Oxaprozin

Oxaprozin is a Cyclooxygenase-1 and 2 (COX-1 and 2) inhibitor belonging to non-steroidal anti-inflammatory drugs (NSAIDs).

Oxaprozin is an NSAID used to treat osteoarthritis, rheumatoid arthritis, and juvenile rheumatoid arthritis.

Oxaprozin is Slowly but extensively absorbed from the GI tract. Time to peak plasma concentration approximately 2-3 hr. Oxaprozin is having volume of distribution of approximately 11 to 17 L/70 kg and it is >99.5% bound to albumin. Oxaprozin is Primarily metabolized via Hepatic route, Ester and ether glucuronide are the major conjugated metabolites of oxaprozin. Oxaprozin is expected to be excreted in human milk based on its physical-chemical properties; however, the amount of oxaprozin excreted in breast milk has not been evaluated. Approximately 95% of oxaprozin is metabolized by the liver. Approximately 5% of the oxaprozin dose is excreted unchanged in the urine. Sixty-five percent (65%) of the dose is excreted in the urine and 35% in the feces as metabolite. Biliary excretion of unchanged oxaprozin is a minor pathway. Several oxaprozin metabolites have been identified in human urine or feces.

Oxaprozin shows common side effects like Diarrhea, constipation, vomiting, gas or bloating, drowsiness, difficulty sleeping, confusion, depression, dizziness, headache, ringing in the ears.

Oxaprozin is available in the form of an Oral tablet.

Oxaprozin is available in India, US, UK, Canada, France, China, Italy, Japan, Australia, Spain, and Russia.

Oxaprozin is a non-steroidal anti-inflammatory drug (NSAIDs) belonging to the class Cyclooxygenase-1 and 2 (COX-1 and 2) inhibitor.

Anti-inflammatory effects of Oxaprozin are believed to be due to inhibition of cyclooxygenase in platelets which leads to the blockage of prostaglandin synthesis. Antipyretic effects may be due to action on the hypothalamus, resulting in an increased peripheral blood flow, vasodilation, and subsequent heat dissipation. Oxaprozin is a non-selective NSAID, with a cell assay system showing lower COX-2 selectivity implying higher COX-1 selectivity.

The effect of Oxaprozin and its duration of action is not clinically established.

The Tmax of Oxaprozin is approximately 2-3 hours.

Oxaprozin is available in the form of an Oral tablet.

Oxaprozin tablet is taken orally, usually once daily.

Oxaprozin is used to relieve pain, stiffness, tenderness, and swelling in conditions such as osteoarthritis and rheumatoid arthritis. It is also used to treat rheumatoid arthritis symptoms in children aged 6 years and above (juvenile rheumatoid arthritis). Patients are advised to undergo physical therapy and take rest along with this medicine to get the best possible effect.

Oxaprozin is a Cyclooxygenase-1 and 2 (COX-1 and 2) inhibitor belonging to non-steroidal anti-inflammatory drugs (NSAIDs).

Oxaprozin reversibly inhibits cyclooxygenase-1 and 2 (COX-1 and 2) enzymes, which results in decreased formation of prostaglandin precursors; has antipyretic, analgesic, and anti-inflammatory properties.

Oxaprozin is approved for use in the following clinical indications

• Osteoarthritis, rheumatoid arthritis and Juvenile rheumatoid arthritis

Oxaprozin is an NSAID used to treat osteoarthritis, rheumatoid arthritis, and juvenile rheumatoid arthritis.

• Osteoarthritis, rheumatoid arthritis

Adult Oral Dose: 1,200 mg once daily.

• Juvenile Idiopathic Arthritis (JIA)

Children ≥6 years and Adolescents

Weight-directed dosing: Oral:

10 to 20 mg/kg/dose once daily; maximum daily dose: 1,200 mg/day.

Fixed dosing: Oral:

22 to 31 kg: 600 mg once daily.

32 to 54 kg: 900 mg once daily.

≥55 kg: 1,200 mg once daily.

Oxaprozin is available in various strengths as 600 mg.

Oxaprozin is available in the form of an Oral Tablet.

• Dosage Adjustment in Kidney Patient

Severe renal impairment or dialysis: 600 mg once daily; may increase cautiously to 1200 mg daily with close monitoring.

• Dosage Adjustment in Hepatic impairment Patient

There are no dosage adjustments provided.

Oxaprozin is contraindicated in patients with

• Oxaprozin is contraindicated in patients with known hypersensitivity to oxaprozin.
• Oxaprozin should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients.
• Oxaprozin is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery.

• Anaphylactoid reactions

Even in patients without prior exposure, anaphylactoid reactions may occur; patients with "aspirin triad" (bronchial asthma, aspirin intolerance, rhinitis) may be at increased risk. Contraindicated in patients who experience bronchospasm, asthma, rhinitis, or urticaria with nonsteroidal anti-inflammatory drug (NSAID) or aspirin therapy.

• Cardiovascular events

Relative risk appears to be similar in those with and without known cardiovascular disease or risk factors for cardiovascular disease; however, absolute incidence of cardiovascular events (which may occur early during treatment) was higher in patients with known cardiovascular disease or risk factors. New-onset hypertension or exacerbation of hypertension may occur (NSAIDs may also impair response to ACE inhibitors, thiazide diuretics, or loop diuretics); may contribute to cardiovascular events; monitor blood pressure; use with caution in patients with hypertension. May cause sodium and fluid retention, use with caution in patients with edema. Avoid use in patients with heart failure. Avoid use in patients with recent MI unless benefits outweigh risk of cardiovascular thrombotic events. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce risk of cardiovascular events; alternate therapies should be considered for patients at high risk.

• CNS effects

May cause drowsiness, dizziness, blurred vision, and other neurologic effects which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Discontinue use with blurred or diminished vision and perform ophthalmologic exam. Periodically evaluate vision in all patients receiving long term therapy.

• Drug reaction with eosinophilia and systemic symptoms

Potentially serious, sometimes fatal, drug reaction with eosinophilia and systemic symptoms (DRESS), also known as multiorgan hypersensitivity reactions, has been reported with NSAIDs. Monitor for signs and symptoms (eg, fever, rash, lymphadenopathy, eosinophilia) in association with other organ system involvement (eg, hepatitis, nephritis, hematological abnormalities, myocarditis, myositis). Early symptoms of hypersensitivity reaction (eg, lymphadenopathy, fever) may occur without rash; discontinue therapy and further evaluate if DRESS is suspected.

• GI events

Avoid use in patients with active GI bleeding. In patients with a history of acute lower GI bleeding, avoid use of non-aspirin NSAIDs, especially if due to angioectasia or diverticulosis (Strate 2016). Use caution with a history of GI ulcers, concurrent therapy known to increase the risk of GI bleeding (eg, aspirin, anticoagulants and/or corticosteroids, selective serotonin reuptake inhibitors), smoking, use of alcohol, or in elderly or debilitated patients. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce risk of GI adverse events; alternate therapies should be considered for patients at high risk. When used concomitantly with aspirin, a substantial increase in the risk of GI complications (eg, ulcer) occurs; concomitant gastroprotective therapy (eg, proton pump inhibitors) is recommended.

• Hematologic effects

Platelet adhesion and aggregation may be decreased; may prolong bleeding time; patients with coagulation disorders or who are receiving anticoagulants should be monitored closely. Anemia may occur; patients on long-term NSAID therapy should be monitored for anemia. Rarely, NSAID use has been associated with potentially severe blood dyscrasias (eg, agranulocytosis, thrombocytopenia, aplastic anemia).

• Hyperkalemia

NSAID use may increase the risk of hyperkalemia, particularly in the elderly, diabetics, renal disease, and with concomitant use of other agents capable of inducing hyperkalemia (eg, ACE-inhibitors). Monitor potassium closely.

• Photosensitivity reactions

May cause mild photosensitivity reactions.

• Skin reactions

NSAIDs may cause serious skin adverse events including exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN); discontinue use at first sign of skin rash or hypersensitivity.

• Asthma

Do not administer to patients with aspirin-sensitive asthma; severe bronchospasm may occur. Use caution in patients with other forms of asthma.

• Bariatric surgery

Gastric ulceration:Avoid chronic use of oral nonselective NSAIDs after bariatric surgery; development of anastomotic ulcerations/perforations may occur. Short-term use of celecoxib or IV ketorolac are recommended as part of a multimodal pain management strategy for postoperative pain.

• Coronary artery bypass graft surgery

Risk of MI and stroke may be increased with use following CABG surgery.

• Hepatic impairment

Use with caution in patients with decreased hepatic function. Closely monitor patients with any abnormal LFT. Rare (sometimes fatal), severe hepatic reactions (eg, fulminant hepatitis, hepatic necrosis, hepatic failure) have occurred with NSAID use; discontinue if signs or symptoms of liver disease develop, if systemic manifestations occur, or with persistent or worsening abnormal hepatic function tests. Patients with advanced hepatic disease are at an increased risk of GI bleeding and kidney failure with NSAIDs.

• Hypertension

Use with caution; may cause new-onset hypertension or worsening of existing hypertension.

• Renal impairment

NSAID use may compromise existing renal function; dose-dependent decreases in prostaglandin synthesis may result from NSAID use, reducing renal blood flow which may cause renal decompensation. Patients with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics, and ACE inhibitors, angiotensin II receptor blockers, and elderly patients are at greater risk of renal toxicity. Rehydrate patient before starting therapy; monitor renal function closely. Avoid use in patients with advanced renal disease; discontinue use with persistent or worsening abnormal renal function tests. Long-term NSAID use may result in renal papillary necrosis.

Consumption of alcohol is not recommended during treatment with this medicine due to the increased risk of serious side effects such as severe gastrointestinal bleeding, dizziness, fatigue, weakness, etc.

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 Oxaprozin, a decision should be made whether to discontinue nursing or to discontinue the drug, considering the importance of the drug to the mother.

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.

• Common

Drowsiness, dizziness, blurred vision, HTN, fluid retention, edema, decreased platelet adhesion and aggregation, prolonged bleeding time, anemia, increased risk of hyperkalemia, photosensitivity reactions, renal papillary necrosis (long term use), blood dyscrasias (e.g. agranulocytosis, thrombocytopenia, aplastic anemia), Headache, CNS inhibition (e.g. depression, sedation, confusion), sleep disturbance, sedation, Abdominal pain/distress, anorexia, constipation, diarrhea, dyspepsia, flatulence, heartburn, nausea, vomiting.

• Rare

Increased risk of CV thrombotic events (e.g. MI, heart failure, stroke); GI adverse events (e.g. inflammation, bleeding, ulceration and perforation of the stomach or intestines); anaphylactoid reactions (e.g. severe bronchospasm); serious skin reactions (e.g. exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis). Rarely, hepatic injury (e.g. fulminant hepatitis, hepatic necrosis, hepatic failure).

• Aspirin

Concomitant administration of Oxaprozin and aspirin is not recommended because oxaprozin displaces salicylates from plasma protein binding sites. Coadministration would be expected to increase the risk of salicylate toxicity. As with other NSAIDs, concomitant administration of oxaprozin and aspirin is not generally recommended because of the potential for increased adverse effects.

• Methotrexate

NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate. Coadministration of oxaprozin with methotrexate results in approximately a 36% reduction in apparent oral clearance of methotrexate. A reduction in methotrexate dosage may be considered due to the potential for increased methotrexate toxicity associated with the increased exposure.

• ACE-inhibitors

Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. Oxaprozin has been shown to alter the pharmacokinetics of enalapril (significant decrease in dose-adjusted AUC0-24 and Cmax) and its active metabolite enalaprilat (significant increase in dose-adjusted AUC0- 24). This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors.

• Diuretics

Clinical studies, as well as post marketing observations, have shown that Oxaprozin can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure, as well as to assure diuretic efficacy.

• Lithium

Oxaprozin, like other NSAIDs, has produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%.These effects have been attributed to inhibition of renal prostaglandin synthesis by the nonsteroidal anti-inflammatory drug. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.

• Glyburide

While oxaprozin does alter the pharmacokinetics of glyburide, coadministration of oxaprozin to type II non-insulin dependent diabetic patients did not affect the area under the glucose concentration curve nor the magnitude or duration of control. However, it is advisable to monitor patients’ blood glucose in the beginning phase of glyburide and oxaprozin cotherapy.

• Warfarin

The effects of warfarin and NSAIDs on gastrointestinal (GI) bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than that of users of either drug alone.

• H2-receptor antagonists

The total body clearance of oxaprozin was reduced by 20% in subjects who concurrently received therapeutic doses of cimetidine or ranitidine; no other pharmacokinetic parameter was affected. A change of clearance of this magnitude lies within the range of normal variation and is unlikely to produce a clinically detectable difference in the outcome of therapy.

• Beta-blockers

Subjects receiving 1200 mg Oxaprozin QD with 100 mg metoprolol bid exhibited statistically significant but transient increases in sitting and standing blood pressures after 14 days. Therefore, as with all NSAIDs, routine blood pressure monitoring should be considered in these patients when starting Oxaprozin therapy.

The common side effects of Oxaprozin include the following

• Common side effects

Diarrhea, constipation, vomiting, gas or bloating, drowsiness, difficulty sleeping, confusion, depression, dizziness, headache, ringing in the ears.

• Rare side effects

Unexplained weight gain, shortness of breath or difficulty breathing, swelling in the abdomen, ankles, feet, or legs, fever, blisters, rash, itching, hives, swelling of the eyes, face, lips, tongue, throat, or hands, hoarseness, difficulty breathing or swallowing, yellowing of the skin or eyes, lack of energy, excessive tiredness, upset stomach, loss of appetite, pain in the upper right part of the stomach, flu-like symptoms, pale skin, fast heartbeat, cloudy, discolored, or bloody urine, back pain, difficult or painful urination.

• Pregnancy

Pregnancy Category C

Teratogenic effects

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.

• Nursing Mothers

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 Oxaprozin, 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.

• Pediatric Use

Safety and effectiveness in pediatric patients below the age of 6 years of age have not been established.

• Geriatric Use

Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects. No adjustment of the dose of Oxaprozin is necessary in the elderly, although many elderly may need to receive a reduced dose because of low body weight or disorders associated with aging. 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. 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.

Symptoms: Lethargy, drowsiness, nausea, vomiting, abdominal pain, GI bleeding, HTN, acute renal failure, resp depression, coma.

Management: Symptomatic and supportive treatment. May consider emesis and/or activated charcoal admin.

• Pharmacodynamic

Oxaprozin is a nonsteroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic properties. Oxaprozin is used to treat rheumatoid arthritis, osteoarthritis, dysmenorrhea, and to alleviate moderate pain.

• Pharmacokinetics

Absorption

Oxaprozin is Slowly but extensively absorbed from the GI tract. Time to peak plasma concentration: Approx 2-3 hr.

Distribution

Oxaprozin is having volume of distribution of approximately 11 to 17 L/70 kg

And it is >99.5% bound to albumin.

Metabolism and Excretion

Oxaprozin is Primirily metabolized via Hepatic route Ester and ether glucuronide are the major conjugated metabolites of oxaprozin. Oxaprozin is expected to be excreted in human milk based on its physical-chemical properties; however, the amount of oxaprozin excreted in breast milk has not been evaluated. Approximately 95% of oxaprozin is metabolized by the liver. Approximately 5% of the oxaprozin dose is excreted unchanged in the urine. Sixty-five percent (65%) of the dose is excreted in the urine and 35% in the feces as metabolite. Biliary excretion of unchanged oxaprozin is a minor pathway. Several oxaprozin metabolites have been identified in human urine or feces.

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