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NIVAGEN PHARMAC
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75834010401

piroxicam 20 mg capsule

Generic
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Uses

Piroxicam is used for anti-inflammatory and analgesic effects in the symptomatic treatment of rheumatoid arthritis, osteoarthritis, and other inflammatory conditions.

The potential benefits and risks of piroxicam therapy as well as alternative therapies should be considered prior to initiating piroxicam therapy. The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed.

Inflammatory Diseases

Rheumatoid Arthritis and Osteoarthritis

Piroxicam is used in the symptomatic treatment of acute and chronic rheumatoid arthritis and osteoarthritis.

When used in the symptomatic treatment of rheumatoid arthritis or osteoarthritis, piroxicam has relieved pain and stiffness and has increased range of motion and functional activity. Anti-inflammatory and analgesic effects of piroxicam usually are observed during initial treatment of rheumatoid arthritis or osteoarthritis with a progressive increase in response occurring over 8-12 weeks. Piroxicam appears to be only palliative in these conditions and has not been shown to permanently arrest or reverse the underlying disease process. Most clinical studies have shown that the anti-inflammatory and analgesic effects of usual dosages of piroxicam in the treatment of rheumatoid arthritis or osteoarthritis are at least equal to those of usual dosages of salicylates, ibuprofen, indomethacin, or naproxen. In controlled clinical trials of 12-weeks' duration, 20 mg of piroxicam daily was as effective as 3-4.2 g of aspirin daily in patients with rheumatoid arthritis or 2.6-3.9 g of aspirin daily in patients with osteoarthritis.

Patient response to oral NSAIAs is variable; patients who do not respond to or cannot tolerate one NSAIA might be successfully treated with a different agent. However, NSAIAs are generally contraindicated in patients in whom sensitivity reactions (e.g., urticaria, bronchospasm, severe rhinitis) are precipitated by aspirin or other NSAIAs.(See Cautions: Precautions and Contraindications.)

In the management of rheumatoid arthritis in adults, NSAIAs may be useful for initial symptomatic treatment; however, NSAIAs do not alter the course of the disease or prevent joint destruction. Disease modifying antirheumatic drugs (DMARDs) (e.g., azathioprine, cyclosporine, etanercept, oral or injectable gold compounds, hydroxychloroquine, infliximab, leflunomide, methotrexate, minocycline, penicillamine, sulfasalazine) have the potential to reduce or prevent joint damage, preserve joint integrity and function, and reduce total health care costs, and all patients with rheumatoid arthritis are candidates for DMARD therapy. DMARDs should be initiated early in the disease course and should not be delayed beyond 3 months in patients with active disease (i.e., ongoing joint pain, substantial morning stiffness, fatigue, active synovitis, persistent elevation of erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP], radiographic evidence of joint damage) despite an adequate regimen of NSAIAs. NSAIA therapy may be continued in conjunction with DMARD therapy or, depending on patient response, may be discontinued.

Piroxicam has been administered concomitantly with a fixed regimen of gold compounds and corticosteroids, but it has not been established whether these combinations are more effective than any of the drugs alone.

Other Inflammatory Conditions

Piroxicam has been effective at higher than usual dosages (i.e., 40 mg daily) for the symptomatic relief of acute gouty arthritis. In one study in patients with gouty arthritis, analgesic effects reportedly occurred within 2-4 hours after the initial dose of piroxicam, and relief from pain and swelling was complete after 5 days of therapy with the drug.

Piroxicam has been used for symptomatic relief of ankylosing spondylitis. The drug appears to be as effective as phenylbutazone (no longer commercially available in the US) or indomethacin for the management of this condition, but is generally better tolerated.

Piroxicam has also been used for symptomatic treatment of acute musculoskeletal disorders. The drug appears to be as effective as phenylbutazone (no longer commercially available in the US), but may be less effective than indomethacin for the management of these conditions.

Other Uses

Piroxicam has been used for symptomatic relief of postoperative or postpartum pain. For the relief of episiotomy pain, piroxicam appears to be as effective as aspirin.

Piroxicam has also been used for symptomatic relief of dysmenorrhea. In patients with severe dysmenorrhea, piroxicam decreased severity of cramps and supplemental analgesic (e.g., acetaminophen) requirements.

Results from a large, prospective, population-based cohort study in geriatric individuals indicate a lower prevalence of Alzheimer's disease among patients who received an NSAIA for 2 years or longer. Similar findings have been reported from some other, but not all, observational studies.

Dosage and Administration

Administration

The potential benefits and risks of piroxicam therapy as well as alternative therapies should be considered prior to initiating piroxicam therapy.

Piroxicam is administered orally. The drug is usually administered as a single daily dose but may be administered in divided doses daily.

Dosage

The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed. Dosage of piroxicam must be adjusted carefully according to individual requirements and response, using the lowest possible effective dosage.

Inflammatory Diseases

Rheumatoid Arthritis and Osteoarthritis

For the symptomatic treatment of acute or chronic rheumatoid arthritis or osteoarthritis, the usual initial adult dosage of piroxicam is 20 mg daily. For maintenance therapy, 20 mg daily is usually adequate. Piroxicam dosages of 30 or 40 mg daily may be required in some patients; however, dosages higher than 20 mg daily have been associated with increased frequency of adverse GI effects. Although symptomatic relief usually begins early in therapy with piroxicam, a progressive increase in response may occur over several weeks since the drug has a long half-life and generally does not achieve steady-state plasma concentrations for 7-12 days after initiation of therapy or adjustment of dosage. Therapeutic efficacy of the drug should not be assessed for at least 2 weeks after initiation of therapy or adjustment of dosage.

Dosage in Renal and Hepatic Impairment

Based on results of pharmacokinetic studies, the manufacturer states that dosage adjustment of piroxicam may not be necessary in patients with mild to moderate renal impairment. However, pharmacokinetics of the drug have not been studied in patients with severe renal insufficiency or those undergoing hemodialysis.

The pharmacokinetics of piroxicam in individuals with hepatic disease have not been determined; however, because of the substantial hepatic metabolism of the drug, the manufacturer suggests that reduced dosage may be required in patients with hepatic impairment.

Cautions

Adverse reactions to piroxicam mainly involve the GI tract.

Cardiovascular Effects

Edema has been reported in 1-10% of piroxicam-treated patients. Congestive heart failure, hypertension, syncope, and tachycardia have been reported occasionally in patients receiving piroxicam, and arrhythmia, exacerbation of angina, hypotension, myocardial infarction, palpitations, and vasculitis have been reported rarely.

Nonsteroidal anti-inflammatory agents (NSAIAs), including selective cyclooxygenase-2 (COX-2) inhibitors and prototypical NSAIAs, increase the risk of serious adverse cardiovascular thrombotic events, including myocardial infarction and stroke (which can be fatal), in patients with or without cardiovascular disease or risk factors for cardiovascular disease. Use of NSAIAs also is associated with an increased risk of heart failure.

The association between cardiovascular complications and use of NSAIAs is an area of ongoing concern and study. Findings of an FDA review of published observational studies of NSAIAs, a meta-analysis of published and unpublished data from randomized controlled trials of these drugs, and other published information indicate that NSAIAs may increase the risk of serious adverse cardiovascular thrombotic events by 10-50% or more, depending on the drugs and dosages studied. Available data suggest that the increase in risk may occur early (within the first weeks) following initiation of therapy and may increase with higher dosages and longer durations of use. Although the relative increase in cardiovascular risk appears to be similar in patients with or without known underlying cardiovascular disease or risk factors for cardiovascular disease, the absolute incidence of serious NSAIA-associated cardiovascular thrombotic events is higher in those with cardiovascular disease or risk factors for cardiovascular disease because of their elevated baseline risk.

Results from observational studies utilizing Danish national registry data indicated that patients receiving NSAIAs following a myocardial infarction were at increased risk of reinfarction, cardiovascular-related death, and all-cause mortality beginning in the first week of treatment. Patients who received NSAIAs following myocardial infarction had a higher 1-year mortality rate compared with those who did not receive NSAIAs (20 versus 12 deaths per 100 person-years). Although the absolute mortality rate declined somewhat after the first year following the myocardial infarction, the increased relative risk of death in patients who received NSAIAs persisted over at least the next 4 years of follow-up.

In 2 large controlled clinical trials of a selective COX-2 inhibitor for the management of pain in the first 10-14 days following coronary artery bypass graft (CABG) surgery, the incidence of myocardial infarction and stroke was increased. Therefore, NSAIAs are contraindicated in the setting of CABG surgery.

Findings from some systematic reviews of controlled observational studies and meta-analyses of data from randomized studies of NSAIAs suggest that naproxen may be associated with a lower risk of cardiovascular thrombotic events compared with other NSAIAs. However, limitations of these observational studies and the indirect comparisons used to assess cardiovascular risk of the prototypical NSAIAs (e.g., variability in patients' risk factors, comorbid conditions, concomitant drug therapy, drug interactions, dosage, and duration of therapy) affect the validity of the comparisons; in addition, these studies were not designed to demonstrate superior safety of one NSAIA compared with another. Therefore, FDA states that definitive conclusions regarding relative risks of NSAIAs are not possible at this time.

Data from observational studies also indicate that use of NSAIAs in patients with heart failure is associated with increased morbidity and mortality. Results from a retrospective study utilizing Danish national registry data indicated that use of selective COX-2 inhibitors or prototypical NSAIAs in patients with chronic heart failure was associated with a dose-dependent increase in the risk of death and an increased risk of hospitalization for myocardial infarction or heart failure. In addition, findings from a meta-analysis of published and unpublished data from randomized controlled trials of NSAIAs indicated that use of selective COX-2 inhibitors or prototypical NSAIAs was associated with an approximate twofold increase in the risk of hospitalization for heart failure. Fluid retention and edema also have been observed in some patients receiving NSAIAs.

There is no consistent evidence that use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.

GI Effects

Adverse GI effects reported in approximately 1-10% of patients receiving piroxicam include anorexia, abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gross bleeding/perforation, heartburn, nausea, gastric and duodenal ulcers, and vomiting. Other adverse GI effects occurring occasionally in patients receiving piroxicam include dry mouth, esophagitis, gastritis, glossitis, hematemesis, melena, rectal bleeding, and stomatitis. Eructation and pancreatitis have been reported rarely in patients receiving the drug.

Some reports have suggested that the incidence of piroxicam-induced peptic ulceration and GI bleeding may be higher with usual dosages (particularly in geriatric patients) and higher than that associated with other currently available NSAIAs; however, these suggestions have not been clearly substantiated, and there are recognized methodologic problems associated with the data on which they are based. An analysis by FDA of spontaneous adverse drug reaction reports, adjusted for the heterogeneity of underlying reporting rates, suggested that although the rate was highest for piroxicam compared with other NSAIAs, large and clinically important differences in the rates of upper GI bleeding, ulcer, and perforation between piroxicam and other NSAIAs probably do not exist; however, the possibility that piroxicam may be more ulcerogenic could not be ruled out by this analysis. Further evaluation is needed. In general, usual dosages of piroxicam reportedly produce fewer adverse GI effects than usual anti-inflammatory dosages of aspirin. In one study, GI bleeding as determined by fecal blood loss was less in patients receiving 20 mg of piroxicam daily than in those receiving 3.9 g of aspirin daily for 4 days. In addition, GI mucosal changes were not observed during gastroscopic examination in patients receiving piroxicam; however, mucosal lesions were seen in aspirin-treated patients.

Serious adverse GI effects (e.g., bleeding, inflammation, ulceration, perforation) can occur at any time in patients receiving NSAIA therapy, and such effects may not be preceded by warning signs or symptoms. Only 1 in 5 patients who develop a serious upper GI adverse event while receiving NSAIA therapy is symptomatic. Therefore, clinicians should remain alert to the possible development of serious GI effects (e.g., bleeding, ulceration) in any patient receiving NSAIA therapy, and such patients should be followed chronically for the development of manifestations of such effects and advised of the importance of this follow-up. In addition, patients should be advised about the signs and symptoms of serious NSAIA-induced GI toxicity and what action to take if they occur. If signs and symptoms of a serious GI event develop, additional evaluation and treatment should be initiated promptly; the NSAIA should be discontinued until appropriate diagnostic studies have ruled out a serious GI event.

Results of studies to date are inconclusive concerning the relative risk of various prototypical NSAIAs in causing serious GI effects. In patients receiving NSAIAs and observed in clinical studies of several months' to 2 years' duration, symptomatic upper GI ulcers, gross bleeding, or perforation appeared to occur in approximately 1% of patients treated for 3-6 months and in about 2-4% of those treated for 1 year. Longer duration of therapy with an NSAIA increases the likelihood of a serious GI event. However, short-term therapy is not without risk. High dosages of any NSAIA probably are associated with increased risk of such effects, although controlled studies documenting this probable association are lacking for most NSAIAs. Therefore, whenever use of relatively high dosages (within the recommended dosage range) is considered, sufficient benefit to offset the potential increased risk of GI toxicity should be anticipated.

Studies have shown that patients with a history of peptic ulcer disease and/or GI bleeding who are receiving NSAIAs have a substantially higher risk of developing GI bleeding than patients without these risk factors. In addition to a history of ulcer disease, pharmacoepidemiologic studies have identified several comorbid conditions and concomitant therapies that may increase the risk for GI bleeding, including concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAIA therapy, smoking, alcoholism, older age, and poor general health status. Patients with rheumatoid arthritis are more likely to experience serious GI complications from NSAIA therapy than are patients with osteoarthritis. In addition, geriatric or debilitated patients appear to tolerate GI ulceration and bleeding less well than other individuals, and most spontaneous reports of fatal GI effects have been in such patients.

For patients at high risk for complications from NSAIA-induced GI ulceration (e.g., bleeding, perforation), concomitant use of misoprostol can be considered for preventive therapy. Alternatively, some clinicians suggest that concomitant use of a proton-pump inhibitor (e.g., omeprazole) may be used concomitantly to decrease the incidence of serious GI toxicity associated with NSAIA therapy. In one study, therapy with high dosages of famotidine (40 mg twice daily) was more effective than placebo in preventing peptic ulcers in NSAIA-treated patients; however, the effect of the drug was modest. In addition, efficacy of usual dosages of H2-receptor antagonists for the prevention of NSAIA-induced gastric and duodenal ulcers has not been established. Therefore, most clinicians do not recommend use of H2-receptor antagonists for the prevention of NSAIA-associated ulcers. Another approach in high-risk patients who would benefit from NSAIA therapy is use of an NSAIA that is a selective inhibitor of COX-2 (e.g., celecoxib), since these agents are associated with a lower incidence of serious GI bleeding than are prototypical NSAIAs. However, while celecoxib (200 mg twice daily) was comparably effective to diclofenac sodium (75 mg twice daily) plus omeprazole (20 mg daily) in preventing recurrent ulcer bleeding (recurrent ulcer bleeding probabilities of 4.9 versus 6.4%, respectively, during the 6-month study) in H. pylori-negative arthritis (principally osteoarthritis) patients with a recent history of ulcer bleeding, the protective efficacy was unexpectedly low for both regimens and it appeared that neither could completely protect patients at high risk. Additional study is necessary to elucidate optimal therapy for preventing GI complications associated with NSAIA therapy in high-risk patients.

Hematologic Effects

Anemia and increased bleeding time has been reported in 1-10% of patients receiving piroxicam. Other adverse hematologic effects occurring occasionally in patients receiving piroxicam include ecchymosis, eosinophilia, epistaxis, leukopenia, and thrombocytopenia. Agranulocytosis, hemolytic anemia, aplastic anemia, lymphadenopathy, and pancytopenia have been reported rarely in patients receiving the drug.

Piroxicam inhibits platelet aggregation and may prolong bleeding time. Patients who may be adversely affected by a prolongation of bleeding time should be carefully observed during piroxicam therapy. One patient developed cutaneous (severe ecchymoses) and occult GI bleeding following 2 months of piroxicam therapy; bleeding subsided following discontinuance of the drug and it was suggested that the hemostatic abnormality may have resulted from a drug-induced increase in antithrombin III activity.

Renal Effects

Abnormal renal function has been reported in 1-10% of patients receiving piroxicam. Other adverse renal effects reported occasionally in patients receiving piroxicam include cystitis, dysuria, hematuria, hyperkalemia, interstitial nephritis, nephrotic syndrome, oliguria/polyuria, proteinuria, and renal failure. Acute nephrotoxicity, manifested as severe azotemia with hyperkalemia or as acute interstitial nephritis with immune complex glomerulonephritis, has occurred rarely in patients receiving piroxicam; in one patient, azotemia resolved following discontinuance of the drug. As with other NSAIAs, long-term piroxicam therapy has resulted in renal papillary necrosis and other renal medullary changes.

Nervous System Effects

Adverse nervous system effects reportedly occurring in 1-10% of patients receiving piroxicam include dizziness and headache. Anxiety, asthenia, confusion, depression, dream abnormalities, drowsiness, insomnia, malaise, nervousness, paresthesia, somnolence, tremors, and vertigo occur occasionally in patients receiving piroxicam. Other adverse effects reported rarely include akathisia, seizures, coma, hallucinations, meningitis, and mood alterations.

Ocular and Otic Effects

Tinnitus has been reported to occur in 1-10% of patients receiving piroxicam. Blurred vision has been reported occasionally and conjunctivitis, hearing impairment, and swollen eyes have been reported rarely in patients receiving piroxicam.

Hepatic Effects

Elevated liver function test results have been reported in 1-10% of patients receiving piroxicam. Hepatitis and jaundice have been reported occasionally and liver failure and pain due to colic have been reported rarely. Studies of piroxicam in patients with impaired liver function have not been performed to date.

Borderline elevations of one or more liver function test results may occur in up to 15% of patients treated with NSAIAs; notable (approximately 3 or more times the upper limit of normal) elevations of serum ALT (SGPT) or AST (SGOT) concentration have occurred in approximately 1% of patients receiving NSAIAs in controlled clinical studies. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. Piroxicam should be discontinued if signs or symptoms of a severe hepatic reaction occur.(See Cautions: Precautions and Contraindications.)

Dermatologic and Sensitivity Reactions

Adverse dermatologic effects including pruritus and rash have occurred in 1-10% of patients receiving piroxicam. Alopecia, bruising, desquamation, erythema, petechial rash, photosensitivity, purpura, and sweating have been reported occasionally. Other adverse effects reported rarely include angioedema, anaphylactic reactions, toxic epidermal necrosis, erythema multiforme, exfoliative dermatitis, onycholysis, positive ANA, Stevens-Johnson syndrome, urticaria, and vesiculobullous reaction. Signs and symptoms suggestive of serum sickness (i.e., arthralgias, pruritus, fever, rash, including vesiculobullous reactions and exfoliative dermatitis) have occurred in patients receiving piroxicam. Pemphigus vulgaris, which was fatal, has been reported in at least one patient receiving piroxicam; however, a causal relationship to the drug has not been established.

Other Adverse Effects

Fever, infection, sepsis, weight changes, asthma, and dyspnea have been reported occasionally in piroxicam-treated patients. Appetite changes, death, flu-like syndrome, hyperglycemia, hypoglycemia, pneumonia, and respiratory depression have been reported rarely in patients receiving the drug.

Precautions and Contraindications

Patients should be advised that piroxicam, like other NSAIAs, is not free of potential adverse effects, including some that can cause discomfort, and that more serious effects (e.g., myocardial infarction, stroke, GI bleeding), which may require hospitalization and may even be fatal, also can occur. Patients also should be informed that, while NSAIAs may be commonly employed for conditions that are less serious, NSAIA therapy often is considered essential for the management of some diseases, and the drugs have a major role in the management of pain. Clinicians may wish to discuss with their patients the potential risks and likely benefits of NSAIA therapy, particularly when consideration is being given to use of these drugs in less serious conditions for which therapy without an NSAIA may represent an acceptable alternative to both the patient and clinician.

Patients should be advised to read the medication guide for NSAIAs that is provided to the patient each time the drug is dispensed.

NSAIAs may increase the risk of serious adverse cardiovascular thrombotic events.(See Cautions: Cardiovascular Effects.) To minimize the potential risk of adverse cardiovascular events, the lowest effective dosage and shortest possible duration of therapy should be employed. Some clinicians suggest that it may be prudent to avoid use of NSAIAs whenever possible in patients with cardiovascular disease. Patients receiving NSAIAs (including those without previous symptoms of cardiovascular disease) should be monitored for the possible development of cardiovascular events throughout therapy. Patients should be informed about the signs and symptoms of serious cardiovascular toxicity (chest pain, dyspnea, weakness, slurring of speech) and instructed to seek immediate medical attention if such toxicity occurs. Piroxicam should be avoided in patients with recent myocardial infarction unless the benefits of therapy are expected to outweigh the risk of recurrent cardiovascular thrombotic events; if piroxicam is used in such patients, the patient should be monitored for cardiac ischemia.

There is no consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs. Concomitant use of aspirin and an NSAIA increases the risk for serious GI events. Because of the potential for increased adverse effects, patients receiving piroxicam should be advised not to take aspirin.

Use of NSAIAs, including piroxicam, can result in the onset of hypertension or worsening of preexisting hypertension; either of these occurrences may contribute to the increased incidence of cardiovascular events. Patients receiving NSAIAs may have an impaired response to diuretics (i.e., thiazide or loop diuretics), angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, or β-adrenergic blocking agents. NSAIAs, including piroxicam, should be used with caution in patients with hypertension. Blood pressure should be monitored closely during initiation of piroxicam therapy and throughout therapy.

Because NSAIAs increase morbidity and mortality in patients with heart failure, the manufacturer states that piroxicam should be avoided in patients with severe heart failure unless the benefits of therapy are expected to outweigh the risk of worsening heart failure; if piroxicam is used in such patients, the patient should be monitored for worsening heart failure. Some experts state that use of NSAIAs should be avoided whenever possible in patients with reduced left ventricular ejection fraction and current or prior symptoms of heart failure. Patients receiving NSAIAs should be advised to inform their clinician if they experience symptoms of heart failure, including dyspnea, unexplained weight gain, and edema. Use of NSAIAs may diminish the cardiovascular effects of certain drugs used to treat heart failure and edema (e.g., diuretics, ACE inhibitors, angiotensin II receptor antagonists).(See Drug Interactions.)

The risk of potentially serious adverse GI effects should be considered in patients receiving piroxicam, particularly in patients receiving chronic therapy with the drug. (See Cautions: GI Effects.) Administration of higher than recommended dosages (i.e., more than 20 mg daily) of piroxicam in clinical trials has been associated with increased frequency of GI irritation and ulceration. Piroxicam should be used with caution and under close supervision in patients with a history of upper GI disease. Since peptic ulceration and/or GI bleeding have been reported in patients receiving the drug, patients should be advised to promptly report signs or symptoms of GI ulceration or bleeding to their clinician.

Piroxicam should be used with extreme caution and under close supervision in patients with a history of GI bleeding or peptic ulceration, and such patients should receive an appropriate ulcer preventive regimen. All patients considered at increased risk of potentially serious adverse GI effects (e.g., geriatric patients, those receiving high therapeutic dosages of NSAIAs, those with a history of peptic ulcer disease, those receiving anticoagulants or corticosteroids concomitantly) should be monitored closely for signs of ulcer perforation or GI bleeding.To minimize the potential risk of adverse GI effects, the lowest effective dosage and shortest possible duration of therapy should be employed. For patients who are at high risk, therapy other than an NSAIA should be considered.

Piroxicam should be used with caution in patients who may be adversely affected by a prolongation of bleeding time (e.g., patients receiving anticoagulant therapy), since the drug inhibits platelet function. If signs and/or symptoms of anemia occur during therapy with piroxicam, hemoglobin concentration and hematocrit should be determined.

Patients who experience signs and/or symptoms suggestive of liver dysfunction or an abnormal liver function test result while receiving piroxicam should be evaluated for evidence of the development of a more severe hepatic reaction. Severe reactions, including jaundice and fatal fulminant hepatitis, liver necrosis, and hepatic failure (sometimes fatal), have occurred in patients receiving NSAIAs. Although such reactions are rare, piroxicam should be discontinued if abnormal liver function test results persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash).(See Cautions: Hepatic Effects.)

Piroxicam is not a substitute for corticosteroid therapy. Use of corticosteroids during NSAIA therapy may increase the risk of GI ulceration and the drugs should be used concomitantly with caution. If corticosteroid dosage is decreased during piroxicam therapy, it should be done gradually, and patients should be observed for adverse effects including adrenocortical insufficiency or symptomatic exacerbation of the inflammatory condition being treated.

Because NSAIAs have caused adverse ocular effects, patients who experience visual disturbances during piroxicam therapy should have an ophthalmologic examination.

The possibility that the antipyretic effects of piroxicam may mask the usual signs and symptoms of infection should be considered.

Renal toxicity has been observed in patients in whom renal prostaglandins have a compensatory role in maintaining renal perfusion. Administration of an NSAIA to such patients may cause a dose-dependent reduction in prostaglandin formation and thereby precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, or hepatic dysfunction, those with extracellular fluid depletion (e.g., patients receiving diuretics); those taking an ACE inhibitor or angiotensin II receptor antagonist concomitantly; and geriatric patients. Patients should be advised to consult their clinician promptly if unexplained weight gain or edema occurs. Recovery of renal function to pretreatment levels usually occurs following discontinuance of NSAIA therapy. Some clinicians recommend that renal function be monitored periodically in patients receiving long-term NSAIA therapy.

Piroxicam has not been evaluated in patients with severe renal impairment, and the manufacturer states that use of piroxicam is not recommended in patients with advanced renal disease. If piroxicam is used in patients with severe renal impairment, close monitoring of renal function is recommended.

Anaphylactoid reactions have been reported in patients receiving piroxicam. Patients receiving piroxicam should be informed of the signs and symptoms of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat) and advised to seek immediate medical attention if an anaphylactoid reaction develops.

Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) can occur in patients receiving piroxicam. These serious skin reactions may occur without warning; patients should be advised to consult their clinician if skin rash and blisters, fever, or other signs of hypersensitivity reaction (e.g., pruritus) occur. Piroxicam should be discontinued at the first appearance of rash or any other sign of hypersensitivity.

Patients receiving long-term NSAIA therapy should have a complete blood cell count and chemistry profile performed periodically.

The manufacturers state that piroxicam is contraindicated in patients with known hypersensitivity to the drug. In addition, NSAIAs, including piroxicam, generally are contraindicated in patients in whom asthma, urticaria, or other sensitivity reactions are precipitated by aspirin or other NSAIAs, since there is potential for cross-sensitivity between NSAIAs and aspirin, and severe, often fatal, anaphylactic reactions may occur in such patients. Although NSAIAs generally are contraindicated in these patients, the drugs have occasionally been used in NSAIA-sensitive patients who have undergone desensitization. Because patients with asthma may have aspirin-sensitivity asthma, piroxicam should be used with caution in patients with asthma. In patients with asthma, aspirin sensitivity is manifested principally as bronchospasm and usually is associated with nasal polyps; the association of aspirin sensitivity, asthma, and nasal polyps is known as the aspirin triad. For a further discussion of cross-sensitivity of NSAIAs,

Piroxicam is contraindicated in the setting of CABG surgery.

Pediatric Precautions

Although some clinicians have used piroxicam in children for symptomatic relief of juvenile rheumatoid arthritis, safety and efficacy of the drug in children have not been established.

Geriatric Precautions

Piroxicam should be used with caution in geriatric individuals 65 years of age or older. Geriatric individuals appear to tolerate GI ulceration and bleeding less well than other individuals, and many of the spontaneous reports of fatal adverse GI effects in patients receiving NSAIAs involve geriatric individuals. Use of the lowest effective dosage for the shortest possible duration should be considered in geriatric patients.

Pregnancy and Lactation

Pregnancy

Although there are no adequate and controlled studies to date in humans, piroxicam has not been shown to be teratogenic in animals. Like other NSAIAs, piroxicam has caused dystocia and prolongation of labor in animals. Although not reported to date with piroxicam, inhibitors of prostaglandin synthesis may have adverse effects on the fetal cardiovascular system (e.g., premature closure of the ductus arteriosus). In addition, the manufacturers state that in animal studies adverse GI effects occurred more frequently in pregnant females receiving the drug during the third trimester than in nonpregnant females or in pregnant females receiving the drug in the first or second trimester. The manufacturer states that piroxicam is not recommended for use during pregnancy (particularly late pregnancy).

Lactation

Piroxicam is distributed into milk, and the manufacturer states that the drug is not recommended for use in nursing women.

Drug Interactions

Protein-bound Drugs

Because piroxicam is highly protein bound, it theoretically could be displaced from binding sites by, or it could displace from binding sites, other protein-bound drugs such as oral anticoagulants, salicylates, and sulfonylureas. Patients receiving any drugs that are highly protein bound should be closely monitored for a change in dosage requirements if piroxicam is administered concomitantly.

Anticoagulants and Thrombolytic Agents

The effects of warfarin and NSAIAs on GI bleeding are synergistic. Concomitant use of piroxicam and warfarin is associated with a higher risk of GI bleeding compared with use of either agent alone.

Concomitant administration of piroxicam and acenocoumarol (not commercially available in the US) has resulted in potentiation of acenocoumarol's anticoagulant effect as determined by slightly prolonged prothrombin and partial thromboplastin times.

Because piroxicam may cause GI bleeding, inhibit platelet aggregation, and/or potentiate anticoagulant effects, the drug should be used with caution in patients receiving any anticoagulant (e.g., warfarin) or thrombolytic agent (e.g., streptokinase). If piroxicam is indicated in patients receiving oral anticoagulants, prothrombin time should be monitored closely and oral anticoagulant dosage should be adjusted accordingly, and patients should be observed for adverse effects.

Nonsteroidal Anti-inflammatory Agents

Concomitant use of aspirin and an NSAIA increases the risk for serious GI events. Because of the potential for increased adverse effects, patients receiving piroxicam should be advised not to take aspirin. There is no consistent evidence that use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.

The manufacturers state that plasma piroxicam concentrations are decreased by about 20% when 20 mg of piroxicam daily is administered concomitantly with 3.9 g of aspirin daily.

Antacids

Concomitant use of piroxicam and antacids does not appear to affect plasma piroxicam concentrations. In one study following concomitant administration of piroxicam and antacid tablets containing aluminum hydroxide alone or combined with magnesium hydroxide for 5 days, substantial differences in mean plasma piroxicam concentrations were not observed during or after concomitant antacid administration.

Angiotensin-converting Enzyme Inhibitors and Angiotensin II Receptor Antagonists

Concomitant use of NSAIAs with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor antagonists may reduce the blood pressure response to the antihypertensive agent.

Diuretics

There is evidence from clinical studies and postmarketing reports that concomitant use of piroxicam can reduce the natriuretic effects of furosemide or thiazide diuretics. This effect may be related to inhibition of renal prostaglandin synthesis. Concomitant use of piroxicam and diuretics may increase the risk of renal failure.(See Cautions: Precautions and Contraindications.)

Lithium

Like other NSAIAs, piroxicam has been reported to increase serum lithium concentrations and may reduce renal clearance of lithium. The mechanism involved in the reduction of lithium clearance by NSAIAs is not known, but has been attributed to inhibition of prostaglandin synthesis, which may interfere with the renal elimination of lithium. In addition, piroxicam-induced inhibition of prostaglandin synthesis may inhibit renal sodium excretion, which may result in increased lithium reabsorption from the renal tubule. When piroxicam therapy is initiated in patients receiving lithium or when dosage of piroxicam is adjusted or the drug is discontinued in these patients, plasma lithium concentrations should be monitored and the patient should be observed for signs and symptoms of lithium intoxication.

Methotrexate

NSAIAs and methotrexate should be used concomitantly with caution. Like other NSAIAs, piroxicam has been reported to decrease the renal clearance of methotrexate and may lead to increased serum methotrexate concentrations and potential toxicity when used concomitantly, particularly with high methotrexate dosage.

Pharmacokinetics

Pharmacokinetic studies to date have not revealed race-related differences in the pharmacokinetics of piroxicam. The pharmacokinetics of piroxicam have not been studied in pediatric patients. Studies in patients with mild to moderate renal impairment have not revealed pharmacokinetic differences that would require dosage adjustment of piroxicam; however, studies have not been conducted in patients with severe renal insufficiency or in those undergoing hemodialysis. The pharmacokinetics of piroxicam in individuals with hepatic disease have not been determined.

Absorption

Piroxicam is well absorbed following oral administration. Food decreases the rate but not the extent of absorption of piroxicam. Absorption of piroxicam does not appear to be affected by concomitant administration of antacids.

Following oral administration of a single 20-mg dose of piroxicam, the drug appears in plasma within 15-30 minutes and peak plasma concentrations of approximately 1.5-2 mcg/mL usually are reached within 3-5 hours. In one study, the presence of a secondary peak in plasma piroxicam concentrations was reported, suggesting that piroxicam may undergo enterohepatic circulation. Peak plasma concentrations of 3-8 mcg/mL are reached following multiple-dose administration of 20 mg daily. Relatively stable plasma concentrations of piroxicam are maintained during the day following administration of single daily doses. Following repeated daily administration of piroxicam, substantial drug accumulation occurs. Steady-state plasma concentrations of piroxicam are usually reached within 7-12 days. In patients with prolonged plasma half-lives (greater than 50 hours) of piroxicam, higher peak plasma concentrations of the drug have been observed with steady-state plasma concentrations being reached in 2-3 weeks. Plasma concentrations of piroxicam required for analgesic effect are approximately 2 mcg/mL. Optimum anti-inflammatory activity of piroxicam reportedly occurs at plasma concentrations of at least 5 mcg/mL.

Distribution

At plasma concentrations of 5-30 mcg/mL, 99.3% of piroxicam is bound to plasma proteins in vitro. In healthy individuals, piroxicam reportedly has an apparent volume of distribution of 0.12-0.14 L/kg.

Piroxicam is distributed into synovial fluid in concentrations about 40% of simultaneous plasma concentrations; however, substantial interindividual variation has been observed. In addition, there is some evidence that piroxicam accumulates slowly in cartilage.

Following oral administration, piroxicam is distributed into milk in concentrations approximately 1-3% of concurrent maternal plasma concentrations. Piroxicam does not appear to accumulate in milk.

Elimination

The plasma half-life of piroxicam has been reported to range from 14-158 hours in healthy adults. The manufacturer states that the half-life of piroxicam averages 50 hours.

Piroxicam appears to be extensively metabolized. The drug is metabolized principally by hydroxylation at the 5-position of the pyridinyl side chain followed by conjugation with glucuronic acid. At steady-state, about 50% of a dose of piroxicam is metabolized via hydroxylation and glucuronide conjugation of the hydroxy metabolite. Although the rate of formation of the hydroxy metabolite is slow, the metabolite appears to be excreted and/or conjugated rapidly since only trace amounts appear in plasma. Cyclodehydration and a sequence of reactions involving hydrolysis of the amide linkage, decarboxylation, ring contraction, and N-demethylation have been shown to occur in animals; however, these appear to be minor metabolic pathways in humans. The metabolites of piroxicam reportedly do not inhibit prostaglandin synthesis and have little or no anti-inflammatory activity.

Piroxicam and its metabolites are excreted principally in urine and feces; urinary excretion of the drug is about twice the fecal excretion. Piroxicam is excreted principally as metabolites and less than 5% of an administered dose is excreted unchanged in urine and feces.

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