Meloxicam

Warnings and Precautions, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) ( 5.10 ) 04/2021 Warnings and Precautions, Fetal Toxicity ( 5.11 ) 04/2021

1 INDICATIONS AND USAGE Meloxicam oral suspension is a non-steroidal anti-inflammatory drug indicated for: Osteoarthritis (OA) ( 1.1 ) Rheumatoid Arthritis (RA) ( 1.2 ) Juvenile Rheumatoid Arthritis (JRA) in patients 2 years of age or older ( 1.3 ) 1.1 Osteoarthritis (OA) Meloxicam oral suspension is indicated for relief of the signs and symptoms of osteoarthritis [see Clinical Studies (14.1) ]. 1.2 Rheumatoid Arthritis (RA) Meloxicam oral suspension 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 oral suspension is indicated for relief of the signs and symptoms of pauciarticular or polyarticular course Juvenile Rheumatoid Arthritis in patients 2 years of age and older [see 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 ): 0.125 mg/kg once daily up to a maximum of 7.5 mg. JRA dosing using the oral suspension should be individualized based on the weight of the child ( 2.4 ) Meloxicam oral suspension is 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 oral suspension and other treatment options before deciding to use meloxicam oral suspension. 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 oral suspension, adjust the dose to suit an individual patient's needs. In adults, the maximum recommended daily oral dose of meloxicam oral suspension 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 oral suspension 7.5 mg/5 mL or 15 mg/10 mL may be substituted for meloxicam tablets 7.5 mg or 15 mg, respectively. Shake the oral suspension gently before using. Meloxicam oral suspension 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 oral suspension 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 oral suspension 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 To improve dosing accuracy in smaller weight children, the use of the meloxicam oral suspension is recommended. Meloxicam oral suspension is available in the strength of 7.5 mg/5 mL. For the treatment of juvenile rheumatoid arthritis, the recommended oral dose of meloxicam oral suspension is 0.125 mg/kg once daily up to a maximum of 7.5 mg. There was no additional benefit demonstrated by increasing the dose above 0.125 mg/kg once daily in these clinical trials. Juvenile Rheumatoid Arthritis dosing using the oral suspension should be individualized based on the weight of the child: 0.125 mg/kg Weight Dose (1.5 mg/mL) Delivered dose 12 kg (26 lb) 1.0 mL 1.5 mg 24 kg (54 lb) 2.0 mL 3.0 mg 36 kg (80 lb) 3.0 mL 4.5 mg 48 kg (106 lb) 4.0 mL 6.0 mg ≥60 kg (132 lb) 5.0 mL 7.5 mg 2.5 Renal Impairment The use of meloxicam oral suspension in subjects with severe renal impairment is not recommended. In patients on hemodialysis, the maximum dosage of meloxicam oral suspension is 7.5 mg per day [see Clinical Pharmacology (12.3) ] . 2.6 Non-Interchangeability with Other Formulations of Meloxicam Meloxicam oral suspension has not shown equivalent systemic exposure to other approved formulations of oral meloxicam. Therefore, meloxicam oral suspension is 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 oral suspension with other formulations of oral meloxicam product.

3 DOSAGE FORMS AND STRENGTHS Meloxicam oral suspension: yellowish green tinged viscous suspension containing 7.5 mg meloxicam per 5 mL. Meloxicam oral suspension: 7.5 mg/5 mL ( 3 )

4 CONTRAINDICATIONS Meloxicam oral suspension 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 )

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) ] 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 Emerald Therapeutics, LLC at (800) 970-1991 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 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 WHO preferred terms edema, edema dependent, edema peripheral, and edema legs combined 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 WHO preferred terms rash, rash erythematous, and rash maculo-papular combined. 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 Placebo Meloxicam 7.5 mg daily Meloxicam 15 mg daily No. of Patients 469 481 477 Gastrointestinal Diso …

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 oral suspension 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 oral suspension 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 oral suspension 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, 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 oral suspension and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of meloxicam oral suspension 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 oral suspension 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%, a …

8 USE IN SPECIFIC POPULATIONS Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of meloxicam oral suspension in women who have difficulties conceiving ( 8.3 ) 8.1 Pregnancy Risk Summary Use of NSAIDs, including meloxicam oral suspension, 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 oral suspension use between about 20 and 30 weeks of gestation, and avoid meloxicam oral suspension 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 oral suspension, 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 to 0.65- and 6.5-times the maximum recommended human dose (MRHD) of meloxicam oral suspension. 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 oral suspension, 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 oral suspension treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue meloxicam oral suspension and follow up according to clinical practice ( see Data ). Labor or Delivery There are no studies on the effects of meloxicam oral suspension during labor or delivery. In animal studies, NSAIDs, including meloxicam, inhibit prostaglandin synthesis, cause delayed parturition, and …

12.1 Mechanism of Action Meloxicam has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of meloxicam oral suspension, 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 oral suspension, USP is a nonsteroidal anti-inflammatory drug (NSAID). Each bottle of meloxicam oral suspension contains 7.5 mg meloxicam per 5 mL. 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 an oral suspension containing 7.5 mg meloxicam per 5 mL. The inactive ingredients in meloxicam oral suspension include colloidal silicon dioxide, hydroxyethylcellulose, sorbitol, glycerol, xylitol, monobasic sodium phosphate (dihydrate), saccharin sodium, sodium benzoate, citric acid (monohydrate), raspberry flavor, and purified water. Chemical Structure

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).

16 HOW SUPPLIED/STORAGE AND HANDLING Meloxicam oral suspension, USP is available as a yellowish green tinged viscous oral suspension containing 7.5 mg meloxicam in 5 mL. Meloxicam oral suspension, USP, 7.5 mg/5 mL: NDC 72919-124-10; Bottles of 100 mL Storage Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep oral suspension container tightly closed. Keep this and all medications out of the reach of children.