 |
 |
 |
 |
 |
 |
 |
 |
 |
 |
 |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Piroxicam
FELDENE® (piroxicam) is 4-Hydroxy-2-methyl-N-2-pyridinyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide, an oxicam. Members of the oxicam family are not carboxylic acids, but they are acidic by virtue of the enolic 4-hydroxy substituent. FELDENE occurs as a white crystalline solid, sparingly soluble in water, dilute acid and most organic solvents. It is slightly soluble in alcohols and in aqueous alkaline solution. It exhibits a weakly acidic 4-hydroxy proton (pKa 5.1) and a weakly basic pyridyl nitrogen (pKa 1.8). Molecular Formula: C15H13N304S Molecular Weight: 331.35 Inert ingredients in the formulations are: hard gelatin
capsules (which may contain Blue 1, Red 3, and other inert
ingredients); lactose; magnesium stearate; sodium
lauryl sulfate; starch.
FELDENE has shown anti-inflammatory, analgesic, and antipyretic properties in animals. Edema, erythema, tissue proliferation, fever, and pain can all be inhibited in laboratory animals by the administration of FELDENE. It is effective regardless of the etiology of the inflammation. The mode of action of FELDENE is not fully established at this time. However, a common mechanism for the above effects may exist in the ability of FELDENE to inhibit the biosynthesis of prostaglandins, known mediators of inflammation. It is established that FELDENE does not act by stimulating the pituitary-adrenal axis. FELDENE is well absorbed following oral administration. Drug plasma concentrations are proportional for 10 and 20 mg doses, generally peak within three to five hours after medication, and subsequently decline with a mean half-life of 50 hours (range of 30 to 86 hours, although values outside of this range have been encountered). This prolonged half-life results in the maintenance of relatively stable plasma concentrations throughout the day on once daily doses and to significant drug accumulation upon multiple dosing. A single 20 mg dose generally produces peak piroxicamplasma levels of 1.5 to 2 mcg/mL, while maximum drug plasma concentrations, after repeated daily ingestion of 20 mg FELDENE, usually stabilize at 3-8 mcg/mL. Most patients approximate steady state plasma levels within 7 to 12 days. Higher levels, which approximate steady state at two to three weeks, have been observed in patients in whom longer plasma half-lives of piroxicam occurred. FELDENE and its biotransformation products are excreted in urine and feces, with about twice as much appearing in the urine as the feces. Metabolism occurs by hydroxylation at the 5 position of the pyridyl side chain and conjugation of this product; by cyclodehydration; and by a sequence of reactions involving hydrolysis of the amide linkage, decarboxylation, ring contraction, and N-demethylation. Less than 5% of the daily dose is excreted unchanged. Concurrent administration of aspirin (3900 mg/day) and FELDENE (20 mg/day), resulted in a reduction of plasma levels of piroxicam to about 80% of their normal values. The use of FELDENE in conjunction with aspirin is not recommended because data are inadequate to demonstrate that the combination produces greater improvement than that achieved with aspirin alone and the potential for adverse reactions is increased. Concomitant administration of antacids had no effect on FELDENE plasma levels. The effects of impaired renal function or hepatic disease on plasma levels have not been established. FELDENE, like salicylates and other nonsteroidal anti-inflammatory agents, is associated with symptoms of gastrointestinal tract irritation (see ADVERSE REACTIONS). However, in a study utilizing 51Cr-tagged red blood cells, 20 mg of FELDENE administered as a single dose for four days did not result in a significant increase in fecal blood loss and did not detectably affect the gastric mucosa. In the same study a total daily dose of 3900 mg of aspirin, i.e., 972 mg q.i.d., caused a significant increase in fecal blood loss and mucosal lesions as demonstrated by gastroscopy. In controlled clinical trials, the effectiveness of FELDENE (piroxicam) has been established for both acute exacerbations and long-term management of rheumatoid arthritis and osteoarthritis. The therapeutic effects of FELDENE 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 FELDENE display a therapeutic effect comparable to therapeutic doses of aspirin, with a lower incidence of minor gastrointestinal effects and tinnitus. FELDENE has been administered concomitantly with fixed doses of
gold and corticosteroids. The existence of a "steroid-sparing"
effect has not been adequately studied to date.
FELDENE is indicated for acute or long-term use in the relief of signs and symptoms of the following: 1. osteoarthritis Dosage recommendations for use in children have not been established.
Rheumatoid Arthritis, Osteoarthritis It is recommended that FELDENE therapy be initiated and maintained at a single daily dose of 20 mg. If desired the daily dose may be divided. Because of the long half-life of FELDENE, steady-state blood levels are not reached for 7 to 12 days. Therefore although the therapeutic effects of FELDENE 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. Dosage recommendations and indications for use in children have not been established. HOW SUPPLIED FELDENE® Capsules for oral administration Bottles of 100:
Bottles of 500:
Unit dose packages of
100:
The incidence of adverse reactions to piroxicam is based on clinical trials involving approximately 2300 patients, about 400 of whom were treated for more than one year and 170 for more than two years. About 30% of all patients receiving daily doses of 20 mg of FELDENE experienced side effects. Gastrointestinal symptoms were the most prominent side effects—occurring in approximately 20% of the patients, which in most instances did not interfere with the course of therapy. Of the patients experiencing gastrointestinal side effects, approximately 5% discontinued therapy with an overall incidence of peptic ulceration of about 1%. Other than the gastrointestinal symptoms, edema, dizziness, headache, changes in hematological parameters, and rash have been reported in a small percentage of patients. Routine ophthalmoscopy and slit-lamp examinations have revealed no evidence of ocular changes in 205 patients followed from 3 to 24 months while on therapy. Incidence Greater Than 1% Gastrointestinal: stomatitis, anorexia, epigastric distress*, nausea*, constipation, abdominal discomfort, flatulence, diarrhea, abdominal pain, indigestion Hematological: decreases in hemoglobin* and hematocrit* (see PRECAUTIONS), anemia, leucopenia, eosinophilia Dermatologic: pruritus, rash Central Nervous System: dizziness, somnolence, vertigo Urogenital: BUN and creatinine elevations (see PRECAUTIONS ) Body as a Whole: headache, malaise Special Senses: tinnitus Cardiovascular/Respiratory: edema (seePRECAUTIONS ) * Reactions occurring in 3% to 9% of patients treated with FELDENE. Reactions occurring in 1-3% of patients are unmarked. Incidence Less Than 1% (Causal Relationship Probable) Gastrointestinal: liver function abnormalities, jaundice, hepatitis (see PRECAUTIONS ), vomiting, hematemesis, melena, gastrointestinal bleeding, perforation and ulceration (see WARNINGS ), dry mouth Hematological: thrombocytopenia, petechial rash, ecchymosis, bone marrow depression including aplastic anemia, epistaxis Dermatologic: sweating, erythema, bruising, desquamation, exfoliative dermatitis, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, vesiculo bullous reaction, photoallergic skin reactions Central Nervous System: depression, insomnia, nervousness Urogenital: hematuria, proteinuria, interstitial nephritis, renal failure, hyperkalemia, glomerulitis, papillary necrosis, nephrotic syndrome (see PRECAUTIONS ) Body as a Whole: pain (colic), fever, flu-like syndrome (see PRECAUTIONS ) Special Senses: swollen eyes, blurred vision, eye irritations Cardiovascular/Respiratory: hypertension, worsening of congestive heart failure (see PRECAUTIONS ), exacerbation of angina Metabolic: hypoglycemia, hyperglycemia, weight increase, weight decrease Hypersensitivity: anaphylaxis, bronchospasm, urticaria/angioedema, vasculitis, "serum sickness" (see PRECAUTIONS ) Incidence Less Than 1% (Causal Relationship Unknown) Gastrointestinal: pancreatitis Dermatologic: onycholysis, loss of hair Central Nervous System: akathisia, hallucinations, mood alterations, dream abnormalities, mental confusion, paresthesias Urogenital System: dysuria Body as a Whole: weakness Cardiovascular/Respiratory: palpitations, dyspnea Hypersensitivity: positive ANA Special Senses: transient hearing loss Hematological: hemolytic
anemia
FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with coumarin-type anticoagulants, interactions with coumarin-type anticoagulants have been reported with FELDENE since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on coumarin-type anticoagulants and other highly protein-bound drugs. Plasma levels of piroxicam are depressed to approximately 80% of their normal values when FELDENE is administered in conjunction with aspirin (3900 mg/day), but concomitant administration of antacids has no effect on piroxicam plasma levels (see CLINICAL PHARMACOLOGY ). Nonsteroidal anti-inflammatory
agents, including FELDENE, have been reported to increase steady
state plasma
lithium levels. It is
recommended that plasma
lithium levels be monitored
when initiating, adjusting and discontinuing FELDENE.
Risk of GI Ulceration, Bleeding, and Perforation with NSAID Therapy Serious gastrointestinal toxicity such as bleeding, ulceration, and perforation can occur at any time, with or without warning symptoms, in patients treated chronically with NSAID therapy. Although minor upper gastrointestinal problems, such as dyspepsia, are common, usually developing early in therapy, physicians should remain alert for ulceration and bleeding in patients treated chronically with NSAIDs even in the absence of previous GI tract symptoms. In patients observed in clinical trials of several months to two years duration, symptomatic upper GI ulcers, gross bleeding or perforation appear to occur in approximately 1% of patients treated for 3 to 6 months, and in about 2 to 4% of patients treated for one year. Physicians should inform patients about the signs and/or symptoms of serious GI toxicity and what steps to take if they occur. Studies to date have not identified any subset of patients not at risk of developing peptic ulceration and bleeding. Except for a prior history of serious GI events and other risk factors known to be associated with peptic ulcer disease, such as alcoholism, smoking, etc., no risk factors (e.g., age, sex) have been associated with increased risk. Elderly or debilitated patients seem to tolerate ulceration or bleeding less well than other individuals and most spontaneous reports of fatal GI events are in this population. Studies to date are inconclusive concerning the relative risk of various NSAIDs in causing such reactions. High doses of any NSAID probably carry a greater risk of these reactions, although controlled clinical trials showing this do not exist in most cases. In considering the use of relatively large doses (within the recommended dosage range), sufficient benefit should be anticipated to offset the potential increased risk of GI toxicity.
Renal Effects: As with other nonsteroidal anti-inflammatory drugs, long-term administration of piroxicam to animals has resulted in renal papillary necrosis and other abnormal renal pathology. In humans, there have been reports of acute interstitial nephritis with hematuria, proteinuria, and occasionally, nephrotic syndrome. A second form of renal toxicity has been seen in patients with prerenal conditions leading to a reduction in renal blood flow or blood volume, where the renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics, and the elderly. Discontinuation of NSAID therapy is typically followed by recovery to the pretreatment state. Because of extensive renal excretion of piroxicam and its biotransformation products (less than 5% of the daily dose excreted unchanged, see CLINICAL PHARMACOLOGY), lower doses of piroxicam should be anticipated in patients with impaired renal function, and they should be carefully monitored. Although other nonsteroidal anti-inflammatory drugs do not have the same direct effects on platelets that aspirin does, all drugs inhibiting prostaglandin biosynthesis do interfere with platelet function to some degree; therefore, patients who may be adversely affected by such an action should be carefully observed when FELDENE is administered. Because of reports of adverse eye findings with nonsteroidal anti-inflammatory agents, it is recommended that patients who develop visual complaints during treatment with FELDENE have ophthalmic evaluation. As with other nonsteroidal anti-inflammatory drugs, borderline elevations of one or more liver tests may occur in up to 15% of patients. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. The SGPT (ALT) test is probably the most sensitive indicator of liver dysfunction. Meaningful (three times the upper limit of normal) elevations of SGPT or SGOT (AST) occurred in controlled clinical trials in less than 1% of patients. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of more severe hepatic reaction while on therapy with FELDENE. Severe hepatic reactions, including jaundice and cases of fatal hepatitis, have been reported with FELDENE. Although such reactions are rare, if abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), FELDENE should be discontinued. (See also ADVERSE REACTIONS.) Although at the recommended dose of 20 mg/day of FELDENE increased fecal blood loss due to gastrointestinal irritation did not occur (see CLINICAL PHARMACOLOGY), in about 4% of the patients treated with FELDENE alone or concomitantly with aspirin, reductions in hemoglobin and hematocrit values were observed. Therefore, these values should be determined if signs or symptoms of anemia occur. Peripheral edema has been observed in approximately 2% of the patients treated with FELDENE. Therefore, as with other nonsteroidal anti-inflammatory drugs, FELDENE should be used with caution in patients with heart failure, hypertension or other conditions predisposing to fluid retention, since its usage may be associated with a worsening of these conditions. A combination of dermatological and/or allergic signs and symptoms suggestive of serum sickness have occasionally occurred in conjunction with the use of FELDENE. These include arthralgias, pruritus, fever, fatigue, and rash including vesiculo bullous reactions and exfoliative dermatitis. Information for Patients FELDENE, like other drugs of its class, is not free of side effects. The side effects of these drugs can cause discomfort and rarely, there are more serious side effects, such as gastrointestinal bleeding, which may result in hospitalization and even fatal outcomes. NSAIDs (Nonsteroidal Anti-Inflammatory Drugs) are often essential agents in the management of arthritis, but they also may be commonly employed for conditions which are less serious. Physicians may w.s. to
discuss with their patients the potential
risks (see Laboratory Tests Because serious GI tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients for the signs and symptoms of ulceration and bleeding and should inform them of the importance of this follow-up (see Risk of GI Ulceration, Bleeding and Perforation with NSAID Therapy). Drug Interactions FELDENE is highly protein bound, and therefore, might be expected to displace other protein-bound drugs. Although this has not occurred in in vitro studies with coumarin-type anticoagulants, interactions with coumarin-type anticoagulants have been reported with FELDENE since marketing, therefore, physicians should closely monitor patients for a change in dosage requirements when administering FELDENE to patients on coumarin-type anticoagulants and other highly protein-bound drugs. Plasma levels of piroxicam are depressed to approximately 80% of their normal values when FELDENE is administered in conjunction with aspirin (3900 mg/day), but concomitant administration of antacids has no effect on piroxicam plasma levels (see CLINICAL PHARMACOLOGY). Nonsteroidal anti-inflammatory agents, including FELDENE, have been reported to increase steady state plasma lithium levels. It is recommended that plasma lithium levels be monitored when initiating, adjusting and discontinuing FELDENE. Carcinogenesis, Chronic Animal Toxicity and Impairment of Fertility Subacute and chronic toxicity studies have been carried out in rats, mice, dogs, and monkeys. The pathology most
often seen was that characteristically associated with the animal
toxicology of anti-inflammatory
agents: renal papillary
necrosis (see In classical studies in laboratory animals piroxicam did not show any teratogenic potential. Reproductive studies revealed no impairment of fertility in animals. Pregnancy and Nursing Mothers Like other drugs that inhibit the synthesis and release of prostaglandins, piroxicam increased the incidence of dystocia and delayed parturition in pregnant animals when piroxicam administration was continued late into pregnancy. Gastrointestinal tract toxicity was increased in pregnant females in the last trimester of pregnancy compared to non-pregnant females or females in earlier trimesters of pregnancy. FELDENE is not recommended for use in nursing mothers or in pregnant women because of the animal findings and since safety for such use has not been established in humans. Use in Children Dosage recommendations and indications for use in children
have not been established.
|
| |||