Oxaprozin Tablets USP

Oxaprozin  is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic properties in animal models. The mechanism of action of oxaprozin, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition.

Oxaprozin  was evaluated for managing the signs and symptoms of rheumatoid arthritis in placebo and active controlled clinical trials in a total of 646 patients.  Oxaprozin  was given in single or divided daily doses of 600  mg/day  to 1800 mg/day and was found to be comparable to 2600 mg/day to 3900 mg/day of aspirin. At these doses there was a trend (over all trials) for oxaprozin to be more effective and cause fewer gastrointestinal side effects than aspirin.

Oxaprozin  was given as a once-a-day dose of 1200 mg in most of the clinical trials, but larger doses (up to 26 mg/kg or 1800 mg/day) were used in selected patients. In some patients, oxaprozin  may be better tolerated in divided doses. Due to its long half-life, several days of oxaprozin  therapy were needed for the drug to reach its full effect (see DOSAGE AND ADMINISTRATION, Individualization of Dosage).

Oxaprozin  was evaluated for the management of the signs and symptoms of osteoarthritis in a total of 616 patients in active controlled clinical trials against aspirin (N=464), piroxicam (N=102), and other NSAIDs. Oxaprozin was given both in variable (600 mg/day to 1200 mg/day) and in fixed (1200 mg/day) dosing schedules in either single or divided doses. In these trials, oxaprozin was found to be comparable to 2600 mg/day to 3200 mg/day doses of aspirin or 20 mg/day doses of piroxicam. Oxaprozin was effective both in once daily and in divided dosing schedules. In controlled clinical trials several days of oxaprozin therapy were needed for the drug to reach its full effects (see DOSAGE AND ADMINISTRATION, Individualization of Dosage ).

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.

No information is available from controlled clinical studies regarding the use of oxaprozin in patients with advanced renal disease. Therefore, treatment with oxaprozin is not recommended in these patients with advanced renal disease. If oxaprozin therapy must be initiated, close monitoring of the patient's renal function is advisable.

As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to oxaprozin. Oxaprozin 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, Pre-existing Asthma ). Emergency help should be sought in cases where an anaphylactoid reaction occurs.

NSAIDs, including oxaprozin, 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 the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

In late pregnancy, as with other NSAIDs, oxaprozin should be avoided because it may cause premature closure of the ductus arteriosus.

Oxaprozin 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 oxaprozin in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.

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.

1. 1.Oxaprozin, 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 ).
2. 2.Oxaprozin, 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 ).
3. 3.Oxaprozin, 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 of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs 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.
4. 4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.
5. 5. 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.
6. 6.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 ReactionsAnaphylactoid).
7. 7. In late pregnancy, as with other NSAIDs, oxaprozin 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 or 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, oxaprozin should be discontinued.

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 mg/kg/day to 150 mg/kg/day (750 mg/m² 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.

Safety and effectiveness in pediatric patients below the age of 6 years of age have not been established. The effectiveness of oxaprozin for the treatment of the signs and symptoms of juvenile rheumatoid arthritis (JRA) in pediatric patients aged 6 to 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 oxaprozin 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 oxaprozin in JRA patients 6 to 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, Special Populations, 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 mg/kg/day to 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 to 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 oxaprozin 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 oxaprozin 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.

Oxaprozin is substantially excreted by the kidney, and the risk of toxic reactions to oxaprozin 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 useful to monitor renal function (see WARNINGS, Renal Effects ).

In clinical trials of oxaprozin or in patients taking other NSAIDs, the following adverse reactions occurred at an incidence greater than 1%.

Cardiovascular System:edema.

Digestive System:abdominal pain/distress, anorexia, constipation, diarrhea, dyspepsia, flatulence, gastrointestinal ulcers (gastric/duodenal), gross bleeding/perforation, heartburn, liver enzyme elevations, nausea, vomiting.

Hematologic System:anemia, increased bleeding time.

Nervous System:CNS inhibition (depression, sedation, somnolence, or confusion), disturbance of sleep, dizziness, headache.

Skin and Appendages:pruritus, rash.

Special Senses:tinnitus.

Urogenital System:abnormal renal function, dysuria or frequency.

The following adverse reactions were reported in clinical trials, from worldwide marketing experience (in italics) or in patients taking other NSAIDs.

Body as a Whole:appetite changes, death, drug hypersensitivity reactions including anaphylaxis, fever, infection, sepsis, serum sickness.

Cardiovascular System:arrhythmia, blood pressure changes, congestive heart failure, hypertension, hypotension, myocardial infarction, palpitations, tachycardia, syncope, vasculitis.

Digestive System:alteration in taste, dry mouth, eructation, esophagitis, gastritis, glossitis, hematemesis, jaundice, liver function abnormalities including hepatitis, liver failure, stomatitis, hemorrhoidal or rectal bleeding, pancreatitis.

Hematologic System:agranulocytosis, aplastic anemia, ecchymoses, eosinophilia, hemolytic anemia, lymphadenopathy, melena, pancytopenia, purpura, thrombocytopenia, leukopenia.

Metabolic System:hyperglycemia, weight changes.

Nervous System:anxiety, asthenia, coma, convulsions, dream abnormalities, drowsiness, hallucinations, insomnia, malaise, meningitis, nervousness, paresthesia, tremors, vertigo, weakness.

Respiratory System:asthma, dyspnea, pulmonary infections, pneumonia, sinusitis, symptoms of upper respiratory tract infection, respiratory depression.

Skin:alopecia, angioedema, urticaria, photosensitivity, pseudoporphyria, exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, sweat, toxic epidermal necrolysis (Lyell’s syndrome).

Special Senses:blurred vision, conjunctivitis, hearing decrease.

Urogenital:acute interstitial nephritis, cystitis, hematuria, increase in menstrual flow, nephrotic syndrome, oliguria/polyuria, proteinuria, renal insufficiency, acute renal failure, decreased menstrual flow.

No patient experienced either an accidental or intentional overdosage of oxaprozin in the clinical trials of the drug. Symptoms following acute overdose with other NSAIDs are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain and are generally reversible with supportive care. Gastrointestinal bleeding and coma have occurred following NSAID overdose. Hypertension, acute renal failure, and respiratory depression are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose.

Patients should be managed by symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. Gut decontamination may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose (5 to 10 times the usual dose). This should be accomplished via emesis and/or activated charcoal (60 g to 100 g in adults, 1 g/kg to 2 g/kg in children) with an osmotic cathartic. Forced diuresis, alkalization of the urine, or hemoperfusion would probably not be useful due to the high degree of protein binding of oxaprozin.

For relief of the signs and symptoms of rheumatoid arthritis, the usual recommended dose of oxaprozin tablets is 1200 mg (two 600 mg tablets) given orally once a day (see Individualization of Dosage).

For relief of the signs and symptoms of osteoarthritis, the usual recommended dose of oxaprozin tablets is 1200 mg (two 600 mg tablets) given orally once a day (see Individualization of Dosage).

For the relief of the signs and symptoms of JRA in patients 6 to 16 years of age, the recommended dose given orally once per day should be based on body weight of the patient as given in Table 3 (see also Individualization of Dosage).

(see CLINICAL PHARMACOLOGY, Special Populations, Pediatric Patients )

As with other NSAIDs, the lowest dose should be sought for each patient. Therefore, after observing the response to initial therapy with oxaprozin tablets, the dose and frequency should be adjusted to suit an individual patient’s needs. In osteoarthritis and rheumatoid arthritis and juvenile rheumatoid arthritis, the dosage should be individualized to the lowest effective dose of oxaprozin tablets to minimize adverse effects. The maximum recommended total daily dose of oxaprozin tablets in adults is 1800 mg (26 mg/kg, whichever is lower) in divided doses. In children, doses greater than 1200 mg have not been studied.

Patients of low body weight should initiate therapy with 600 mg once daily. Patients with severe renal impairment or on dialysis should also initiate therapy with 600 mg once daily. If there is insufficient relief of symptoms in such patients, the dose may be cautiously increased to 1200 mg, but only with close monitoring (see CLINICAL PHARMACOLOGY, Special Populations ).

In adults, in cases where a quick onset of action is important, the pharmacokinetics of oxaprozin allows therapy to be started with a one-time loading dose of 1200 mg to 1800 mg (not to exceed 26 mg/kg). Doses larger than 1200 mg/day on a chronic basis 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 doses in the 600 mg/day to 1200 mg/day range without gastroenterologic, renal, hepatic, or dermatologic adverse effects before advancing to the larger doses. Most patients will tolerate once-a-day dosing with oxaprozin, although divided doses may be tried in patients unable to tolerate single doses.

Oxaprozin  is supplied as a solid dosage form in closed containers, is not known to produce contact dermatitis, and poses no known risk to healthcare workers. It may be disposed of in accordance with applicable local regulations governing the disposal of pharmaceuticals.