| FELDENE™ |
|Anti-inflammatory - Analgesic |
|Action And Clinical Pharmacology: Piroxicam is a nonsteroidal anti-inflammatory agent with analgesic and antipyretic properties. Its mechanism of action is incompletely known. Piroxicam inhibits the activity of prostaglandin synthetase. The resulting decrease in prostaglandin biosynthesis may partially explain its anti-inflammatory action. Piroxicam does not act by pituitary-adrenal stimulation.
In rheumatoid arthritis the efficacy of piroxicam 20 mg daily has been found to be similar to 4.5 g daily of ASA.
Piroxicam is well absorbed following oral or rectal administration. After a single oral dose of 20 mg, peak plasma levels are achieved in about 4 hours. When the drug is administered daily, plasma concentrations increase for 7 to 12 days during which a steady state is reached. Concentrations attained are not exceeded following further constant daily drug intake. The plasma half-life is approximately 50 hours in man. The extent and rate of absorption are not influenced by administration with food or antacids.
After a single rectal dose of 20 mg, the pharmacokinetics are similar to that obtained after oral administration except for peak plasma levels which are achieved at about 10 hours.
Piroxicam is extensively metabolized and less than 5% of the daily dose is excreted unchanged in urine and feces. The main metabolic pathway is hydroxylation of the pyridyl ring, followed by conjugation with glucuronic acid and urinary elimination. Approximately 5% of the dose is metabolized to and excreted as saccharin.
Over a 4-day period of observation, 20 healthy men, taking piroxicam 20 mg daily in single or divided doses, showed significantly less mean daily fecal blood loss than did 10 healthy male controls taking 3.9 g of ASA daily.
The effects of age and sex on the pharmacokinetics of piroxicam have been examined in 3 single-dose, 3 multiple-dose, and 5 therapeutic drug-monitoring studies. Although not consistent across all studies, some indicated a tendency towards a modest decrease in total body clearances and an increase in elimination half-life and steady-state plasma concentrations in the elderly, particularly elderly females. Irrespective of age, some patients had plasma concentration levels that are substantially greater than the mean.
Indications And Clinical Uses: The symptomatic treatment of rheumatoid arthritis, osteoarthritis (degenerative joint disease) and ankylosing spondylitis and primary dysmenorrhea.
Contra-Indications: Peptic ulcer or active inflammatory disease of the gastrointestinal system, or patients with a recent or recurrent history of these conditions.
Known or suspected hypersensitivity to the drug. Piroxicam should not be used in patients in whom acute asthmatic attacks or symptoms of asthma, urticaria, rhinitis (nasal polyps), angioedema or other allergic manifestations are precipitated by ASA or other nonsteroidal anti-inflammatory agents since cross-sensitivity exists. Fatal anaphylactoid reactions have occurred in such individuals.
Piroxicam suppositories should not be used in patients with any inflammatory lesions of the rectum or anus, or in patients with a recent history of rectal or anal bleeding.
Manufacturers' Warnings In Clinical States: Peptic ulceration, perforation and gastrointestinal bleeding, sometimes severe, and occasionally fatal, have been reported during therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) including piroxicam.
Piroxicam should be given under close medical supervision to patients prone to gastrointestinal tract irritation particularly those with a history of peptic ulcer, diverticulosis or other inflammatory disease of the gastrointestinal tract. In these cases the physician must weigh the benefits of treatment against the possible hazards.
Patients taking any NSAID including this drug should be instructed to contact a physician immediately if they experience symptoms or signs suggestive of peptic ulceration or gastrointestinal bleeding. These reactions can occur without warning symptoms or signs and at any time during the treatment.
Elderly, frail and debilitated patients appear to be at higher risk from a variety of adverse reactions from nonsteroidal anti-inflammatory drugs. For such patients, consideration should be given to a starting dose lower than usual, with individual adjustment when necessary and under close supervision (see Precautions for further advice).
Gastrointestinal side effects are dose-related and doses greater than 20 mg daily should not be used. The minimum maintenance dose needed to control symptoms is recommended.
Pregnancy and Lactation: The use of piroxicam during pregnancy or lactation is not recommended as its safety in these conditions has not been established. The presence of piroxicam in breast milk has been determined during initial and long-term dosing conditions (52 days). Piroxicam appeared in breast milk at about 1 to 3% of the maternal plasma concentration. No accumulation of piroxicam occurred in milk relative to that in plasma during treatment.
No teratogenic effects have been observed in animal reproductive studies. Rats and rabbits receiving piroxicam during pregnancy have shown an increased frequency of dystocia and delayed parturition. Rats have exhibited suppression of lactation.
Precautions: Gastrointestinal System: If peptic ulceration is suspected or confirmed, or if gastrointestinal bleeding or perforation occurs piroxicam should be discontinued, an appropriate treatment instituted and patient closely monitored.
There is no definitive evidence that the concomitant administration of histamine H2-receptor antagonists and/or antacids will either prevent the occurrence of gastrointestinal side effects or allow continuation of therapy when and if these adverse reactions appear (see Drug Interactions).
Renal Function: 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.
Acute renal failure and hyperkalemia as well as reversible elevations of BUN and serum creatinine have been reported with piroxicam. The effect is thought to result from inhibition of renal prostaglandin synthesis resulting in a change in medullary and deep cortical blood flow with an attendant effect on renal function. Patients with impaired renal function or on diuretics, as well as elderly patients and those with congestive heart failure or liver cirrhosis with ascites are more at risk. Because of the extensive renal excretion of piroxicam and its biotransformation products (less than 5% of the daily dose excreted unchanged), lower doses of piroxicam should be anticipated in patients with impaired renal function and they should be carefully monitored.
During long-term therapy kidney function should be monitored periodically.
Hepatic Function: As with other nonsteroidal anti-inflammatory drugs, borderline elevations of one or more liver test may occur. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. The ALT test is probably the most sensitive indicator of liver dysfunction. Meaningful (3 times the upper limit of normal) elevations of ALT or 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 this drug. Severe hepatic reactions, including jaundice and cases of fatal hepatitis, have been reported with this drug as with other nonsteroidal anti-inflammatory drugs. 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.), this drug should be discontinued (see Adverse Effects).
During long-term therapy, liver function tests should be monitored periodically. If this drug is to be used in the presence of impaired liver function, it must be done under strict observation.
Fluid and Electrolyte Balance: Fluid retention and edema have been observed in patients treated with piroxicam. Therefore, as with many other nonsteroidal anti-inflammatory drugs, the possibility of precipitating congestive heart failure in elderly patients or those with compromised cardiac function should be borne in mind. The drug should be used with caution in patients with heart failure, hypertension or other conditions predisposing to fluid retention since its use may be associated with worsening of these conditions.
Serum electrolytes should be monitored periodically during long-term therapy, especially in those patients at risk.
Hematology: 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 piroxicam is administered.
At the recommended dose of 20 mg/day increased fecal blood loss due to gastrointestinal irritation did not occur, but in about 4% of the patients treated with piroxicam alone or concomitantly with ASA, reductions in hemoglobin and hematocrit values were observed. Therefore, these values should be determined periodically.
Blood dyscrasias associated with the use of nonsteroidal anti-inflammatory drugs are rare, but could be with severe consequences.
Infection: In common with other anti-inflammatory drugs, piroxicam may mask the usual signs of infection.
Dermatological and/or Allergic: A combination of dermatological and/or allergic signs and symptoms suggestive of serum sickness have occasionally occurred in conjunction with the use of piroxicam. These include arthralgias, pruritus, fever, fatigue and rash including vesiculo bullous reactions and exfoliative dermatitis.
Ophthalmology: Blurred and/or diminished vision has been reported with the use of piroxicam and other nonsteroidal anti-inflammatory drugs. If such symptoms develop this drug should be discontinued and an ophthalmologic examination performed; ophthalmic examination should be performed at periodic intervals in any patient receiving this drug for an extended period of time.
Children: Piroxicam is not recommended for use in children under 16 years of age as the dose and indications have not been established.
Drug Interactions: ASA or other NSAIDs: Plasma concentrations of piroxicam are reduced to approximately 80% of their normal concentrations when piroxicam is administered in conjunction with ASA (3.9 g/day). The use of piroxicam in conjunction with ASA or another nonsteroidal anti-inflammatory agent is not recommended since data are not available demonstrating that the combination produces greater improvement than that achieved with either drug alone and the potential for adverse reactions is increased.
Anticoagulants: Piroxicam is highly protein bound, and therefore, might be expected to displace other protein bound drugs. The physician should closely monitor dosage requirements of coumarin anticoagulants and other drugs that are highly protein bound when these are administered concomitantly with piroxicam.
Lithium: Nonsteroidal anti-inflammatory agents, including piroxicam, have been reported to increase steady-state plasma lithium concentrations. It is recommended that these concentrations are monitored when initiating, adjusting and discontinuing drug treatment.
Cimetidine: Results of 2 separate studies indicate a slight increase in absorption of piroxicam following cimetidine administration but no significant changes in elimination parameters. Cimetidine increases the area under the curve (AUC 0 to 120 hours) and Cmax of piroxicam by approximately 13 to 15%. Elimination rate constants and half-life show no significant differences. The clinical significance of this small but significant increase in absorption is yet unknown.
Digoxin or Digitoxin: Concurrent therapy with piroxicam and digoxin and/or piroxicam and digitoxin did not affect the plasma levels of either drug.
Antacids: Concomitant administration of antacids had no effect on piroxicam plasma levels.
Diuretics: Nonsteroidal anti-inflammatory drugs, including piroxicam may cause sodium and fluid retention, and may interfere with the natriuretic action of diuretic agents. These properties should be kept in mind when treating patients with compromised cardiac function or hypertension since they may be responsible for a worsening of those conditions.
Methotrexate: Although up to date there have been no reports of an interaction with piroxicam, isolated cases indicate that the concomitant use of some NSAIDs in patients receiving methotrexate may be associated with severe or sometimes fatal methotrexate toxicity.
Until more information is available on this interaction, caution should be used if piroxicam as well as other NSAIDs, are administered concomitantly with methotrexate, particularly in patients with pre-existing renal impairment, who may be more susceptible.
Beta-adrenergic Blockers: As with other nonsteroidal anti-inflammatory drugs, concomitant administration of piroxicam with propranolol can reduce the hypotensive effect. Patients should be monitored for altered antihypertensive or antianginal response to beta-blockers when piroxicam is initiated or discontinued.
Cholestyramine: Preliminary study indicates that in healthy subjects coadministration of cholestyramine to piroxicam results in enhanced elimination of piroxicam (i.e., reduction in half-life by 40% and increase in clearance by 52%). Although the magnitude of these changes in piroxicam disposition appear sufficient to inhibit its therapeutic effects, studies in patients are needed to confirm this. It is suggested that the doses of piroxicam and cholestyramine be separated as much as possible, and that the patients be monitored for inadequate response to therapy. If an inadequate anti-inflammatory response appears to be related to the concomitant use of cholestyramine, consideration should be given to the use of alternative hypolipidemic therapy.
Adverse Reactions: The most common adverse reactions encountered with nonsteroidal anti-inflammatory drugs are gastrointestinal, of which peptic ulcer, with or without bleeding is the most severe. Fatalities have occurred on occasion, particularly in the elderly.
In approximately 2 300 patients receiving a daily dose of 20 mg or less of piroxicam in clinical trials, the most frequent side effects observed have been gastrointestinal (approximately 20% of patients). Of the patients experiencing gastrointestinal side effects, approximately 5% discontinued therapy with an overall incidence of peptic ulceration of about 1% and gastrointestinal bleeding of approximately 0.1%. The incidence of adverse reactions is summarized below.
Gastrointestinal (17.4%): epigastric distress (6.4%), nausea (4.1%), constipation (2.4%), abdominal discomfort (2.2%), flatulence (2.1%), diarrhea (1.8%), abdominal pain (1.5%), indigestion (1.3%), anorexia (1.2%), peptic ulceration (about 1%); stomatitis, vomiting, hematemesis, melena, perforation, dry mouth, pancreatitis, each in less than 1% of patients.
Ano-rectal reaction presenting as local pain, burning, pruritus, tenesmus and rare instances of rectal bleeding have been reported in 2.9% of patients with the use of piroxicam suppositories.
Allergic (<1%): anaphylaxis, bronchospasm, urticaria/angioedema, vasculitis, serum sickness (see Precautions), each in less than 1% of patients.
CNS (5%): headache (1.8%), malaise (1%); dizziness, drowsiness/sedation (somnolence), vertigo, depression, hallucinations, insomnia, nervousness, paresthesia, personality change, dream abnormalities, mental confusion, each in less than 1% of patients.
Dermatologic (2%): rash (2%); pruritus, erythema, bruising, desquamation, exfoliative dermatitis, erythema multiforme, toxic epidermal necrolysis (Lyell's Disease), vesiculo bullous reaction, onycholysis, Stevens-Johnson syndrome, photoallergic skin reactions, each in less than 1% of patients.
Cardiovascular (<1%): hypertension, palpitations, worsening of congestive heart failure (see Precautions), exacerbation of angina, each in less than 1% of patients.
Special Senses: Eyes, ears, nose and throat reactions (<1%): tinnitus (about 1%); blurred vision, eye irritation/swelling, each in less than 1% of patients.
Hematologic (15%): decreases in hemoglobin (4.6%) and hematocrit (4.2%) (see Precautions), thrombocytopenia (2.4%), eosinophilia (1.8%), leukocytosis (1.7%), basophilia (1.7%), leukopenia (1.4%); petechial rash, ecchymosis, bone marrow depression including aplastic anemia, epistaxis, each in less than 1% of patients.
Renal (1%): edema (1.6%) (see Precautions); dysuria, hematuria, proteinuria, interstitial nephritis, renal failure, hyperkalemia, glomerulitis, nephrotic syndrome (see Precautions), each in less than 1% of patients.
Hepatic (<1%): jaundice, hepatitis (see Precautions), each in less than 1% of patients.
Respiratory (<1%): dyspnea.
Metabolic (<1%): hypoglycemia, hyperglycemia, weight increase/decrease, each in less than 1% of patients.
Miscellaneous (<1%): sweating, pain (colic), fever, flu-like syndrome (see Precautions), weakness, each in less than 1% of patients.
Primary Dysmenorrhea: In primary dysmenorrhea the side effect profile of piroxicam is similar in nature to that observed in rheumatic diseases.
Laboratory Parameters: Changes in laboratory parameters observed during piroxicam therapy have included an elevation of BUN, creatinine (see Precautions), uric acid and liver enzymes LDH, AST, ALT and alkaline phosphatase.
Other: Since market introduction, isolated reports have included delayed wound healing, thrombophlebitis, pemphigus, alopecia, mastodynia, reduction or loss of libido, impotence, urinary frequency, oliguria, menorrhagia, amnesia, anxiety, tremor, hearing impairment, deafness, thirst, chills, increased appetite, akathisia, tachycardia, flushing, tooth discoloration, glossitis, chest pain, anemia, hemolytic anemia, pancreatitis, and positive antinuclear factor (ANA); a causal relationship has not been established for those rarely reported events.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: In the event treatment for overdosage is required, the long plasma half-life (see Pharmacology) of piroxicam should be considered. The absence of experience with acute overdosage precludes characterization of sequelae and recommendation of specific antidotal efficacy at this time. It is reasonable to assume, however, that the standard measures of gastric evacuation and general supportive therapy would apply. In addition to supportive measure, the use of activated charcoal may effectively reduce the absorption and reabsorption of piroxicam. Experiments in dogs have demonstrated that the use of multiple-dose treatments with activated charcoal could reduce the half-life of piroxicam elimination from 27 hours (without charcoal) to 11 hours and reduce the systemic bioavailability of piroxicam by as much as 37% when activated charcoal is given as late as 6 hours after administration of piroxicam. tag_DosageDosage
Dosage And Administration: Oral: In rheumatoid arthritis and ankylosing spondylitis it is recommended that therapy with piroxicam be initiated as a single daily dose of 20 mg. If desired, this dose may be given as 10 mg twice a day. Most patients will be maintained on 20 mg daily. A relatively small number of patients may be maintained on 10 mg daily.
In osteoarthritis the recommended starting dosage of piroxicam is 20 mg once daily. If desired, this dose may be given as 10 mg twice a day. The usual maintenance dose is 10 to 20 mg daily.
Piroxicam should not be given in doses greater than 20 mg daily owing to an increased incidence of gastrointestinal side effects.
Geriatrics and Debilitated: As elderly patients appear to be at higher risk from a variety of adverse reactions from nonsteroidal anti-inflammatory drugs and as elderly, frail or debilitated patients tolerate gastrointestinal side effects less well, consideration should be given to a starting dose that is lower than usual and to an increase of the dose only if symptoms remain uncontrolled. Such patients must be very carefully supervised.
In primary dysmenorrhea the treatment is initiated at the earliest onset of symptoms with a recommended starting dose of 40 mg given as a single daily dose on the first day. For the remainder of the treatment period (usually 2 to 4 days), the dose should be reduced to 20 mg daily.
Rectal: For each indication, the dosage of piroxicam suppositories, when used alone, is identical with the dosage of piroxicam capsules.
Suppositories offer an alternative route of administration for those physicians who may wish to prescribe them in certain patients, or for those patients who prefer them.
Combined Administration: The total daily dose administered as capsules and/or suppositories should not exceed 20 mg/day.
Availability And Storage: Capsules: 10 mg: Each No. 2 maroon/blue opaque hard gelatin capsule, printed with Feldene and Pfizer, contains: piroxicam 10 mg. Nonmedicinal ingredients: cornstarch, lactose and magnesium stearate/sodium lauryl sulfate; capsule shell: gelatin, silicon dioxide, titanium dioxide and dyes FD&C Red No. 3 and FD&C Blue No 1. Tartrazine-free. Bottles of 100.
20 mg: Each No. 2 maroon/opaque hard gelatin capsule, printed with Feldene and Pfizer, contains: piroxican 20 mg. Nonmedicinal ingredients: cornstarch, lactose and magnesium stearate/sodium lauryl sulfate; capsule shell: gelatin, silicon dioxide, titanium dioxide and dyes FD&C Red No. 3 and FD&C Blue No 1. Tartrazine-free. Bottles of 100.
Suppositories: 10 mg: Each white to off-white torpedo-shaped suppository contains: piroxicam 10 mg. Nonmedicinal ingredients: semisynthetic glycerides, microcrystalline wax and propyl gallate. Packages of 30.
20 mg: Each white to off-white torpedo-shaped suppository contains: piroxicam 20 mg. Nonmedicinal ingredients: semisynthetic glycerides, microcrystalline wax and propyl gallate. Packages of 30.
Store at 15 to 30°C.