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Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin miti- gates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see WARNINGS, Gastrointestinal Effects Risk of Ulceration, Bleeding and Perforation).
Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS).
NSAIDs including DAYPRO (oxaprozin caplets) , can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including DAYPRO (oxaprozin caplets) , should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.
Congestive Heart Failure and Edema
Fluid retention and edema have been observed in some patients taking NSAIDs. DAYPRO (oxaprozin caplets) should be used with caution in patients with fluid retention or heart failure.
Gastrointestinal Effects-Risk of Ulceration, Bleeding, and Perforation
NSAIDs, including DAYPRO (oxaprozin caplets) , can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.
NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients treated with neither of these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population.
To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulcerations and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory 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, secondarily, in renal blood flow, which 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 ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
Advanced renal disease
No information is available from controlled clinical studies regarding the use of DAYPRO (oxaprozin caplets) in patients with advanced renal disease. Therefore, treatment with DAYPRO (oxaprozin caplets) is not recommended in these patients with advanced renal disease. If DAYPRO (oxaprozin caplets) therapy must be initiated, close monitoring of the patients renal function is advisable. Anaphylactoid reactions: As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to DAYPRO (oxaprozin caplets) . DAYPRO (oxaprozin caplets) should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS, Preexisting asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs.
NSAIDs, including DAYPRO (oxaprozin caplets) , can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.
Pregnancy: In late pregnancy, as with other NSAIDs, DAYPRO (oxaprozin caplets) should be avoided because it may cause premature closure of the ductus arteriosus.
DAYPRO (oxaprozin caplets) cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.
The pharmacological activity of DAYPRO (oxaprozin caplets) in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including DAYPRO (oxaprozin caplets) . These laboratory abnormalities may progress, remain unchanged, or may be transient with continued therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminate hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.
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 a more severe hepatic reaction while on therapy with DAYPRO (oxaprozin caplets) . If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), DAYPRO (oxaprozin caplets) should be discontinued.
Photosensitivity: Oxaprozin has been associated with rash and/or mild photosensitivity in dermatologic testing. An increased incidence of rash on sun-exposed skin was seen in some patients in the clinical trials.
Anemia is sometimes seen in patients receiving NSAIDs, including DAYPRO (oxaprozin caplets) . This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythrogenesis. Patients on long-term treatment with DAYPRO (oxaprozin caplets) should have their hemoglobin or hematocrit values determined if they exhibit any signs or symptoms of anemia.
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving DAYPRO (oxaprozin caplets) who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with the severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, DAYPRO (oxaprozin caplets) should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.
Information for patients
Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.
- DAYPRO (oxaprozin caplets) , like other NSAIDs, may cause CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects).
- DAYPRO (oxaprozin caplets) , like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects-Risk of Ulceration, Bleeding and Perforation).
- DAYPRO (oxaprozin caplets) , like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS and TEN, which may result in hospitalization and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs hypersensitivity such as itching, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.
- Patients should promptly report, signs or symptoms of unexplained weight gain, or edema to their physicians.
- Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness and "flu-like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
- Patients should be informed of the signs of an anaphylactoid reaction (e.g. difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS, Anaphylactoid reactions).
- In late pregnancy, as with other NSAIDs, DAYPRO (oxaprozin caplets) should be avoided because it may cause premature closure of the ductus arteriosus.
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs of symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g. eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, DAYPRO (oxaprozin caplets) should be discontinued.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In oncogenicity studies, oxaprozin administration for 2 years was associated with the exacerbation of liver neoplasms (hepatic adenomas and carcinomas) in male CD mice, but not in female CD mice or rats. The significance of this species-specific finding to man is unknown.
Oxaprozin did not display mutagenic potential. Results from the Ames test, forward mutation in yeast and Chinese hamster ovary (CHO) cells, DNA repair testing in CHO cells, micronucleus testing in mouse bone marrow, chromosomal aberration testing in human lymphocytes, and cell transformation testing in mouse fibroblast all showed no evidence of genetic toxicity or cell-transforming ability.
Oxaprozin administration was not associated with impairment of fertility in male and female rats at oral doses up to 200 mg/kg/day (1180 mg/m2); the usual human dose is 17 mg/kg/day (629 mg/m2). However, testicular degeneration was observed in beagle dogs treated with 37.5 to 150 mg/kg/day (750 to 3000 mg/m2) of oxaprozin for 6 months, or 37.5 mg/kg/day for 42 days, a finding not confirmed in other species. The clinical relevance of this finding is not known.
Teratogenic effects-Pregnancy Category C
Teratology studies with oxaprozin were performed in mice, rats, and rabbits. In mice and rats, no drug-related developmental abnormalities were observed at 50 to 200 mg/kg/day of oxaprozin (225 to 900 mg/m2). However, in rabbits, infrequent malformed fetuses were observed in dams treated with 7.5 to 30 mg/kg/day of oxaprozin (the usual human dosage range). Animal reproductive studies are not always predictive of human response. There are no adequate or well-controlled studies in pregnant women. Oxaprozin should be used during pregnancy only if the potential benefits justify the potential risks to the fetus.
Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.
Labor and delivery
In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of DAYPRO (oxaprozin caplets) on labor and delivery in pregnant women are unknown.
It is not known whether this drug is excreted in human milk; however, oxaprozin was found in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from DAYPRO (oxaprozin caplets) , a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Safety and effectiveness in pediatric patients below the age of 6 years of age have not been established. The effectiveness of DAYPRO (oxaprozin caplets) for the treatment of the signs and symptoms of juvenile rheumatoid arthritis (JRA) in pediatric patients aged 6-16 years is supported by evidence from adequate and well controlled studies in adult rheumatoid arthritis patients, and is based on an extrapolation of the demonstrated efficacy of DAYPRO (oxaprozin caplets) in adults with rheumatoid arthritis and the similarity in the course of the disease and the drug's mechanism of effect between these two patient populations. Use of DAYPRO (oxaprozin caplets) in JRA patients 6-16 years of age is also supported by the following pediatric studies.
The pharmacokinetic profile and tolerability of oxaprozin were assessed in JRA patients relative to adult rheumatoid arthritis patients in a 14 day multiple dose pharmacokinetic study. Apparent clearance of unbound oxaprozin in JRA patients was reduced compared to adult rheumatoid arthritis patients, but this reduction could be accounted for by differences in body weight (see Pharmacokinetics, Pediatric patients) . No pharmacokinetic data are available for pediatric patients under 6 years. Adverse events were reported by approximately 45% of JRA patients versus an approximate 30% incidence of adverse events in the adult rheumatoid arthritis patient cohort. Most of the adverse events were related to the gastrointestinal tract and were mild to moderate.
In a 3 month open label study, 10-20 mg/kg/day of oxaprozin were administered to 59 JRA patients. Adverse events were reported by 58% of JRA patients. Most of those reported were generally mild to moderate, tolerated by the patients, and did not interfere with continuing treatment. Gastrointestinal symptoms were the most frequently reported adverse effects and occurred at a higher incidence than those historically seen in controlled studies in adults. Fifty-two patients completed 3 months of treatment with a mean daily dose of 20 mg/kg. Of 30 patients who continued treatment (19-48 week range total treatment duration), nine (30%) experienced rash on sun-exposed areas of the skin and 5 of those discontinued treatment. Controlled clinical trials with oxaprozin in pediatric patients have not been conducted.
No adjustment of the dose of DAYPRO (oxaprozin caplets) is necessary in the elderly for pharmacokinetic reasons, although many elderly may need to receive a reduced dose because of low body weight or disorders associated with aging. No significant differences in the pharmacokinetic profile for oxaprozin were seen in studies in the healthy elderly (see CLINICAL PHARMACOLOGY, Special populations).
Of the total number of subjects evaluated in four placebo controlled clinical studies of oxaprozin, 39% were 65 and over, and 11% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Although selected elderly patients in controlled clinical trials tolerated as well as younger patients, caution should be exercised in treating the elderly, and extra care should be taken when choosing a dose. As with any NSAID, the elderly are likely to tolerate adverse reactions less well than younger patients.
DAYPRO (oxaprozin caplets) is substantially excreted by the kidney, and the risk of toxic reactions to DAYPRO (oxaprozin caplets) may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be use- ful to monitor renal function (see WARNINGS, Renal effects) .This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 4/17/2008
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