These Highlights Do Not Include All The Information Needed To Use Piroxicam Capsules, Usp Safely And Effectively. See Full Prescribing Information For Piroxicam Capsules, Usp.

Cardiovascular Thrombotic Events

• •
  Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use. [see Warnings and Precautions (5.1)] .
• •
  Piroxicam capsules are contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1)].

Storage

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Dispense in tight, light-resistant containers as defined in the USP.

Principal Display Panel - 20mg Bottle Label

NDC 71205-032-30

Piroxicam

Capsules, USP

20 mg

Pharmacist: Dispense the accompanying

Medication Guide to each patient.

Rx Only

30 Capsules

Symptoms following acute NSAID overdoses have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are 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 overdose. There are no specific antidotes. Consider emesis and/or activated charcoal (60–100 grams in adults, 1–2 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).

The long plasma half-life of piroxicam should be considered when treating an overdose with piroxicam. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

For additional information about overdosage treatment contact a poison control center (1-800-222-1222).

Pregnancy Category C prior to 30 weeks gestation; Category D starting at 30 weeks gestation.

Piroxicam capsules, USP are a nonsteroidal anti-inflammatory drug, available as white opaque/red opaque 10 mg capsules and red opaque 20 mg capsules for oral administration. The chemical name is 4-hydroxyl-2-methyl-N-2- pyridinyl-2H-1,2,-benzothiazine-3-carboxamide 1,1-dioxide. The molecular weight is 331.35. Its molecular formula is C₁₅H₁₃N₃O₄S, and it has the following chemical structure.

Piroxicam occurs as a white crystalline solid, sparingly soluble in water, dilute acid, and most organic solvents. It is slightly soluble in alcohol and in aqueous solutions. It exhibits a weakly acidic 4-hydroxy proton (pKa 5.1) and a weakly basic pyridyl nitrogen (pKa 1.8).

The inactive ingredients in piroxicam capsules, USP include: corn starch, FD & C Blue 1, FD & C Red 40, gelatin, lactose monohydrate, magnesium stearate, sodium lauryl sulfate and titanium dioxide.

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.

Piroxicam capsules have not been investigated in pediatric patients. The safety and effectiveness of piroxicam capsules have not been established.

Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.13)].

Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported.

Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including 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, etc.), discontinue piroxicam capsules immediately, and perform a clinical evaluation of the patient.

In controlled clinical trials, the effectiveness of piroxicam capsules has been established for both acute exacerbations and long term management of rheumatoid arthritis and osteoarthritis.

The therapeutic effects of piroxicam capsules are evident early in the treatment of both diseases with a progressive increase in response over several (8–12) weeks. Efficacy is seen in terms of pain relief and, when present, subsidence of inflammation.

Doses of 20 mg/day piroxicam capsules display a therapeutic effect comparable to therapeutic doses of aspirin, with a lower incidence of minor gastrointestinal effects and tinnitus.

Piroxicam capsules have been administered concomitantly with fixed doses of gold and corticosteroids. The existence of a “steroid sparing” effect has not been adequately studied to date.

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 coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1 )]

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)]

See Table 1 for clinically significant drug interactions with piroxicam.

CYP2C9 activity is reduced in individuals with genetic polymorphisms, such as the CYP2C9*2 and CYP2C9*3 polymorphisms. Limited data from two published reports showed that subjects with heterozygous CYP2C9*1/*2 (n=9), heterozygous CYP2C9*1/*3 (n=9), and homozygous CYP2C9*3/*3 (n=1) genotypes showed 1.7-, 1.7-, and 5.3-fold higher piroxicam systemic levels, respectively, than the subjects with CYP2C9*1/*1 (n=17, normal metabolizer genotype) following administration of a single oral dose. The mean elimination half-life values of piroxicam for subjects with CYP2C9*1/*3 (n=9) and CYP2C9*3/*3 (n=1) genotypes were 1.7- and 8.8-fold higher than subjects with CYP2C9*1/*1 (n=17). It is estimated that the frequency of the homozygous*3/*3 genotype is 0% to 1% in the population at large; however, frequencies as high as 5.7% have been reported in certain ethnic groups.

Poor Metabolizers of CYP2C9 Substrates: In patients who are known or suspected to be poor CYP2C9 metabolizers based on genotype or previous history/experience with other CYP2C9 substrates (such as warfarin and phenytoin) consider dose reduction as they may have abnormally high plasma levels due to reduced metabolic clearance.

Piroxicam capsules, USP are indicated:

• •
  For relief of the signs and symptoms of osteoarthritis.
• •
  For relief of the signs and symptoms of rheumatoid arthritis.

Piroxicam has analgesic, anti-inflammatory, and antipyretic properties.

The mechanism of action of piroxicam capsules, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).

Piroxicam is a potent inhibitor of prostaglandin (PG) synthesis in vitro. Piroxicam 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 piroxicam is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

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 agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)].

• •
  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)

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 CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)].

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.

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)].

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 7–12 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.

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.

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.

Piroxicam capsules, USP:

10 mg: White Opaque/ Red Opaque Size 2 Capsules printed with “P” on cap and “233” on body.

20 mg: Red Opaque/Red Opaque Size 2 Capsules printed with “P” on cap and “234” on body.

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

Pregnancy: Use of NSAIDs during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs in pregnant women starting at 30 weeks gestation (5.10, 8.1)

Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of piroxicam capsules in women who have difficulties conceiving (8.3)

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 1–10% 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

Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with piroxicam capsules and periodically during the course of ongoing therapy.

Piroxicam capsules, USP 20 mg for oral administration:

20 mg

Red Opaque/Red Opaque Size 2 Capsules printed with “P” on cap and “234” on body.

NDC 71205-032-30: Bottles of 30 capsules

NDC 71205-032-60: Bottles of 60 capsules

NDC 71205-032-30: Bottles of 90 capsules

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 piroxicam, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)].

The pharmacological activity of piroxicam capsules in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.

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)].

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.

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 3–6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.

WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS

See full prescribing information for complete boxed warning.

• •
  Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (5.1)
• •
  Piroxicam capsules are contraindicated in the setting of coronary artery bypass graft (CABG) surgery (4, 5.1)
• •
  NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (5.2)

Cardiovascular Thrombotic Events

• •
  Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use. [see Warnings and Precautions (5.1)] .
• •
  Piroxicam capsules are contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1)].

Storage

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Dispense in tight, light-resistant containers as defined in the USP.

Principal Display Panel - 20mg Bottle Label

NDC 71205-032-30

Piroxicam

Capsules, USP

20 mg

Pharmacist: Dispense the accompanying

Medication Guide to each patient.

Rx Only

30 Capsules

Symptoms following acute NSAID overdoses have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are 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 overdose. There are no specific antidotes. Consider emesis and/or activated charcoal (60–100 grams in adults, 1–2 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).

The long plasma half-life of piroxicam should be considered when treating an overdose with piroxicam. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

For additional information about overdosage treatment contact a poison control center (1-800-222-1222).

Pregnancy Category C prior to 30 weeks gestation; Category D starting at 30 weeks gestation.

Piroxicam capsules, USP are a nonsteroidal anti-inflammatory drug, available as white opaque/red opaque 10 mg capsules and red opaque 20 mg capsules for oral administration. The chemical name is 4-hydroxyl-2-methyl-N-2- pyridinyl-2H-1,2,-benzothiazine-3-carboxamide 1,1-dioxide. The molecular weight is 331.35. Its molecular formula is C₁₅H₁₃N₃O₄S, and it has the following chemical structure.

Piroxicam occurs as a white crystalline solid, sparingly soluble in water, dilute acid, and most organic solvents. It is slightly soluble in alcohol and in aqueous solutions. It exhibits a weakly acidic 4-hydroxy proton (pKa 5.1) and a weakly basic pyridyl nitrogen (pKa 1.8).

The inactive ingredients in piroxicam capsules, USP include: corn starch, FD & C Blue 1, FD & C Red 40, gelatin, lactose monohydrate, magnesium stearate, sodium lauryl sulfate and titanium dioxide.

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.

Piroxicam capsules have not been investigated in pediatric patients. The safety and effectiveness of piroxicam capsules have not been established.

Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.13)].

Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported.

Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including 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, etc.), discontinue piroxicam capsules immediately, and perform a clinical evaluation of the patient.

In controlled clinical trials, the effectiveness of piroxicam capsules has been established for both acute exacerbations and long term management of rheumatoid arthritis and osteoarthritis.

The therapeutic effects of piroxicam capsules are evident early in the treatment of both diseases with a progressive increase in response over several (8–12) weeks. Efficacy is seen in terms of pain relief and, when present, subsidence of inflammation.

Doses of 20 mg/day piroxicam capsules display a therapeutic effect comparable to therapeutic doses of aspirin, with a lower incidence of minor gastrointestinal effects and tinnitus.

Piroxicam capsules have been administered concomitantly with fixed doses of gold and corticosteroids. The existence of a “steroid sparing” effect has not been adequately studied to date.

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 coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1 )]

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)]

See Table 1 for clinically significant drug interactions with piroxicam.

CYP2C9 activity is reduced in individuals with genetic polymorphisms, such as the CYP2C9*2 and CYP2C9*3 polymorphisms. Limited data from two published reports showed that subjects with heterozygous CYP2C9*1/*2 (n=9), heterozygous CYP2C9*1/*3 (n=9), and homozygous CYP2C9*3/*3 (n=1) genotypes showed 1.7-, 1.7-, and 5.3-fold higher piroxicam systemic levels, respectively, than the subjects with CYP2C9*1/*1 (n=17, normal metabolizer genotype) following administration of a single oral dose. The mean elimination half-life values of piroxicam for subjects with CYP2C9*1/*3 (n=9) and CYP2C9*3/*3 (n=1) genotypes were 1.7- and 8.8-fold higher than subjects with CYP2C9*1/*1 (n=17). It is estimated that the frequency of the homozygous*3/*3 genotype is 0% to 1% in the population at large; however, frequencies as high as 5.7% have been reported in certain ethnic groups.

Poor Metabolizers of CYP2C9 Substrates: In patients who are known or suspected to be poor CYP2C9 metabolizers based on genotype or previous history/experience with other CYP2C9 substrates (such as warfarin and phenytoin) consider dose reduction as they may have abnormally high plasma levels due to reduced metabolic clearance.

Piroxicam capsules, USP are indicated:

• •
  For relief of the signs and symptoms of osteoarthritis.
• •
  For relief of the signs and symptoms of rheumatoid arthritis.

Piroxicam has analgesic, anti-inflammatory, and antipyretic properties.

The mechanism of action of piroxicam capsules, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).

Piroxicam is a potent inhibitor of prostaglandin (PG) synthesis in vitro. Piroxicam 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 piroxicam is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

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 agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)].

• •
  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)
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  Serious Skin Reactions: Discontinue piroxicam capsules at first appearance of skin rash or other signs of hypersensitivity (5.9)
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  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)

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 CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)].

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.

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)].

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 7–12 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.

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.

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.

Piroxicam capsules, USP:

10 mg: White Opaque/ Red Opaque Size 2 Capsules printed with “P” on cap and “233” on body.

20 mg: Red Opaque/Red Opaque Size 2 Capsules printed with “P” on cap and “234” on body.

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
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  (colic), serum sickness
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  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

Pregnancy: Use of NSAIDs during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs in pregnant women starting at 30 weeks gestation (5.10, 8.1)

Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of piroxicam capsules in women who have difficulties conceiving (8.3)

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 1–10% of patients are:

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  Cardiovascular System: Edema
•  
  Digestive System: Anorexia, abdominal pain, constipation, diarrhea, flatulence, nausea, vomiting
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  Nervous System: Dizziness, headache, vertigo
•  
  Skin and Appendages: Pruritus, rash
•  
  Special Senses: Tinnitus

Additional adverse experiences reported occasionally include:

•  
  Cardiovascular System: Palpitations
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  Digestive System: Stomatitis
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  Nervous System: Drowsiness
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  Special Senses: Blurred vision

Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with piroxicam capsules and periodically during the course of ongoing therapy.

Piroxicam capsules, USP 20 mg for oral administration:

20 mg

Red Opaque/Red Opaque Size 2 Capsules printed with “P” on cap and “234” on body.

NDC 71205-032-30: Bottles of 30 capsules

NDC 71205-032-60: Bottles of 60 capsules

NDC 71205-032-30: Bottles of 90 capsules

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 piroxicam, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)].

The pharmacological activity of piroxicam capsules in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.

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)].

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.

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 3–6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.

WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS

See full prescribing information for complete boxed warning.

• •
  Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (5.1)
• •
  Piroxicam capsules are contraindicated in the setting of coronary artery bypass graft (CABG) surgery (4, 5.1)
• •
  NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (5.2)