Oxaprozin (Page 3 of 7)

5.10 Premature Closure of Fetal Ductus Arteriosus

Oxaprozin may cause premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including oxaprozin, in pregnant women starting at 30 weeks of gestation (third trimester) [see USE IN SPECIFIC POPULATIONS (8.1)].

5.11 Hematologic Toxicity

Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with oxaprozin has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.

NSAIDs, including oxaprozin, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see DRUG INTERACTIONS (7)].

5.12 Masking of Inflammation and Fever

The pharmacological activity of oxaprozin in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.

5.13 Laboratory Monitoring

Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see WARNINGS AND PRECAUTIONS (5.2, 5.3, 5.6)].

5.14 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.

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

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Cardiovascular Thrombotic Events [see WARNINGS AND PRECAUTIONS (5.1)]

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GI Bleeding, Ulceration and Perforation [see WARNINGS AND PRECAUTIONS (5.2)]

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Hepatotoxicity [see WARNINGS AND PRECAUTIONS (5.3)]

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Hypertension [see WARNINGS AND PRECAUTIONS (5.4)]

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Heart Failure and Edema [see WARNINGS AND PRECAUTIONS (5.5)]

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Renal Toxicity and Hyperkalemia [see WARNINGS AND PRECAUTIONS (5.6)]

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Anaphylactic Reactions [see WARNINGS AND PRECAUTIONS (5.7)]

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Serious Skin Reactions [see WARNINGS AND PRECAUTIONS (5.9)]

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Hematologic Toxicity [see WARNINGS AND PRECAUTIONS (5.11)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse reaction data were derived from patients who received oxaprozin in multidose, controlled, and open-label clinical trials. Rates for events from clinical trial experience are based on 2,253 patients who took 1200 mg to 1800 mg oxaprozin per 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.

Incidence Greater Than 1%

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.

Incidence Less Than 1%

The following adverse reactions were reported in clinical trials or in patients taking other NSAIDs.

Body as a whole

Appetite changes, death, drug hypersensitivity reactions including anaphylaxis, fever, infection, sepsis.

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 liver failure, stomatitis, hemorrhoidal or rectal bleeding.

Hematologic system

Aplastic anemia, ecchymoses, eosinophilia, hemolytic anemia, lymphadenopathy, melena, 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, sweat.

Special senses

Blurred vision, conjunctivitis, hearing decrease.

Urogenital

Cystitis, hematuria, increase in menstrual flow, oliguria/ polyuria, proteinuria, renal insufficiency, decreased menstrual flow.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of oxaprozin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a whole

Serum sickness.

Digestive system

Hepatitis, pancreatitis.

Hematologic system

Agranulocytosis, pancytopenia.

Skin

Pseudoporphyria, exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome).

Urogenital

Acute interstitial nephritis, nephrotic syndrome, acute renal failure.

7 DRUG INTERACTIONS

See Table 2 for clinically significant drug interactions with oxaprozin [see CLINICAL PHARMACOLOGY (12.3)].

Table 2. Clinically Significant Drug Interactions with Oxaprozin

Drugs That Interfere with Hemostasis
Clinical Impact:	• Oxaprozin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of oxaprozin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of oxaprozin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see WARNINGS AND PRECAUTIONS (5.11)].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see WARNINGS AND PRECAUTIONS (5.2)].
Intervention:	Concomitant use of oxaprozin and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see WARNINGS AND PRECAUTIONS (5.11)].
	Oxaprozin is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	• During concomitant use of oxaprozin and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of oxaprozin and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see WARNINGS AND PRECAUTIONS (5.6)]. • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of oxaprozin with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see WARNINGS AND PRECAUTIONS (5.6)].
Digoxin
Clinical Impact:	The concomitant use of oxaprozin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of oxaprozin and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of oxaprozin and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction) because NSAID administration may result in increased plasma levels of methotrexate, especially in patients receiving high doses of methotrexate.
Intervention:	During concomitant use of oxaprozin and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of oxaprozin and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of oxaprozin and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of oxaprozin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see WARNINGS AND PRECAUTIONS (5.2)].
Intervention:	The concomitant use of oxaprozin with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of oxaprozin and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of oxaprozin and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 mL/min to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
	NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.
	In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Corticosteroids
Clinical Impact:	Concomitant use of corticosteroids with oxaprozin may increase the risk of GI ulceration or bleeding.
Intervention:	Monitor patients with concomitant use of oxaprozin with corticosteroids for signs of bleeding [see WARNINGS AND PRECAUTIONS (5.2)].
Glyburide
Clinical Impact:	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.
Intervention:	During concomitant use of oxaprozin and glyburide, monitor patient’s blood glucose in the beginning phase of cotherapy.

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.