meloxicam

RECENT MAJOR CHANGES Boxed Warning 5/2016 Indications and Usage, Juvenile Rheumatoid Arthritis (JRA) Pauciarticular and Polyarticular Course (1.3) 6/2016 Dosage and Administration, Juvenile Rheumatoid Arthritis (JRA) Pauciarticular and Ployarticular Course (2.4) 6/2016 Warnings and Precautions, Cardiovascular Thrombotic Events (5.1) Warninigs and Precautions, Heart Failure and Edema (5.5) 5/2016 Warnings and Precautions, Drug Reaction with Eosinophilia and Systemic Symptoms (5.10) 04/2021 Warnings and Precautions, Fetal Toxicity (5.11) 04/2021

1 INDICATIONS AND USAGE Meloxicam tablets are 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)

Meloxicam tablets are 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 are indicated for relief of the signs and symptoms of osteoarthritis [see Clinical Studies (14.1) ] . 1.2 Rheumatoid Arthritis (RA) Meloxicam tablets 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 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) ] .

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 ) 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 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 symptom …

3 DOSAGE FORMS AND STRENGTHS Meloxicam Tablets: 7.5 mg: pastel yellow, round, biconvex, uncoated tablet containing meloxicam 7.5 mg. The 7.5 mg tablet is impressed with “5” mark on one side. 15 mg: pastel yellow, round, biconvex, uncoated tablet containing meloxicam 15 mg. The 15 mg tablet is impressed with “100” mark on one side. Meloxicam Tablets: 7.5 mg and 15 mg ( 3 )

4. CONTRAINDICATIONS • Known hypersensitivity (e.g., analphylactoid reactions and serious skin reactions) to meloxicam ( 4.1 ) • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs ( 4.1 ) • Use during the peri-operative period in the setting of coronary artery bypass graft (CABG) surgery ( 4.2 ) 4.1 Allergic Reactions Meloxicam tablets are contraindicated in patients with known hypersensitivity (e.g. anaphylactoid reactions and serious skin reactions) to meloxicam. Meloxicam tablets should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7 , 5.13 )]. 4.2 Coronary Surgery Meloxicam tablets are contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery [ see Warnings and Precautions (5.1) ].

6 ADVERSE REACTIONS • Most common (≥5% and greater than placebo) adverse events in adults are diarrhea, upper respiratory tract infections, dyspepsia, and influenza-like symptoms (6.1) • Adverse events observed in pediatric studies were similar in nature to the adult clinical trial experience (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 () ] • GI Bleeding, Ulceration, and Perforation [ see Boxed Warning and Warnings and Precautions ( 5.2 ) ] • Hepatotoxicity [ see Warnings and Precautions () ] • Hypertension [ see Warnings and Precautions () ] • Heart Failure and Edema [ see Warnings and Precautions () ] • Renal Toxicity and Hyperkalemia [ see Warnings and Precautions () ] • Anaphylactic Reactions [ see Warnings and Precautions () ] • Serious Skin Reactions [ see Warnings and Precautions () ] • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions ()] • Fetal Toxicity [see Warnings and Precautions ()] • Hematologic Toxicity [ see Warnings and Precautions () ] 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. 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 Header$ 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 1 MedDRA high level term (preferred terms): dyspeptic signs and symptoms (dyspepsia, dyspepsia aggravated, eructation, gastrointestinal irritation), upper respiratory tract infections-path …

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 tablets 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 tablets 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 tablets are 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, 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 tablets and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of meloxicam tablets 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. Intervention: During concomitant use of meloxicam tablets 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 approx …

8. Use in Specific Populations 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). 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 s …

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.

11 DESCRIPTION Meloxicam, an oxicam derivative, is a member of the enolic acid group of nonsteroidal anti-inflammatory drugs (NSAIDs). Each pastel yellow Meloxicam Tablets, USP contains 7.5 mg or 15 mg meloxicam 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 pastel 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. The inactive ingredients in Meloxicam Tablets, USP include Colloidal Silicon Dioxide, Sodium Starch Glycolate, Lactose, Magnesium Stearate, Microcrystalline Cellulose, Povidone K-30, and Sodium Citrate. Structural Formula

OVERDOSAGE There is limited experience with meloxicam overdose. Four cases have taken 6 to 11 times the highest recommended dose; all recovered. Cholestyramine is known to accelerate the clearance of meloxicam. Symptoms following acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Severe poisoning may result in hypertension, acute renal failure, hepatic dysfunction, respiratory depression, coma, convulsions, cardiovascular collapse, and cardiac arrest. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose. Patients should be managed with symptomatic and supportive care following an NSAID overdose. In cases of acute overdose, gastric lavage followed by activated charcoal is recommended. Gastric lavage performed more than one hour after overdose has little benefit in the treatment of overdose. Administration of activated charcoal is recommended for patients who present 1-2 hours after overdose. For substantial overdose or severely symptomatic patients, activated charcoal may be administered repeatedly. Accelerated removal of meloxicam by 4 gm oral doses of cholestyramine given three times a day was demonstrated in a clinical trial. Administration of cholestyramine may be useful following an overdose. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

16 HOW SUPPLIED/STORAGE AND HANDLING Meloxicam tablets USP are available as a light yellow, round, flat, uncoated tablet containing meloxicam 7.5 mg or as light yellow, oblong, biconvex, uncoated tablet containing meloxicam 15 mg. The 7.5 mg tablet is impressed with letter U and L on one side and tablet code 7.5 on the other side. The 15 mg tablet is impressed with letter U and L on one side and tablet code 15 on the other side. Meloxicam Tablets USP 15 mg are available as follows: NDC 85509-1125-3; Bottles of 30 NDC 85509-1125-6; Bottles of 60 NDC 85509-1125-9; Bottles of 90 Storage Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Keep Meloxicam Tablets USP in a dry place Dispense tablets in a tight container. Keep this and all medications out of the reach of children. Repackaged/Relabeled by: PHOENIX RX LLC Hatboro, PA 19040 Meloxicam tablets USP are available as a light yellow, round, flat, uncoated tablet containing meloxicam 7.5 mg or as light yellow, oblong, biconvex, uncoated tablet containing meloxicam 15 mg. The 7.5 mg tablet is impressed with letter U and L on one side and tablet code 7.5 on the other side. The 15 mg tablet is impressed with letter U and L on one side and tablet code 15 on the other side. Meloxicam Tablets USP 15 mg are available as follows: NDC 85509-1125-03; Bottles of 30 NDC 85509-1125-06; Bottles of 60 NDC 85509-1125-09; Bottles of 90 Storage Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Keep Meloxicam Tablets USP in a dry place Dispense tablets in a tight container. Keep this and all medications out of the reach of children. "Repackaged/Relabeled by: PHOENIX RX LLC Hatboro, PA 19040 "