FEXICAM
Technilab
Piroxicam
Nonsteroidal Anti-inflammatory – Analgesic – Antipyretic
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. Its anti-inflammatory action may be partially explained by the resulting decrease in prostaglandin biosynthesis. Its therapeutic action is not due to 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 of piroxicam are achieved in about 4 hours. When the drug is administered daily, the 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 an observation period of 4 days, 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 five 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 were substantially greater than the mean.
Indications And Clinical Uses: For the symptomatic treatment of rheumatoid arthritis, osteoarthritis (degenerative joint disease) and ankylosing spondylitis and primary dysmenorrhea.
Contra-Indications: Active peptic ulcer, a history of recurrent ulceration or active inflammatory disease of the gastrointestinal system.
Known or suspected hypersensitivity to the drug or other nonsteroidal anti-inflammatory drugs. The potential for cross-reactivity between different NSAIDs must be kept in mind.
Piroxicam should not be used in patients with the complete or partial syndrome of nasal polyps, or in whom asthma, anaphylaxis, urticaria, rhinitis or other allergic manifestations are precipitated by ASA or other nonsteroidal anti-inflammatory agents. Fatal anaphylactoid reactions have occurred in such individuals. As well, individuals with the above medical problems are at risk of a severe reaction even if they have taken NSAIDs in the past without any adverse effects.
Significant hepatic impairment or active liver disease.
Piroxicam is not recommended for use with other NSAIDs because of the absence of any evidence demonstrating synergistic benefits and the potential for additive side effects.
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: Gastrointestinal: Serious gastrointestinal toxicity, such as peptic ulceration, perforation and gastrointestinal bleeding, sometimes severe and occasionally fatal can occur at any time, with or without symptoms in patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs) including piroxicam.
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 with nonsteroidal anti-inflammatory drugs, even in the absence of previous gastrointestinal tract symptoms.
In patients observed in clinical trials of such agents, symptomatic upper gastrointestinal 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 1 year. The risk continues beyond 1 year and possibly increases.
The incidence of these complications increases with increasing dose.
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 such as ulcerative colitis and Crohn’s disease. In these cases, the physician must weigh the benefits of treatment against the possible hazards.
Physicians should inform patients about the signs and/or symptoms of serious gastrointestinal toxicity and instruct them to contact a physician immediately if they experience persistent dyspepsia or other symptoms or signs suggestive of gastrointestinal ulceration or bleeding.
Because serious gastrointestinal tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients by checking their hemoglobin periodically and by being vigilant for the signs and symptoms of ulceration and bleeding and should inform the patients of the importance of this follow-up.
If ulceration is suspected or confirmed, or if gastrointestinal bleeding occurs, piroxicam should be discontinued immediately, appropriate treatment instituted and the patient monitored closely.
No studies, to date, have identified any group of patients not at risk of developing ulceration and bleeding. A prior history of serious gastrointestinal events and other factors such as excess alcohol intake, smoking, age, female gender and concomitant oral steroid and anticoagulant use have been associated with increased risk.
Studies to date show that all NSAIDs can cause gastrointestinal tract adverse events. Although existing data does not clearly identify differences in risk between various NSAIDs, this may be shown in the future.
Geriatrics: Patients older than 65 years and frail or debilitated patients are most susceptible to a variety of adverse reactions from nonsteroidal anti-inflammatory drugs: the incidence of these adverse reactions increases with dose and duration of treatment. In addition, these patients are less tolerant to ulceration and bleeding. Most reports of fatal gastrointestinal events are in this population. Older patients are also at risk of lower esophageal ulceration and bleeding.
For such patients, consideration should be given to a starting dose lower than the one usually recommended, with individual adjustment when necessary and under close supervision. See Precautions for further advice.
Cross-sensitivity: Patients sensitive to any one of the nonsteroidal anti-inflammatory drugs may also be sensitive to any of the other NSAIDs.
Aseptic Meningitis: In occasional cases, with some NSAIDs, the symptoms of aseptic meningitis (stiff neck, severe headaches, nausea and vomiting, fever or clouding of consciousness) have been observed. Patients with autoimmune disorders (systemic lupus erythematosus, mixed connective tissues diseases, etc.) seem to be predisposed. Therefore, in such patients, the physician must be vigilant to the development of this complication.
Pregnancy , Labor 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.
Children: The administration of piroxicam is not recommended in children under 16 years of age as the dose and indications have not been established.
Doses of piroxicam greater than 20 mg daily should not be used. The minimum maintenance dose needed to control symptoms is recommended.
Precautions: Gastrointestinal: 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 the continuation of piroxicam therapy when and if these adverse reactions appear.
Renal Function: Long-term administration of nonsteroidal anti-inflammatory drugs 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 the 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 a nonsteroidal anti-inflammatory drug 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 nonsteroidal anti-inflammatory therapy is usually followed by recovery to the pretreatment state.
Piroxicam and its metabolites are eliminated primarily by the kidneys; therefore, the drug should be used with great caution in patients with impaired renal function. In these cases, utilization of lower doses of piroxicam should be considered and patients carefully monitored.
During long-term therapy, kidney function should be monitored periodically.
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.
Genitourinary: Some NSAIDs are known to cause persistent urinary symptoms (bladder pain, dysuria, urinary frequency), hematuria or cystitis. The onset of these symptoms may occur at any time after the initiation of therapy with an NSAID. Some cases have become severe on continued treatment. Should urinary symptoms occur, treatment with piroxicam must be stopped immediately to obtain recovery. This should be done before any urological investigations or treatments are carried out.
Hepatic Function: As with other nonsteroidal anti-inflammatory drugs, borderline elevations of one or more liver function tests may occur in up to 15% of patients. The ALT test is probably the most sensitive indication 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. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. 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 NSAIDs.
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.
During long-term therapy, liver function tests should be monitored periodically. If there is a need to prescribe this drug 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. Piroxicam should be used with caution in patients with heart failure, hypertension or other conditions predisposing to fluid retention.
With nonsteroidal anti-inflammatory treatment there is a potential risk of hyperkalemia, particularly in patients with conditions such as diabetes mellitus or renal failure; elderly patients; or in patients receiving concomitant therapy with b-adrenergic blockers, angiotensin-converting enzyme inhibitors or some diuretics. Serum electrolytes should be monitored periodically during long-term therapy, especially in those patients who are at risk.
Hematology: Drugs inhibiting prostaglandin biosynthesis do interfere with platelet function to varying degrees; therefore, patients who may be adversely affected by such an action should be carefully observed when piroxicam is administered.
Blood dyscrasias (such as neutropenia, leukopenia, thrombocytopenia, aplastic anemia and agranulocytosis) associated with the use of nonsteroidal anti-inflammatory drugs are rare, but could occur with severe consequences.
At the recommended dose of 20 mg/day of piroxicam, 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.
Infection: In common with other anti-inflammatory drugs, piroxicam may mask the usual signs of infection.
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.
CNS: Some patients may experience drowsiness, dizziness, vertigo, insomnia or depression with the use of piroxicam. If patients experience these side effects, they should exercise caution in carrying out activities that require alertness.
Hypersensitivity Reactions: 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 arthralgia, pruritus, fever, fatigue and rash including vesiculo bullous reactions and exfoliative dermatitis.
Drug Interactions: ASA or other NSAIDs: The use of piroxicam in addition to any other NSAID, including those over-the-counter drugs (such as ASA and ibuprofen), is not recommended due to the possibility of additive side effects.
Plasma concentrations of piroxicam are reduced to approximately 80% of their normal concentrations when piroxicam is administered in conjunction with ASA (3 900 mg/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.
Digoxin or Digitoxin: Concurrent therapy with piroxicam and digoxin and/or piroxicam and digitoxin did not affect the plasma levels of either drug.
Anticoagulants: Numerous studies have shown that the concomitant use of NSAIDs and anticoagulants increases the risk of gastrointestinal adverse events such as ulceration and bleeding.
Because prostaglandins play an important role in hemostasis, and NSAIDs affect platelet function, concurrent therapy of piroxicam with warfarin requires close monitoring to be certain that no change in anticoagulant dosage is necessary.
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.
Diuretics: As with other nonsteroidal anti-inflammatory drugs, 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.
Antihypertensives: 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.
Glucocorticoids: Numerous studies have shown that the concomitant use of NSAIDs and oral glucocorticoids increases the risk of gastrointestinal side effects such as ulceration and bleeding. This is especially the case in older (>65 years of age) individuals.
Antacids: Concomitant administration of antacids had no effect on piroxicam plasma levels.
Methotrexate: Although 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.
Lithium: As with other nonsteroidal anti-inflammatory drugs, piroxicam has been reported to increase steady-state plasma lithium concentrations. It is recommended that these concentrations are monitored when initiating, adjusting and discontinuing piroxicam treatment.
Other Drug Interactions : 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.
Cholestyramine: Preliminary study indicates that in healthy subjects co-administration 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 appears 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 piroxicam 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, 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 the 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.
Anorectal 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.
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.
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.
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, ALT, AST 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 that 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 measures, 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.
Dosage And Administration: Adults: Oral: In rheumatoid arthritis and ankylosing spondylitis it is recommended that therapy with piroxicam capsules be initiated as a single daily dose of 20 mg. If desired, this dose may be given as 10 mg b.i.d. 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 b.i.d. 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: 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 Fexicam suppositories, when used alone, is identical with the dosage of piroxicam capsules.
Fexicam 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.
Use whole suppositories. Do not split or use portions of suppositories.
Combined Administration: The total daily dose of piroxicam administered as capsule and/or suppositories should not exceed 20 mg/day.
Fexicam is available only as a 20 mg suppository.
Availability And Storage: Each white to yellowish, smooth torpedo-shaped suppository contains: piroxicam USP 20 mg. Nonmedicinal ingredients: semisynthetic glycerides. Boxes of 30. Store between 15 and 30°C.
FEXICAM Technilab Piroxicam Nonsteroidal Anti-inflammatory – Analgesic – Antipyretic
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