meloxicam 5 MG/ML Injectable Solution [Alloxate]

INDICATIONS AND USAGE Meloxicam tablet USP 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 tablets USP are indicated for relief of the signs and symptoms of osteoarthritis [see Clinical Studies ( 14.1 )] . 1.2 Rheumatoid Arthritis (RA) Meloxicam tablets USP are 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 tablets USP 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 ( 2.4 ) and Clinical Studies ( 14.2 )] .

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/kg 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 tablets. 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 tablets 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 tablets in subjects with severe renal impairment is not recommended. In patients on hemodialysis, the maximum dosage of meloxicam tablets 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. 2.1 General Dosing Instructions Carefully consider the potential benefits and risks of meloxicam and other treatment options before deciding to use meloxicam tablets. 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 tablets 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. 2.6 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.

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 ( 5.11 , 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. 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 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 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 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. 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 immediate

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 )

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 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 ) 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 C max [mcg/mL] 1.05 (20) 2.3 (59) 3.2 (24) 0.59 (36) 0.84 (29) t max [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) 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 (V ss ) 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. 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