrule Rrule"/></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Arthralgia </td><td align="left" styleCode=" Botrule Rrule">0.5 </td><td align="left" styleCode=" Botrule Rrule">0.0 </td><td align="left" styleCode=" Botrule Rrule">5.3 </td><td align="left" styleCode=" Botrule Rrule">1.3 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Back pain </td><td align="left" styleCode=" Botrule Rrule">0.5 </td><td align="left" styleCode=" Botrule Rrule">0.4 </td><td align="left" styleCode=" Botrule Rrule">3.0 </td><td align="left" styleCode=" Botrule Rrule">0.7 </td></tr><tr><td align="left" styleCode=" Lrule Botrule"><content styleCode="bold">Psychiatric</content> </td><td styleCode=" Botrule"/><td styleCode=" Botrule"/><td styleCode=" Botrule"/><td styleCode=" Botrule Rrule"/></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Insomnia </td><td align="left" styleCode=" Botrule Rrule">0.4 </td><td align="left" styleCode=" Botrule Rrule">0.0 </td><td align="left" styleCode=" Botrule Rrule">3.6 </td><td align="left" styleCode=" Botrule Rrule">1.6 </td></tr><tr><td align="left" styleCode=" Lrule Botrule"><content styleCode="bold">Respiratory</content> </td><td styleCode=" Botrule"/><td styleCode=" Botrule"/><td styleCode=" Botrule"/><td styleCode=" Botrule Rrule"/></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Coughing </td><td align="left" styleCode=" Botrule Rrule">0.2 </td><td align="left" styleCode=" Botrule Rrule">0.8 </td><td align="left" styleCode=" Botrule Rrule">2.4 </td><td align="left" styleCode=" Botrule Rrule">1.0 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Upper respirator

rule Botrule Rrule">Coughing </td><td align="left" styleCode=" Botrule Rrule">0.2 </td><td align="left" styleCode=" Botrule Rrule">0.8 </td><td align="left" styleCode=" Botrule Rrule">2.4 </td><td align="left" styleCode=" Botrule Rrule">1.0 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Upper respirator y tract infection </td><td align="left" styleCode=" Botrule Rrule">0.2 </td><td align="left" styleCode=" Botrule Rrule">0.0 </td><td align="left" styleCode=" Botrule Rrule">8.3 </td><td align="left" styleCode=" Botrule Rrule">7.5 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule"><content styleCode="bold">Skin</content> </td><td styleCode=" Botrule Rrule"/><td styleCode=" Botrule Rrule"/><td styleCode=" Botrule Rrule"/><td styleCode=" Botrule Rrule"/></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Pruritus </td><td align="left" styleCode=" Botrule Rrule">0.4 </td><td align="left" styleCode=" Botrule Rrule">1.2 </td><td align="left" styleCode=" Botrule Rrule">2.4 </td><td align="left" styleCode=" Botrule Rrule">0.0 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Rash ² </td><td align="left" styleCode=" Botrule Rrule">0.3 </td><td align="left" styleCode=" Botrule Rrule">1.2 </td><td align="left" styleCode=" Botrule Rrule">3.0 </td><td align="left" styleCode=" Botrule Rrule">1.3 </td></tr><tr><td align="left" styleCode=" Lrule Botrule"><content styleCode="bold">Urinary</content> </td><td styleCode=" Botrule"/><td styleCode=" Botrule"/><td styleCode=" Botrule"/><td styleCode=" Botrule Rrule"/></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Micturition frequency </td><td align="left" styleCode=" Botrule Rrule">0.1 </td><td align="left" styleCode=" Botrule Rrule">0.4 </td><td align="left" styleCode=" Botrule Rrule">2.4 </td><td align="left" styleCode=" Botrule Rrule">1.3 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Urinary tract infection </td><td align="left" styleCode=" Botrule Rrule">0.3 </td><td align="left" styleCode=" Botrule Rrule">0.4 </td><td align="left" styleCode=" Botrule Rrule">4.7 </td><td align="left" styleCode=" Botrule Rrule">6.9 </td></tr></tbody></table>

</tr><tr><td align="left" styleCode="Lrule Botrule Rrule">Urinary tract infection </td><td align="left" styleCode=" Botrule Rrule">0.3 </td><td align="left" styleCode=" Botrule Rrule">0.4 </td><td align="left" styleCode=" Botrule Rrule">4.7 </td><td align="left" styleCode=" Botrule Rrule">6.9 </td></tr></tbody></table> <table ID="ID283" width="100%"><col width="42%"/><col width="58%"/><tbody><tr><td align="left" styleCode=" Botrule Toprule" valign="top"><content styleCode="bold">Body </content><content styleCode="bold">as </content><content styleCode="bold">a </content><content styleCode="bold">Whole </content> </td><td align="justify" styleCode=" Botrule Toprule" valign="top">allergic reaction, face edema, fatigue, fever, hot flushes, malaise, syncope, weight decrease, weight increase </td></tr><tr><td align="left" styleCode=" Botrule Toprule" valign="top"><content styleCode="bold">Cardiovascular </content> </td><td align="justify" styleCode=" Botrule Toprule" valign="top">angina pectoris, cardiac failure, hypertension, hypotension, myocardial infarction, vasculitis </td></tr><tr><td align="left" styleCode=" Botrule Toprule" valign="top"><content styleCode="bold">Central </content><content styleCode="bold">and </content><content styleCode="bold">Peripheral </content><content styleCode="bold">Nervous </content><content styleCode="bold">System</content><content styleCode="bold"> </content></td><td align="justify" styleCode=" Botrule Toprule" valign="top">convulsions, paresthesia, tremor, vertigo </td></tr><tr><td align="left" styleCode=" Botrule Toprule" valign="top"><content styleCode="bold">Gastrointestinal</content><content styleCode="bold"> </content></td><td align="justify" styleCode=" Botrule Toprule" valign="top">colitis, dry mouth, duodenal ulcer, eructation, esophagitis, gastric ulcer, gastritis, gastroesophageal reflux, gastrointestinal hemorrhage, hematemesis, hemorrhagic duodenal ulcer, hemorrhagic gastric ulcer, intestinal perforation, melena, pancreatitis, perforated duodenal ulcer, perforated gastric ulcer, stomatitis ulcerative </td></tr><tr><td align="left" styleCode=" Botrule Toprule" valign="top"><content styleCode="bold">Heart </content><content styleCode="bold">Rate </content><content styleCode="bold">and </content><content styleCode="bold">Rhythm</content><content styleCode="bold"> </content></td><td align="justify" styleCode=" Botrule Toprule" valign="top">arrhythmia, palpitation, tachycardia </td></tr><tr><td align="left" styleCode=" Botrule Toprule" valign="top"><content styleCode="bold">Hematologic</content><content styleCode="bold"> </content></td><td align="justify" styleCode=" Botrule Toprule" valign="top">leukopenia, purpura, thrombocytopenia </td></tr><tr><td align="left" styleCode=" Botrule Toprule" valign="top"><content styleCode="bold">Liver </content><content styleCode="bold">and </content><content styleCode="bold">Biliary </content><content styleCode="bold">System</content><content styleCode="bold"> </content></td><td align="justify" styleCode=" Botrule Toprule" valign="top">ALT increased, AST increased, bilirubinemia, GGT increased, hepatitis </td></tr><tr><td align="left" styleCode=" Botrule Toprule" valign="top"><content styleCode="bold">Metabolic </content><content styleCode="bold">and </content><content styleCode="bold">Nutritional</content><content styleCode="bold"> </content></td><td align="justify" styleCode=" Botrule Toprule" valign="top">dehydration </td></tr><tr><td align="left" styleCode=" Botrule Toprule" valign="top"><content styleCode="bold">Psychiatric</content><content styleCode="bold"> </content></td><td align="justify" styleCode=" Botrule Toprule" valign="top">abnormal dreaming, anxiety, appetite increased, confusion, depression, nervousness, somnolence </td></tr><tr><td align="left" styleCode=" Bo

otrule Toprule" valign="top"><content styleCode="bold">Psychiatric</content><content styleCode="bold"> </content></td><td align="justify" styleCode=" Botrule Toprule" valign="top">abnormal dreaming, anxiety, appetite increased, confusion, depression, nervousness, somnolence </td></tr><tr><td align="left" styleCode=" Bo trule Toprule" valign="top"><content styleCode="bold">Respiratory </content> </td><td align="justify" styleCode=" Botrule Toprule" valign="top">asthma, bronchospasm, dyspnea </td></tr><tr><td align="left" styleCode=" Botrule Toprule" valign="top"><content styleCode="bold">Skin </content><content styleCode="bold">and </content><content styleCode="bold">Appendages</content><content styleCode="bold"> </content></td><td align="justify" styleCode=" Botrule Toprule" valign="top">alopecia, angioedema, bullous eruption, photosensitivity reaction, pruritus, sweating increased, urticaria </td></tr><tr><td align="left" styleCode=" Botrule Toprule" valign="top"><content styleCode="bold">Special </content><content styleCode="bold">Senses</content><content styleCode="bold"> </content></td><td align="justify" styleCode=" Botrule Toprule" valign="top">abnormal vision, conjunctivitis, taste perversion, tinnitus </td></tr><tr><td align="left" styleCode=" Botrule Toprule" valign="top"><content styleCode="bold">Urinary </content><content styleCode="bold">System</content><content styleCode="bold"> </content></td><td align="justify" styleCode=" Botrule Toprule" valign="top">albuminuria, BUN increased, creatinine increased, hematuria, renal failure </td></tr></tbody></table>

7 DRUG INTERACTIONS See Table 3 for clinically significant drug interactions with meloxicam. See also Warnings and Precautions ( 5.2 , 5.6 , 5.12 ) and Clinical Pharmacology ( 12.3 ). Table 3 Clinically Significant Drug Interactions with Meloxicam Drugs that Interfere with Hemostasis Clinical Impact: Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions ( 5.12 ) ]. Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions ( 5.2 ) ]. Intervention: Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5.12 ) ]. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, or Beta-Blockers Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions ( 5.6 )]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID 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.

s effect has been attributed to the NSAID 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. Intervention: During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions ( 5.6 ) ]. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [ see Clinical Pharmacology ( 12.3 ) ]. Intervention: During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of meloxicam and cyclosporine may increase cyclosporine's nephrotoxicity. Intervention: During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions ( 5.2 ) ]. Intervention: The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. Drugs that Interfere with Hemostasis (e.g., warfarin, aspirin, SSRIs/SNRIs) : Monitor patients for bleeding who are concomitantly taking meloxicam with drugs that interfere with hemostasis. Concomitant use of meloxicam and analgesic doses of aspirin is not generally recommended. ACE Inhibitors, Angiotensin Receptor Blockers (ARBs) or Beta-Blockers : Concomitant use with meloxicam may diminish the antihypertensive effect of these drugs. Monitor blood pressure. ACE Inhibitors and ARBs : Concomitant use with meloxicam in elderly, volume-depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function. Diuretics : NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects.

<table ID="ID435" width="629" styleCode="Noautorules"><col width="118"/><col width="511"/><tbody><tr><td colspan="2" align="left" styleCode="Lrule Toprule Botrule Rrule" valign="top"><content styleCode="bold">Drugs that Interfere with Hemostasis</content> </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="italics">Clinical Impact:</content> </td><td align="left" styleCode=" Botrule Rrule" valign="top"> Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="italics">Intervention:</content> </td><td align="left" styleCode=" Botrule Rrule" valign="top">Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ <content styleCode="italics">see Warnings and Precautions ( <linkHtml href="#ID259">5.12</linkHtml>) </content>]. </td></tr><tr><td colspan="2" align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">Aspirin</content> </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="italics">Clinical Impact:</content> </td><td align="left" styleCode=" Botrule Rrule" valign="top">Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ <content styleCode="italics">see Warnings and Precautions ( <linkHtml href="#ID241">5.2</linkHtml>) </content>]. </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="italics">Intervention:</content> </td><td align="left" styleCode=" Botrule Rrule" valign="top">Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ <content styleCode="italics">see Warnings and Precautions ( <linkHtml href="#ID259">5.12</linkHtml>) </content>]. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection. </td></tr><tr><td colspan="2" align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">ACE Inhibitors, Angiotensin Receptor Blockers, or Beta-Blockers</content> </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="italics">Clinical Impact:</content> </td><td align="left" styleCode=" Botrule Rrule" valign="top"> NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).

le Rrule" valign="top"><content styleCode="italics">Clinical Impact:</content> </td><td align="left" styleCode=" Botrule Rrule" valign="top"> NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="italics">Intervention:</content> </td><td align="left" styleCode=" Botrule Rrule" valign="top"> During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ <content styleCode="italics">see Warnings and Precautions ( <linkHtml href="#ID249">5.6</linkHtml>)]. </content> When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. </td></tr><tr><td colspan="2" align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">Diuretics</content> </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="italics">Clinical Impact:</content> </td><td align="left" styleCode=" Botrule Rrule" valign="top">Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID 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. </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="italics">Intervention:</content> </td><td align="left" styleCode=" Botrule Rrule" valign="top">During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ <content styleCode="italics">see Warnings and Precautions ( <linkHtml href="#ID249">5.6</linkHtml>) </content>]. </td></tr><tr><td colspan="2" align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">Lithium</content> </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="italics">Clinical Impact:</content> </td><td align="left" styleCode=" Botrule Rrule" valign="top">NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [ <content styleCode="italics">see Clinical Pharmacology ( <linkHtml href="#ID336">12.3</linkHtml>) </content>]. </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="italics">Intervention:</content> </td><td align="left" styleCode=" Botrule Rrule" valign="top">During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity.

6">12.3</linkHtml>) </content>]. </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="italics">Intervention:</content> </td><td align="left" styleCode=" Botrule Rrule" valign="top">During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity. </td></tr><tr><td colspan="2" align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">Methotrexate</content> </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="italics">Clinical Impact:</content> </td><td align="left" styleCode=" Botrule Rrule" valign="top">Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="italics">Intervention:</content> </td><td align="left" styleCode=" Botrule Rrule" valign="top">During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity. </td></tr><tr><td colspan="2" align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">Cyclosporine</content> </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="italics">Clinical Impact:</content> </td><td align="left" styleCode=" Botrule Rrule" valign="top">Concomitant use of meloxicam and cyclosporine may increase cyclosporine&apos;s nephrotoxicity. </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="italics">Intervention:</content> </td><td align="left" styleCode=" Botrule Rrule" valign="top">During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function. </td></tr><tr><td colspan="2" align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">NSAIDs and Salicylates</content> </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="italics">Clinical Impact:</content> </td><td align="left" styleCode=" Botrule Rrule" valign="top">Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ <content styleCode="italics">see Warnings and Precautions ( <linkHtml href="#ID241">5.2</linkHtml>) </content>]. </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="italics">Intervention:</content> </td><td align="left" styleCode=" Botrule Rrule" valign="top">The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended. </td></tr><tr><td colspan="2" align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="bold">Pemetrexed</content> </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="italics">Clinical Impact:</content> </td><td align="left" styleCode=" Botrule Rrule" valign="top">Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top"><content styleCode="italics">Intervention:</content> </td><td align="left" styleCode=" Botrule Rrule" valign="top">During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.

t use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. </td></tr></tbody></table>

8 USE IN SPECIFIC POPULATIONS Infertility : NSAIDs are associated with reversible infertility. Consider withdrawal of meloxicam in women who have difficulties conceiving ( 8.3 ) 8.1 Pregnancy Risk Summary Use of NSAIDs, including meloxicam, 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 meloxicam use between about 20 and 30 weeks of gestation, and avoid meloxicam use at about 30 weeks of gestation and later in pregnancy ( see Clinical Considerations, Data ). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including meloxicam, 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 some cases, neonatal renal impairment. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, embryofetal death was observed in rats and rabbits treated during the period of organogenesis with meloxicam at oral doses equivalent to 0.65- and 6.5-times the maximum recommended human dose (MRHD) of meloxicam. Increased incidence of septal heart defects were observed in rabbits treated throughout embryogenesis with meloxicam at an oral dose equivalent to 78-times the MRHD. In pre- and post-natal reproduction studies, there was an increased incidence of dystocia, delayed parturition, and decreased offspring survival at 0.08-times MRHD of meloxicam. No teratogenic effects were observed in rats and rabbits treated with meloxicam during organogenesis at an oral dose equivalent to 2.6 and 26-times the MRHD [see Data] . Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as meloxicam, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including meloxicam, can cause premature closure of the fetal ductus arteriosus ( see Data ). Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible.

er in pregnancy, because NSAIDs, including meloxicam, can cause premature closure of the fetal ductus arteriosus ( see Data ). Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If meloxicam treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue meloxicam and follow up according to clinical practice ( see Data ). Labor or Delivery There are no studies on the effects of meloxicam during labor or delivery. In animal studies, NSAIDs, including meloxicam, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal Data Meloxicam was not teratogenic when administered to pregnant rats during fetal organogenesis at oral doses up to 4 mg/kg/day (2.6-fold greater than the MRHD of 15 mg of meloxicam based on BSA comparison). Administration of meloxicam to pregnant rabbits throughout embryogenesis produced an increased incidence of septal defects of the heart at an oral dose of 60 mg/kg/day (78-fold greater than the MRHD based on BSA comparison). The no effect level was 20 mg/kg/day (26-fold greater than the MRHD based on BSA conversion). In rats and rabbits, embryolethality occurred at oral meloxicam doses of 1 mg/kg/day and 5 mg/kg/day, respectively (0.65- and 6.5-fold greater, respectively, than the MRHD based on BSA comparison) when administered throughout organogenesis. Oral administration of meloxicam to pregnant rats during late gestation through lactation increased the incidence of dystocia, delayed parturition, and decreased offspring survival at meloxicam doses of 0.125 mg/kg/day or greater (0.08-times MRHD based on BSA comparison). 8.2 Lactation Risk Summary There are no human data available on whether meloxicam is present in human milk, or on the effects on breastfed infants, or on milk production.

ia, delayed parturition, and decreased offspring survival at meloxicam doses of 0.125 mg/kg/day or greater (0.08-times MRHD based on BSA comparison). 8.2 Lactation Risk Summary There are no human data available on whether meloxicam is present in human milk, or on the effects on breastfed infants, or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for meloxicam and any potential adverse effects on the breastfed infant from the meloxicam or from the underlying maternal condition. Data Animal Data Meloxicam was present in the milk of lactating rats at concentrations higher than those in plasma. 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including meloxicam, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including meloxicam, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use The safety and effectiveness of meloxicam in pediatric JRA patients from 2 to 17 years of age has been evaluated in three clinical trials [ see Dosage and Administration ( 2.3 ), Adverse Reactions ( 6.1 ) and Clinical Studies ( 14.2 ) ]. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [ see Warnings and Precautions ( 5.1 , 5.2 , 5.3 , 5.6 , 5.14 ) ]. 8.6 Hepatic Impairment No dose adjustment is necessary in patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment have not been adequately studied. Since meloxicam is significantly metabolized in the liver and hepatotoxicity may occur, use meloxicam with caution in patients with hepatic impairment [ see Warnings and Precautions ( 5.3 ) and Clinical Pharmacology ( 12.3 ) ]. 8.7 Renal Impairment No dose adjustment is necessary in patients with mild to moderate renal impairment. Patients with severe renal impairment have not been studied. The use of meloxicam in subjects with severe renal impairment is not recommended. In patients on hemodialysis, meloxicam should not exceed 7.5 mg per day. Meloxicam is not dialyzable [ see Dosage and Administration ( 2.1 ) and Clinical Pharmacology ( 12.3 ) ].

8.2 Lactation Risk Summary There are no human data available on whether meloxicam is present in human milk, or on the effects on breastfed infants, or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for meloxicam and any potential adverse effects on the breastfed infant from the meloxicam or from the underlying maternal condition. Data Animal Data Meloxicam was present in the milk of lactating rats at concentrations higher than those in plasma.

8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including meloxicam, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including meloxicam, in women who have difficulties conceiving or who are undergoing investigation of infertility.

8.4 Pediatric Use The safety and effectiveness of meloxicam in pediatric JRA patients from 2 to 17 years of age has been evaluated in three clinical trials [ see Dosage and Administration ( 2.3 ), Adverse Reactions ( 6.1 ) and Clinical Studies ( 14.2 ) ].

8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [ see Warnings and Precautions ( 5.1 , 5.2 , 5.3 , 5.6 , 5.14 ) ].

10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [ see Warnings and Precautions ( 5.1 , 5.2 , 5.4 , 5.6 ) ]. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding There is limited experience with meloxicam overdosage. Cholestyramine is known to accelerate the clearance of meloxicam. Accelerated removal of meloxicam by 4 g oral doses of cholestyramine given three times a day was demonstrated in a clinical trial. Administration of cholestyramine may be useful following an overdosage. For additional information about overdosage treatment, call a poison control center (1-800-222-1222).

11 DESCRIPTION Meloxicam is a nonsteroidal anti-inflammatory drug (NSAID). Each tablet contains 7.5 mg or 15 mg meloxicam, USP for oral administration. Meloxicam is chemically designated as 4-hydroxy-2-methyl- N -(5-methyl-2-thiazolyl)-2 H -1,2-benzothiazine-3-carboxamide-1,1-dioxide. The molecular weight is 351.4. Its empirical formula is C 14 H 13 N 3 O 4 S 2 and it has the following structural formula: Meloxicam is a pale yellow solid, practically insoluble in water, with higher solubility observed in strong acids and bases. It is very slightly soluble in methanol. Meloxicam has an apparent partition coefficient (log P) app = 0.1 in n -octanol/buffer pH 7.4. Meloxicam has pKa values of 1.1 and 4.2. Meloxicam is available as a tablet for oral administration containing 7.5 mg or 15 mg meloxicam, USP. The inactive ingredients in meloxicam tablets, USP include starch, microcrystalline cellulose, lactose anhydrous, colloidal silicon dioxide, sodium citrate dihydrate, magnesium stearate. structure

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Meloxicam has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of meloxicam, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Meloxicam is a potent inhibitor of prostaglandin synthesis in vitro . Meloxicam concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because meloxicam is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. 12.3 Pharmacokinetics Absorption The absolute bioavailability of meloxicam capsules was 89% following a single oral dose of 30 mg compared with 30 mg IV bolus injection. Following single intravenous doses, dose-proportional pharmacokinetics were shown in the range of 5 mg to 60 mg. After multiple oral doses the pharmacokinetics of meloxicam capsules were dose-proportional over the range of 7.5 mg to 15 mg. Mean C max was achieved within four to five hours after a 7.5 mg meloxicam tablet was taken under fasted conditions, indicating a prolonged drug absorption. With multiple dosing, steady-state concentrations were reached by Day 5. A second meloxicam concentration peak occurs around 12 to 14 hours post-dose suggesting biliary recycling. Meloxicam capsules have been shown to be bioequivalent to meloxicam tablets. Table 4 Single Dose and Steady-State Pharmacokinetic Parameters for Oral 7.5 mg and 15 mg Meloxicam (Mean and % CV)1 Pharmacokinetic Parameters (%CV) Steady State Single Dose Healthy male adults (Fed) 2 Elderly males (Fed) 2 Elderly females (Fed) 2 Renal failure (Fasted) Hepatic insufficiency (Fasted) 7.5 mg 3 tablets 15 mg capsules 15 mg capsules 15 mg capsules 15 mg capsules N 18 5 8 12 12 Cmax [μg/mL] 1.05 (20) 2.3 (59) 3.2 (24) 0.59 (36) 0.84 (29) tmax [h] 4.9 (8) 5 (12) 6 (27) 4 (65) 10 (87) t 1/2 [h] 20.1 (29) 21 (34) 24 (34) 18 (46) 16 (29) CL/f [mL/min] 8.8 (29) 9.9 (76) 5.1 (22) 19 (43) 11 (44) V z /f 4 [L] 14.7 (32) 15 (42) 10 (30) 26 (44) 14 (29) 1 The parameter values in the table are from various studies 2 not under high fat conditions 3 Meloxicam tablets 4 V z /f = Dose/(AUC•K el ) Food and Antacid Effects Administration of meloxicam capsules following a high fat breakfast (75 g of fat) resulted in mean peak drug levels (i.e., C max ) being increased by approximately 22% while the extent of absorption (AUC) was unchanged. The time to maximum concentration (T max ) was achieved between 5 and 6 hours. In comparison, neither the AUC nor the C max values for meloxicam suspension were affected following a similar high fat meal, while mean T max values were increased to approximately 7 hours. No pharmacokinetic interaction was detected with concomitant administration of antacids. Based on these results, meloxicam can be administered without regard to timing of meals or concomitant administration of antacids. Distribution The mean volume of distribution (Vss) of meloxicam is approximately 10 L. Meloxicam is ~99.4% bound to human plasma proteins (primarily albumin) within the therapeutic dose range. The fraction of protein binding is independent of drug concentration, over the clinically relevant concentration range, but decreases to ~99% in patients with renal disease.

Vss) of meloxicam is approximately 10 L. Meloxicam is ~99.4% bound to human plasma proteins (primarily albumin) within the therapeutic dose range. The fraction of protein binding is independent of drug concentration, over the clinically relevant concentration range, but decreases to ~99% in patients with renal disease. Meloxicam penetration into human red blood cells, after oral dosing, is less than 10%. Following a radiolabeled dose, over 90% of the radioactivity detected in the plasma was present as unchanged meloxicam. Meloxicam concentrations in synovial fluid, after a single oral dose, range from 40% to 50% of those in plasma. The free fraction in synovial fluid is 2.5 times higher than in plasma, due to the lower albumin content in synovial fluid as compared to plasma. The significance of this penetration is unknown. Elimination Metabolism Meloxicam is extensively metabolized in the liver. Meloxicam metabolites include 5'-carboxy meloxicam (60% of dose), from P-450 mediated metabolism formed by oxidation of an intermediate metabolite 5'-hydroxymethyl meloxicam which is also excreted to a lesser extent (9% of dose). In vitro studies indicate that CYP2C9 (cytochrome P450 metabolizing enzyme) plays an important role in this metabolic pathway with a minor contribution of the CYP3A4 isozyme. Patients' peroxidase activity is probably responsible for the other two metabolites which account for 16% and 4% of the administered dose, respectively. All the four metabolites are not known to have any in vivo pharmacological activity. Excretion Meloxicam excretion is predominantly in the form of metabolites, and occurs to equal extents in the urine and feces. Only traces of the unchanged parent compound are excreted in the urine (0.2%) and feces (1.6%). The extent of the urinary excretion was confirmed for unlabeled multiple 7.5 mg doses: 0.5%, 6%, and 13% of the dose were found in urine in the form of meloxicam, and the 5'-hydroxymethyl and 5'-carboxy metabolites, respectively. There is significant biliary and/or enteral secretion of the drug. This was demonstrated when oral administration of cholestyramine following a single IV dose of meloxicam decreased the AUC of meloxicam by 50%. The mean elimination half-life (t 1/2 ) ranges from 15 hours to 20 hours. The elimination half-life is constant across dose levels indicating linear metabolism within the therapeutic dose range. Plasma clearance ranges from 7 to 9 mL/min. Specific Populations Pediatric After single (0.25 mg/kg) dose administration and after achieving steady state (0.375 mg/kg/day), there was a general trend of approximately 30% lower exposure in younger patients (2 to 6 years old) as compared to the older patients (7 to 16 years old). The older patients had meloxicam exposures similar (single dose) or slightly reduced (steady state) to those in the adult patients, when using AUC values normalized to a dose of 0.25 mg/kg [ see Dosage and Administration ( 2.4 ) ]. The meloxicam mean (SD) elimination half-life was 15.2 (10.1) and 13.0 hours (3.0) for the 2 to 6 year old patients, and 7 to 16 year old patients, respectively. In a covariate analysis, utilizing population pharmacokinetics body-weight, but not age, was the single predictive covariate for differences in the meloxicam apparent oral plasma clearance. The body-weight normalized apparent oral clearance values were adequate predictors of meloxicam exposure in pediatric patients. The pharmacokinetics of meloxicam in pediatric patients under 2 years of age have not been investigated. Geriatric Elderly males (≥65 years of age) exhibited meloxicam plasma concentrations and steady-state pharmacokinetics similar to young males.

es were adequate predictors of meloxicam exposure in pediatric patients. The pharmacokinetics of meloxicam in pediatric patients under 2 years of age have not been investigated. Geriatric Elderly males (≥65 years of age) exhibited meloxicam plasma concentrations and steady-state pharmacokinetics similar to young males. Elderly females (≥65 years of age) had a 47% higher AUC ss and 32% higher C max,ss as compared to younger females (≤55 years of age) after body weight normalization. Despite the increased total concentrations in the elderly females, the adverse event profile was comparable for both elderly patient populations. A smaller free fraction was found in elderly female patients in comparison to elderly male patients. Sex Young females exhibited slightly lower plasma concentrations relative to young males. After single doses of 7.5 mg meloxicam, the mean elimination half-life was 19.5 hours for the female group as compared to 23.4 hours for the male group. At steady state, the data were similar (17.9 hours vs 21.4 hours). This pharmacokinetic difference due to gender is likely to be of little clinical importance. There was linearity of pharmacokinetics and no appreciable difference in the C max or T max across genders. Hepatic Impairment Following a single 15 mg dose of meloxicam there was no marked difference in plasma concentrations in patients with mild (Child-Pugh Class I) or moderate (Child-Pugh Class II) hepatic impairment compared to healthy volunteers. Protein binding of meloxicam was not affected by hepatic impairment. No dosage adjustment is necessary in patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment (Child-Pugh Class III) have not been adequately studied [ see Warnings and Precautions ( 5.3 ) and Use in Specific Populations ( 8.6 ) ]. Renal Impairment Meloxicam pharmacokinetics have been investigated in subjects with mild and moderate renal impairment. Total drug plasma concentrations of meloxicam decreased and total clearance of meloxicam increased with the degree of renal impairment while free AUC values were similar in all groups. The higher meloxicam clearance in subjects with renal impairment may be due to increased fraction of unbound meloxicam which is available for hepatic metabolism and subsequent excretion. No dosage adjustment is necessary in patients with mild to moderate renal impairment. Patients with severe renal impairment have not been adequately studied. The use of meloxicam in subjects with severe renal impairment is not recommended [ see Dosage and Administration ( 2.5 ), Warnings and Precautions ( 5.6 ) and Use in Specific Populations ( 8.7 ) ]. Hemodialysis Following a single dose of meloxicam, the free C max plasma concentrations were higher in patients with renal failure on chronic hemodialysis (1% free fraction) in comparison to healthy volunteers (0.3% free fraction). Hemodialysis did not lower the total drug concentration in plasma; therefore, additional doses are not necessary after hemodialysis. Meloxicam is not dialyzable [ see Dosage and Administration ( 2.1 ) and Use in Specific Populations ( 8.7 ) ]. Drug Interaction Studies Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. When meloxicam is administered with aspirin (1000 mg three times daily) to healthy volunteers, it tended to increase the AUC (10%) and C max (24%) of meloxicam. The clinical significance of this interaction is not known. See Table 3 for clinically significant drug interactions of NSAIDs with aspirin [ see Drug Interactions ( 7 ) ]. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%.

C max (24%) of meloxicam. The clinical significance of this interaction is not known. See Table 3 for clinically significant drug interactions of NSAIDs with aspirin [ see Drug Interactions ( 7 ) ]. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine four times daily did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after β-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Lithium: 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 QD every day as compared to subjects receiving lithium alone [ see Drug Interactions ( 7 )]. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro , methotrexate did not displace meloxicam from its human serum binding sites [ see Drug Interactions ( 7 ) ]. Warfarin: The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used 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 Drug Interactions ( 7 ) ].

12.1 Mechanism of Action Meloxicam has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of meloxicam, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Meloxicam is a potent inhibitor of prostaglandin synthesis in vitro . Meloxicam concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because meloxicam is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

12.3 Pharmacokinetics Absorption The absolute bioavailability of meloxicam capsules was 89% following a single oral dose of 30 mg compared with 30 mg IV bolus injection. Following single intravenous doses, dose-proportional pharmacokinetics were shown in the range of 5 mg to 60 mg. After multiple oral doses the pharmacokinetics of meloxicam capsules were dose-proportional over the range of 7.5 mg to 15 mg. Mean C max was achieved within four to five hours after a 7.5 mg meloxicam tablet was taken under fasted conditions, indicating a prolonged drug absorption. With multiple dosing, steady-state concentrations were reached by Day 5. A second meloxicam concentration peak occurs around 12 to 14 hours post-dose suggesting biliary recycling. Meloxicam capsules have been shown to be bioequivalent to meloxicam tablets. Table 4 Single Dose and Steady-State Pharmacokinetic Parameters for Oral 7.5 mg and 15 mg Meloxicam (Mean and % CV)1 Pharmacokinetic Parameters (%CV) Steady State Single Dose Healthy male adults (Fed) 2 Elderly males (Fed) 2 Elderly females (Fed) 2 Renal failure (Fasted) Hepatic insufficiency (Fasted) 7.5 mg 3 tablets 15 mg capsules 15 mg capsules 15 mg capsules 15 mg capsules N 18 5 8 12 12 Cmax [μg/mL] 1.05 (20) 2.3 (59) 3.2 (24) 0.59 (36) 0.84 (29) tmax [h] 4.9 (8) 5 (12) 6 (27) 4 (65) 10 (87) t 1/2 [h] 20.1 (29) 21 (34) 24 (34) 18 (46) 16 (29) CL/f [mL/min] 8.8 (29) 9.9 (76) 5.1 (22) 19 (43) 11 (44) V z /f 4 [L] 14.7 (32) 15 (42) 10 (30) 26 (44) 14 (29) 1 The parameter values in the table are from various studies 2 not under high fat conditions 3 Meloxicam tablets 4 V z /f = Dose/(AUC•K el ) Food and Antacid Effects Administration of meloxicam capsules following a high fat breakfast (75 g of fat) resulted in mean peak drug levels (i.e., C max ) being increased by approximately 22% while the extent of absorption (AUC) was unchanged. The time to maximum concentration (T max ) was achieved between 5 and 6 hours. In comparison, neither the AUC nor the C max values for meloxicam suspension were affected following a similar high fat meal, while mean T max values were increased to approximately 7 hours. No pharmacokinetic interaction was detected with concomitant administration of antacids. Based on these results, meloxicam can be administered without regard to timing of meals or concomitant administration of antacids. Distribution The mean volume of distribution (Vss) of meloxicam is approximately 10 L. Meloxicam is ~99.4% bound to human plasma proteins (primarily albumin) within the therapeutic dose range. The fraction of protein binding is independent of drug concentration, over the clinically relevant concentration range, but decreases to ~99% in patients with renal disease. Meloxicam penetration into human red blood cells, after oral dosing, is less than 10%. Following a radiolabeled dose, over 90% of the radioactivity detected in the plasma was present as unchanged meloxicam. Meloxicam concentrations in synovial fluid, after a single oral dose, range from 40% to 50% of those in plasma. The free fraction in synovial fluid is 2.5 times higher than in plasma, due to the lower albumin content in synovial fluid as compared to plasma. The significance of this penetration is unknown. Elimination Metabolism Meloxicam is extensively metabolized in the liver.

ral dose, range from 40% to 50% of those in plasma. The free fraction in synovial fluid is 2.5 times higher than in plasma, due to the lower albumin content in synovial fluid as compared to plasma. The significance of this penetration is unknown. Elimination Metabolism Meloxicam is extensively metabolized in the liver. Meloxicam metabolites include 5'-carboxy meloxicam (60% of dose), from P-450 mediated metabolism formed by oxidation of an intermediate metabolite 5'-hydroxymethyl meloxicam which is also excreted to a lesser extent (9% of dose). In vitro studies indicate that CYP2C9 (cytochrome P450 metabolizing enzyme) plays an important role in this metabolic pathway with a minor contribution of the CYP3A4 isozyme. Patients' peroxidase activity is probably responsible for the other two metabolites which account for 16% and 4% of the administered dose, respectively. All the four metabolites are not known to have any in vivo pharmacological activity. Excretion Meloxicam excretion is predominantly in the form of metabolites, and occurs to equal extents in the urine and feces. Only traces of the unchanged parent compound are excreted in the urine (0.2%) and feces (1.6%). The extent of the urinary excretion was confirmed for unlabeled multiple 7.5 mg doses: 0.5%, 6%, and 13% of the dose were found in urine in the form of meloxicam, and the 5'-hydroxymethyl and 5'-carboxy metabolites, respectively. There is significant biliary and/or enteral secretion of the drug. This was demonstrated when oral administration of cholestyramine following a single IV dose of meloxicam decreased the AUC of meloxicam by 50%. The mean elimination half-life (t 1/2 ) ranges from 15 hours to 20 hours. The elimination half-life is constant across dose levels indicating linear metabolism within the therapeutic dose range. Plasma clearance ranges from 7 to 9 mL/min. Specific Populations Pediatric After single (0.25 mg/kg) dose administration and after achieving steady state (0.375 mg/kg/day), there was a general trend of approximately 30% lower exposure in younger patients (2 to 6 years old) as compared to the older patients (7 to 16 years old). The older patients had meloxicam exposures similar (single dose) or slightly reduced (steady state) to those in the adult patients, when using AUC values normalized to a dose of 0.25 mg/kg [ see Dosage and Administration ( 2.4 ) ]. The meloxicam mean (SD) elimination half-life was 15.2 (10.1) and 13.0 hours (3.0) for the 2 to 6 year old patients, and 7 to 16 year old patients, respectively. In a covariate analysis, utilizing population pharmacokinetics body-weight, but not age, was the single predictive covariate for differences in the meloxicam apparent oral plasma clearance. The body-weight normalized apparent oral clearance values were adequate predictors of meloxicam exposure in pediatric patients. The pharmacokinetics of meloxicam in pediatric patients under 2 years of age have not been investigated. Geriatric Elderly males (≥65 years of age) exhibited meloxicam plasma concentrations and steady-state pharmacokinetics similar to young males. Elderly females (≥65 years of age) had a 47% higher AUC ss and 32% higher C max,ss as compared to younger females (≤55 years of age) after body weight normalization. Despite the increased total concentrations in the elderly females, the adverse event profile was comparable for both elderly patient populations. A smaller free fraction was found in elderly female patients in comparison to elderly male patients. Sex Young females exhibited slightly lower plasma concentrations relative to young males. After single doses of 7.5 mg meloxicam, the mean elimination half-life was 19.5 hours for the female group as compared to 23.4 hours for the male group.

was found in elderly female patients in comparison to elderly male patients. Sex Young females exhibited slightly lower plasma concentrations relative to young males. After single doses of 7.5 mg meloxicam, the mean elimination half-life was 19.5 hours for the female group as compared to 23.4 hours for the male group. At steady state, the data were similar (17.9 hours vs 21.4 hours). This pharmacokinetic difference due to gender is likely to be of little clinical importance. There was linearity of pharmacokinetics and no appreciable difference in the C max or T max across genders. Hepatic Impairment Following a single 15 mg dose of meloxicam there was no marked difference in plasma concentrations in patients with mild (Child-Pugh Class I) or moderate (Child-Pugh Class II) hepatic impairment compared to healthy volunteers. Protein binding of meloxicam was not affected by hepatic impairment. No dosage adjustment is necessary in patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment (Child-Pugh Class III) have not been adequately studied [ see Warnings and Precautions ( 5.3 ) and Use in Specific Populations ( 8.6 ) ]. Renal Impairment Meloxicam pharmacokinetics have been investigated in subjects with mild and moderate renal impairment. Total drug plasma concentrations of meloxicam decreased and total clearance of meloxicam increased with the degree of renal impairment while free AUC values were similar in all groups. The higher meloxicam clearance in subjects with renal impairment may be due to increased fraction of unbound meloxicam which is available for hepatic metabolism and subsequent excretion. No dosage adjustment is necessary in patients with mild to moderate renal impairment. Patients with severe renal impairment have not been adequately studied. The use of meloxicam in subjects with severe renal impairment is not recommended [ see Dosage and Administration ( 2.5 ), Warnings and Precautions ( 5.6 ) and Use in Specific Populations ( 8.7 ) ]. Hemodialysis Following a single dose of meloxicam, the free C max plasma concentrations were higher in patients with renal failure on chronic hemodialysis (1% free fraction) in comparison to healthy volunteers (0.3% free fraction). Hemodialysis did not lower the total drug concentration in plasma; therefore, additional doses are not necessary after hemodialysis. Meloxicam is not dialyzable [ see Dosage and Administration ( 2.1 ) and Use in Specific Populations ( 8.7 ) ]. Drug Interaction Studies Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. When meloxicam is administered with aspirin (1000 mg three times daily) to healthy volunteers, it tended to increase the AUC (10%) and C max (24%) of meloxicam. The clinical significance of this interaction is not known. See Table 3 for clinically significant drug interactions of NSAIDs with aspirin [ see Drug Interactions ( 7 ) ]. Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine four times daily did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after β-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam.

alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after β-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam. Lithium: 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 QD every day as compared to subjects receiving lithium alone [ see Drug Interactions ( 7 )]. Methotrexate: A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro , methotrexate did not displace meloxicam from its human serum binding sites [ see Drug Interactions ( 7 ) ]. Warfarin: The effect of meloxicam on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used 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 Drug Interactions ( 7 ) ].

<table width="100%"><col width="20%" align="left" valign="middle"/><col width="16%" align="left" valign="middle"/><col width="16%" align="left" valign="middle"/><col width="16%" align="left" valign="middle"/><col width="16%" align="left" valign="middle"/><col width="16%" align="left" valign="middle"/><thead><tr><th rowspan="2" styleCode="Toprule Botrule"><content styleCode="bold">Pharmacokinetic Parameters (%CV)</content></th><th colspan="3" styleCode="Toprule Rrule Botrule"><content styleCode="bold">Steady State</content></th><th colspan="2" styleCode="Toprule Lrule Botrule"><content styleCode="bold">Single Dose</content></th></tr><tr><th styleCode="Toprule Botrule" valign="top"><content styleCode="bold">Healthy male adults (Fed)</content>²</th><th styleCode="Toprule Botrule" valign="top"><content styleCode="bold">Elderly males (Fed)</content>²</th><th styleCode="Toprule Rrule Botrule" valign="top"><content styleCode="bold">Elderly females (Fed)</content>²</th><th styleCode="Toprule Lrule Botrule" valign="top"><content styleCode="bold">Renal failure (Fasted)</content></th><th styleCode="Toprule Botrule" valign="top"><content styleCode="bold">Hepatic insufficiency (Fasted)</content></th></tr></thead><tbody><tr><td styleCode="Toprule Botrule" valign="top"/><td styleCode="Toprule Botrule" valign="top"><paragraph><content styleCode="bold">7.5 mg</content>³<content styleCode="bold">tablets</content></paragraph></td><td styleCode="Toprule Botrule" valign="top"><paragraph><content styleCode="bold">15 mg capsules</content></paragraph></td><td styleCode="Toprule Rrule Botrule" valign="top"><paragraph><content styleCode="bold">15 mg capsules</content></paragraph></td><td styleCode="Toprule Lrule Botrule" valign="top"><paragraph><content styleCode="bold">15 mg capsules</content></paragraph></td><td styleCode="Toprule Botrule" valign="top"><paragraph><content styleCode="bold">15 mg capsules</content></paragraph></td></tr><tr><td styleCode="Toprule Botrule" valign="top"><paragraph><content styleCode="bold">N</content></paragraph></td><td styleCode="Toprule Botrule" valign="top"><paragraph><content styleCode="bold">18</content></paragraph></td><td styleCode="Toprule Botrule" valign="top"><paragraph><content styleCode="bold">5</content></paragraph></td><td styleCode="Toprule Rrule Botrule" valign="top"><paragraph><content styleCode="bold">8</content></paragraph></td><td styleCode="Toprule Lrule Botrule" valign="top"><paragraph><content styleCode="bold">12</content></paragraph></td><td styleCode="Toprule Botrule" valign="top"><paragraph><content styleCode="bold">12</content></paragraph></td></tr><tr><td styleCode="Toprule Botrule" valign="top"><paragraph>Cmax [&#x3BC;g/mL]</paragraph></td><td styleCode="Toprule Botrule" valign="top"><paragraph>1.05 (20)</paragraph></td><td styleCode="Toprule Botrule" valign="top"><paragraph>2.3 (59)</paragraph></td><td styleCode="Toprule Rrule Botrule" valign="top"><paragraph>3.2 (24)</paragraph></td><td styleCode="Toprule Lrule Botrule" valign="top"><paragraph>0.59 (36)</paragraph></td><td styleCode="Toprule Botrule" valign="top"><paragraph>0.84 (29)</paragraph></td></tr><tr><td styleCode="Toprule Botrule" valign="top"><paragraph>tmax [h]</paragraph></td><td styleCode="Toprule Botrule" valign="top"><paragraph>4.9 (8)</paragraph></td><td styleCode="Toprule Botrule" valign="top"><paragraph>5 (12)</paragraph></td><td styleCode="Toprule Rrule Botrule" valign="top"><paragraph>6

h></td></tr><tr><td styleCode="Toprule Botrule" valign="top"><paragraph>tmax [h]</paragraph></td><td styleCode="Toprule Botrule" valign="top"><paragraph>4.9 (8)</paragraph></td><td styleCode="Toprule Botrule" valign="top"><paragraph>5 (12)</paragraph></td><td styleCode="Toprule Rrule Botrule" valign="top"><paragraph>6 (27)</paragraph></td><td styleCode="Toprule Lrule Botrule" valign="top"><paragraph>4 (65)</paragraph></td><td styleCode="Toprule Botrule" valign="top"><paragraph>10 (87)</paragraph></td></tr><tr><td styleCode="Toprule Botrule"><paragraph>t _1/2[h] </paragraph></td><td styleCode="Toprule Botrule"><paragraph>20.1 (29)</paragraph></td><td styleCode="Toprule Botrule"><paragraph>21 (34)</paragraph></td><td styleCode="Toprule Rrule Botrule"><paragraph>24 (34)</paragraph></td><td styleCode="Toprule Lrule Botrule"><paragraph>18 (46)</paragraph></td><td styleCode="Toprule Botrule"><paragraph>16 (29)</paragraph></td></tr><tr><td styleCode="Toprule Botrule"><paragraph>CL/f [mL/min]</paragraph></td><td styleCode="Toprule Botrule"><paragraph>8.8 (29)</paragraph></td><td styleCode="Toprule Botrule"><paragraph>9.9 (76)</paragraph></td><td styleCode="Toprule Rrule Botrule"><paragraph>5.1 (22)</paragraph></td><td styleCode="Toprule Lrule Botrule"><paragraph>19 (43)</paragraph></td><td styleCode="Toprule Botrule"><paragraph>11 (44)</paragraph></td></tr><tr><td styleCode="Toprule Botrule"><paragraph>V _z/f ⁴[L] </paragraph></td><td styleCode="Toprule Botrule" valign="top"><paragraph>14.7 (32)</paragraph></td><td styleCode="Toprule Botrule" valign="top"><paragraph>15 (42)</paragraph></td><td styleCode="Toprule Rrule Botrule" valign="top"><paragraph>10 (30)</paragraph></td><td styleCode="Toprule Lrule Botrule" valign="top"><paragraph>26 (44)</paragraph></td><td styleCode="Toprule Botrule" valign="top"><paragraph>14 (29)</paragraph></td></tr></tbody></table>

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis There was no increase in tumor incidence in long-term carcinogenicity studies in rats (104 weeks) and mice (99 weeks) administered meloxicam at oral doses up to 0.8 mg/kg/day in rats and up to 8.0 mg/kg/day in mice (up to 0.5- and 2.6-times, respectively, the maximum recommended human dose [MRHD] of 15 mg/day meloxicam based on body surface area [BSA] comparison). Mutagenesis Meloxicam was not mutagenic in an Ames assay, or clastogenic in a chromosome aberration assay with human lymphocytes and an in vivo micronucleus test in mouse bone marrow. Impairment of Fertility Meloxicam did not impair male and female fertility in rats at oral doses up to 9 mg/kg/day in males and 5 mg/kg/day in females (up to 5.8- and 3.2-times greater, respectively, than the MRHD based on BSA comparison).

14 CLINICAL STUDIES 14.1 Osteoarthritis and Rheumatoid Arthritis The use of meloxicam for the treatment of the signs and symptoms of osteoarthritis of the knee and hip was evaluated in a 12-week, double-blind, controlled trial. Meloxicam (3.75 mg, 7.5 mg, and 15 mg daily) was compared to placebo. The four primary endpoints were investigator's global assessment, patient global assessment, patient pain assessment, and total WOMAC score (a self-administered questionnaire addressing pain, function, and stiffness). Patients on meloxicam 7.5 mg daily and meloxicam 15 mg daily showed significant improvement in each of these endpoints compared with placebo. The use of meloxicam for the management of signs and symptoms of osteoarthritis was evaluated in six double-blind, active-controlled trials outside the U.S. ranging from 4 weeks' to 6 months' duration. In these trials, the efficacy of meloxicam, in doses of 7.5 mg/day and 15 mg/day, was comparable to piroxicam 20 mg/day and diclofenac SR 100 mg/day and consistent with the efficacy seen in the U.S. trial. The use of meloxicam for the treatment of the signs and symptoms of rheumatoid arthritis was evaluated in a 12-week, double-blind, controlled multinational trial. Meloxicam (7.5 mg, 15 mg, and 22.5 mg daily) was compared to placebo. The primary endpoint in this study was the ACR20 response rate, a composite measure of clinical, laboratory, and functional measures of RA response. Patients receiving meloxicam 7.5 mg and 15 mg daily showed significant improvement in the primary endpoint compared with placebo. No incremental benefit was observed with the 22.5 mg dose compared to the 15 mg dose. 14.2 Juvenile Rheumatoid Arthritis (JRA) Pauciarticular and Polyarticular Course The use of meloxicam for the treatment of the signs and symptoms of pauciarticular or polyarticular course Juvenile Rheumatoid Arthritis in patients 2 years of age and older was evaluated in two 12-week, double-blind, parallel-arm, active-controlled trials. Both studies included three arms: naproxen and two doses of meloxicam. In both studies, meloxicam dosing began at 0.125 mg/kg/day (7.5 mg maximum) or 0.25 mg/kg/day (15 mg maximum), and naproxen dosing began at 10 mg/kg/day. One study used these doses throughout the 12-week dosing period, while the other incorporated a titration after 4 weeks to doses of 0.25 mg/kg/day and 0.375 mg/kg/day (22.5 mg maximum) of meloxicam and 15 mg/kg/day of naproxen. The efficacy analysis used the ACR Pediatric 30 responder definition, a composite of parent and investigator assessments, counts of active joints and joints with limited range of motion, and erythrocyte sedimentation rate. The proportion of responders were similar in all three groups in both studies, and no difference was observed between the meloxicam dose groups.

16 HOW SUPPLIED/STORAGE AND HANDLING Meloxicam tablets, USP 15 mg are yellow coloured, round, flat bevelled tablets, debossed with "CIPLA" on one side and "159" on the other. Meloxicam tablets, USP 15 mg are available as follows: NDC: 70518-1630-00 NDC: 70518-1630-01 NDC: 70518-1630-02 NDC: 70518-1630-03 NDC: 70518-1630-04 NDC: 70518-1630-05 NDC: 70518-1630-06 NDC: 70518-1630-07 NDC: 70518-1630-08 PACKAGING: 30 in 1 BOTTLE PLASTIC PACKAGING: 90 in 1 BOTTLE PLASTIC PACKAGING: 60 in 1 BOTTLE PLASTIC PACKAGING: 14 in 1 BOTTLE PLASTIC PACKAGING: 45 in 1 BOTTLE PLASTIC PACKAGING: 10 in 1 BOTTLE PLASTIC PACKAGING: 30 in 1 BLISTER PACK PACKAGING: 20 in 1 BOTTLE PLASTIC PACKAGING: 100 in 1 BOTTLE PLASTIC Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Keep meloxicam tablets in a dry place. Dispense tablets in a tight container. Keep this and all medications out of the reach of children. Repackaged and Distributed By: Remedy Repack, Inc. 625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families or their caregivers of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their healthcare provider immediately [ see Warnings and Precautions ( 5.1 ) ]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their healthcare provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for the signs and symptoms of GI bleeding [ see Warnings and Precautions ( 5.2 ) ]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, instruct patients to stop meloxicam and seek immediate medical therapy [ see Warnings and Precautions ( 5.3 ) ]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [ see Warnings and Precautions ( 5.5 ) ]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [ see Contraindications ( 4 ) and Warnings and Precautions ( 5.7 ) ]. Serious Skin Reactions, including DRESS Advise patients to stop taking meloxicam immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [ see Warnings and Precautions ( 5.9 ), 5.10 ) ]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including meloxicam, may be associated with a reversible delay in ovulation [ see Use in Specific Populations ( 8.3 ) ]. Fetal Toxicity Inform pregnant women to avoid use of meloxicam and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with meloxicam is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [ see Warnings and Precautions( 5.11 ) and Use in Specific Populations ( 8.1 ) ]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [ see Warnings and Precautions ( 5.2 ) and Drug Interactions ( 7 ) ]. Alert patients that NSAIDs may be present in "over the counter" medications for treatment of colds, fever, or insomnia.

nisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [ see Warnings and Precautions ( 5.2 ) and Drug Interactions ( 7 ) ]. Alert patients that NSAIDs may be present in "over the counter" medications for treatment of colds, fever, or insomnia. Use of NSAIDs and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with meloxicam until they talk to their healthcare provider [ see Drug Interactions ( 7 ) ]. Repackaged By / Distributed By: RemedyRepack Inc. 625 Kolter Drive, Indiana, PA 15701 (724) 465-8762

Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: Increased risk of a heart attack or stroke that can lead to death . This risk may happen early in treatment and may increase : with increasing doses of NSAIDs with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a "coronary artery bypass graft (CABG)." Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: anytime during use without warning symptoms that may cause death The risk of getting an ulcer or bleeding increases with : ○ past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs ○ older age ○ taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” ○ poor health ○ increasing doses of NSAIDs ○ advanced liver disease ○ longer use of NSAIDs ○ bleeding problems ○ smoking ○ drinking alcohol NSAIDs should only be used : exactly as prescribed at the lowest dose possible for your treatment for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. Who should not take NSAIDs? Do not take NSAIDs : if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. right before or after heart bypass surgery. Before taking NSAIDS, tell your healthcare provider about all of your medical conditions, including if you: have liver or kidney problems have high blood pressure have asthma are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy. are breastfeeding or plan to breast feed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements . NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See "What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?" new or worse high blood pressure heart failure liver problems including liver failure kidney problems including kidney failure low red blood cells (anemia) life-threatening skin reactions life-threatening allergic reactions Other side effects of NSAIDs include : stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness.

ure heart failure liver problems including liver failure kidney problems including kidney failure low red blood cells (anemia) life-threatening skin reactions life-threatening allergic reactions Other side effects of NSAIDs include : stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms : ● shortness of breath or trouble breathing ● slurred speech ● chest pain ● swelling of the face or throat ● weakness in one part or side of your body Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: ● nausea ● there is blood in your bowel movement or it is black ● more tired or weaker than usual ● vomit blood ● diarrhea ● there is blood in your bowel movement or it is black and sticky like tar ● itching ● unusual weight gain ● your skin or eyes look yellow ● skin rash or blisters with fever ● indigestion or stomach pain ● swelling of the arms, legs, hands and feet ● flu-like symptoms If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs: Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. This Medication Guide has been approved by the U.S. Food and Drug Administration. Repackaged By / Distributed By: RemedyRepack Inc. 625 Kolter Drive, Indiana, PA 15701 (724) 465-8762

<table width="100%" styleCode="Noautorules"><colgroup><col align="left" valign="middle" width="50%"/><col align="left" valign="middle" width="50%"/></colgroup><thead><tr><td><paragraph>&#x25CB; past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs</paragraph></td><td><paragraph>&#x25CB; older age</paragraph></td></tr></thead><tbody><tr><td valign="top"><paragraph>&#x25CB; taking medicines called &#x201C;corticosteroids&#x201D;, &#x201C;anticoagulants&#x201D;, &#x201C;SSRIs&#x201D;, or &#x201C;SNRIs&#x201D;</paragraph></td><td valign="top"><paragraph>&#x25CB; poor health</paragraph></td></tr><tr><td valign="top"><paragraph>&#x25CB; increasing doses of NSAIDs</paragraph></td><td valign="top"><paragraph>&#x25CB; advanced liver disease</paragraph></td></tr><tr><td valign="top"><paragraph>&#x25CB; longer use of NSAIDs</paragraph></td><td valign="top"><paragraph>&#x25CB; bleeding problems</paragraph></td></tr><tr><td valign="top"><paragraph>&#x25CB; smoking</paragraph></td><td valign="top"><paragraph/></td></tr><tr><td valign="top"><paragraph>&#x25CB; drinking alcohol</paragraph></td><td valign="top"><paragraph/></td></tr></tbody></table> <table width="100%" styleCode="Noautorules"><colgroup><col align="left" valign="middle" width="50%"/><col align="left" valign="middle" width="50%"/></colgroup><thead><tr><td><paragraph>&#x25CF; shortness of breath or trouble breathing </paragraph></td><td><paragraph>&#x25CF; slurred speech</paragraph></td></tr></thead><tbody><tr><td valign="top"><paragraph>&#x25CF; chest pain</paragraph></td><td valign="top"><paragraph>&#x25CF; swelling of the face or throat</paragraph></td></tr><tr><td valign="top"><paragraph>&#x25CF; weakness in one part or side of your body</paragraph></td><td valign="top"><paragraph/></td></tr></tbody></table>

d><tbody><tr><td valign="top"><paragraph>&#x25CF; chest pain</paragraph></td><td valign="top"><paragraph>&#x25CF; swelling of the face or throat</paragraph></td></tr><tr><td valign="top"><paragraph>&#x25CF; weakness in one part or side of your body</paragraph></td><td valign="top"><paragraph/></td></tr></tbody></table> <table width="100%" styleCode="Noautorules"><colgroup><col align="left" valign="middle" width="50%"/><col align="left" valign="middle" width="50%"/></colgroup><thead><tr><td><paragraph>&#x25CF; nausea </paragraph></td><td><paragraph>&#x25CF; there is blood in your bowel movement or it is black </paragraph></td></tr></thead><tbody><tr><td valign="top"><paragraph>&#x25CF; more tired or weaker than usual</paragraph></td><td valign="top"><paragraph>&#x25CF; vomit blood </paragraph></td></tr><tr><td valign="top"><paragraph>&#x25CF; diarrhea</paragraph></td><td valign="top"><paragraph>&#x25CF; there is blood in your bowel movement or it is black and sticky like tar </paragraph></td></tr><tr><td valign="top"><paragraph>&#x25CF; itching</paragraph></td><td valign="top"><paragraph>&#x25CF; unusual weight gain </paragraph></td></tr><tr><td valign="top"><paragraph>&#x25CF; your skin or eyes look yellow</paragraph></td><td valign="top"><paragraph>&#x25CF; skin rash or blisters with fever </paragraph></td></tr><tr><td valign="top"><paragraph>&#x25CF; indigestion or stomach pain </paragraph></td><td valign="top"><paragraph>&#x25CF; swelling of the arms, legs, hands and feet</paragraph></td></tr><tr><td valign="top"><paragraph>&#x25CF; flu-like symptoms</paragraph></td><td valign="top"><paragraph/></td></tr></tbody></table>

WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [ see Warnings and Precautions ( 5.1 ) ]. • Meloxicam capsules are contraindicated in the setting of coronary artery bypass graft (CABG) surgery [ see Contraindications ( 4 ), Warnings and Precautions ( 5.1 ) ] . Gastrointestinal Bleeding, Ulceration, and Perforation • NSAIDs cause an increased risk of serious gastrointestinal (GI) 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 and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [ see Warnings and Precautions ( 5.2 )]. WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use. ( 5.1 ) • Meloxicam capsules are contraindicated in the setting of coronary artery bypass graft (CABG) surgery. ( 4 , 5.1 ) • NSAIDs cause an increased risk of serious gastrointestinal (GI) 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 and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events. ( 5.2 )

1 INDICATIONS AND USAGE Meloxicam capsules are indicated for management of osteoarthritis pain. Meloxicam capsule is a non-steroidal anti-inflammatory drug indicated for management of osteoarthritis (OA) pain. ( 1 )

2 DOSAGE AND ADMINISTRATION • Start with 5 mg orally once daily. May increase dose to 10 mg in patients who require additional analgesia ( 2.1 ) • Use the lowest effective dose for shortest duration consistent with individual patient treatment goals ( 2.1 ) • Meloxicam capsules are not interchangeable with other formulations of oral meloxicam even if the milligram strength is the same. ( 2.2 ) 2.1 Dosage Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions ( 5 )] . For management of osteoarthritis pain, the recommended starting dosage is 5 mg orally once daily. Dose may be increased to 10 mg in patients who require additional analgesia. The maximum recommended daily oral dose of meloxicam capsules is 10 mg. In patients on hemodialysis, the maximum daily dosage is 5 mg [ see Warnings and Precautions ( 5.6 ), Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 )] 2.2 Non-Interchangeability with Other Formulations of Meloxicam Meloxicam capsules have not shown equivalent systemic exposure to other formulations of oral meloxicam. Therefore, meloxicam capsules are not interchangeable with other formulations of oral meloxicam even if the total milligram strength is the same. Do not substitute similar dose strengths of other meloxicam products [ see Clinical Pharmacology ( 12.3 ) ].

3 DOSAGE FORMS AND STRENGTHS Meloxicam Capsules: 5 mg – Size '4' Hard Gelatin Capsules having yellow opaque cap and yellow opaque body, imprinted with "LU" on cap and "M76" on body in black ink containing light yellow to yellow colored granules. Meloxicam Capsules: 10 mg – Size '3' Hard Gelatin Capsules having green opaque cap and green opaque body, imprinted with "LU" on cap and "M78" on body in black ink containing light yellow to yellow colored granules. Meloxicam Capsules: 5 mg or 10 mg ( 3 )

4 CONTRAINDICATIONS Meloxicam capsules are contraindicated in the following patients: • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to meloxicam or any components of the drug product [ see Warnings and Precautions ( 5.7 , 5.9 ) ] • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [ see Warnings and Precautions ( 5.7 , 5.8 ) ] • In the setting of coronary artery bypass graft (CABG) surgery [ see Warnings and Precautions ( 5.1 ) ] • Known hypersensitivity to meloxicam or any components of the drug product ( 4 ) • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs ( 4 ) • In the setting of CABG surgery ( 4 )

5 WARNINGS AND PRECAUTIONS • Hepatotoxicity : Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop ( 5.3 ) • Hypertension : Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure ( 5.4 , 7 ) • Heart Failure and Edema : Avoid use of meloxicam capsules in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure ( 5.5 ) • Renal Toxicity : Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of meloxicam capsules in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function ( 5.6 ) • Anaphylactic Reactions : Seek emergency help if an anaphylactic reaction occurs ( 5.7 ) • Exacerbation of Asthma Related to Aspirin Sensitivity : Meloxicam capsules are contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) ( 5.8 ) • Serious Skin Reactions : Discontinue meloxicam capsules at first appearance of skin rash or other signs of hypersensitivity ( 5.9 ) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically ( 5.10 ) Fetal Toxicity: Limit use of NSAIDs, including meloxicam capsules, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal dysfunction and premature closure of the fetal ductus arteriosus ( 5.11 , 8.1 ) • Hematologic Toxicity : Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia ( 5.12 , 7 ) 5.1 Cardiovascular 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, 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.

e 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 meloxicam, increases the risk of serious gastrointestinal (GI) events [ see Warnings and Precautions ( 5.2 ) ]. Status Post Coronary Artery Bypass Graft (CABG) Surgery 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. NSAIDs are contraindicated in the setting of CABG [ see Contraindications ( 4 ) ]. Post-MI Patients 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 meloxicam capsules in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If meloxicam capsules are used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including meloxicam, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, 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 meloxicam capsules. 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 occurred in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients • Use the lowest effective dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For high risk patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.

ime. • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For high risk patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue meloxicam capsules until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [ see Drug Interactions ( 7 ) ]. 5.3 Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including meloxicam. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flulike" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue meloxicam capsules immediately, and perform a clinical evaluation of the patient. 5.4 Hypertension NSAIDs, including meloxicam, can lead to new onset or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [ see Drug Interactions ( 7 ) ]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.5 Heart Failure and Edema 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 meloxicam 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 ( 7 ) ]. Avoid the use of meloxicam capsules in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If meloxicam capsules is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity 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 may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation.

s 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 may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy was usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of meloxicam capsules in patients with advanced renal disease. The renal effects of meloxicam capsules may hasten the progression of renal dysfunction in patients with pre-existing renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating meloxicam capsules. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of meloxicam capsules [ see DRUG INTERACTIONS ( 7 ) ] . Avoid the use of meloxicam capsules in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If meloxicam capsules are used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. 5.7 Anaphylactic Reactions Meloxicam has been associated with anaphylactic reactions in patients with and without known hypersensitivity to meloxicam and in patients with aspirin-sensitive asthma [ see Contraindications ( 4 ), Warnings and Precautions ( 5.8 ) ]. Seek emergency help if an anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, meloxicam is contraindicated in patients with this form of aspirin sensitivity [ see Contraindications ( 4 ) ]. When meloxicam capsules are used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.9 Serious Skin Reactions NSAIDs, including meloxicam, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of meloxicam capsules at the first appearance of skin rash or any other sign of hypersensitivity. Meloxicam capsules are contraindicated in patients with previous serious skin reactions to NSAIDs [ see Contraindications ( 4 ) ]. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as meloxicam. Some of these events have been fatal or life- threatening.

ous serious skin reactions to NSAIDs [ see Contraindications ( 4 ) ]. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as meloxicam. Some of these events have been fatal or life- threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue meloxicam and evaluate the patient immediately. 5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDS, including meloxicam capsules, in pregnant women at about 30 weeks of gestation and later. NSAIDs, including meloxicam, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including meloxicam capsules, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit meloxicam capsules use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if meloxicam capsules treatment extends beyond 48 hours. Discontinue meloxicam capsules if oligohydramnios occurs and follow up according to clinical practice [ see Use in Specific Populations ( 8.1 ) ]. 5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect upon erythropoiesis. If a patient treated with meloxicam capsules have any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including meloxicam, may increase the risk of bleeding events. Concomitant use of warfarin and other anticoagulants, antiplatelet agents (e.g., aspirin), and serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [ see Drug Interactions ( 7 ) ]. 5.13 Masking of Inflammation and Fever The pharmacological activity of meloxicam capsules in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.14 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [ see Warnings and Precautions ( 5.2 , 5.3 , 5.6 ) ].

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiovascular Thrombotic Events [ see Warnings and Precautions ( 5.1 ) ] • GI Bleeding, Ulceration and Perforation [ see Warnings and Precautions ( 5.2 ) ] • Hepatotoxicity [ see Warnings and Precautions ( 5.3 ) ] • Hypertension [ see Warnings and Precautions ( 5.4 ) ] • Heart Failure and Edema [ see Warnings and Precautions ( 5.5 ) ] • Renal Toxicity and Hyperkalemia [ see Warnings and Precautions ( 5.6 ) ] • Anaphylactic Reactions [ see Warnings and Precautions ( 5.7 ) ] • Serious Skin Reactions [ see Warnings and Precautions ( 5.9 ) ] • Hematologic Toxicity [ see Warnings and Precautions ( 5.11 ) ] Most common adverse reactions (incidence ≥2% in controlled clinical trials of meloxicam capsules 5 mg or 10 mg group) are diarrhea, nausea, abdominal discomfort. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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. Adverse Reactions in Patients with Osteoarthritis Pain Eight hundred sixty-eight (868) patients with osteoarthritis pain, ranging in age from 40 to 87 years, were enrolled in two Phase 3 clinical trials and received meloxicam capsules 5 mg or 10 mg once daily. Fifty percent (50%) of patients were aged 61 years or older. Two hundred sixty-nine (269) patients received meloxicam capsules 5 mg or 10 mg once daily in the 12-week, double-blind, placebo-controlled, clinical trial of osteoarthritis pain of the knee or hip. The most frequent adverse reactions in this study are summarized in Table 1. Table 1 Summary of Adverse Reactions (2%) – 12-Week Phase 3 Study in Patients With Osteoarthritis Pain Adverse Reactions Meloxicam Capsules 5 mg or 10 mg N=269 Placebo N=133 Diarrhea 3% 1% Nausea 2% 0 Abdominal Discomfort 2% 0 Six hundred (600) patients received meloxicam capsules 10 mg once daily in a 52-week, open-label, clinical trial in osteoarthritis pain of the knee or hip. Of these, 390 (65%) patients completed the trial. The most frequent adverse reactions in this study are summarized in Table 2.

Nausea 2% 0 Abdominal Discomfort 2% 0 Six hundred (600) patients received meloxicam capsules 10 mg once daily in a 52-week, open-label, clinical trial in osteoarthritis pain of the knee or hip. Of these, 390 (65%) patients completed the trial. The most frequent adverse reactions in this study are summarized in Table 2. Table 2 Summary of Adverse Reactions (2%) – 52-Week Open-Label Study in Patients With Osteoarthritis Pain Adverse Reactions Meloxicam Capsules 10 mg N=600 Arthralgia 6% Urinary Tract Infection 6% Osteoarthritis 5% Hypertension 4% Diarrhea 4% Headache 4% Upper Respiratory Tract Infection 4% Back Pain 4% Nasopharyngitis 4% Bronchitis 3% Sinusitis 3% Constipation 3% Dyspepsia 3% Nausea 2% Edema Peripheral 2% Pain in Extremity 2% Additional adverse reactions reported for meloxicam: Body as a Whole allergic reaction, face edema, fatigue, fever, hot flushes, malaise, syncope, weight decrease, weight increase Cardiovascular angina pectoris, cardiac failure, hypertension, hypotension, myocardial infarction, vasculitis Central and Peripheral Nervous System convulsions, paresthesia, tremor, vertigo Gastrointestinal colitis, dry mouth, duodenal ulcer, eructation, esophagitis, gastric ulcer, gastritis, gastroesophageal reflux, gastrointestinal hemorrhage, hematemesis, hemorrhagic duodenal ulcer, hemorrhagic gastric ulcer, intestinal perforation, melena, pancreatitis, perforated duodenal ulcer, perforated gastric ulcer, stomatitis ulcerative Heart Rate and Rhythm arrhythmia, palpitation, tachycardia Hematologic agranulocytosis, leukopenia, purpura, thrombocytopenia Immune System anaphylactoid reactions (including shock) Liver and Biliary System ALT increased, AST increased, bilirubinemia, GGT increased, hepatitis, jaundice, liver failure Metabolic and Nutritional dehydration Psychiatric abnormal dreaming, alterations in mood (such as mood elevation), anxiety, appetite increased, confusion, depression, nervousness, somnolence, Respiratory asthma, bronchospasm, dyspnea Skin and Appendages alopecia, angioedema, bullous eruption, erythema multiforme, exfoliative dermatitis, photosensitivity reaction, pruritus, Stevens-Johnson Syndrome, toxic epidermal necrolysis, sweating increased, urticaria Special Senses abnormal vision, conjunctivitis, taste perversion, tinnitus Urinary System albuminuria, acute urinary retention, BUN increased, creatinine increased, hematuria, interstitial nephritis, renal failure, 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of meloxicam. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and Appendages: Exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE).

<table ID="ID57" width="95%" styleCode="Noautorules"><caption> Table 1 Summary of Adverse Reactions (2%) &#x2013; 12-Week Phase 3 Study in Patients With Osteoarthritis Pain </caption><col width="216"/><col width="253"/><col width="203"/><tbody><tr><td styleCode="Lrule Toprule Botrule Rrule" align="left"><content styleCode="bold"> Adverse Reactions</content> </td><td styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Meloxicam Capsules</content> <content styleCode="bold"> 5 mg or 10 mg</content> <content styleCode="bold"> N=269</content> </td><td styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Placebo</content> <content styleCode="bold"> N=133</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Diarrhea </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Nausea </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Abdominal Discomfort </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td></tr></tbody></table>

td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Abdominal Discomfort </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td></tr></tbody></table> <table ID="ID59" width="100%" styleCode="Noautorules"><caption> Table 2 Summary of Adverse Reactions (2%) &#x2013; 52-Week Open-Label Study in Patients With Osteoarthritis Pain </caption><col width="288"/><col width="419"/><tbody><tr><td styleCode="Lrule Toprule Botrule Rrule" align="center"><content styleCode="bold"> Adverse Reactions</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Meloxicam Capsules 10 mg</content> <content styleCode="bold"> N=600</content> </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Arthralgia </td><td styleCode=" Botrule Rrule" align="center"> 6% </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Urinary Tract Infection </td><td styleCode=" Botrule Rrule" align="center"> 6% </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Osteoarthritis </td><td styleCode=" Botrule Rrule" align="center"> 5% </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Hypertension </td><td styleCode=" Botrule Rrule" align="center"> 4% </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Diarrhea </td><td styleCode=" Botrule Rrule" align="center"> 4% </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Headache </td><td styleCode=" Botrule Rrule" align="center"> 4% </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Upper Respiratory Tract Infection </td><td styleCode=" Botrule Rrule" align="center"> 4% </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Back Pain </td><td styleCode=" Botrule Rrule" align="center"> 4% </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Nasopharyngitis </td><td styleCode=" Botrule Rrule" align="center"> 4% </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Bronchitis </td><td styleCode=" Botrule Rrule" align="center"> 3% </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Sinusitis </td><td styleCode=" Botrule Rrule" align="center"> 3% </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Constipation </td><td styleCode=" Botrule Rrule" align="center"> 3% </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Dyspepsia </td><td styleCode=" Botrule Rrule" align="center"> 3% </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Nausea </td><td styleCode=" Botrule Rrule" align="center"> 2% </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Edema Peripheral </td><td styleCode=" Botrule Rrule" align="center"> 2% </td></tr><tr><td styleCode="Lrule Botrule Rrule" align="left"> Pain in Extremity </td><td styleCode=" Botrule Rrule" align="center"> 2% </td></tr><tr><td styleCode=" Lrule Botrule" align="left"> Additional adverse reactions reported for meloxicam: </td><td styleCode=" Botrule Rrule"/></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Body as a Whole</content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> allergic reaction, face edema, fatigue, fever, hot flushes, malaise, syncope, weight decrease, weight increase </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Cardiovascular</content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> angina pectoris, cardiac failure, hypertension, hypotension, myocardial infarction, vasculitis </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Central

content styleCode="bold"> Cardiovascular</content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> angina pectoris, cardiac failure, hypertension, hypotension, myocardial infarction, vasculitis </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Central and Peripheral Nervous System</content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> convulsions, paresthesia, tremor, vertigo </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Gastrointestinal</content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> colitis, dry mouth, duodenal ulcer, eructation, esophagitis, gastric ulcer, gastritis, gastroesophageal reflux, gastrointestinal hemorrhage, hematemesis, hemorrhagic duodenal ulcer, hemorrhagic gastric ulcer, intestinal perforation, melena, pancreatitis, perforated duodenal ulcer, perforated gastric ulcer, stomatitis ulcerative </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Heart Rate and Rhythm</content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> arrhythmia, palpitation, tachycardia </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Hematologic</content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> agranulocytosis, leukopenia, purpura, thrombocytopenia </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Immune System</content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> anaphylactoid reactions (including shock) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Liver and Biliary System</content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> ALT increased, AST increased, bilirubinemia, GGT increased, hepatitis, jaundice, liver failure </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Metabolic and Nutritional</content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> dehydration </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Psychiatric</content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> abnormal dreaming, alterations in mood (such as mood elevation), anxiety, appetite increased, confusion, depression, nervousness, somnolence, </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Respiratory</content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> asthma, bronchospasm, dyspnea </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Skin and Appendages</content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> alopecia, angioedema, bullous eruption, erythema multiforme, exfoliative dermatitis, photosensitivity reaction, pruritus, Stevens-Johnson Syndrome, toxic epidermal necrolysis, sweating increased, urticaria </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Special Senses</content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> abnormal vision, conjunctivitis, taste perversion, tinnitus </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Urinary System</content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> albuminuria, acute urinary retention, BUN increased, creatinine increased, hematuria, interstitial nephritis, renal failure, </td></tr></tbody></table>

7 DRUG INTERACTIONS See Table 3 for clinically significant drug interactions with meloxicam. Table 3 Clinically Significant Drug Interactions with meloxicam Drugs That Interfere with Hemostasis Clinical Impact Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention : Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11) ]. Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2) ]. Meloxicam is not a substitute for aspirin for cardiovascular prophylaxis. Intervention: Concomitant use of meloxicam and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11) ]. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-blockers Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta- blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention During concomitant use of meloxicam and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of meloxicam and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6) ]. Diuretics Clinical Impact : Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings And Precautions (5.6) ]. Digoxin Clinical Impact The concomitant use of meloxicam with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.

ts for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings And Precautions (5.6) ]. Digoxin Clinical Impact The concomitant use of meloxicam with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention During concomitant use of meloxicam and digoxin, monitor serum digoxin levels Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. intervention: During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity Methotrexate Clinical Impact Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact Concomitant use of meloxicam and cyclosporine may increase cyclosporine's nephrotoxicity. Intervention During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2) ]. Intervention: The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. • Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs) : Monitor patients for bleeding who are concomitantly taking meloxicam with drugs that interfere with hemostasis. Concomitant use of meloxicam and analgesic doses of aspirin is not generally recommended ( 7 ) • ACE inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers : Concomitant use with meloxicam capsules may diminish the antihypertensive effect of these drugs. Monitor blood pressure ( 7 ) • ACE Inhibitors and ARBs : Concomitant use with meloxicam capsules in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function ( 7 ) • Diuretics : NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects ( 7 ) • Digoxin : Concomitant use with meloxicam capsules can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels ( 7 ).

<table ID="ID142" width="707" styleCode="Noautorules"><caption> Table 3 Clinically Significant Drug Interactions with meloxicam </caption><col width="150"/><col width="1"/><col width="1"/><col width="555"/><tbody><tr><td colspan="4" valign="top" styleCode="Lrule Toprule Botrule Rrule" align="left"><content styleCode="bold"> Drugs That Interfere with Hemostasis</content> </td></tr><tr><td colspan="3" valign="top" styleCode="Lrule Botrule Rrule" align="left"> <content styleCode="italics">Clinical Impact</content> </td><td valign="top" styleCode=" Botrule Rrule"><list listType="unordered" styleCode="disc"><item>Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.</item><item>Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.</item></list></td></tr><tr><td colspan="3" valign="top" styleCode="Lrule Botrule Rrule" align="left"> <content styleCode="italics">Intervention</content> : </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding <content styleCode="italics">[see <linkHtml href="#ID139">Warnings and Precautions (5.11)</linkHtml>].</content> </td></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Aspirin</content> </td></tr><tr><td colspan="2" valign="top" styleCode="Lrule Botrule Rrule" align="left"> <content styleCode="italics">Clinical Impact:</content> </td><td colspan="2" valign="top" styleCode=" Botrule Rrule" align="left"> Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone <content styleCode="italics">[see <linkHtml href="#ID27">Warnings and Precautions (5.2)</linkHtml>].</content> Meloxicam is not a substitute for aspirin for cardiovascular prophylaxis.

NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone <content styleCode="italics">[see <linkHtml href="#ID27">Warnings and Precautions (5.2)</linkHtml>].</content> Meloxicam is not a substitute for aspirin for cardiovascular prophylaxis. </td></tr><tr><td colspan="2" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Intervention:</content> </td><td colspan="2" valign="top" styleCode=" Botrule Rrule" align="left"> Concomitant use of meloxicam and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding <content styleCode="italics">[see <linkHtml href="#ID139">Warnings and Precautions (5.11)</linkHtml>].</content> </td></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-blockers</content> </td></tr><tr><td colspan="2" valign="top" styleCode="Lrule Botrule Rrule" align="left"> <content styleCode="italics">Clinical Impact:</content> </td><td colspan="2" valign="top" styleCode=" Botrule Rrule"><list listType="unordered" styleCode="disc"><item>NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta- blockers (including propranolol).</item><item>In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.</item></list></td></tr><tr><td colspan="2" valign="top" styleCode="Lrule Botrule Rrule" align="left"> <content styleCode="italics">Intervention</content> </td><td colspan="2" valign="top" styleCode=" Botrule Rrule"><list listType="unordered" styleCode="disc"><item>During concomitant use of meloxicam and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.</item><item>During concomitant use of meloxicam and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function <content styleCode="italics">[see <linkHtml href="#ID35">Warnings and Precautions (5.6)</linkHtml>].</content></item></list></td></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Diuretics</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> <content styleCode="italics">Clinical Impact</content> : </td><td colspan="3" valign="top" styleCode=" Botrule Rrule" align="left"> Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Intervention:</content> </td><td colspan="3" valign="top" styleCode=" Botrule Rrule" align="left"> During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [<content styleCode="italics">see Warnings And Precautions (5.6)</content> ].

"3" valign="top" styleCode=" Botrule Rrule" align="left"> During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [<content styleCode="italics">see Warnings And Precautions (5.6)</content> ]. </td></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Digoxin</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Clinical Impact</content> </td><td colspan="3" valign="top" styleCode=" Botrule Rrule" align="left"> The concomitant use of meloxicam with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Intervention</content> </td><td colspan="3" valign="top" styleCode=" Botrule Rrule" align="left"> During concomitant use of meloxicam and digoxin, monitor serum digoxin levels </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Lithium</content> </td><td colspan="3" valign="top" styleCode=" Botrule Rrule"/></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Clinical Impact:</content> </td><td colspan="3" valign="top" styleCode=" Botrule Rrule" align="left"> NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">intervention:</content> </td><td colspan="3" valign="top" styleCode=" Botrule Rrule" align="left"> During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity </td></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Methotrexate</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Clinical Impact</content> </td><td colspan="3" valign="top" styleCode=" Botrule Rrule" align="left"> Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Intervention</content> </td><td colspan="3" valign="top" styleCode=" Botrule Rrule" align="left"> During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity. </td></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Cyclosporine</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Clinical Impact</content> </td><td colspan="3" valign="top" styleCode=" Botrule Rrule" align="left"> Concomitant use of meloxicam and cyclosporine may increase cyclosporine&apos;s nephrotoxicity. </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Intervention</content> </td><td colspan="3" valign="top" styleCode=" Botrule Rrule" align="left"> During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function.

xicity. </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Intervention</content> </td><td colspan="3" valign="top" styleCode=" Botrule Rrule" align="left"> During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function. </td></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> NSAIDs and Salicylates</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Clinical Impact:</content> </td><td colspan="3" valign="top" styleCode=" Botrule Rrule" align="left"> Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy <content styleCode="italics">[see <linkHtml href="#ID27">Warnings and Precautions (5.2)</linkHtml>].</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Intervention:</content> </td><td colspan="3" valign="top" styleCode=" Botrule Rrule" align="left"> The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended. </td></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Pemetrexed</content> </td></tr><tr><td colspan="2" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="italics">Clinical Impact:</content> </td><td colspan="2" valign="top" styleCode=" Botrule Rrule" align="left"> Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). </td></tr><tr><td colspan="2" valign="top" styleCode="Lrule Botrule Rrule" align="left"> <content styleCode="italics">Intervention</content> </td><td colspan="2" valign="top" styleCode=" Botrule Rrule" align="left"> During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. </td></tr></tbody></table>

8 USE IN SPECIFIC POPULATIONS Infertility : NSAIDs are associated with reversible infertility. Consider withdrawal of meloxicam capsules in women who have difficulties conceiving ( 8.3 ) 8.1 Pregnancy Risk Summary Use of NSAIDs, including meloxicam, 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 meloxicam capsules use between about 20 and 30 weeks of gestation, and avoid meloxicam capsules use at about 30 weeks of gestation and later in pregnancy ( see Clinical Considerations, Data ). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including meloxicam capsules, 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 some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, embryofetal death was observed in rats and rabbits treated during the period of organogenesis with meloxicam at oral doses equivalent 1- and 10-times, respectively, the maximum recommended daily dose (MRDD) of meloxicam capsules. Increased incidence of septal heart defects were observed in rabbits treated throughout embryogenesis with meloxicam at an oral dose equivalent to 116-times the MRDD. In pre- and post-natal reproduction studies, increased incidence of dystocia, delayed parturition, and decreased offspring survival were observed in rats treated with meloxicam at an oral dose equivalent to 0.12-times the MRDD of meloxicam capsules. No teratogenic effects were observed in rats treated with meloxicam during organogenesis at an oral dose equivalent to 3.9- times the MRDD [see Data] . Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as meloxicam, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including meloxicam capsules, can cause premature closure of the fetal ductus arteriosus ( see Data ).

0%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including meloxicam capsules, can cause premature closure of the fetal ductus arteriosus ( see Data ). Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If meloxicam capsules treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue meloxicam capsules and follow up according to clinical practice ( see Data ). Labor or Delivery: There are no studies on the effects of meloxicam capsules during labor or delivery. In animal studies, NSAIDs, including meloxicam, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Human Data Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal data: Meloxicam was not teratogenic when administered to pregnant rats during fetal organogenesis at oral doses up to 4 mg/kg/day (3.9-times the maximum recommended daily dose (MRDD) of 10 mg of meloxicam capsules based on body surface area [BSA] comparison). Administration of meloxicam to pregnant rabbits throughout embryogenesis produced an increased incidence of septal defects of the heart at an oral dose of 60 mg/kg/day (116-times the MRDD based on BSA comparison). The no effect level was 20 mg/kg/day (39-times the MRDD based on BSA comparison). In rats and rabbits, embryolethality occurred at oral meloxicam doses of 1 mg/kg/day and 5 mg/kg/day, respectively (1- and 10-times the MRDD based on BSA comparison) when administered throughout organogenesis. Oral administration of meloxicam to pregnant rats during late gestation through lactation increased the incidence of dystocia, delayed parturition, and decreased offspring survival at meloxicam doses of 0.125 mg/kg/day or greater (0.12-times the MRDD based on BSA comparison).

when administered throughout organogenesis. Oral administration of meloxicam to pregnant rats during late gestation through lactation increased the incidence of dystocia, delayed parturition, and decreased offspring survival at meloxicam doses of 0.125 mg/kg/day or greater (0.12-times the MRDD based on BSA comparison). 8.2 Lactation Risk Summary There are no human data available on whether meloxicam is present in human milk, or on the effects on breastfed infants, or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for meloxicam capsules and any potential adverse effects on the breastfed infant from the meloxicam capsules or from the underlying maternal condition Data Animal data: Meloxicam was excreted in the milk of lactating rats at concentrations higher than those in plasma. 8.3 Females and Males of Reproductive Potential Infertility Females: Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including meloxicam, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin- mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including meloxicam, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use The safety and effectiveness of meloxicam capsules in pediatric patients has not been established. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [ see Warnings and Precautions ( 5.1 , 5.2 , 5.3 , 5.6 , 5.13 ) ]. Of the total number of patients in clinical studies of meloxicam capsules, 291 were age 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment No dose adjustment is necessary in patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment have not been adequately studied. Because meloxicam is significantly metabolized in the liver; use meloxicam capsules in patients with severe hepatic impairment only if the benefits are expected to outweigh the risks. If meloxicam capsules are used in patients with severe hepatic impairment, monitor patients for signs of worsening liver function [ see Warnings and Precautions ( 5.3 ), Clinical Pharmacology ( 12.3 ) ]. 8.7 Renal Impairment No dose adjustment is necessary in patients with mild to moderate renal impairment. Patients with severe renal impairment have not been studied. The use of meloxicam capsules in subjects with severe renal impairment is not recommended. In a previous study, the free C max plasma concentrations following a single dose of meloxicam were higher in patients with renal failure on chronic hemodialysis (1% free fraction) in comparison to healthy volunteers (0.3% free fraction). Therefore, the maximum meloxicam capsules dosage in this population is 5 mg per day. Hemodialysis did not lower the total drug concentration in plasma; therefore, additional doses are not necessary after hemodialysis.

e on chronic hemodialysis (1% free fraction) in comparison to healthy volunteers (0.3% free fraction). Therefore, the maximum meloxicam capsules dosage in this population is 5 mg per day. Hemodialysis did not lower the total drug concentration in plasma; therefore, additional doses are not necessary after hemodialysis. Meloxicam is not dialyzable [ see Warnings and Precautions ( 5.6 ), Clinical Pharmacology ( 12.3 ) ].

8.1 Pregnancy Risk Summary Use of NSAIDs, including meloxicam, 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 meloxicam capsules use between about 20 and 30 weeks of gestation, and avoid meloxicam capsules use at about 30 weeks of gestation and later in pregnancy ( see Clinical Considerations, Data ). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including meloxicam capsules, 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 some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, embryofetal death was observed in rats and rabbits treated during the period of organogenesis with meloxicam at oral doses equivalent 1- and 10-times, respectively, the maximum recommended daily dose (MRDD) of meloxicam capsules. Increased incidence of septal heart defects were observed in rabbits treated throughout embryogenesis with meloxicam at an oral dose equivalent to 116-times the MRDD. In pre- and post-natal reproduction studies, increased incidence of dystocia, delayed parturition, and decreased offspring survival were observed in rats treated with meloxicam at an oral dose equivalent to 0.12-times the MRDD of meloxicam capsules. No teratogenic effects were observed in rats treated with meloxicam during organogenesis at an oral dose equivalent to 3.9- times the MRDD [see Data] . Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as meloxicam, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including meloxicam capsules, can cause premature closure of the fetal ductus arteriosus ( see Data ). Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If meloxicam capsules treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios.

see Data ). Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If meloxicam capsules treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue meloxicam capsules and follow up according to clinical practice ( see Data ). Labor or Delivery: There are no studies on the effects of meloxicam capsules during labor or delivery. In animal studies, NSAIDs, including meloxicam, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Human Data Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal data: Meloxicam was not teratogenic when administered to pregnant rats during fetal organogenesis at oral doses up to 4 mg/kg/day (3.9-times the maximum recommended daily dose (MRDD) of 10 mg of meloxicam capsules based on body surface area [BSA] comparison). Administration of meloxicam to pregnant rabbits throughout embryogenesis produced an increased incidence of septal defects of the heart at an oral dose of 60 mg/kg/day (116-times the MRDD based on BSA comparison). The no effect level was 20 mg/kg/day (39-times the MRDD based on BSA comparison). In rats and rabbits, embryolethality occurred at oral meloxicam doses of 1 mg/kg/day and 5 mg/kg/day, respectively (1- and 10-times the MRDD based on BSA comparison) when administered throughout organogenesis. Oral administration of meloxicam to pregnant rats during late gestation through lactation increased the incidence of dystocia, delayed parturition, and decreased offspring survival at meloxicam doses of 0.125 mg/kg/day or greater (0.12-times the MRDD based on BSA comparison).

8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [ see Warnings and Precautions ( 5.1 , 5.2 , 5.3 , 5.6 , 5.13 ) ]. Of the total number of patients in clinical studies of meloxicam capsules, 291 were age 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [ see Warnings and Precautions ( 5.1 , 5.2 ) ]. There is limited experience with meloxicam overdose. In four reported cases of meloxicam overdose, patients took 6 to 11 times the highest available dose of meloxicam tablets (15 mg); all recovered. Cholestyramine is known to accelerate the clearance of meloxicam. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Accelerated removal of meloxicam by 4 g oral doses of cholestyramine given three times a day was demonstrated in a previous clinical trial. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center (1800-222-1222).

11 DESCRIPTION Meloxicam Capsules are a nonsteroidal anti-inflammatory drug, available as yellow and green capsules containing 5 mg or 10 mg for oral administration. The chemical name is 4-Hydroxy-2-methyl- N -(5-methyl-2-thiazolyl)-2 H -1,2-benzothiazine-3-carboxamide-1,1-dioxide. The molecular weight is 351.40. Its molecular formula is C 14 H 13 N 3 O 4 S 2 , and it has the following chemical structure. Meloxicam is a pale yellow powder, practically insoluble in water, with higher solubility observed in strong acids and bases. It is very slightly soluble in methanol. Meloxicam has a partition coefficient (Log P) = 2.662 ± 0.848 at 25°C. Meloxicam has pKa values of 1.1 and 4.2. The inactive ingredients in meloxicam capsules include: crospovidone, lactose monohydrate, magnesium stearate, povidone and sodium lauryl sulfate. The capsule shells contain D & C Yellow No. 10, FD & C Blue No. 1, FD & C Red No. 40 (for 10 mg strength only), FD & C Yellow No. 6 (for 5 mg strength only), gelatin and titanium dioxide. The imprinting on the gelatin capsules is black edible ink which contains black iron oxide, potassium hydroxide, propylene glycol, shellac and titanium dioxide. The 5 mg capsules have a yellow opaque cap and yellow opaque body, imprinted with "LU" on cap and "M76" on body in black ink. The 10 mg capsules have a green opaque cap and green opaque body, imprinted with "LU" on cap and "M78" on body in black ink. structure

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Meloxicam has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of meloxicam, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Meloxicam is a potent inhibitor of prostaglandin synthesis in vitro. Meloxicam concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because meloxicam is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. 12.3 Pharmacokinetics The relative bioavailability of meloxicam 10 mg capsules compared to meloxicam 15 mg tablets was assessed in 28 healthy subjects under fasted and fed conditions in a single-dose crossover study. Meloxicam 10 mg capsules do not result in an equivalent systemic exposure compared to 15 mg meloxicam tablets. When taken under fasted conditions, a 33% lower dose of meloxicam in meloxicam 10 mg capsules resulted in a 33% lower overall systemic exposure (AUC inf ) and a comparable mean peak plasma concentration (C max ) to meloxicam 15 mg tablets. The median time to maximum plasma concentration (T max ) occurred earlier for meloxicam capsules (2 hours for both 5 mg and 10 mg) than for meloxicam tablets (4 hours for 15 mg). Absorption Single oral doses of meloxicam capsules 5 mg and 10 mg were associated with dose-proportional pharmacokinetics. Mean C max was achieved within 2 hours post-dose for both meloxicam capsules 5 mg and 10 mg capsules when taken under fasted conditions. A second meloxicam concentration peak occurs around 8 hours post-dose. Taking meloxicam capsules with food causes a decrease in the rate but not the overall extent of systemic meloxicam absorption compared with taking meloxicam capsules on an empty stomach. Meloxicam capsules administered under fed conditions results in 22% lower mean C max and a 3 hour delay in median T max (5 hours for fed versus 2 hours for fasted) compared to the fasted condition. Significant changes in AUC inf were not observed. Meloxicam capsules can be administered without regard to timing of meals. Distribution The mean volume of distribution (Vss) of meloxicam is approximately 10 L. Meloxicam is ~99.4% bound to human plasma proteins (primarily albumin) within the therapeutic dose range. The fraction of protein binding is independent of drug concentration, over the clinically relevant concentration range, but decreases to ~99% in patients with renal disease. Meloxicam penetration into human red blood cells, after oral dosing, is less than 10%. Following a radiolabeled dose, over 90% of the radioactivity detected in the plasma was present as unchanged meloxicam. Meloxicam concentrations in synovial fluid, after a single oral dose, range from 40% to 50% of those in plasma. The free fraction in synovial fluid is 2.5 times higher than in plasma, due to the lower albumin content in synovial fluid as compared to plasma. The significance of this penetration is unknown. Elimination Metabolism: Meloxicam is extensively metabolized in the liver.

al dose, range from 40% to 50% of those in plasma. The free fraction in synovial fluid is 2.5 times higher than in plasma, due to the lower albumin content in synovial fluid as compared to plasma. The significance of this penetration is unknown. Elimination Metabolism: Meloxicam is extensively metabolized in the liver. Meloxicam metabolites include 5'-carboxy meloxicam (60% of dose), from P-450 mediated metabolism formed by oxidation of an intermediate metabolite 5'-hydroxymethyl meloxicam which is also excreted to a lesser extent (9% of dose). In vitro studies indicate that CYP2C9 (cytochrome P450 metabolizing enzyme) plays an important role in this metabolic pathway with a minor contribution of the CYP3A4 isozyme. Patients' peroxidase activity is probably responsible for the other two metabolites which account for 16% and 4% of the administered dose, respectively. The four metabolites are not known to have any in vivo pharmacological activity. Excretion: Meloxicam excretion is predominantly in the form of metabolites, and occurs to equal extents in the urine and feces. Only traces of the unchanged parent compound are excreted in the urine (0.2%) and feces (1.6%). The extent of the urinary excretion was confirmed for unlabeled multiple 7.5 mg doses: 0.5%, 6%, and 13% of the dose were found in urine in the form of meloxicam, and the 5'-hydroxymethyl and 5'-carboxy metabolites, respectively. There is significant biliary and/or enteral secretion of the drug. This was demonstrated when oral administration of cholestyramine following a single IV dose of meloxicam decreased the AUC of meloxicam by 50%. The mean elimination half-life (t 1/2 ) for meloxicam capsules 5 mg and 10 mg is approximately 22 hours. Specific Populations Pediatric: The pharmacokinetics of meloxicam capsules have not been investigated in pediatric patients. Hepatic Impairment: Following a single 15 mg dose of meloxicam tablets there was no marked difference in plasma concentrations in patients with mild (Child-Pugh Class I) or moderate (Child-Pugh Class II) hepatic impairment compared to healthy volunteers. Protein binding of meloxicam was not affected by hepatic impairment. No dosage adjustment is necessary in patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment (Child-Pugh Class III) have not been adequately studied [ see Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.6 ) ]. Renal Impairment: Meloxicam pharmacokinetics have been investigated in subjects with mild and moderate renal impairment. Total drug plasma concentrations of meloxicam decreased and total clearance of meloxicam increased with the degree of renal impairment while free AUC values were similar in all groups. The higher meloxicam clearance in subjects with renal impairment may be due to increased fraction of unbound meloxicam which is available for hepatic metabolism and subsequent excretion. No dosage adjustment is necessary in patients with mild to moderate renal impairment. Patients with severe renal impairment have not been adequately studied. The use of meloxicam capsules in subjects with severe renal impairment is not recommended. Following a single dose of meloxicam, the free C max plasma concentrations were higher in patients with renal failure on chronic hemodialysis (1% free fraction) in comparison to healthy volunteers (0.3% free fraction). Hemodialysis did not lower the total drug concentration in plasma; therefore, additional doses are not necessary after hemodialysis. Meloxicam is not dialyzable [ see Warnings and Precautions ( 5.6 ) , Use in Specific Populations ( 8.7 ) ]. Drug Interaction Studies Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered.

re not necessary after hemodialysis. Meloxicam is not dialyzable [ see Warnings and Precautions ( 5.6 ) , Use in Specific Populations ( 8.7 ) ]. Drug Interaction Studies Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 3 clinically significant drug interactions of NSAIDs with aspirin [ see Drug Interactions ( 7 ) ] . Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t 1/2 , from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine four times daily did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam tablets 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after β-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam [ see Drug Interactions ( 7 ) ]. Lithium: 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 tablets 15 mg once per day every day as compared to subjects receiving lithium alone [ see Drug Interactions ( 7 ) ]. Methotrexate: A previous study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites [ see Drug Interactions ( 7 ) ]. Warfarin: The effect of meloxicam tablets on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering meloxicam capsules 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 Drug Interactions ( 7 ) ].

12.1 Mechanism of Action Meloxicam has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of meloxicam, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Meloxicam is a potent inhibitor of prostaglandin synthesis in vitro. Meloxicam concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because meloxicam is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

12.3 Pharmacokinetics The relative bioavailability of meloxicam 10 mg capsules compared to meloxicam 15 mg tablets was assessed in 28 healthy subjects under fasted and fed conditions in a single-dose crossover study. Meloxicam 10 mg capsules do not result in an equivalent systemic exposure compared to 15 mg meloxicam tablets. When taken under fasted conditions, a 33% lower dose of meloxicam in meloxicam 10 mg capsules resulted in a 33% lower overall systemic exposure (AUC inf ) and a comparable mean peak plasma concentration (C max ) to meloxicam 15 mg tablets. The median time to maximum plasma concentration (T max ) occurred earlier for meloxicam capsules (2 hours for both 5 mg and 10 mg) than for meloxicam tablets (4 hours for 15 mg). Absorption Single oral doses of meloxicam capsules 5 mg and 10 mg were associated with dose-proportional pharmacokinetics. Mean C max was achieved within 2 hours post-dose for both meloxicam capsules 5 mg and 10 mg capsules when taken under fasted conditions. A second meloxicam concentration peak occurs around 8 hours post-dose. Taking meloxicam capsules with food causes a decrease in the rate but not the overall extent of systemic meloxicam absorption compared with taking meloxicam capsules on an empty stomach. Meloxicam capsules administered under fed conditions results in 22% lower mean C max and a 3 hour delay in median T max (5 hours for fed versus 2 hours for fasted) compared to the fasted condition. Significant changes in AUC inf were not observed. Meloxicam capsules can be administered without regard to timing of meals. Distribution The mean volume of distribution (Vss) of meloxicam is approximately 10 L. Meloxicam is ~99.4% bound to human plasma proteins (primarily albumin) within the therapeutic dose range. The fraction of protein binding is independent of drug concentration, over the clinically relevant concentration range, but decreases to ~99% in patients with renal disease. Meloxicam penetration into human red blood cells, after oral dosing, is less than 10%. Following a radiolabeled dose, over 90% of the radioactivity detected in the plasma was present as unchanged meloxicam. Meloxicam concentrations in synovial fluid, after a single oral dose, range from 40% to 50% of those in plasma. The free fraction in synovial fluid is 2.5 times higher than in plasma, due to the lower albumin content in synovial fluid as compared to plasma. The significance of this penetration is unknown. Elimination Metabolism: Meloxicam is extensively metabolized in the liver. Meloxicam metabolites include 5'-carboxy meloxicam (60% of dose), from P-450 mediated metabolism formed by oxidation of an intermediate metabolite 5'-hydroxymethyl meloxicam which is also excreted to a lesser extent (9% of dose). In vitro studies indicate that CYP2C9 (cytochrome P450 metabolizing enzyme) plays an important role in this metabolic pathway with a minor contribution of the CYP3A4 isozyme. Patients' peroxidase activity is probably responsible for the other two metabolites which account for 16% and 4% of the administered dose, respectively. The four metabolites are not known to have any in vivo pharmacological activity. Excretion: Meloxicam excretion is predominantly in the form of metabolites, and occurs to equal extents in the urine and feces. Only traces of the unchanged parent compound are excreted in the urine (0.2%) and feces (1.6%).

, respectively. The four metabolites are not known to have any in vivo pharmacological activity. Excretion: Meloxicam excretion is predominantly in the form of metabolites, and occurs to equal extents in the urine and feces. Only traces of the unchanged parent compound are excreted in the urine (0.2%) and feces (1.6%). The extent of the urinary excretion was confirmed for unlabeled multiple 7.5 mg doses: 0.5%, 6%, and 13% of the dose were found in urine in the form of meloxicam, and the 5'-hydroxymethyl and 5'-carboxy metabolites, respectively. There is significant biliary and/or enteral secretion of the drug. This was demonstrated when oral administration of cholestyramine following a single IV dose of meloxicam decreased the AUC of meloxicam by 50%. The mean elimination half-life (t 1/2 ) for meloxicam capsules 5 mg and 10 mg is approximately 22 hours. Specific Populations Pediatric: The pharmacokinetics of meloxicam capsules have not been investigated in pediatric patients. Hepatic Impairment: Following a single 15 mg dose of meloxicam tablets there was no marked difference in plasma concentrations in patients with mild (Child-Pugh Class I) or moderate (Child-Pugh Class II) hepatic impairment compared to healthy volunteers. Protein binding of meloxicam was not affected by hepatic impairment. No dosage adjustment is necessary in patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment (Child-Pugh Class III) have not been adequately studied [ see Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.6 ) ]. Renal Impairment: Meloxicam pharmacokinetics have been investigated in subjects with mild and moderate renal impairment. Total drug plasma concentrations of meloxicam decreased and total clearance of meloxicam increased with the degree of renal impairment while free AUC values were similar in all groups. The higher meloxicam clearance in subjects with renal impairment may be due to increased fraction of unbound meloxicam which is available for hepatic metabolism and subsequent excretion. No dosage adjustment is necessary in patients with mild to moderate renal impairment. Patients with severe renal impairment have not been adequately studied. The use of meloxicam capsules in subjects with severe renal impairment is not recommended. Following a single dose of meloxicam, the free C max plasma concentrations were higher in patients with renal failure on chronic hemodialysis (1% free fraction) in comparison to healthy volunteers (0.3% free fraction). Hemodialysis did not lower the total drug concentration in plasma; therefore, additional doses are not necessary after hemodialysis. Meloxicam is not dialyzable [ see Warnings and Precautions ( 5.6 ) , Use in Specific Populations ( 8.7 ) ]. Drug Interaction Studies Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 3 clinically significant drug interactions of NSAIDs with aspirin [ see Drug Interactions ( 7 ) ] . Cholestyramine: Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t 1/2 , from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine four times daily did not alter the single-dose pharmacokinetics of 30 mg meloxicam.

in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine: Concomitant administration of 200 mg cimetidine four times daily did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin: Meloxicam tablets 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after β-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam [ see Drug Interactions ( 7 ) ]. Lithium: 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 tablets 15 mg once per day every day as compared to subjects receiving lithium alone [ see Drug Interactions ( 7 ) ]. Methotrexate: A previous study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro, methotrexate did not displace meloxicam from its human serum binding sites [ see Drug Interactions ( 7 ) ]. Warfarin: The effect of meloxicam tablets on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering meloxicam capsules 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 Drug Interactions ( 7 ) ].

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis There was no increase in tumor incidence in long-term carcinogenicity studies in rats (104 weeks) and mice (99 weeks) administered meloxicam at oral doses up to 0.8 mg/kg/day in rats and up to 8.0 mg/kg/day in mice (up to 0.8- and 3.9-times, respectively, the maximum recommended daily dose (MRDD) of 10 mg of meloxicam capsules based on body surface area (BSA) comparison). Mutagenesis Meloxicam was not mutagenic in an Ames assay, or clastogenic in a chromosome aberration assay with human lymphocytes and an in vivo micronucleus test in mouse bone marrow. Impairment of Fertility In previous studies of meloxicam, there was no impairment of male or female fertility in rats at oral doses up to 9 mg/kg/day in males and 5 mg/kg/day in females (up to 8.7 and 4.8-times, respectively, the MRDD based on BSA comparison).

14 CLINICAL STUDIES 14.1 Osteoarthritis Pain The efficacy of meloxicam capsules in the management of osteoarthritis pain was demonstrated in a randomized, double-blind, multicenter, parallel-arm, placebo-controlled study comparing meloxicam capsules 5 mg or 10 mg taken once daily and placebo in patients with pain due to osteoarthritis of the knee or hip. The study evaluated 402 patients with a mean age of 61 (range 40 to 87 years). Osteoarthritis pain was measured using the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) Pain Subscale. The mean baseline WOMAC Pain Subscale Score across treatment groups was 73 mm using a 0 to 100 mm visual analog scale. The primary efficacy endpoint was the change from baseline to Week 12 in the WOMAC Pain Subscale Score. Meloxicam capsules 5 mg and 10 mg once daily significantly reduced osteoarthritis pain compared with placebo, as measured by changes in WOMAC Pain Subscale Scores. Although both the 5 mg and 10 mg doses significantly reduced pain compared to placebo, the proportion of responders achieving various percentage reductions in pain intensity from baseline to Week 12 is similar for both the 5 mg and 10 mg once daily doses. The proportion (%) of patients in each group who demonstrated reduction in their pain intensity score from baseline to Week 12 is shown in Figure 1. The figure is cumulative, so patients whose change from baseline is, for example, 30%, are also included in every level of pain reduction below 30%. Patients who did not complete the study were classified as non- responders. Figure 1 Proportion (%) of Patients Achieving Various Percentage Reductions in Pain Intensity from Baseline to Week 12 fig1

16 HOW SUPPLIED/STORAGE AND HANDLING Meloxicam capsules are supplied as: • 5 mg - yellow opaque cap and yellow opaque body (imprinted "M76" on the body and "LU" on the cap in black ink) NDC (68180-188-06), Bottles of 30 capsules • 10 mg - green opaque cap and green opaque body (imprinted "M78" on the body and "LU" on the cap in black ink) NDC (68180-189-06), Bottles of 30 capsules Storage Store at 25 °C (77 °F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Store in the original container and keep the bottle tightly closed to protect from moisture. Dispense in a tight container if package is subdivided.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Patients, families, or their caregivers should be informed of the following information before initiating therapy with meloxicam capsules and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [ see Warnings and Precautions ( 5.1 ) ]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [ see Warnings and Precautions ( 5.2 ) ]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, instruct patients to stop meloxicam capsules and seek immediate medical therapy [ see Warnings and Precautions ( 5.3 )]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [ see Warnings and Precautions ( 5.5 ) ]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [ see Contraindications ( 4 ), Warnings and Precautions ( 5.7 )]. Serious Skin Reactions, including DRESS Advise patients to stop taking meloxicam capsules immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [ see Warnings and Precautions ( 5.9 ), ( 5.10 ) ]. Fetal Toxicity Inform pregnant women to avoid use of meloxicam capsules and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with meloxicam capsules is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [ see Warnings and Precautions ( 5.10 ) and Use in Specific Populations ( 8.1 ) ]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of meloxicam capsules with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions ( 5.2 ), Drug Interactions ( 7 ) ]. Alert patients that NSAIDs may be present in "over the counter" medications for treatment of colds, fever, or insomnia. Use of NSAIDs and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with meloxicam capsules until they talk to their healthcare provider [ see Drug Interactions ( 7 ) ]. LUPIN and the are registered trademarks of Lupin Pharmaceuticals, Inc. Manufactured for: Lupin Pharmaceuticals, Inc.

nsomnia. Use of NSAIDs and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with meloxicam capsules until they talk to their healthcare provider [ see Drug Interactions ( 7 ) ]. LUPIN and the are registered trademarks of Lupin Pharmaceuticals, Inc. Manufactured for: Lupin Pharmaceuticals, Inc. Naples, FL 34108 United States Manufactured by: Lupin Limited Chhatrapati Sambhajinagar – 431 210 India Revised: November 2024 ID#: 275810 Image

Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Nonsteroidal Anti- inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: • Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: ο with increasing doses of NSAIDs ο with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a "coronary artery bypass graft (CABG)." Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. • Increased risk of bleeding, ulcers, and tears ( perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: ο anytime during use ο without warning symptoms ο that may cause death The risk of getting an ulcer or bleeding increases with: ο past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs ο taking medicines called "corticosteroids", "anticoagulants", "SSRIs", or "SNRIs" ο increasing doses of NSAIDs ο older age ο longer use of NSAIDs ο poor health ο smoking ο advanced liver disease ο drinking alcohol ο bleeding problems NSAIDs should only be used: ο exactly as prescribed ο at the lowest dose possible for your treatment ο for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. Who should not take NSAIDs? Do not take NSAIDs: • if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. • right before or after heart bypass surgery. Before taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you: • have liver or kidney problems • have high blood pressure • have asthma • are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy. • are breastfeeding or plan to breast feed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the- counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See "What is the most important information I should know about medicines called Nonsteroidal Anti- inflammatory Drugs (NSAIDs)?" • new or worse high blood pressure • heart failure • liver problems including liver failure • kidney problems including kidney failure • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness.

ailure • liver problems including liver failure • kidney problems including kidney failure • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms: • shortness of breath or trouble breathing • slurred speech • chest pain • swelling of the face or throat • weakness in one part or side of your body Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: • nausea • vomit blood • more tired or weaker than usual • there is blood in your bowel movement or it is black and sticky like tar • diarrhea • itching • unusual weight gain • your skin or eyes look yellow • skin rash or blisters with fever • indigestion or stomach pain • swelling of the arms, legs, hands and feet • flu-like symptoms If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs • Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. LUPIN and the are registered trademarks of Lupin Pharmaceuticals, Inc. Manufactured for: Lupin Pharmaceuticals, Inc. Naples, FL 34108 United States Manufactured by: Lupin Limited Chhatrapati Sambhajinagar – 431 210 India For more information, go to www.lupinpharmaceuticals.com or call Lupin Pharmaceuticals, Inc., at 1-800-399-2561. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: November 2024 ID#: 276173 Image

WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Risk Non-steroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [ see Warnings and Precautions ( 5.1 ) ]. QAMZOVA is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [ see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 ) ]. Gastrointestinal Risk NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during us e and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [ see Warnings and Precautions ( 5.2 ) ]. WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. Non-steroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction, and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use. ( 5.1 ) QAMZOVA is contraindicated in the setting of coronary artery bypass graft (CABG) surgery. ( 4 , 5.1 ) NSAIDs cause an increased risk of serious gastrointestinal (GI) 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 and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events. ( 5.2 )

1 INDICATIONS AND USAGE QAMZOVA is indicated for use in adults for the management of moderate-to-severe pain, alone or in combination with non-NSAID analgesics. Limitation of Use Because of delayed onset of analgesia, QAMZOVA alone is not recommended for use when rapid onset of analgesia is required. QAMZOVA contains meloxicam, which is an NSAID, and is indicated for use in adults for the management of moderate-to-severe pain, alone or in combination with non-NSAID analgesics. Limitation of Use Because of delayed onset of analgesia, QAMZOVA alone is not recommended for use when rapid onset of analgesia is required. ( 1 )

2 DOSAGE AND ADMINISTRATION Use for the shortest duration consistent with individual patient treatment goals [ see Warnings and Precautions ( 5 ) ]. For intravenous administration only. The recommended dose of QAMZOVA is 30 mg once daily, administered by intravenous bolus injection over 15 seconds. When initiating QAMZOVA, monitor patient analgesic response. Because the median time to meaningful pain relief was 2 and 3 hours after meloxicam injection administration in two clinical studies, a non-NSAID analgesic with a rapid onset of effect may be needed, for example, upon anesthetic emergence or resolution of local or regional anesthetic blocks [ see Clinical Studies ( 14) ] . Some patients may not experience adequate analgesia for the entire 24-hour dosing interval and may require administration of a short-acting, non-NSAID, immediate-release analgesic [ see Clinical Studies ( 14 ) ]. To reduce the risk of renal toxicity, patients must be well hydrated prior to administration of QAMZOVA. Visually inspect parenteral drug products for particulate matter and discoloration prior to administration. Should the contents appear discolored or contain particulate matter, discard the vial [ see Dosage Forms and Strengths ( 3 ) ]. Use for the shortest duration consistent with individual patient treatment goals. ( 2 ) The recommended dose is 30 mg once daily, administered by intravenous bolus injection over 15 seconds. ( 2 ) Monitor patient analgesic response and administer a short-acting, non-NSAID, immediate-release analgesic if response is inadequate. ( 2 ) Patients must be well hydrated before QAMZOVA administration. ( 2 )

3 DOSAGE FORMS AND STRENGTHS QAMZOVA (meloxicam) injection is a sterile, clear, greenish-yellow, non-pyrogenic, aqueous solution intended for intravenous use available as a clear, single-dose vial containing 30 mg/mL per vial. QAMZOVA (meloxicam) injection, single-dose vial containing 30 mg/mL per vial. ( 3 )

4 CONTRAINDICATIONS QAMZOVA is contraindicated in the following patients: Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to meloxicam or any components of the drug product [ see Warnings and Precautions ( 5.7 ) ]. History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal anaphylactic-like reactions to NSAIDs have been reported in such patients [ see Warnings and Precautions ( 5.8 ) ]. In the setting of coronary artery bypass graft (CABG) surgery [ see Warnings and Precautions ( 5.1 ) ]. Moderate to severe renal insufficiency patients who are at risk for renal failure due to volume depletion [ see Warnings and Precautions ( 5.6 ) ]. Known hypersensitivity to meloxicam or any components of the drug product. ( 4 ) History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. ( 4 ) In the setting of coronary artery bypass graft (CABG) surgery. ( 4 ) Moderate to severe renal insufficiency patients who are at risk for renal failure due to volume depletion. ( 4 )

5 WARNINGS AND PRECAUTIONS Hepatotoxicity : Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue QAMZOVA immediately if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop. ( 5.3 ) Hypertension : Patients taking some antihypertensive medications may have impaired response to these therapies when taking QAMZOVA. Monitor blood pressure. ( 5.4 , 7 ) Heart Failure and Edema : Avoid use of QAMZOVA in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure. ( 5.5 ) Renal Toxicity : Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of QAMZOVA in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function. ( 5.6 ) Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs. ( 5.7 ) Exacerbation of Asthma Related to Aspirin Sensitivity : QAMZOVA is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity). ( 5.8 ) Serious Skin Reactions : Discontinue QAMZOVA at first appearance of skin rash or other signs of hypersensitivity. ( 5.9 ) Drug Reaction with Eosinophilia and Systemic Symptoms (DRES S): Discontinue and evaluate clinically. ( 5.10 ) Hematologic Toxicity : Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia. ( 5.12 , 7 ) Fetal Toxicity : Limit use of NSAIDs, including QAMZOVA, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus. ( 5.11 , 8.1 ) 5.1 Cardiovascular 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, 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.

e 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 meloxicam, increases the risk of serious gastrointestinal (GI) events [ see Warnings and Precautions ( 5.2 ) ]. Status Post Coronary Artery Bypass Graft (CABG) Surgery 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 ( 4 ) ]. Post-MI Patients 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 QAMZOVA in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If QAMZOVA is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Effects- Risk of Ulceration, Bleeding, and Perforation NSAIDs, including meloxicam, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, 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 QAMZOVA. 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 occurred in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients: Use the lowest effective dosage for the shortest possible duration. Avoid administration of more than one NSAID at a time. Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.

ID at a time. Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue QAMZOVA until a serious GI adverse event is ruled out. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [ see Drug Interactions ( 7 ) ]. 5.3 Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including meloxicam. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue QAMZOVA immediately, and perform a clinical evaluation of the patient [ see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 ) ]. 5.4 Hypertension NSAIDs, including QAMZOVA, can lead to new onset of hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs [ see Drug Interactions ( 7 ) ]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.5 Heart Failure and Edema 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 meloxicam 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 ( 7 ) ]. Avoid the use of QAMZOVA in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If QAMZOVA is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis, renal insufficiency, acute renal failure, 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 may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation.

s 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 may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. QAMZOVA is not recommended in patients with moderate to severe renal insufficiency and is contraindicated in patients with moderate to severe renal insufficiency who are at risk for renal failure due to volume depletion. No information is available from controlled clinical studies regarding the use of QAMZOVA in patients with advanced renal disease. The renal effects of QAMZOVA may hasten the progression of renal dysfunction in patients with pre-existing renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating QAMZOVA. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of QAMZOVA [ see Drug Interactions ( 7 ) ]. Avoid the use of QAMZOVA in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If QAMZOVA is used in patients with advanced renal disease, monitor patients for signs of worsening renal function [ see Clinical Pharmacology ( 12.3 ) ]. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. 5.7 Anaphylactic Reactions Meloxicam has been associated with anaphylactic reactions in patients with and without known hypersensitivity to meloxicam and in patients with aspirin-sensitive asthma [ see Contraindications ( 4 ) and Warnings and Precautions ( 5.8 ) ]. Seek emergency help if an anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, QAMZOVA is contraindicated in patients with this form of aspirin sensitivity [ see Contraindications ( 4 ) ]. When QAMZOVA is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.9 Serious Skin Reactions NSAIDs, including QAMZOVA, 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. QAMZOVA is contraindicated in patients with previous serious skin reactions to NSAIDs [ see Contraindications ( 4 ) ]. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as QAMZOVA. Some of these events have been fatal or life-threatening.

evious serious skin reactions to NSAIDs [ see Contraindications ( 4 ) ]. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as QAMZOVA. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue QAMZOVA and evaluate the patient immediately. 5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including QAMZOVA, in pregnant women at about 30 weeks gestation and later. NSAIDs, including QAMZOVA, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including QAMZOVA, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit QAMZOVA use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if QAMZOVA treatment extends beyond 48 hours. Discontinue QAMZOVA if oligohydramnios occurs and follow up according to clinical practice [ see Use in Specific Populations ( 8.1 ) ] 5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with QAMZOVA has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including QAMZOVA, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [ see Drug Interactions ( 7 ) ]. 5.13 Masking of Inflammation and Fever The pharmacological activity of QAMZOVA in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.14 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [ see Warnings and Precautions ( 5.2 , 5.3 , 5.6 ) ]. QAMZOVA is not indicated for long-term treatment.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in the other sections of the labeling: Cardiovascular Thrombotic Events [ see Warnings and Precautions ( 5.1 ) ] GI Bleeding, Ulceration, and Perforation [ see Warnings and Precautions ( 5.2 ) ] Hepatotoxicity [ see Warnings and Precautions ( 5.3 ) ] Hypertension [ see Warnings and Precautions ( 5.4 ) ] Heart Failure and Edema [ see Warnings and Precautions ( 5.5 ) ] Renal Toxicity and Hyperkalemia [ see Warnings and Precautions ( 5.6 ) ] Anaphylactic Reactions [ see Warnings and Precautions ( 5.7 ) ] Serious Skin Reactions [ see Warnings and Precautions ( 5.9 ) ] Hematologic Toxicity [ see Warnings and Precautions ( 5.12 )] The most common adverse reactions (≥ 2% and greater than placebo) in controlled clinical trials include constipation, GGT increased, and anemia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Nanjing Delova Biotech Co., Ltd. at 1-844-406-8288 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience 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. During clinical development, 1426 patients were exposed to meloxicam injection in controlled and open-label Phase 2 and Phase 3 trials. Meloxicam injection was studied across a range of surgical procedures, including bunionectomy, abdominoplasty, soft tissue surgery, total knee replacement surgery, gynecologic surgery, complex foot surgery and total hip replacement surgery. In these trials, 381 patients received a single dose of meloxicam injection and 1045 patients received multiple doses of meloxicam injection daily for up to 7 days. The incidence rates of adverse reactions listed in Table 1 are derived from the three Phase 3 trials comparing meloxicam injection to placebo in patients who may have also received opioid rescue medication. Table 1: Proportion of Patients Experiencing Common Adverse Reactions in Placebo-Controlled Phase 3 Clinical Trials occurring in greater than or equal to 2% of Patients Treated with Meloxicam Injection and at a greater frequency than Placebo Meloxicam Injection Placebo Adverse Reaction N=748 N=393 Constipation 57 (7.6%) 24 (6.1%) Gamma-Glutamyl transferase Increased 21 (2.8%) 6 (1.5%) Anemia 18 (2.4%) 4 (1.0%) The following is a list of adverse drug reactions occurring in <2% of patients receiving meloxicam injection in clinical trials.

quency than Placebo Meloxicam Injection Placebo Adverse Reaction N=748 N=393 Constipation 57 (7.6%) 24 (6.1%) Gamma-Glutamyl transferase Increased 21 (2.8%) 6 (1.5%) Anemia 18 (2.4%) 4 (1.0%) The following is a list of adverse drug reactions occurring in <2% of patients receiving meloxicam injection in clinical trials. Table 2: Additional Adverse Reactions for Meloxicam Injection Body as a Whole asthenia, back pain, edema, fatigue, hyperthermia, infusion site reactions (including pain, pruritus, phlebitis and thrombosis), muscle spasms, noncardiac chest pain, pyrexia, vaginal discharge, weight decrease Central and Peripheral Nervous System disturbance in attention, migraine, presyncope, somnolence, syncope Gastrointestinal abdominal discomfort, abdominal distension, abdominal pain, diarrhea, dry mouth, epigastric discomfort, flatulence, frequent bowel movements, gastritis, gastroesophageal reflux, gastrointestinal pain, rectal hemorrhage Heart Rate and Rhythm tachycardia Hematologic increased bleeding time, neutropenia, thrombocytosis Infections and Infestations cellulitis, gastroenteritis, urinary tract infection, vulval abscess Liver and Biliary System liver function test abnormal Metabolic and Nutritional hypokalemia, hypomagnesemia Procedural Complications incision site hemorrhage, incision site rash, wound dehiscence, wound hematoma Psychiatric confusion, hallucination, insomnia Respiratory dyspnea, epistaxis, hypoxia, oropharyngeal pain Skin and Appendages contact dermatitis, ecchymosis, rash Urinary System pollakiuria, urinary retention 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of meloxicam. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions reported in worldwide post marketing experience or the literature include: acute urinary retention; agranulocytosis; alterations in mood (such as mood elevation); anaphylactoid reactions including shock; erythema multiforme; exfoliative dermatitis; interstitial nephritis; jaundice; liver failure; Stevens-Johnson syndrome; toxic epidermal necrolysis, and infertility female.

<table ID="table1" width="800px"><caption>Table 1: Proportion of Patients Experiencing Common Adverse Reactions in Placebo-Controlled Phase 3 Clinical Trials occurring in greater than or equal to 2% of Patients Treated with Meloxicam Injection and at a greater frequency than Placebo</caption><tbody><tr><td/><td><content styleCode="bold"> Meloxicam Injection </content></td><td><content styleCode="bold"> Placebo </content></td></tr><tr><td styleCode="Botrule"><content styleCode="bold">Adverse Reaction</content></td><td styleCode="Botrule"><content styleCode="bold"> N=748</content></td><td styleCode="Botrule"><content styleCode="bold"> N=393 </content></td></tr><tr><td> Constipation</td><td> 57 (7.6%)</td><td> 24 (6.1%)</td></tr><tr><td> Gamma-Glutamyl transferase Increased</td><td> 21 (2.8%)</td><td> 6 (1.5%)</td></tr><tr><td> Anemia</td><td> 18 (2.4%)</td><td> 4 (1.0%)</td></tr></tbody></table>

/td><td styleCode="Botrule"><content styleCode="bold"> N=393 </content></td></tr><tr><td> Constipation</td><td> 57 (7.6%)</td><td> 24 (6.1%)</td></tr><tr><td> Gamma-Glutamyl transferase Increased</td><td> 21 (2.8%)</td><td> 6 (1.5%)</td></tr><tr><td> Anemia</td><td> 18 (2.4%)</td><td> 4 (1.0%)</td></tr></tbody></table> <table ID="table2" width="800px"><caption>Table 2: Additional Adverse Reactions for Meloxicam Injection </caption><tbody><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Body as a Whole </content></td><td styleCode="Botrule Lrule Rrule Toprule">asthenia, back pain, edema, fatigue, hyperthermia, infusion site reactions (including pain, pruritus, phlebitis and thrombosis), muscle spasms, noncardiac chest pain, pyrexia, vaginal discharge, weight decrease</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Central and Peripheral Nervous System</content></td><td styleCode="Botrule Lrule Rrule Toprule">disturbance in attention, migraine, presyncope, somnolence, syncope</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Gastrointestinal</content></td><td styleCode="Botrule Lrule Rrule Toprule">abdominal discomfort, abdominal distension, abdominal pain, diarrhea, dry mouth, epigastric discomfort, flatulence, frequent bowel movements, gastritis, gastroesophageal reflux, gastrointestinal pain, rectal hemorrhage</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Heart Rate and Rhythm</content></td><td styleCode="Botrule Lrule Rrule Toprule">tachycardia</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Hematologic</content></td><td styleCode="Botrule Lrule Rrule Toprule">increased bleeding time, neutropenia, thrombocytosis</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Infections and Infestations</content></td><td styleCode="Botrule Lrule Rrule Toprule">cellulitis, gastroenteritis, urinary tract infection, vulval abscess</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Liver and Biliary System </content></td><td styleCode="Botrule Lrule Rrule Toprule">liver function test abnormal</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Metabolic and Nutritional</content></td><td styleCode="Botrule Lrule Rrule Toprule">hypokalemia, hypomagnesemia</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Procedural Complications</content></td><td styleCode="Botrule Lrule Rrule Toprule">incision site hemorrhage, incision site rash, wound dehiscence, wound hematoma</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Psychiatric</content></td><td styleCode="Botrule Lrule Rrule Toprule">confusion, hallucination, insomnia</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Respiratory</content></td><td styleCode="Botrule Lrule Rrule Toprule">dyspnea, epistaxis, hypoxia, oropharyngeal pain</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Skin and Appendages</content></td><td styleCode="Botrule Lrule Rrule Toprule">contact dermatitis, ecchymosis, rash</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Urinary System</content></td><td styleCode="Botrule Lrule Rrule Toprule">pollakiuria, urinary retention</td></tr></tbody></table>

7 DRUG INTERACTIONS See Table 3 for clinically significant drug interactions with meloxicam. Table 3: Clinically Significant Drug Interactions with Meloxicam Drugs That Interfere with Hemostasis Clinical Impact: Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of QAMZOVA with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions ( 5.12 ) ]. Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions ( 5.2 ) ]. Intervention: Concomitant use of QAMZOVA and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5.12 ) ]. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [ see Warnings and Precautions ( 5.2 ) ]. QAMZOVA is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: During concomitant use of QAMZOVA and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of QAMZOVA and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions ( 5.6 ) ]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect.

hat NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID 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. Intervention: During concomitant use of QAMZOVA with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions ( 5.6 ) ]. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [ see Clinical Pharmacology ( 12.3 ) ]. Intervention: During concomitant use of QAMZOVA and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of QAMZOVA and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of QAMZOVA and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of QAMZOVA and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions ( 5.2 ) ]. Intervention: The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of QAMZOVA and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of QAMZOVA and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended. CYP2C9 Inhibitors Clinical Impact: In vitro studies indicate that CYP2C9 (cytochrome P450 metabolizing enzyme) plays an important role in this metabolic pathway with a minor contribution of the CYP3A4 isozyme. Thus concomitant usage of CYP2C9 inhibitors (such as amiodarone, fluconazole, and sulphaphenazole) may lead to abnormally high plasma levels of meloxicam due to reduced metabolic clearance [ see Use in Specific Populations ( 8.8 ); and Clinical Pharmacology ( 12.3 , 12.5 ) ]. Intervention: Consider dose reduction in patients undergoing treatment with CYP2C9 inhibitors, and monitor patients for adverse effects. Drugs that Interfere with Hemostasis (e.g., warfarin, aspirin, SSRIs/SNRIs) : Monitor patients for bleeding who are concomitantly taking QAMZOVA with drugs that interfere with hemostasis. Concomitant use of QAMZOVA and analgesic doses of aspirin is not generally recommended. ( 7 ) ACE Inhibitors, Angiotensin Receptor Blockers (ARBs), or Beta-Blockers : Concomitant use with QAMZOVA may diminish the antihypertensive effect of these drugs. Monitor blood pressure.

with drugs that interfere with hemostasis. Concomitant use of QAMZOVA and analgesic doses of aspirin is not generally recommended. ( 7 ) ACE Inhibitors, Angiotensin Receptor Blockers (ARBs), or Beta-Blockers : Concomitant use with QAMZOVA may diminish the antihypertensive effect of these drugs. Monitor blood pressure. ( 7 ) ACE Inhibitors and ARBs : Concomitant use with QAMZOVA in elderly, volume-depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function. ( 7 ) Diuretics : NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects. ( 7 )

<table ID="table3" width="800px"><caption>Table 3: Clinically Significant Drug Interactions with Meloxicam </caption><tbody><tr><td colspan="2" styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Drugs That Interfere with Hemostasis</content></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Botrule Lrule Rrule Toprule"><list listType="unordered"><item>Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.</item><item>Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.</item></list></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="italics">Intervention:</content></td><td styleCode="Botrule Lrule Rrule Toprule">Monitor patients with concomitant use of QAMZOVA with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ <content styleCode="italics">see Warnings and Precautions ( <linkHtml href="#Lbf4e01a7-5a03-4f78-aa6d-627df6632520">5.12</linkHtml>) </content>]. </td></tr><tr><td colspan="2" styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Aspirin</content></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Botrule Lrule Rrule Toprule">Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ <content styleCode="italics">see Warnings and Precautions ( <linkHtml href="#L06d11851-1cf6-4ac8-b21b-800eba703205">5.2</linkHtml>) </content>]. </td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="italics">Intervention:</content></td><td styleCode="Botrule Lrule Rrule Toprule">Concomitant use of QAMZOVA and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ <content styleCode="italics">see Warnings and Precautions ( <linkHtml href="http://5.12%20Hematologic%20Toxicity">5.12</linkHtml>) </content>]. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [ <content styleCode="italics">see Warnings and Precautions ( <linkHtml href="#L06d11851-1cf6-4ac8-b21b-800eba703205">5.2</linkHtml>) </content>]. QAMZOVA is not a substitute for low dose aspirin for cardiovascular protection.

se aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [ <content styleCode="italics">see Warnings and Precautions ( <linkHtml href="#L06d11851-1cf6-4ac8-b21b-800eba703205">5.2</linkHtml>) </content>]. QAMZOVA is not a substitute for low dose aspirin for cardiovascular protection. </td></tr><tr><td colspan="2" styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers</content></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Botrule Lrule Rrule Toprule"><list listType="unordered"><item>NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).</item><item>In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.</item></list></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="italics">Intervention:</content></td><td styleCode="Botrule Lrule Rrule Toprule"><list listType="unordered"><item>During concomitant use of QAMZOVA and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.</item><item>During concomitant use of QAMZOVA and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ <content styleCode="italics">see Warnings and Precautions ( <linkHtml href="#Lc684c183-dce7-4d55-83ae-d22d70103760">5.6</linkHtml>) </content>]. </item><item>When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.</item></list></td></tr><tr><td colspan="2" styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Diuretics</content></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Botrule Lrule Rrule Toprule">Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID 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.</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="italics">Intervention:</content></td><td styleCode="Botrule Lrule Rrule Toprule">During concomitant use of QAMZOVA with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ <content styleCode="italics">see Warnings and Precautions ( <linkHtml href="#Lc684c183-dce7-4d55-83ae-d22d70103760">5.6</linkHtml>) </content>]. </td></tr><tr><td colspan="2" styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Lithium</content></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Botrule Lrule Rrule Toprule">NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance.

Rrule Toprule"><content styleCode="bold">Lithium</content></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Botrule Lrule Rrule Toprule">NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [ <content styleCode="italics">see Clinical Pharmacology ( <linkHtml href="#L56c8fad2-dbb5-4f98-8ebf-9c01aa7fc805">12.3</linkHtml>) </content>]. </td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="italics">Intervention:</content></td><td styleCode="Botrule Lrule Rrule Toprule">During concomitant use of QAMZOVA and lithium, monitor patients for signs of lithium toxicity.</td></tr><tr><td colspan="2" styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Methotrexate</content></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Botrule Lrule Rrule Toprule">Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="italics">Intervention:</content></td><td styleCode="Botrule Lrule Rrule Toprule">During concomitant use of QAMZOVA and methotrexate, monitor patients for methotrexate toxicity.</td></tr><tr><td colspan="2" styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Cyclosporine</content></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Botrule Lrule Rrule Toprule">Concomitant use of QAMZOVA and cyclosporine may increase cyclosporine&#x2019;s nephrotoxicity.</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="italics">Intervention:</content></td><td styleCode="Botrule Lrule Rrule Toprule">During concomitant use of QAMZOVA and cyclosporine, monitor patients for signs of worsening renal function.</td></tr><tr><td colspan="2" styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">NSAIDs and Salicylates</content></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Botrule Lrule Rrule Toprule">Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ <content styleCode="italics">see Warnings and Precautions ( <linkHtml href="#L06d11851-1cf6-4ac8-b21b-800eba703205">5.2</linkHtml>) </content>].

oprule">Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ <content styleCode="italics">see Warnings and Precautions ( <linkHtml href="#L06d11851-1cf6-4ac8-b21b-800eba703205">5.2</linkHtml>) </content>]. </td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="italics">Intervention:</content></td><td styleCode="Botrule Lrule Rrule Toprule">The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.</td></tr><tr><td colspan="2" styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Pemetrexed</content></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Botrule Lrule Rrule Toprule">Concomitant use of QAMZOVA and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="italics">Intervention:</content></td><td styleCode="Botrule Lrule Rrule Toprule">During concomitant use of QAMZOVA and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. <paragraph>Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.</paragraph><paragraph>In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.</paragraph></td></tr><tr><td colspan="2" styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">CYP2C9 Inhibitors</content></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="italics">In vitro</content>studies indicate that CYP2C9 (cytochrome P450 metabolizing enzyme) plays an important role in this metabolic pathway with a minor contribution of the CYP3A4 isozyme. Thus concomitant usage of CYP2C9 inhibitors (such as amiodarone, fluconazole, and sulphaphenazole) may lead to abnormally high plasma levels of meloxicam due to reduced metabolic clearance [ <content styleCode="italics">see Use in Specific Populations ( <linkHtml href="#Led6cb3ed-c503-4b0e-8163-4920c94e7687">8.8</linkHtml>); and Clinical Pharmacology ( <linkHtml href="#L56c8fad2-dbb5-4f98-8ebf-9c01aa7fc805">12.3</linkHtml>, <linkHtml href="#Led089e03-9a6b-4349-b03a-b67b68e1ff0a">12.5</linkHtml>) </content>]. </td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="italics">Intervention:</content></td><td styleCode="Botrule Lrule Rrule Toprule">Consider dose reduction in patients undergoing treatment with CYP2C9 inhibitors, and monitor patients for adverse effects.</td></tr></tbody></table>

8 USE IN SPECIFIC POPULATIONS Infertility : NSAIDs are associated with reversible infertility. Consider withdrawal of QAMZOVA in women who have difficulties conceiving. ( 8.3 ) 8.1 Pregnancy Risk Summary Use of NSAIDs, including QAMZOVA, 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 QAMZOVA use between about 20 and 30 weeks of gestation, and avoid QAMZOVA use at about 30 weeks of gestation and later in pregnancy ( see Clinical Considerations, Data ). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including QAMZOVA, 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 some cases, neonatal renal impairment. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, embryofetal death was observed in rats and rabbits treated during the period of organogenesis with meloxicam at oral doses equivalent to 0.32- and 3.24-times the maximum recommended human dose (MRHD) of 30 mg of QAMZOVA. Increased incidence of septal heart defects were observed in rabbits treated throughout embryogenesis with meloxicam at an oral dose equivalent to 39-times the MRHD. In pre- and post-natal reproduction studies, there was an increased incidence of dystocia, delayed parturition, and decreased offspring survival at 0.04-times the MRHD. No teratogenic effects were observed in rats and rabbits treated with meloxicam during organogenesis at an oral dose equivalent to 1.3- and 13-times the MRHD [ see Data ]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors, such as meloxicam, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including QAMZOVA, can cause premature closure of the fetal ductus arteriosus [ see Data ]. Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible.

ater in pregnancy, because NSAIDs, including QAMZOVA, can cause premature closure of the fetal ductus arteriosus [ see Data ]. Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If QAMZOVA treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue QAMZOVA and follow up according to clinical practice [ see Data ]. Labor or delivery There are no studies on the effects of meloxicam during labor or delivery. In animal studies, NSAIDs, including meloxicam, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal Data Meloxicam was not teratogenic when administered to pregnant rats during fetal organogenesis at oral doses up to 4 mg/kg/day (1.3-times the MRHD of 30 mg based on body surface area (BSA) comparison). Administration of meloxicam to pregnant rabbits throughout embryogenesis produced an increased incidence of septal defects of the heart at an oral dose of 60 mg/kg/day (39-times the MRHD based on BSA comparison). The no effect level was 20 mg/kg/day (13-times the MRHD based on BSA comparision). In rats and rabbits, embryolethality occurred at oral meloxicam doses of 1 mg/kg/day and 5 mg/kg/day, respectively (0.32- and 3.24-times, respectively, the MRHD based on BSA comparison) when administered throughout organogenesis. Oral administration of meloxicam to pregnant rats during late gestation through lactation increased the incidence of dystocia, delayed parturition, and decreased offspring survival at meloxicam doses of 0.125 mg/kg/day or greater (0.04-times the MRHD based on BSA comparison). 8.2 Lactation Risk Summary There are no human data available on whether meloxicam is present in human milk, or on the effects on breastfed infants, or on milk production.

delayed parturition, and decreased offspring survival at meloxicam doses of 0.125 mg/kg/day or greater (0.04-times the MRHD based on BSA comparison). 8.2 Lactation Risk Summary There are no human data available on whether meloxicam is present in human milk, or on the effects on breastfed infants, or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for QAMZOVA and any potential adverse effects on the breastfed infant from the QAMZOVA or from the underlying maternal condition. Data Animal Data Meloxicam was present in the milk of lactating rats at concentrations higher than those in plasma. 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including QAMZOVA, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including QAMZOVA, in women who have difficulties conceiving or who are undergoing investigation of infertility. Males QAMZOVA may compromise fertility in males of reproductive potential. In a published study, oral administration of meloxicam to male rats for 35 days resulted in decreased sperm count and motility and histopathological evidence of testicular degeneration at 0.3-times the MRHD based on BSA comparison [ see Nonclinical Toxicology ( 13.1 ) ]. It is not known if these effects on fertility are reversible. The clinical relevance of these findings is unknown. 8.4 Pediatric Use The safety and efficacy of QAMZOVA has not been established in pediatric patients. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks monitor patients for adverse effects [ see Warnings and Precautions ( 5.1 , 5.2 , 5.3 , 5.6 , 5.14 ) ]. Of the total number of patients in clinical studies of meloxicam injection, 197 patients were age 65 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. 8.6 Hepatic Impairment QAMZOVA has not been studied in patients with hepatic impairment. For oral meloxicam, no dose adjustment is necessary in patients with mild to moderate hepatic impairment. Since meloxicam is significantly metabolized in the liver and hepatotoxicity may occur, monitor for adverse events in patients with severe hepatic impairment [ see Warnings and Precautions ( 5.3 ) and Clinical Pharmacology ( 12.3 ) ]. 8.7 Renal Impairment Pharmacokinetics of meloxicam injection in elderly subjects with mild renal impairment is similar to healthy young subjects. Patients with moderate or severe renal impairment have not been studied. QAMZOVA is not recommended in patients with moderate to severe renal insufficiency. QAMZOVA is contraindicated in patients with moderate to severe renal insufficiency who are at risk for renal failure due to volume depletion [ see Contraindications ( 4 ), Warnings and Precautions ( 5.6 ) and Clinical Pharmacology ( 12.3 ) ].

A is not recommended in patients with moderate to severe renal insufficiency. QAMZOVA is contraindicated in patients with moderate to severe renal insufficiency who are at risk for renal failure due to volume depletion [ see Contraindications ( 4 ), Warnings and Precautions ( 5.6 ) and Clinical Pharmacology ( 12.3 ) ]. 8.8 Poor Metabolizers of CYP2C9 Substrates In patients who are known or suspected to be poor CYP2C9 metabolizers based on genotype or previous history/experience with other CYP2C9 substrates (such as warfarin and phenytoin) consider dose reduction as they may have abnormally high plasma levels due to reduced metabolic clearance, and monitor patients for adverse effects.

8.1 Pregnancy Risk Summary Use of NSAIDs, including QAMZOVA, 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 QAMZOVA use between about 20 and 30 weeks of gestation, and avoid QAMZOVA use at about 30 weeks of gestation and later in pregnancy ( see Clinical Considerations, Data ). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including QAMZOVA, 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 some cases, neonatal renal impairment. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, embryofetal death was observed in rats and rabbits treated during the period of organogenesis with meloxicam at oral doses equivalent to 0.32- and 3.24-times the maximum recommended human dose (MRHD) of 30 mg of QAMZOVA. Increased incidence of septal heart defects were observed in rabbits treated throughout embryogenesis with meloxicam at an oral dose equivalent to 39-times the MRHD. In pre- and post-natal reproduction studies, there was an increased incidence of dystocia, delayed parturition, and decreased offspring survival at 0.04-times the MRHD. No teratogenic effects were observed in rats and rabbits treated with meloxicam during organogenesis at an oral dose equivalent to 1.3- and 13-times the MRHD [ see Data ]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors, such as meloxicam, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including QAMZOVA, can cause premature closure of the fetal ductus arteriosus [ see Data ]. Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If QAMZOVA treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue QAMZOVA and follow up according to clinical practice [ see Data ].

eks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If QAMZOVA treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue QAMZOVA and follow up according to clinical practice [ see Data ]. Labor or delivery There are no studies on the effects of meloxicam during labor or delivery. In animal studies, NSAIDs, including meloxicam, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal Data Meloxicam was not teratogenic when administered to pregnant rats during fetal organogenesis at oral doses up to 4 mg/kg/day (1.3-times the MRHD of 30 mg based on body surface area (BSA) comparison). Administration of meloxicam to pregnant rabbits throughout embryogenesis produced an increased incidence of septal defects of the heart at an oral dose of 60 mg/kg/day (39-times the MRHD based on BSA comparison). The no effect level was 20 mg/kg/day (13-times the MRHD based on BSA comparision). In rats and rabbits, embryolethality occurred at oral meloxicam doses of 1 mg/kg/day and 5 mg/kg/day, respectively (0.32- and 3.24-times, respectively, the MRHD based on BSA comparison) when administered throughout organogenesis. Oral administration of meloxicam to pregnant rats during late gestation through lactation increased the incidence of dystocia, delayed parturition, and decreased offspring survival at meloxicam doses of 0.125 mg/kg/day or greater (0.04-times the MRHD based on BSA comparison).

8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks monitor patients for adverse effects [ see Warnings and Precautions ( 5.1 , 5.2 , 5.3 , 5.6 , 5.14 ) ]. Of the total number of patients in clinical studies of meloxicam injection, 197 patients were age 65 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients.

10 OVERDOSAGE Symptoms following acute NSAID overdoses have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression and coma have occurred, but were rare [ see Warnings and Precautions ( 5.1 , 5.2 , 5.4 , 5.6 ) ]. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may be employed but are not likely to be useful due to high protein binding. There is limited experience with meloxicam overdose. In four reported cases of meloxicam overdose, patients took 6 to 11 times the highest available oral dose of meloxicam tablets (15 mg); all recovered. Cholestyramine is known to accelerate the clearance of meloxicam. Accelerated removal of meloxicam by 4 g doses of cholestyramine given three times a day was demonstrated in a clinical trial. Administration of cholestyramine may be useful following an overdosage. In case of an overdosage, discontinue QAMZOVA therapy and contact a regional poison control center at 1-800-222-1222.

11 DESCRIPTION QAMZOVA contains meloxicam, which is a nonsteroidal anti-inflammatory drug (NSAID). It is a sterile clear, greenish-yellow, aqueous solution containing the active pharmaceutical ingredient meloxicam for intravenous administration. Each mL of aqueous solution contains 30 mg of meloxicam and 300 mg of polyethylene glycol 400 in water for injection. The pH of the solution is adjusted with sodium hydroxide and citric acid monohydrate if necessary. The solution pH ranges from 7.4 to 8.4. Meloxicam is a pale yellow powder, practically insoluble in water, slightly soluble in acetone, soluble in dimethylformamide, and very slightly soluble in methanol and in alcohol. Meloxicam is designated chemically as 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2- benzothiazine-3-carboxamide-1,1-dioxide. The molecular weight is 351.4. Its molecular formula is C14H13N3O4S2 and the structural formula of meloxicam is: Figure 1: Structural Formula of Meloxicam Figure 1: Structural Formula of Meloxicam

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Meloxicam has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of meloxicam, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Meloxicam is a potent inhibitor of prostaglandin synthesis in vitro . Meloxicam concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because meloxicam is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. 12.2 Pharmacodynamics Cardiac Electrophysiology The effect of meloxicam injection on QTc prolongation was evaluated in a randomized, double-blind, placebo-controlled crossover study in healthy subjects. A total of 48 subjects were administered intravenous meloxicam 30 mg, 120 mg, and 180 mg. In a study with demonstrated ability to detect small effects, the upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline- corrected QTc based on Fridericia correction method (QTcF) was below 10 ms, the threshold for regulatory concern. 12.3 Pharmacokinetics Absorption Following intravenous administration of meloxicam injection to healthy volunteers, plasma concentrations of 30 mg meloxicam injection exceed that of 15 mg oral meloxicam for the first 24 hours. The single-dose pharmacokinetics of meloxicam following intravenous administration of QAMZOVA are presented in Table 4 . Table 4: Single-Dose Pharmacokinetics of QAMZOVA Injection QAMZOVA 30 mg IV Parameter C max (ng/mL) 6667.2±984.0 T max (h) 0.10±0.04 AUC inf (ng*hr/mL) 102301.5±31999.9 T ½ (h) 21.1±6.2 Following multiple dosing, QAMZOVA is predicted to have slightly higher than 2-fold accumulation without a change in the terminal elimination half-life. Meloxicam injection exhibits linear pharmacokinetics over intravenous doses ranging from 15 mg to 180 mg. Distribution Following administration of meloxicam injection, the apparent volume of distribution during the terminal elimination phase (Vz) of meloxicam is 9.63 L. Meloxicam is ~99.4% bound to human plasma proteins (primarily albumin) within the therapeutic dose range. The fraction of protein binding is independent of drug concentration, over the clinically relevant concentration range, but decreases to ~99% in patients with renal disease. Meloxicam penetration into human red blood cells, after oral dosing, is less than 10%. Following a radiolabeled dose, over 90% of the radioactivity detected in the plasma was present as unchanged meloxicam. Meloxicam concentrations in synovial fluid, after a single oral dose, range from 40% to 50% of those in plasma. The free fraction in synovial fluid is 2.5 times higher than in plasma, due to the lower albumin content in synovial fluid as compared to plasma. The significance of this penetration is unknown. Elimination Metabolism Meloxicam is extensively metabolized in the liver. Meloxicam metabolites include 5'-carboxy meloxicam (60% of dose), from P-450 mediated metabolism formed by oxidation of an intermediate metabolite 5'-hydroxymethyl meloxicam which is also excreted to a lesser extent (9% of dose).

tion is unknown. Elimination Metabolism Meloxicam is extensively metabolized in the liver. Meloxicam metabolites include 5'-carboxy meloxicam (60% of dose), from P-450 mediated metabolism formed by oxidation of an intermediate metabolite 5'-hydroxymethyl meloxicam which is also excreted to a lesser extent (9% of dose). In vitro studies indicate that CYP2C9 (cytochrome P450 metabolizing enzyme) plays an important role in this metabolic pathway with a minor contribution of the CYP3A4 isozyme. Patients’ peroxidase activity is probably responsible for the other two metabolites which account for 16% and 4% of the administered dose, respectively. The four metabolites are not known to have any in vivo pharmacological activity. Excretion Meloxicam excretion is predominantly in the form of metabolites, and occurs to equal extents in the urine and feces. Only traces of the unchanged parent compound are excreted in the urine (0.2%) and feces (1.6%). The extent of the urinary excretion was confirmed for unlabeled multiple 7.5 mg doses: 0.5%, 6%, and 13% of the dose were found in urine in the form of meloxicam, and the 5'-hydroxymethyl and 5'-carboxy metabolites, respectively. There is significant biliary and/or enteral secretion of the drug. This was demonstrated when oral administration of cholestyramine following a single IV dose of meloxicam decreased the AUC of meloxicam by 50%. The mean elimination half-life (t 1/2 ) for QAMZOVA 30 mg is approximately 21 hours. Specific Populations Based on population pharmacokinetics analyses, age, sex and race do not have a clinically meaningful effect on the PK of meloxicam injection. Hepatic Impairment : The pharmacokinetics of QAMZOVA have not been investigated in patients with hepatic impairment. However, following a single 15 mg dose of meloxicam tablets there was no marked difference in plasma concentrations in patients with mild (Child-Pugh Class I) or moderate (Child-Pugh Class II) hepatic impairment compared to healthy volunteers. Protein binding of meloxicam was not affected by hepatic impairment. No dosage adjustment is necessary in patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment (Child-Pugh Class III) have not been adequately studied. Monitor for adverse events when used in patients with severe hepatic impairment [ see Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.6 ) ]. Renal Impairment : Meloxicam injection pharmacokinetics have been investigated in elderly subjects with mild renal impairment (eGFR 60 - 90) compared to young healthy volunteers. A 5% and 7% increase of Cmax and AUC, respectively, was observed in elderly subjects with mild renal impairment. No dosage adjustment is necessary in patients with mild renal impairment. Patients with moderate and severe renal impairment have not been adequately studied. The use of QAMZOVA in patients with moderate to severe renal impairment is not recommended. QAMZOVA is contraindicated in patients with moderate to severe renal insufficiency who are at risk for renal failure due to volume depletion [ see Contraindications ( 4 ), Warnings and Precautions ( 5.6 ), Use in Specific Populations ( 8.7 ) ]. Drug Interaction Studies Aspirin : When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 3 clinically significant drug interactions of NSAIDs with aspirin [ see Drug Interactions ( 7 ) ]. Cholestyramine : Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t 1/2 , from 19.2 hours to 12.5 hours, and a 35% reduction in AUC.

3 clinically significant drug interactions of NSAIDs with aspirin [ see Drug Interactions ( 7 ) ]. Cholestyramine : Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t 1/2 , from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine : Concomitant administration of 200 mg cimetidine four times daily did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin : Meloxicam tablets 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after β-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam [ see Drug Interactions ( 7 ) ]. Lithium : 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 tablets 15 mg once per day every day as compared to subjects receiving lithium alone [ see Drug Interactions ( 7 ) ]. Methotrexate : A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple oral doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro , methotrexate did not displace meloxicam from its human serum binding sites [ see Drug Interactions ( 7 ) ]. Warfarin : The effect of meloxicam tablets on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering QAMZOVA 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 Drug Interactions ( 7 ) ]. 12.5 Pharmacogenomics CYP2C9 activity is reduced in individuals with genetic variants such as CYP2C9*2 and CYP2C9*3 polymorphisms. Limited data from three published reports showed that meloxicam AUC was substantially higher in individuals with reduced CYP2C9 activity, particularly in poor metabolizers (e.g., *3/*3), compared to normal metabolizers (*1/*1). The frequency of CYP2C9 poor metabolizer genotypes varies based on racial/ethnic background but is generally present in <5% of the population.

12.2 Pharmacodynamics Cardiac Electrophysiology The effect of meloxicam injection on QTc prolongation was evaluated in a randomized, double-blind, placebo-controlled crossover study in healthy subjects. A total of 48 subjects were administered intravenous meloxicam 30 mg, 120 mg, and 180 mg. In a study with demonstrated ability to detect small effects, the upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline- corrected QTc based on Fridericia correction method (QTcF) was below 10 ms, the threshold for regulatory concern.

12.3 Pharmacokinetics Absorption Following intravenous administration of meloxicam injection to healthy volunteers, plasma concentrations of 30 mg meloxicam injection exceed that of 15 mg oral meloxicam for the first 24 hours. The single-dose pharmacokinetics of meloxicam following intravenous administration of QAMZOVA are presented in Table 4 . Table 4: Single-Dose Pharmacokinetics of QAMZOVA Injection QAMZOVA 30 mg IV Parameter C max (ng/mL) 6667.2±984.0 T max (h) 0.10±0.04 AUC inf (ng*hr/mL) 102301.5±31999.9 T ½ (h) 21.1±6.2 Following multiple dosing, QAMZOVA is predicted to have slightly higher than 2-fold accumulation without a change in the terminal elimination half-life. Meloxicam injection exhibits linear pharmacokinetics over intravenous doses ranging from 15 mg to 180 mg. Distribution Following administration of meloxicam injection, the apparent volume of distribution during the terminal elimination phase (Vz) of meloxicam is 9.63 L. Meloxicam is ~99.4% bound to human plasma proteins (primarily albumin) within the therapeutic dose range. The fraction of protein binding is independent of drug concentration, over the clinically relevant concentration range, but decreases to ~99% in patients with renal disease. Meloxicam penetration into human red blood cells, after oral dosing, is less than 10%. Following a radiolabeled dose, over 90% of the radioactivity detected in the plasma was present as unchanged meloxicam. Meloxicam concentrations in synovial fluid, after a single oral dose, range from 40% to 50% of those in plasma. The free fraction in synovial fluid is 2.5 times higher than in plasma, due to the lower albumin content in synovial fluid as compared to plasma. The significance of this penetration is unknown. Elimination Metabolism Meloxicam is extensively metabolized in the liver. Meloxicam metabolites include 5'-carboxy meloxicam (60% of dose), from P-450 mediated metabolism formed by oxidation of an intermediate metabolite 5'-hydroxymethyl meloxicam which is also excreted to a lesser extent (9% of dose). In vitro studies indicate that CYP2C9 (cytochrome P450 metabolizing enzyme) plays an important role in this metabolic pathway with a minor contribution of the CYP3A4 isozyme. Patients’ peroxidase activity is probably responsible for the other two metabolites which account for 16% and 4% of the administered dose, respectively. The four metabolites are not known to have any in vivo pharmacological activity. Excretion Meloxicam excretion is predominantly in the form of metabolites, and occurs to equal extents in the urine and feces. Only traces of the unchanged parent compound are excreted in the urine (0.2%) and feces (1.6%). The extent of the urinary excretion was confirmed for unlabeled multiple 7.5 mg doses: 0.5%, 6%, and 13% of the dose were found in urine in the form of meloxicam, and the 5'-hydroxymethyl and 5'-carboxy metabolites, respectively. There is significant biliary and/or enteral secretion of the drug. This was demonstrated when oral administration of cholestyramine following a single IV dose of meloxicam decreased the AUC of meloxicam by 50%. The mean elimination half-life (t 1/2 ) for QAMZOVA 30 mg is approximately 21 hours. Specific Populations Based on population pharmacokinetics analyses, age, sex and race do not have a clinically meaningful effect on the PK of meloxicam injection. Hepatic Impairment : The pharmacokinetics of QAMZOVA have not been investigated in patients with hepatic impairment.

QAMZOVA 30 mg is approximately 21 hours. Specific Populations Based on population pharmacokinetics analyses, age, sex and race do not have a clinically meaningful effect on the PK of meloxicam injection. Hepatic Impairment : The pharmacokinetics of QAMZOVA have not been investigated in patients with hepatic impairment. However, following a single 15 mg dose of meloxicam tablets there was no marked difference in plasma concentrations in patients with mild (Child-Pugh Class I) or moderate (Child-Pugh Class II) hepatic impairment compared to healthy volunteers. Protein binding of meloxicam was not affected by hepatic impairment. No dosage adjustment is necessary in patients with mild to moderate hepatic impairment. Patients with severe hepatic impairment (Child-Pugh Class III) have not been adequately studied. Monitor for adverse events when used in patients with severe hepatic impairment [ see Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.6 ) ]. Renal Impairment : Meloxicam injection pharmacokinetics have been investigated in elderly subjects with mild renal impairment (eGFR 60 - 90) compared to young healthy volunteers. A 5% and 7% increase of Cmax and AUC, respectively, was observed in elderly subjects with mild renal impairment. No dosage adjustment is necessary in patients with mild renal impairment. Patients with moderate and severe renal impairment have not been adequately studied. The use of QAMZOVA in patients with moderate to severe renal impairment is not recommended. QAMZOVA is contraindicated in patients with moderate to severe renal insufficiency who are at risk for renal failure due to volume depletion [ see Contraindications ( 4 ), Warnings and Precautions ( 5.6 ), Use in Specific Populations ( 8.7 ) ]. Drug Interaction Studies Aspirin : When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 3 clinically significant drug interactions of NSAIDs with aspirin [ see Drug Interactions ( 7 ) ]. Cholestyramine : Pretreatment for four days with cholestyramine significantly increased the clearance of meloxicam by 50%. This resulted in a decrease in t 1/2 , from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This suggests the existence of a recirculation pathway for meloxicam in the gastrointestinal tract. The clinical relevance of this interaction has not been established. Cimetidine : Concomitant administration of 200 mg cimetidine four times daily did not alter the single-dose pharmacokinetics of 30 mg meloxicam. Digoxin : Meloxicam tablets 15 mg once daily for 7 days did not alter the plasma concentration profile of digoxin after β-acetyldigoxin administration for 7 days at clinical doses. In vitro testing found no protein binding drug interaction between digoxin and meloxicam [ see Drug Interactions ( 7 ) ]. Lithium : 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 tablets 15 mg once per day every day as compared to subjects receiving lithium alone [ see Drug Interactions ( 7 ) ]. Methotrexate : A study in 13 rheumatoid arthritis (RA) patients evaluated the effects of multiple oral doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro , methotrexate did not displace meloxicam from its human serum binding sites [ see Drug Interactions ( 7 ) ].

fects of multiple oral doses of meloxicam on the pharmacokinetics of methotrexate taken once weekly. Meloxicam did not have a significant effect on the pharmacokinetics of single doses of methotrexate. In vitro , methotrexate did not displace meloxicam from its human serum binding sites [ see Drug Interactions ( 7 ) ]. Warfarin : The effect of meloxicam tablets on the anticoagulant effect of warfarin was studied in a group of healthy subjects receiving daily doses of warfarin that produced an INR (International Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam did not alter warfarin pharmacokinetics and the average anticoagulant effect of warfarin as determined by prothrombin time. However, one subject showed an increase in INR from 1.5 to 2.1. Caution should be used when administering QAMZOVA 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 Drug Interactions ( 7 ) ].

<table width="800px"><caption>Table 4: Single-Dose Pharmacokinetics of QAMZOVA Injection</caption><tbody><tr><td/><td align="center">QAMZOVA</td></tr><tr><td styleCode="Botrule"/><td align="center" styleCode="Botrule">30 mg IV</td></tr><tr><td><content styleCode="bold">Parameter</content></td><td/></tr><tr><td>C _max(ng/mL) </td><td align="center">6667.2&#xB1;984.0</td></tr><tr><td>T _max(h) </td><td align="center">0.10&#xB1;0.04</td></tr><tr><td>AUC _inf(ng*hr/mL) </td><td align="center">102301.5&#xB1;31999.9</td></tr><tr><td>T _&#xBD;(h) </td><td align="center">21.1&#xB1;6.2</td></tr></tbody></table>

12.5 Pharmacogenomics CYP2C9 activity is reduced in individuals with genetic variants such as CYP2C9*2 and CYP2C9*3 polymorphisms. Limited data from three published reports showed that meloxicam AUC was substantially higher in individuals with reduced CYP2C9 activity, particularly in poor metabolizers (e.g., *3/*3), compared to normal metabolizers (*1/*1). The frequency of CYP2C9 poor metabolizer genotypes varies based on racial/ethnic background but is generally present in <5% of the population.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis There was no increase in tumor incidence in long-term carcinogenicity studies in rats (104 weeks) and mice (99 weeks) administered meloxicam at oral doses up to 0.8 mg/kg/day in rats and up to 8.0 mg/kg/day in mice (up to 0.26- and 1.3-times, respectively, the MRHD of 30 mg/day of QAMZOVA based on BSA comparison). Mutagenesis Meloxicam was not mutagenic in an Ames assay. Meloxicam was not clastogenic in a chromosome aberration assay with human lymphocytes and an in vivo micronucleus test in mouse bone marrow. Impairment of Fertility Meloxicam did not impair male and female fertility in rats at oral doses up to 9 mg/kg/day in males and 5 mg/kg/day in females (up to 2.9- and 1.6-times, respectively, the MRHD based on BSA comparison). In a published study, oral administration of 1 mg/kg (0.3-times the MRHD based on BSA comparison) meloxicam to male rats for 35 days resulted in decreased sperm count and motility and histopathological evidence of testicular degeneration. The clinical relevance of these findings is unknown.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis There was no increase in tumor incidence in long-term carcinogenicity studies in rats (104 weeks) and mice (99 weeks) administered meloxicam at oral doses up to 0.8 mg/kg/day in rats and up to 8.0 mg/kg/day in mice (up to 0.26- and 1.3-times, respectively, the MRHD of 30 mg/day of QAMZOVA based on BSA comparison). Mutagenesis Meloxicam was not mutagenic in an Ames assay. Meloxicam was not clastogenic in a chromosome aberration assay with human lymphocytes and an in vivo micronucleus test in mouse bone marrow. Impairment of Fertility Meloxicam did not impair male and female fertility in rats at oral doses up to 9 mg/kg/day in males and 5 mg/kg/day in females (up to 2.9- and 1.6-times, respectively, the MRHD based on BSA comparison). In a published study, oral administration of 1 mg/kg (0.3-times the MRHD based on BSA comparison) meloxicam to male rats for 35 days resulted in decreased sperm count and motility and histopathological evidence of testicular degeneration. The clinical relevance of these findings is unknown.

14 CLINICAL STUDIES The efficacy and safety of meloxicam injection in the treatment of moderate to severe pain was evaluated in two Phase 3 randomized, double-blind, placebo-controlled, multiple-dose clinical trials in patients with postoperative pain. In both trials, oral oxycodone 5 mg was permitted as rescue medication for pain management. Study 1 (Bunionectomy Surgery) In the first controlled, multiple-dose trial (NCT02675907) of adult patients with postoperative pain who underwent bunionectomy surgery, 201 patients were treated with meloxicam injection 30 mg or placebo administered once daily for two days starting on the day after surgery. An optional third dose was permitted just prior to discharge. A minimum postoperative baseline pain intensity of 4 on the Numeric Pain Rating Scale (NPRS) (range 0-10) and pain categorized as moderate or severe were required for randomization. The majority of patients were female (85%). The average age was 48 years. The mean overall baseline pain intensity on the NPRS was 6.8. A statistically significant difference demonstrating efficacy was observed in the primary efficacy endpoint of the summed pain intensity difference over the first 48 hours (SPID48). The average pain intensity over time is depicted for the treatment groups in Figure 2 . A generally consistent separation in pain scores between meloxicam injection and placebo groups was observed from time of onset through most of the dosing interval with a narrowing at the end of the first 24-hour dosing interval. Figure 2 Study 2 (Abdominoplasty Surgery) In the second controlled, multiple-dose trial (NCT02678286) of adult patients with postoperative pain who underwent elective abdominoplasty surgery, 219 patients were treated with meloxicam injection 30 mg or placebo administered once daily for two days starting on the day of surgery. An optional third dose was permitted just prior to discharge. A minimum postoperative baseline pain intensity of 4 on the NPRS (range 0-10) and pain categorized as moderate or severe were required for randomization. The majority of patients were female (98%). The average age was 40 years. The mean overall baseline pain intensity on the NPRS was 7.3. A statistically significant difference demonstrating efficacy was observed in the primary efficacy endpoint of the summed pain intensity difference over the first 24 hours (SPID24) as well as over the first 48 hours (SPID48). The average pain intensity over time is depicted for the treatment groups in Figure 3 . A generally consistent separation in pain scores between the meloxicam injection and placebo group was observed from time of onset through most of the dosing interval with a narrowing at the end of the first 24-hour dosing interval. Figure 3 Onset of Meaningful Pain Relief and Use of Rescue Analgesic Medication The median time to first rescue analgesic use in patients treated with meloxicam injection (2 hours in Study 1 and 1 hour in Study 2) came before the median time to patient-reported meaningful pain relief in both studies (2 hours in Study 1 and 3 hours in Study 2). Fifty percent of patients treated with meloxicam injection and 49% of patients treated with placebo in Study 1 received rescue analgesia medication in the first 2 hours after the start of dosing. Seventy-eight percent of patients treated with meloxicam injection and 78% of patients treated with placebo in Study 2 received rescue in the first 3 hours after the start of dosing.

and 49% of patients treated with placebo in Study 1 received rescue analgesia medication in the first 2 hours after the start of dosing. Seventy-eight percent of patients treated with meloxicam injection and 78% of patients treated with placebo in Study 2 received rescue in the first 3 hours after the start of dosing. figure 2 figure 3

16 HOW SUPPLIED/STORAGE AND HANDLING QAMZOVA (meloxicam) injection, is a clear, greenish-yellow aqueous solution intended for intravenous use supplied as a 1 mL fill (30 mg/mL) in a clear single-dose vial with a blue flip-off cap. Single-dose vial: NDC 82972-001-30

17 PATIENT COUNSELING INFORMATION Inform patients of the following information before initiating therapy with QAMZOVA. Cardiovascular Thrombotic Effects Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their healthcare provider immediately[ see Warnings and Precautions ( 5.1 ) ]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their healthcare provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for the signs and symptoms of GI bleeding [ see Warnings and Precautions ( 5.2 ) ]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, instruct patients to stop QAMZOVA and seek immediate medical therapy [ see Warnings and Precautions ( 5.3 ) ]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [ see Warnings and Precautions ( 5.5 ) ]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [ see Contraindications ( 4 ) and Warnings and Precautions ( 5.7 ) ]. Serious Skin Reactions including DRESS Advise patients to stop taking QAMZOVA immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [ see Warnings and Precautions ( 5.9 , 5.10 ) ]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including QAMZOVA, may be associated with a reversible delay in ovulation [ see Use in Specific Populations ( 8.3 ) ]. Fetal Toxicity Inform pregnant women to avoid use of QAMZOVA and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with QAMZOVA is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [ see Warnings and Precautions ( 5.11 ) and Use in Specific Populations ( 8.1 ) ]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of QAMZOVA with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [ see Warnings and Precautions ( 5.2 ) and Drug Interactions ( 7 ) ]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDs and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with QAMZOVA until they talk to their healthcare provider [ see Drug Interactions ( 7 ) ]. This PRESCRIBING INFORMATION has been approved by the US Food and Drug Administration. Manufactured for: Nanjing Delova Biotech Co., Ltd.

se of NSAIDs and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with QAMZOVA until they talk to their healthcare provider [ see Drug Interactions ( 7 ) ]. This PRESCRIBING INFORMATION has been approved by the US Food and Drug Administration. Manufactured for: Nanjing Delova Biotech Co., Ltd. Nanjing, Jiangsu 210042, China Made in China Prescribing Information issued: April 2025