MELOXICAM- meloxicam_tablet

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 in vivo 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 Table 5 Single Dose and Steady-State Pharmacokinetic Parameters for Oral 7. 5 mg and 15 mg Meloxicam (Mean and % CV) 1 Steady State Single Dose Pharmacokinetic Parameters (% CV) Healthy male adults (Fed) 2 Elderly males (Fed) 2 Elderly females (Fed) 2 Renal failure (Fasted) Hepatic insufficiency (Fasted) 7. 5 mg 3 15 mg capsules 15 mg capsules 15 mg capsules 15 mg capsules N 18 5 8 12 12 C max 1. 84 (29) t max 4. 9 (8) 5 (12) 6 (27) 4 (65) 10 (87) t 1/2 20. 1 (29) 21 (34) 24 (34) 18 (46) 16 (29) CL/f [mL/min] 8. 1 (22) 19 (43) 11 (44) V z 4 14. 7 (32) 15 (42) 10 (30) 26 (44) 14 (29) 1. z 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. , C max max 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 in vivo 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. 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 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 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 max,ss 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. 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 max 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. 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. 7 Hemodialysis Following a single dose of meloxicam, the free C max see Dosage and Administration ( 2. 7 Drug Interaction Studies Aspirin: max see Drug Interactions ( 7. Cholestyramine: 1/2 Cimetidine: Digoxin: In vitro Lithium: see Drug Interactions ( 7 Methotrexate: In vitro see Drug Interactions ( 7 Warfarin: see Drug Interactions ( 7.

Meloxicam tablets are a non-steroidal anti-inflammatory drug indicated for: 1. 3 Meloxicam tablets are indicated for relief of the signs and symptoms of osteoarthritis [ see Clinical Studies ( 14. 1 Meloxicam tablets are indicated for relief of the signs and symptoms of rheumatoid arthritis[ see Clinical Studies ( 14. 1 Meloxicam tablets are 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.

1 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. Meloxicam may be taken without regard to timing of meals. 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. For the relief of the signs and symptoms of rheumatoid arthritis, the recommended starting and maintenance oral dose of meloxicam is 7. 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. 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.

1 To report SUSPECTED ADVERSE REACTIONS, contact Glenmark Pharmaceuticals Inc. , USA at 1 (888) 721-7115 or FDA at 1-800-FDA-1088 or www. gov/medwatch. The following adverse reactions are discussed in greater detail in other sections of the labeling: see Boxed Warning and Warnings and Precautions ( 5. 1 see Boxed Warning and Warnings and Precautions ( 5. 2 see Warnings and Precautions ( 5. 3 see Warnings and Precautions ( 5. 4 see Warnings and Precautions ( 5. 5 [see Warnings and Precautions ( 5. 6 see Warnings and Precautions ( 5. 7 see Warnings and Precautions ( 5. 9 see Warnings and Precautions ( 5. 10 see Warnings and Precautions ( 5. 11 see Warnings and Precautions ( 5. 12 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 Placebo Meloxicam 7. 5 mg daily Meloxicam 15 mg daily Diclofenac 100 mg daily No. of Patients 157 154 156 153 Gastrointestinal 17. 1 Abdominal pain 2. 3 Diarrhea 3. 2 Dyspepsia 4. 5 Flatulence 4. 2 Body as a Whole Accident household 1. 6 Edema 1 2. 3 Influenza-like symptoms 5. 6 Central and Peripheral Nervous System Dizziness 3. 8 2 Headache 10. 9 Respiratory Pharyngitis 1. 3 Upper respiratory tract infection 1. 3 Skin Rash 2 2. WHO preferred terms edema, edema dependent, edema peripheral, and edema legs combined 2. WHO preferred terms rash, rash erythematous, and rash maculo-papular combined Table 2b Adverse Events (%) Occurring in >=2% of Meloxicam Patients in two 12-Week Rheumatoid Arthritis Placebo-Controlled Trials Placebo Meloxicam 7. 5 mg daily Meloxicam 15 mg daily No. of Patients 469 481 477 Gastrointestinal Disorders 14. 8 Abdominal pain NOS 2 0. 3 Dyspeptic signs and symptoms 1 3. 8 4 Nausea 2 2. 8 General Disorders and Administration Site Conditions Influenza-like illness 2 2. 3 Infection and Infestations Upper respiratory tract infections-pathogen class unspecified 1 4. 5 Musculoskeletal and Connective Tissue Disorders Joint related signs and symptoms 1 1. 3 Nervous System Disorders Headaches NOS 2 6. 5 Skin and Subcutaneous Tissue Disorders Rash NOS 2 1. 1 1 2 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 3 Adverse Events (%) Occurring in >=2% of Meloxicam Patients in 4 to 6 Weeks and 6 Month Active-Controlled Osteoarthritis Trials 4 to 6 Weeks Controlled Trials 6 Month Controlled Trials Meloxicam 7. 5 mg daily Meloxicam 15 mg daily Meloxicam 7. of Patients 8955 256 169 306 Gastrointestinal 11. 6 Body as a Whole 0 0 0. 2 Central and Peripheral Nervous System 1. 6 Hematologic 0. 9 Musculoskeletal 0. 7 Psychiatric 0. 6 Respiratory 0. 3 Urinary 0. 9 1 2 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. 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 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. 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.

Meloxicam tablets are contraindicated in the following patients: see Warnings and Precautions ( 5. 9 see Warnings and Precautions ( 5. 8 see Warnings and Precautions ( 5. 1 4 4 4.

Infertility 8. 3 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. 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. 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) 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. 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). 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. 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. 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. 2 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. 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. 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.

RECENT MAJOR CHANGES
5.9
DRUG INTERACTIONS
See Table 3 for clinically significant drug interactions with meloxicam. See also Warnings and Precautions ( 5. 3 Table 4 Clinically Significant Drug Interactions with Meloxicam Drugs that Interfere with Hemostasis Clinical Impact: Intervention: Monitor patients with concomitant use of meloxicam with anticoagulants (e. , warfarin), antiplatelet agents (e. , 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: Intervention: 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. , 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 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. , 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. , 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. , warfarin, aspirin, SSRIs/SNRIs) 7 ACE Inhibitors, Angiotensin Receptor Blockers (ARBs) or Beta-Blockers 7 ACE Inhibitors and ARBs 7 Diuretics 7.

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).
NONCLINICAL TOXICOLOGY
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 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 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).
CLINICAL STUDIES
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. 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. 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. 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. 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.
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Glenmark Pharmaceuticals Inc., USA

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