PIROXICAM

1 INDICATIONS AND USAGE Piroxicam capsules are indicated: • For relief of the signs and symptoms of osteoarthritis. • For relief of the signs and symptoms of rheumatoid arthritis. Piroxicam capsules are a nonsteroidal anti-inflammatory drug indicated for •Relief of the signs and symptoms of osteoarthritis (OA) ( 1 )•Relief of the signs and symptoms of rheumatoid arthritis (RA) ( 1 )

2 DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of piroxicam capsules and other treatment options before deciding to use piroxicam capsules. 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 piroxicam capsules, the dose and frequency should be adjusted to suit an individual patient’s needs. For the relief of rheumatoid arthritis and osteoarthritis, the dosage is 20 mg given orally once per day. If desired, the daily dose may be divided. Because of the long half-life of piroxicam capsules, steady-state blood levels are not reached for 7 to 12 days. Therefore, although the therapeutic effects of piroxicam capsules are evident early in treatment, there is a progressive increase in response over several weeks and the effect of therapy should not be assessed for two weeks. • Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals ( 2 ) • OA and RA: 20 mg once daily ( 2 )

4 CONTRAINDICATIONS Piroxicam capsules are contraindicated in the following patients: • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to piroxicam 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 CABG surgery [see Warnings and Precautions (5.1) ] • Known hypersensitivity to piroxicam 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 )

5 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 piroxicam capsules 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 piroxicam capsules 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 : Piroxicam capsules are contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) ( 5.8 ) • Serious Skin Reactions : Discontinue piroxicam capsules at first appearance of skin rash or other signs of hypersensitivity ( 5.9 ) • Premature Closure of Fetal Ductus Arteriosus : Avoid use in pregnant women starting at 30 weeks gestation ( 5.10 , 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 cyclooxygenase-2 (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 piroxicam, 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 piroxicam capsules in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If piroxicam capsules are used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including piroxicam capsules, 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, antiplatelet drugs (such as 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 piroxicam capsules 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 alanine aminotransferase (ALT) or aspartate aminotransferase (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 piroxicam. 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), discontinue piroxicam capsules immediately, and perform a clinical evaluation of the patient. 5.4 Hypertension NSAIDs, including piroxicam capsules, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7) ] . Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of piroxicam may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7) ] . Avoid the use of piroxicam capsules in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If piroxicam capsules are used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of piroxicam capsules in patients with advanced renal disease. The renal effects of piroxicam capsules may hasten the progression of renal dysfunction in patients with preexisting renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating piroxicam capsules. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of piroxicam capsules [see Drug Interactions (7) ]. Avoid the use of piroxicam capsules in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If piroxicam capsules are used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. 5.7 Anaphylactic Reactions Piroxicam has been associated with anaphylactic reactions in patients with and without known hypersensitivity to piroxicam and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8) ] . Seek emergency help if an anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, piroxicam capsules are contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4) ] . When piroxicam capsules are used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.9 Serious Skin Reactions NSAIDs, including piroxicam, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of piroxicam capsules at the first appearance of skin rash or any other sign of hypersensitivity. Piroxicam capsules are contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4) ] . 5.10 Premature Closure of Fetal Ductus Arteriosus Piroxicam may cause premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including piroxicam capsules, in pregnant women starting at 30 weeks of gestation (third trimester) [see Use in Specific Populations (8.1) ] . 5.11 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with piroxicam capsules has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including piroxicam capsules, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders, concomitant use of warfarin, other anticoagulants, antiplatelet drugs (e.g., aspirin), SSRIs, and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7) ] . 5.12 Masking of Inflammation and Fever The pharmacological activity of piroxicam capsules in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.13 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a complete blood count (CBC) and a chemistry profile periodically [see Warnings and Precautions (5.2 , 5.3 , 5.6) ] . 5.14 Ophthalmologic Effects Because of reports of adverse eye findings with nonsteroidal anti-inflammatory agents, it is recommended that patients who develop visual complaints during treatment with piroxicam capsules have ophthalmic evaluations.

7 DRUG INTERACTIONS See Table 1 for clinically significant drug interactions with piroxicam. Table 1: Clinically Significant Drug Interactions with Piroxicam Drugs That Interfere with Hemostasis Clinical Impact: •Piroxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of piroxicam 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 piroxicam capsules with anticoagulants (e.g., warfarin), antiplatelet drugs (e.g., aspirin), SSRIs, and SNRIs for signs of bleeding [see Warnings and Precautions (5.11) ] . 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 piroxicam capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11) ] . Piroxicam capsules are 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 ACE inhibitors, 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 piroxicam capsules and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.•During concomitant use of piroxicam capsules 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. Intervention: During concomitant use of piroxicam capsules 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) ] . Digoxin Clinical Impact: The concomitant use of piroxicam with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of piroxicam capsules and digoxin, monitor serum digoxin levels. 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. Intervention: During concomitant use of piroxicam capsules 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.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of piroxicam capsules and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of piroxicam capsules and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of piroxicam capsules and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of piroxicam with other NSAIDs or salicylates (e.g., 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 piroxicam with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of piroxicam capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of piroxicam capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Highly Protein Bound Drugs Clinical Impact : Piroxicam capsules is highly protein bound and, therefore, might be expected to displace other protein bound drugs. Intervention : Physicians should closely monitor patients for a change in dosage requirements when administering piroxicam capsules to patients on other highly protein bound drugs. Corticosteroids Clinical Impact: Concomitant use of corticosteroids with piroxicam capsules may increase the risk of GI ulceration or bleeding. Intervention: Monitor patients with concomitant use of piroxicam capsules with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2) ] . • Drugs that Interfere with Hemostasis (e.g., warfarin, aspirin, selective serotonin reuptake inhibitors [SSRIs]/serotonin norepinephrine reuptake inhibitors [SNRIs]): Monitor patients for bleeding who are concomitantly taking piroxicam capsules with drugs that interfere with hemostasis. Concomitant use of piroxicam capsules and analgesic doses of aspirin is not generally recommended ( 7 ) • Angiotensin Converting Enzyme (ACE) Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers : Concomitant use with piroxicam capsules may diminish the antihypertensive effect of these drugs. Monitor blood pressure ( 7 ) • ACE Inhibitors and ARBs : Concomitant use with piroxicam capsules in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function ( 7 ) • Diuretics : NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects ( 7 ) • Digoxin : Concomitant use of piroxicam capsules can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels ( 7 )

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in 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 (5.11) ] Most common adverse reactions (incidence > 2% from clinical trials) are: nausea, constipation, flatulence, abdominal pain, diarrhea, headache, dizziness, edema, rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Nostrum Laboratories, Inc. at quality@nostrumpharma.com or 1-877-770-1288 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. In patients taking piroxicam capsules or other NSAIDs, the most frequently reported adverse experiences occurring in approximately 1% to 10% of patients are: Cardiovascular System: Edema Digestive System: Anorexia, abdominal pain, constipation, diarrhea, flatulence, nausea, vomiting Nervous System: Dizziness, headache, vertigo Skin and Appendages: Pruritus, rash Special Senses: Tinnitus Additional adverse experiences reported occasionally include: Cardiovascular System: Palpitations Digestive System: Stomatitis Nervous System: Drowsiness Special Senses: Blurred vision 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of piroxicam capsules. 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. Body As a Whole: Fever, infection, sepsis, anaphylactic reactions, appetite changes, death, flu-like syndrome, pain (colic), serum sickness Cardiovascular System: Congestive heart failure, hypertension, tachycardia, syncope, arrhythmia, exacerbation of angina, hypotension, myocardial infarction, vasculitis Digestive System: Dyspepsia, elevated liver enzymes, gross bleeding/perforation, heartburn, ulcers (gastric/duodenal), dry mouth, esophagitis, gastritis, glossitis, hematemesis, hepatitis, jaundice, melena, rectal bleeding, eructation, liver failure, pancreatitis Hemic and Lymphatic System: Anemia, increased bleeding time, ecchymosis, eosinophilia, epistaxis, leukopenia, purpura, petechial rash, thrombocytopenia, agranulocytosis, hemolytic anemia, aplastic anemia, lymphadenopathy, pancytopenia Hypersensitivity: Positive ANA Metabolic and Nutritional: Weight changes, Fluid retention, hyperglycemia, hypoglycemia Nervous System: Anxiety, asthenia, confusion, depression, dream abnormalities, insomnia, malaise, nervousness, paresthesia, somnolence, tremors, akathisia, convulsions, coma, hallucinations, meningitis, mood alterations Respiratory System: Asthma, dyspnea, respiratory depression, pneumonia Skin and Appendages: Alopecia, bruising, desquamation, erythema, photosensitivity, sweat, angioedema, toxic epidermal necrosis, erythema multiforme, exfoliative dermatitis, onycholysis, Stevens Johnson Syndrome, urticaria, vesiculobullous reaction Special Senses: Conjunctivitis, hearing impairment, swollen eyes Urogenital System: Abnormal renal function, cystitis, dysuria, hematuria, hyperkalemia, interstitial nephritis, nephrotic syndrome, oliguria/polyuria, proteinuria, renal failure, glomerulonephritis Reproductive System and Breast Disorders: Female fertility decreased

8.1 Pregnancy Risk Summary Use of NSAIDs, including piroxicam capsules, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including piroxicam capsules, in pregnant women starting at 30 weeks of gestation (third trimester). There are no adequate and well-controlled studies of piroxicam capsules in pregnant women. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major malformations, and 15% to 20% for pregnancy loss. In animal reproduction studies in rats and rabbits, there was no evidence of teratogenicity at exposures up to 5 and 10 times the maximum recommended human dose (MRHD), respectively. In rat studies with piroxicam, fetotoxicity (postimplantation loss) was observed at exposures 2 times the MRHD, and delayed parturition and an increased incidence of stillbirth were noted at doses equivalent to the MRHD of piroxicam. 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 piroxicam, resulted in increased pre- and post-implantation loss. Clinical Considerations Labor or Delivery There are no studies on the effects of piroxicam capsules during labor or delivery. In animal studies, NSAIDs, including piroxicam inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Animal Data Pregnant rats administered piroxicam at 2, 5, or 10 mg/kg/day during the period of organogenesis (Gestation Days 6 to 15) demonstrated increased post-implantation losses with 5 and 10 mg/kg/day of piroxicam (equivalent to 2 and 5 times the MRHD, of 20 mg respectively, based on a mg/m 2 body surface area [BSA]). There were no drug-related developmental abnormalities noted in offspring. Gastrointestinal tract toxicity was increased in pregnant rats in the last trimester of pregnancy compared to non-pregnant rats or rats in earlier trimesters of pregnancy. Pregnant rabbits administered piroxicam at 2, 5, or 10 mg/kg/day during the period of organogenesis (Gestation Days 7 to 18) demonstrated no drug-related developmental abnormalities in offspring (up to 10 times the MRHD based on a mg/m 2 BSA). In a pre- and post-natal development study in which pregnant rats were administered piroxicam at 2, 5, or 10 mg/kg/day on Gestation Day 15 through delivery and weaning of offspring, reduced weight gain and death were observed in dams at 10 mg/kg/day (5 times the MRHD based on a mg/m 2 BSA) starting on Gestation Day 20. Treated dams revealed peritonitis, adhesions, gastric bleeding, hemorrhagic enteritis and dead fetuses in utero. Parturition was delayed and there was an increased incidence of stillbirth in all piroxicam-treated groups (at doses equivalent to the MRHD). Postnatal development could not be reliably assessed due to the absence of maternal care secondary to severe maternal toxicity.