XIFYRM

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

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

5 WARNINGS AND PRECAUTIONS • Hepatotoxicity : Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue XIFYRM immediately if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop. ( 5.3 ) • Hypertension : Patients taking some antihypertensive medications may have impaired response to these therapies when taking XIFYRM injection, monitor blood pressure. ( 5.4 , 7 ) • Heart Failure and Edema : Avoid use of XIFYRM 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 XIFYRM 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 : XIFYRM is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity). ( 5.8 ) • Serious Skin Reactions : Discontinue XIFYRM at first appearance of skin rash or other signs of hypersensitivity. ( 5.9 ) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) : Discontinue and evaluate clinically. ( 5.10 ) • Hematologic Toxicity : Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia. ( 5.12 , 7 ) • Fetal Toxicity : Limit use of NSAIDs, including XIFYRM, between about 20 to 30 weeks in pregnancy due to the risk of renal oligohydramnios/fetal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus. ( 5.11 , 8.1 ) 5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as meloxicam, increases the risk of serious gastrointestinal (GI) events [ see Warnings and Precautions ( 5.2 ) ]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [ see Contraindications ( 4 ) ]. Post-MI Patients Observational studies conducted in the Dani…

4 CONTRAINDICATIONS XIFYRM 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 )

7 DRUG INTERACTIONS See Table 3 for clinically significant drug interactions with meloxicam. Table 3: Clinically Significant Drug Interactions with Meloxicam Drugs That Interfere with Hemostasis Clinical Impact: Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case- control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of XIFYRM 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 [se e 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 XIFYRM and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5.12 ) ]. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [ see Warnings and Precautions ( 5.2 ) ]. XIFYRM is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta- blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: During concomitant use of XIFYRM and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of XIFYRM 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 XIFYRM 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 …

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

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in the other sections of the labeling: • Cardiovascular Thrombotic Events [ see Warnings and Precautions ( 5.1 ) ] • GI Bleeding, Ulceration, and Perforation [ see Warnings and Precautions ( 5.2 ) ] • Hepatotoxicity [ see Warnings and Precautions ( 5.3 ) ] • Hypertension [ see Warnings and Precautions ( 5.4 ) ] • Heart Failure and Edema [ see Warnings and Precautions ( 5.5 ) ] • Renal Toxicity and Hyperkalemia [ see Warnings and Precautions ( 5.6 ) ] • Anaphylactic Reactions [ see Warnings and Precautions ( 5.7 ) ] • Serious Skin Reactions [ see Warnings and Precautions ( 5.9 ) ] • Hematologic Toxicity [ see Warnings and Precautions ( 5.12 ) ] The most common adverse reactions (≥ 2% and greater than placebo) in controlled clinical trials include constipation, GGT increased, and anemia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Azurity Pharmaceuticals, Inc. at 1-800-461-7449 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. During clinical development, 1426 patients were exposed to meloxicam injection in controlled and open- label Phase 2 and Phase 3 trials. Meloxicam injection was studied across a range of surgical procedures, including bunionectomy, abdominoplasty, soft tissue surgery, total knee replacement surgery, gynecologic surgery, complex foot surgery and total hip replacement surgery. In these trials, 381 patients received a single dose of meloxicam injection and 1045 patients received multiple doses of meloxicam injection daily for up to 7 days. The incidence rates of adverse reactions listed in Table 1 are derived from the three Phase 3 trials comparing meloxicam injection to placebo in patients who may have also received opioid rescue medication. Table 1: Proportion of Patients Experiencing Common Adverse Reactions in Placebo- Controlled Phase 3 Clinical Trials occurring in greater than or equal to 2% of Patients Treated with Meloxicam injection and at a greater frequency than Placebo Meloxicam injection Placebo Adverse Reaction N=748 N=393 Constipation 57 (7.6%) 24 (6.1%) Gamma-Glutamyl transferase Increased 21 (2.8%) 6 (1.5%) Anemia 18 (2.4%) 4 (1.0%) The following is a list of adverse drug reactions occurring in <2% of patients receiving meloxicam injection in clinical trials. Table 2: Additional Adverse Reactions for Meloxicam Injection Body as a Whole asthenia, back pain, edema, fatigue, hyperthermia, infusion site reactions (including pain, pruritus, phlebitis and thrombosis), muscle spasms, non-cardiac chest pain, pyrexia, vaginal discharge, weight decrease Central and Peripheral Nervous System disturbance in attention, migraine, presyncope, somnolence, syncope Gastrointestinal abdominal discomfort, abdominal distension, abdominal pain, diarrhea, dry mouth, epigastric discomfort, flatulence, frequent bowel movements, gastritis, gastroesophageal reflux, gastrointestinal pain, rectal hemorrhage Heart Rate and Rhythm tachycardia Hematologic increased bleeding time, neutropenia, thrombocytosis Infections and Infestations cellulitis, gastroenteritis, urinary tract infection, vulval abscess Liver and Biliary System liver function test abnormal Metabolic and Nutritional hypokalemia, hypomagnesemia Procedural Complications incision site hemorrhage, incision site rash, wound dehiscence, wound hematoma Psychiatric confusion, hallucination, insomnia Respiratory dyspnea, epistaxis, hypoxia, oropharyngeal pain Skin and Appendages contact dermatitis, ecchymosis, rash Urinary System pollakiuria, urinary retention 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of meloxicam. Because …