DAYPRO
Searle
Oxaprozin
Anti-inflammatory – Analgesic
Action And Clinical Pharmacology: Oxaprozin is a nonsteroidal anti-inflammatory agent with analgesic and antipyretic properties. The modes of action of oxaprozin, like that of other nonsteroidal anti-inflammatory agents, are not fully established. It is known, however, that it does inhibit prostaglandin synthesis.
Pharmacokinetics: Oxaprozin is almost completely absorbed from the gastrointestinal tract, with peak plasma levels attained 2 to 4 hours after administration. The mean peak plasma concentration (Cmax) is approximately 120 µg/mL with a single dose of 1 200 mg and approximately 190 µg/mL at steady-state. At therapeutic levels, more than 99% of oxaprozin is bound to plasma proteins, mostly albumin. The mean biological half-life in humans is approximately 50 hours. Total body clearance of oxaprozin rises from 2.5 mL/h/kg after a single 1 200 mg dose to 5 mL/h/kg at steady-state. The apparent volume of distribution rises from 180 to 300 mL/kg from single dose to steady-state. These increases are due to nonlinear protein binding. One study demonstrated that food had no effect on the extent of absorption of oral doses of oxaprozin in healthy subjects, whereas the rate of absorption was slightly slower. No abnormal drug accumulation occurred in patients treated with multiple doses (1 200 mg/day) for up to 6 months.
A dual metabolism has been identified for oxaprozin. Approximately 60% of the drug is oxidized to hydroxyoxaprozin I or II and approximately 30% is glucuronidated to form oxaprozin acyl glucuronide. These inactive metabolic products are excreted in the feces (one third) and in the urine (two thirds). About 30% of an oral dose is recovered as conjugates in urine.
Less than 5% is recovered as oxaprozin. Biliary excretion in cholecystectomized humans accounts for 5% of the drug in 5 days. Oxaprozin does not induce its own metabolism.
Oxaprozin disposition during steady-state conditions is not affected by either subject age or sex. However the volume of distribution declined with increasing age (see Dosage).
The pharmacokinetics of oxaprozin in patients with impaired renal function, patients maintained on hemodialysis, and healthy subjects were evaluated following a single 600 mg oral dose. Total body clearance and elimination half-life did not differ substantially among the 3 groups. In a multiple dose study of subjects and patients with normal albumin levels, who were undergoing hemodialysis, total body clearance and volume of distribution of unbound drug were higher in patients undergoing hemodialysis. Total oxaprozin levels were not affected and there was no evidence of accumulation in subjects or renally impaired patients. Caution should be used when oxaprozin is given to patients with renal impairment (see Dosage).
One study compared the pharmacokinetics of a single dose of oxaprozin in patients with cirrhosis. Elimination half-life, and clearance of unbound drug were unchanged.
The elimination half-life, volume of distribution, and total body clearance of unbound oxaprozin following a single dose were similar for patients with congestive heart failure as compared to healthy subjects.
The effects of therapeutic doses of oxaprozin (1 200 mg) and ASA (3 900 mg) on the gastric mucosa and fecal blood were studied in healthy subjects. Oxaprozin produced significantly less submucosal hemorrhage or bleeding than did ASA in a 10-day crossover study utilizing gastroscopic evaluation of the gastric mucosa. The average amount of fecal blood loss that was induced by oxaprozin during a 2 week study using 1r-labelled autologous red blood cells was similar to that caused by placebo during the second week, but was significantly greater during the first week. The fecal blood loss induced by oxaprozin was significantly less than that caused by ASA throughout the 2-week study.
The effects of oxaprozin on renal function were studied in normal subjects and in patients with impaired renal function. In clearance studies of normal subjects during sustained water diuresis, oxaprozin caused no acute reduction in glomerular filtration rate (GFR), had no effect on overall sodium clearance, and had no long-term effect on serum creatinine, blood urea nitrogen, or serum potassium. In renally impaired patients with a GFR below 30 to 40 mL/min and in patients undergoing hemodialysis, oxaprozin was distributed more extensively because of a reduction in binding to plasma proteins. The mean biological half-life was not altered by renal disease, although urinary excretion of both oxaprozin and its conjugates was greatly reduced. A multiple-dose study in patients undergoing hemodialysis demonstrated no impairment of total or unbound clearance in the disease state.
Indications And Clinical Uses: For acute and chronic use in the relief of the signs and symptoms of rheumatoid arthritis and osteoarthritis.
Contra-Indications: Active peptic ulcer, a history of recurrent ulceration or active inflammatory disease of the gastrointestinal system. Known or suspected hypersensitivity to oxaprozin, its components, or other NSAIDs. The potential for cross-reactivity between different NSAIDs must be kept in mind. Oxaprozin 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 with other NSAIDs. 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. Severely impaired or deteriorating renal function (creatinine clearance
Manufacturers’ Warnings In Clinical States: 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 NSAIDs, including oxaprozin.
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 NSAIDs, 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.
Oxaprozin 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, oxaprozin 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 NSAIDs; their incidence increases with dose and duration of treatment. In addition, these patients are less tolerant of ulceration and bleeding and 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 usual, with individual adjustment when necessary, and under close supervision (see Precautions).
Cross-sensitivity: Patients sensitive to any one of the NSAIDs may be sensitive to any of the other NSAIDs also.
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 weigh the benefits of therapy against the possible hazards before prescribing and must be vigilant to the development of this complication.
Pregnancy and Lactation : The use of oxaprozin during pregnancy is not recommended as its safety in this condition has not been established. Oxaprozin should be used during pregnancy only if the benefit justifies the potential risk to the fetus and/or mother.
Oxaprozin is not recommended for use in nursing mothers, since many NSAIDs have been shown to be partially excreted in breast milk. Oxaprozin has been found in the milk of lactating rats.
Children: Oxaprozin is not recommended for use in patients less than 18 years of age.
Precautions: Gastrointestinal System: If gastrointestinal bleeding or perforation is suspected or occurs, oxaprozin should be discontinued, and appropriate treatment instituted and the patient closely monitored.
If gastric ulceration is suspected or confirmed, oxaprozin should be discontinued, and appropriate treatment instituted and the patient closely monitored.
There is no definitive evidence that the concomitant administration of sucralfate, omeprazole, histamine H2-receptor antagonists and/or antacids will either prevent the occurrence of gastrointestinal side effects or allow continuation of the NSAID therapy when and if these adverse reactions appear.
Renal Function: Long-term administration of some NSAIDs 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 NSAID may cause a dose-dependent reduction in prostaglandin formation and may precipitate overt renal decompensation.
Patients at greater 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.
Oxaprozin and its metabolites are eliminated primarily by the kidneys and therefore, the drug should be used with great caution in patients with impaired renal function. In these cases, lower doses of oxaprozin should be anticipated and patients carefully monitored.
During long-term therapy, kidney function should be monitored periodically.
Genitourinary Tract: 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 oxaprozin 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 NSAIDs, borderline elevations of one or more liver function tests may occur in up to 15% 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 oxaprozin. Severe hepatic reactions including jaundice and cases of fatal hepatitis have been reported with oxaprozin as with other 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.), oxaprozin should be discontinued.
During long-term therapy, liver function tests should be monitored periodically. If oxaprozin needs 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 oxaprozin. Therefore, as with many other NSAIDs, the possibility of precipitating congestive heart failure in elderly patients or those with compromised cardiac function should be born in mind.
Oxaprozin should be used with caution in patients with heart failure, hypertension or other conditions predisposing to fluid retention. With NSAID 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 beta-adrenergic blockers, angiotensin converting enzyme inhibitors or some diuretics.
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 varying degrees, therefore, patients who may be adversely affected by such an action should be carefully observed when oxaprozin is administered.
Blood dyscrasias (such as neutropenia, leukopenia, thrombocytopenia, aplastic anemia and agranulocytosis) associated with the use of NSAIDs are rare, but could occur with severe consequences.
Anemia may occur in patients receiving oxaprozin or other NSAIDs. This may be due to fluid retention, gastrointestinal blood loss, or an incompletely described effect upon erythrogenesis. Patients on long-term treatment with oxaprozin should have their hemoglobin or hematocrit values determined at appropriate intervals as determined by the clinical situation.
Infection: In common with other anti-inflammatory drugs, oxaprozin may mask the usual signs of infection.
Ophthalmology: Blurred and/or diminished vision has been reported with the use of oxaprozin and other NSAIDs. If such symptoms develop, this drug should be discontinued and an ophthalmologic examination performed; ophthalmologic examination should be carried out at periodic intervals in any patient receiving this drug for an extended period of time.
Occupational Hazards: CNS: Some patients may experience drowsiness, dizziness, vertigo, insomnia or depression with the use of oxaprozin. If patients experience these side effects, they should exercise caution in carrying out activities that require alertness.
Drug Interactions: ASA or other NSAIDs: The use of oxaprozin and any other NSAID, including over the counter ones (such as ASA and ibuprofen) is not recommended due to the possibility of additive side effects. Studies in man have shown that such combined administration produces decreased protein-binding of oxaprozin, with a reduced biological half-life, and increased clearance of oxaprozin.
Because of the long biological half-life of oxaprozin (approximately 50 hours), a clinical study of patients with rheumatoid arthritis was conducted to determine its interactions with ASA, naproxen, ibuprofen, and tolmetin sodium after therapy with oxaprozin was discontinued and the other drugs were started. In the same manner, patients with osteoarthritis were studied for interactions between oxaprozin and ASA, naproxen, ibuprofen and indomethacin. No clinically detectable interactions were found.
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 hemostatis, and NSAIDs affect platelet functions as well, concurrent therapy of oxaprozin with warfarin requires close monitoring to be certain no change in anticoagulant dosage is necessary.
Concomitant warfarin and oxaprozin therapy did not produce further alterations of prothrombin times or a variety of other clotting factors when administered to normal subjects. Patients stabilized on phenprocoumon showed significant potentiation of the anticoagulation effect after 2.5 weeks of oxaprozin therapy. The values returned to pretreatment levels within 1 week after stopping oxaprozin.
Gold Salts, Antimalarial Agents, Corticosteroids: Oxaprozin may be used in combination with gold salts, antimalarial agents, or corticosteroids in the treatment of rheumatoid arthritis in adults.
In patients who received concomitant antimalarial therapy, a significantly higher incidence of muscular cramps/aching/pain, gastrointestinal bleeding, vision disorders and edema of the lower extremities was found. In patients who received concomitant gold therapy, a significantly higher incidence of sedation, skin disorders and E.N.T. disorders or symptoms was found.
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 old) individuals. In patients who received concomitant steroid therapy, significantly higher incidences of constipation, dyspepsia and alteration in taste were found.
Cimetidine/Ranitidine: Concomitant administration of cimetidine or ranitidine results in a clinically insignificant reduction of oxaprozin clearance. This does not require dosage adjustment.
Conjugated Estrogens: No interaction was observed when oxaprozin was administered concomitantly with conjugated estrogens.
Antihypertensives: Some NSAIDs have been reported to reduce the effects of antihypertensive agents. Hypertensive patients treated with the beta-adrenergic blocker, metoprolol, showed a small and transient increase in systolic blood pressure after 2 weeks on oxaprozin, with a return to baseline values at 4 weeks of therapy.
Diuretics: NSAIDs have been shown to interfere with the action of thiazide diuretics and potassium-sparing diuretics.
Lithium: NSAIDs have been reported to increase steady-state plasma lithium concentrations. It is recommended that these concentrations be monitored when initiating, adjusting and discontinuing drug treatment.
Clinical Laboratory Test Interactions : False-positive urine immunoassay screening tests for benzodiazepines have been reported in patients taking oxaprozin. This is due to lack of specificity of the screening tests. False-positive test results may be expected for several days following discontinuation of oxaprozin therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish oxaprozin from benzodiazepines.
Adverse Reactions: The most common adverse reactions encountered with NSAIDs are gastrointestinal, of which peptic ulcer, with or without bleeding, is the most severe. Fatalities have occurred, particularly in the elderly.
Adverse reaction data were derived from patients who received oxaprozin in multidose, controlled, and open-label clinical trials, and from worldwide marketing experience. Rates for events occurring in more than 1% of patients, and for most of the less common events, are based on 2 253 patients who took 1 200 to 1 800 mg oxaprozin/day in clinical trials. Of these, 1 721 were treated for at least 1 month, 971 for at least 3 months, and 366 for more than 1 year. Rates for rarer events and for events reported from worldwide marketing experience are difficult to estimate accurately and are only listed as less than 1%.
Listed below are the adverse events and their incidences in the first month of use in clinical trials. Most of the events were seen by this time for common adverse reactions. However, the cumulative incidence can be expected to rise with continued therapy, and some events, such as gastrointestinal bleeding seem to occur at a constant or possibly increasing rising rate over time.
The most frequently reported adverse reactions were related to the gastrointestinal tract. They were nausea (8%) and dyspepsia (8%).
Incidence greater than 1%: In clinical trials the following adverse reactions occurred at an incidence greater than 1% and are probably related to treatment. Reactions occurring in 3 to 9% of patients treated with oxaprozin are indicated by an asterisk (*); those reactions occurring in less than 3% of patients are unmarked.
Gastrointestinal: abdominal pain/distress, anorexia, constipation*, diarrhea*, dyspepsia*, flatulence, nausea*, vomiting.
CNS: CNS inhibition (depression, sedation, somnolence, or confusion), disturbance of sleep.
Dermatologic: rash*.
Special Senses: tinnitus.
Urogenital: dysuria or frequency.
Incidence less than 1%: Probable causal relationship: The following adverse reactions were reported in clinical trials or from worldwide marketing experience at an incidence of less than 1%. Those reactions reported only from worldwide marketing experience are in italics . The probability of a causal relationship exists between the drug and these adverse reactions.
Gastrointestinal: peptic ulceration and/or gastrointestinal bleeding, liver function abnormalities including hepatitis, stomatitis, hemorrhoidal or rectal bleeding, pancreatitis .
Allergic: drug hypersensitivity reactions including anaphylaxis and serum sickness .
CNS: weakness, malaise.
Dermatologic: pruritus, urticaria, photosensitivity, pseudoporphyria, exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s Syndrome).
Cardiovascular: edema, blood pressure changes.
Special Senses: blurred vision, conjunctivitis.
Hematologic: anemia, thrombocytopenia, leukopenia, ecchymoses.
Metabolic: weight gain, weight loss.
Respiratory: symptoms of upper respiratory tract infection.
Urogenital: acute interstitial nephritis , hematuria, renal insufficiency, acute renal failure , decreased menstrual flow.
Causal relationship unknown: The following adverse reactions occurred at an incidence of less than 1% in clinical trials, or were suggested from marketing experience, under circumstances where a causal relationship could not be definitely established. They are listed as alerting information for the physician.
Gastrointestinal: alteration in taste.
Dermatologic: alopecia.
Cardiovascular: palpitations.
Special Senses: hearing decrease.
Respiratory: sinusitis, pulmonary infections.
Urogenital: increase in menstrual flow.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: In the event of overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage. The patient should be carefully observed and given symptomatic and supportive treatment for as long as necessary. The symptoms of overdosage may include: lethargy, drowsiness, nausea, vomiting, and epigastric pain.
Dosage And Administration: In a clinical study in which healthy volunteers were administered oxaprozin after a meal, the extent of absorption was unchanged while the rate of absorption was slightly delayed. Oxaprozin may be administered orally once or twice daily with food or milk, and dosage adjusted for optimal response as described below.
Rheumatoid Arthritis: The initial therapy is 1 200 mg once daily. This may be decreased or increased depending on the patient’s response. The maximum daily dose should not exceed 1 800 mg, or 26 mg/kg, whichever is less. Doses larger than 1 200 mg/day should be reserved for patients who weigh more than 50 kg, have normal renal and hepatic function, are at low risk of peptic ulcer and whose severity of disease justifies maximal therapy. Physicians should ensure that patients are tolerating lower doses before advancing to the larger doses.
The 1 800 mg dose should be divided into 2 doses (1 200 mg in the morning and 600 mg in the evening).
Osteoarthritis: The initial therapy is 1 200 mg once daily. This may be decreased to 600 mg once daily depending on the patient’s response.
For patients of low body weight or with milder disease, an initial dose of 600 mg once daily may be appropriate.
Note: Consideration should be given to reducing the starting dose in elderly patients. In patients with moderate to severe renal impairment, and in those on hemodialysis, a maximum daily dosage of 600 mg administered under careful monitoring is recommended.
Availability And Storage: Each white, film-coated, capsule-shaped, scored caplet, with “DAYPRO” debossed on one side and “1381” on the other side, contains: oxaprozin 600 mg. Nonmedicinal ingredients: cellulose, cornstarch, hydroxypropyl methylcellulose, magnesium stearate, methylcellulose, polacrilin potassium, polyethylene glycol and titanium dioxide. HDPE bottles with plastic caps of 100. Store at room temperature at or below 25°C. Protect from light. Keep bottles tightly closed.
DAYPROÂ Searle Oxaprozin Anti-inflammatory – Analgesic
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