Oxaprozin is an oral nonsteroidal antiinflammatory agent (NSAID) of the propionic acid chemical class. It is used for the relief of pain and inflammation associated with rheumatoid arthritis and osteoarthritis. In patients with rheumatoid arthritis, the efficacy of oxaprozin 1200 mg/day is comparable to aspirin 3900 mg/day. Oxaprozin is the only NSAID of the propionic acid class with a half-life long enough to support once daily administration. Other NSAIDs that can be given as a single daily dose include piroxicam (anthranilic acid derivative) and nabumetone (acetic acid derivative).
Mecanismo de acción: Oxaprozin has antiinflammatory, analgesic, and antipyretic properties. Higher doses are required for an antiinflammatory effect than for analgesia. The antiinflammatory effect of oxaprozin may result from the peripheral inhibition of prostaglandin synthesis secondary to inhibition of the enzyme cyclooxygenase. Unlike aspirin, which irreversibly inhibits cyclooxygenase, oxaprozin and other NSAIDs are reversible inhibitors of this enzyme. Other mechanisms may also be responsible for the antiinflammatory actions of oxaprozin, such as inhibition of neutrophil aggregation. Like other NSAIDs, oxaprozin prevents the formation by the platelets of thromboxane A2, a potent aggregating agent. Thus, oxaprozin alters platelet function and has a tendency to prolong bleeding time. Oxaprozin has little effect on renal function in healthy subjects. However, oxaprozin and other NSAIDs decrease renal blood flow and glomerular filtration rate in patients with congestive heart failure, hepatic cirrhosis with ascites, chronic renal disease, or in those who are hypovolemic. In patients with these clinical conditions, renal perfusion is more dependent on vasodilatory prostaglandins than in normal individuals. In addition to their hemodynamic effects in the kidney, NSAIDs promote salt and water retention by reducing prostaglandin-induced inhibition of both the reabsorption of chloride and the action of antidiuretic hormone. NSAIDs inhibit the biosynthesis of gastric prostaglandins, especially PGI2 and PGE2, that serve as cytoprotective agents in the gastric mucosa. These prostaglandins inhibit acid secretion by the stomach, enhance mucosal blood flow, and promote secretion of cytoprotective mucus in the intestine. Thus, by inhibiting the biosynthesis of these gastric prostaglandins, oxaprozin and other NSAIDs can cause gastric or intestinal ulceration. Pharmacokinetics: Oxaprozin is administered orally. Oral bioavailability is roughly 95% and peak plasma concentrations occur between 3 and 6 hours after dosing. Food may reduce the rate, but not the extent of absorption. Oxaprozin, like most other NSAIDs, is highly bound to albumin (99.9%). Renal dysfunction alters oxaprozin binding and reduces the clearance of unbound drug. The fraction of drug present in tissues ranges between 40—60% of the total drug in the body and is proportional to dose, since the tissue sites are not saturated with usual clinical doses. As the amount of oxaprozin in the tissues increases with higher doses, the plasma concentration of oxaprozin is limited by saturation of plasma protein binding. In addition, the increase in unbound oxaprozin results in an increase in clearance. Both of these effects contribute to the total plasma concentration of oxaprozin increasing less than proportionately with dose. Oxaprozin is primarily metabolized in the liver, by both microsomal oxidation (65%) and glucuronic acid conjugation (35%). All conjugated metabolites are inactive. Biliary excretion of unchanged oxaprozin is a minor elimination pathway, and enterohepatic recycling of oxaprozin is insignificant. The glucuronide metabolites of oxaprozin can be recovered from the urine (65%) and feces (35%), while unchanged oxaprozin is poorly excreted. The terminal elimination half-life of oxaprozin is roughly 59 hours (range: 36—92 hours). The terminal elimination half-life is approximately twice as long as the accumulation half-life because of increased protein binding and decreased clearance at lower plasma concentrations. Steady state concentrations are usually achieved in 4—7 days.
Indications...Dosage For the treatment of moderate pain including arthralgia†, myalgia†, and bone pain† and the management of the signs and symptoms of moderate to severe rheumatoid arthritis: Oral dosage: Adults: The usual daily dosage is 1200 mg PO once daily. In cases where a quick onset of action is important, a one-time loading dose of up to 1800 mg (not to exceed 26 mg/kg) may be given. Dosage should be individualized to the lowest effective dose. Doses greater than 1200 mg/day PO should be reserved for patients with normal renal function who weigh more than 50 kg and are at low risk of peptic ulcer. The maximum recommended daily dosage is 1800 mg (or 26 mg/kg, whichever is lower). For the treatment of juvenile rheumatoid arthritis (JRA)†: Oral dosage: Children: Dosages of 10—20 mg/kg/day PO have been used. For the management of the signs and symptoms of osteoarthritis: Oral dosage: Adults: In patients with moderate to severe osteoarthritis, the usual daily dosage is 1200 mg PO once daily. For patients with low body weight or mild disease, an initial dosage of 600 mg PO once daily may be appropriate. In cases where a quick onset of action is important, a one-time loading dose of up to 1800 mg (not to exceed 26 mg/kg) may be given. Doses greater than 1200 mg/day PO should be reserved for patients with normal renal function who weigh more than 50 kg and are at low risk of peptic ulcer. Dosage should be individualized to the lowest effective dose. The maximum recommended daily dosage is 1800 mg (or 26 mg/kg, whichever is lower). Maximum Dosage Limits: •Adults: 1800 mg/day or 26 mg/kg/day PO, whichever is lower. •Elderly: 1800 mg/day or 26 mg/kg/day PO, whichever is lower. •Adolescents: Maximum dosage information is not available. •Children: Maximum dosage information is not available. Patients with hepatic impairment: Although specific guidelines are not available, dosage reduction may be necessary in patients with hepatic dysfunction. Patients with renal impairment: An initial dosage of 600 mg PO once daily is recommended with cautious dosage titration if the desired effect is not obtained. Intermittent hemodialysis: Oxaprozin is not dialyzed due to its high protein binding. If oxaprozin is used in a patient undergoing hemodialysis, an initial dosage of 600 mg PO once daily is recommended. †non-FDA-approved indication
Oral Administration •May be administered with food to minimize GI irritation. In some patients, oxaprozin may be better tolerated when given in divided doses.
Contraindications Oxaprozin is not recommended in patients who have experienced a severe salicylate hypersensitivity reaction with symptoms such as angioedema, bronchospasm, or shock because of the approximate 5% cross-sensitivity that occurs between salicylates (e.g., aspirin) and NSAIDs. Milder reactions to aspirin or other salicylates are not contraindications to therapy with oxaprozin. Patients with salicylate- or NSAID-induced nasal polyps, asthma, or urticaria are at the highest risk of developing bronchoconstriction or anaphylaxis and should not receive oxaprozin. Serious gastrointestinal toxicity, such as bleeding, ulceration, and perforation, can occur at any time during treatment with oxaprozin or other NSAIDs. Patients at greatest risk are those with a history of GI bleeding, peptic ulcer disease, ulcerative colitis, alcoholism, tobacco smoking, or other factors known to be associated with peptic ulcer disease. Elderly or debilitated patients may not tolerate ulceration or bleeding as well as other individuals, and most spontaneous reports of fatal GI events occur in these populations. High dosages of oxaprozin (e.g., 1800 mg/day) should be reserved for patients who weigh more than 50 kg, have normal renal and hepatic function, are at low risk of developing a peptic ulcer, and whose severity of disease justifies maximal therapy. Oxaprozin should be used cautiously in patients with preexisting coagulopathy or hemophilia due to the effect of the drug on platelet function. Like other NSAIDs, oxaprozin can alter platelet aggregation and prolong bleeding time. Oxaprozin should also be used with caution in patients undergoing surgery when a high degree of hemostasis is required. NSAIDs should be used with caution in patients with immunosuppression or neutropenia following myelosuppressive chemotherapy. NSAIDs may mask the signs of infection such as fever or pain in patients with bone marrow suppression. Because the primary route of elimination of oxaprozin is hepatic metabolism, the drug should be used with caution in patients with severe hepatic disease. As with other NSAIDs, borderline elevations of liver function tests may occur in up to 15% of patients. Because well-compensated hepatic cirrhosis does not appear to alter the disposition of unbound oxaprozin, no dosage adjustment is necessary. Oxaprozin can reduce renal blood flow due to inhibition of prostaglandin-synthesis, potentially leading to overt renal decompensation. Patients with renal disease, hepatic disease, heart failure, those taking diuretics or nephrotoxic drugs, and the elderly are at the highest risk for this reaction. Like other NSAIDs, oxaprozin may worsen fluid retention by the kidneys in susceptible individuals due to its effect on vasodilatory prostaglandins. Therefore, oxaprozin should be used with caution in patients with a history of hypertension, cardiac decompensation, in patients on chronic diuretic therapy, or in those with other conditions predisposing to fluid retention. The pharmacokinetics of oxaprozin may be significantly altered in patients with renal impairment or in patients undergoing hemodialysis. Therefore, low initial dosages should be used in these patients. Oxaprozin is classified as pregnancy category C. Teratology studies in mice and rats revealed no drug-related developmental abnormalities. However, in rabbits, infrequent malformed fetuses were observed in dams treated with 7.5—30 mg/kg/day of oxaprozin (the usual human dosage range). The effect of oxaprozin in pregnant women is unknown. However, NSAIDs are known to delay parturition, to accelerate closure of the fetal ductus arteriosus, and to be associated with dystocia. In addition, oxaprozin is known to have caused decreases in pup survival in rat studies. Thus, use of oxaprozin during late pregnancy should be avoided. It is not known if oxaprozin is excreted in human milk; however, the drug has been found in the milk of lactating rats. Due to the potential for adverse effects in the nursing infant, oxaprozin should be used with caution in a woman who is breast-feeding. Safe and effective use of oxaprozin has not been established in children.
Interactions Concomitant use of oxaprozin with ethanol, corticosteroids, salicylates, or other NSAIDs can enhance the risk of gastrointestinal side effects. In addition, oxaprozin displaces salicylates from plasma protein binding sites. Therefore, coadministration of oxaprozin and aspirin is not recommended due to the potential increased risk of salicylate toxicity. Because NSAIDs can cause GI bleeding, inhibit platelet aggregation, and prolong bleeding time, additive effects may be seen in patients receiving platelet inhibitors, anticoagulants, or thrombolytic agents. Garlic, Allium sativum, ginger, Zingiber officinale, and ginkgo, Ginkgo biloba, also have clinically significant effects on platelet aggregation leading to a potential increased risk of bleeding when used with NSAIDs. An increased risk of bleeding may occur when NSAIDs are used with agents that cause clinically significant thrombocytopenia due to decreases in platelet aggregation. Notable interactions may occur with myelosuppressive antineoplastic agents, antithymocyte globulin and strontium-89 chloride. The concomitant administration of cidofovir and NSAIDs is contraindicated due to the potential for increased nephrotoxicity. NSAIDs should be discontinued 7 days prior to beginning cidofovir. Although clearance of oxaprozin is reduced 20% with concomitant administration of cimetidine, the degree of change is within the range of normal variation and is unlikely to produce a clinically detectable difference in outcome of therapy. Subjects receiving oxaprozin with metoprolol exhibited statistically significant but transient increases in sitting and standing blood pressure after 14 days. NSAIDs may also blunt the antihypertensive response to other beta-blockers, ACE inhibitors or thiazide diuretics. Due to their effect on prostaglandin synthesis, oxaprozin and other NSAIDs may worsen fluid retention by the kidneys and thus, increase blood pressure in susceptible individuals. This effect may be more likely to occur in low renin hypertensive patients whose renal perfusion is more dependent on vasodilatory prostaglandins than patients with normal or high renin levels. Thus, routine blood pressure monitoring is recommended in patients receiving antihypertensive agents when oxaprozin therapy is started. In some patients with compromised renal function who are being treated with NSAIDs, the coadministration of ACE inhibitors (e.g., enalapril and lisinopril) may result in a further deterioration of renal function. These effects are usually reversible. Therefore, blood pressure and renal function should be monitored closely when an NSAID is administered to a patient taking an ACE inhibitor. In single- and/or multiple-dose studies, coadministration of oxaprozin and antacids, acetaminophen, or conjugated estrogens resulted in no statistically significant changes in pharmacokinetic parameters. The interaction of oxaprozin with lithium has not been studied. However, multiple case reports and studies document that the addition of other NSAIDs to stable lithium dosage regimens may reduce lithium clearance, resulting in elevated serum lithium concentrations. If oxaprozin is given to a patient taking lithium, serum lithium concentrations should be monitored and the lithium dosage adjusted, if necessary. Indomethacin has been shown to increase serum aminoglycoside concentrations in premature infants receiving indomethacin for patent ductus arteriosus. Urine output decreased and serum creatinine increased in these infants during indomethacin administration. It is likely that other NSAIDs such as oxaprozin may cause a similar interaction with aminoglycosides. It is also possible that additive nephrotoxicity may occur in patients who receive aminoglycosides and NSAIDs concomitantly. NSAIDs can decrease the renal clearance of methotrexate, resulting in elevated serum methotrexate levels and increased methotrexate toxicity. Although the effect of coadministration of oxaprozin and methotrexate has not been evaluated, severe or fatal complications have occurred when other NSAIDs were given to patients receiving high-dose methotrexate. Because of the serious nature of this drug interaction, NSAIDs should be avoided or withheld during and shortly after high-dose methotrexate therapy. Preclinical data suggest agents that inhibit prostaglandin synthesis such as NSAIDs could decrease the efficacy of porfimer or verteporfin photodynamic therapy. In a retrospective study, women taking concomitant NSAIDs and alendronate had a 70% increased risk of developing a GI adverse event, such as gastric ulceration. In contrast, concomitant treatment with corticosteroids was not associated with an increased risk of GI adverse effects.
Adverse Reactions The most frequently reported adverse events related to use of oxaprozin are nausea/vomiting (8%) and dyspepsia (8%). Adverse events that occurred in at least 3% of patients during initial clinical trials include constipation, diarrhea, and maculopapular rash. Adverse reactions that occurred in 1—3% of patients were abdominal pain, anorexia, flatulence, CNS depression (including sedation, drowsiness, or confusion), insomnia, tinnitus, dysuria, and increased urinary frequency. The following adverse reactions occurred in less than 1% of patients but were thought to have a probable causal relationship to oxaprozin therapy: serum sickness, edema, hypertension, stomatitis, pancreatitis, anemia, thrombocytopenia, leukopenia, ecchymosis, agranulocytosis, pancytopenia, weight gain, asthenia, malaise, symptoms of upper respiratory tract infection, pruritus, urticaria, pseudoporphyria, exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, blurred vision, conjunctivitis, acute interstitial nephritis, nephrotic syndrome, hematuria, azotemia, and amenorrhea. Serious gastrointestinal toxicity, such as GI bleeding, gastritis, peptic ulcer, and GI perforation, can occur at any time, with or without symptoms, in patients treated with NSAIDs such as oxaprozin. In patients observed in clinical trials for several months to 2 years, symptomatic GI ulcers, gross bleeding, or perforation occurred in roughly 1% of patients treated with an NSAID for 3—6 months and in 2—4% of patients treated for 1 year. Patients at risk include those with a prior history of serious GI events, alcoholism, smoking, or other factors known to be associated with peptic ulcer disease (see Precautions). Rare cases of anaphylactic shock have been reported in patients taking oxaprozin. In general, all NSAIDs have been associated with severe and occasionally fatal asthmatic and anaphylactic reactions. In the overall population exposed to NSAIDs, approximately 1% experience urticaria or angioedema, while about 0.5% develop a syndrome characterized by rhinorrhea, cutaneous flushing, and/or bronchospasm. The overall incidence of NSAID-intolerance (e.g., rhinorrhea, bronchospasm) in patients with asthma is not known. However, aspirin-intolerance has been reported to occur in about 10—16% of asthmatics. Patients with nasal polyps and/or sinusitis may also be predisposed to NSAID-intolerance. The proposed mechanism is inhibition of cyclooxygenase, which may facilitate production of alternative arachidonic acid metabolites (e.g., leukotrienes). During dermatologic testing, oxaprozin has been associated with rash and/or mild photosensitivity. An increased incidence of rash on sun-exposed skin was seen in some patients in clinical trials. As with other NSAIDs, elevated hepatic enzymes may occur in up to 15% of patients who receive oxaprozin. These abnormalities may progress, remain essentially unchanged, or resolve with continued therapy. Significant elevations of AST (3 times the upper limit of normal) occur in just under 1% of patients. Severe hepatic reactions, including jaundice, have been reported with oxaprozin and there may be a risk of fatal hepatitis with oxaprozin, as has been seen with other NSAIDs. Although severe hepatic reactions are rare, if abnormal liver tests persist or worsen, clinical signs and symptoms consistent with liver disease develop, or systemic manifestations occur (eosinophilia, rash, fever), oxaprozin should be discontinued. Teratology studies of oxaprozin in mice and rats revealed no drug-related developmental abnormalities. However, in rabbits, infrequent malformed fetuses were observed in dams treated with 7.5—30 mg/kg/day of oxaprozin (the usual human dosage range). The effect of oxaprozin in pregnant women is unknown. NSAIDs are known to delay parturition, to accelerate closure of the fetal ductus arteriosus, and to be associated with dystocia. In addition, oxaprozin is known to have caused decreases in pup survival in rat studies. Thus, use of oxaprozin during late pregnancy should be avoided (pregnancy category C). When oxaprozin was administered to male mice for 2 years, the drug was associated with exacerbation of liver neoplasms. This effect did not occur in female mice or rats. The significance of this species-specific finding is unknown. Oxaprozin was not mutagenic when evaluated in 6 different assays. Oxaprozin administration was not associated with impairment of fertility in male and female rats at oral doses up to 200 mg/kg/day. However, testicular degeneration was observed in dogs treated with up to 150 mg/kg/day for 6 months. The clinical relevance of this finding is not known.
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