Daypro Alta

DAYPRO ALTA (oxaprozin potassium) tablet is a member of the propionic acid group of nonsteroidal anti-inflammatory drugs (NSAIDs), available as tablets of 600 mg (678 mg of oxaprozin potassium equivalent to 600 mg of oxaprozin) for oral administration. The chemical name for oxaprozin potassium is 4,5-diphenyl-2-oxazolepropionic acid, potassium salt. The molecular weight is 331. Its molecular formula is C18H14NO3K, and it has the following chemical structure.

It has the following structural formula:

Oxaprozin potassium is a white to off white powder with a melting point of 215°C. It is slightly soluble in alcohol and very soluble in water. The PK in water is 9.7.

The inactive ingredients in DAYPRO ALTA include: microcrystalline cellulose, hydroxypropyl methylcellulose, pregelatinized corn starch, stearic acid, colloidal silicon dioxide, polyethylene glycol, titanium dioxide, FD&C Blue #1 Aluminum Lake, and pharmaceutical glaze. Daypro ALTA 600 mg tablets are blue, capsule-shaped, film-coated, with Searle 1391 printed on one side.

Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see WARNINGS AND PRECAUTIONS].

Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10-times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

For additional information about overdosage treatment contact a poison control center (1-800-2221222).

Taking an NSAID can increase your risk of life-threatening heart or circulation problems, including heart attack or stroke. This risk will increase the longer you use an NSAID. Do not use this medicine just before or after having heart bypass surgery (also called coronary artery bypass graft, or CABG).

NSAIDs can also increase your risk of serious effects on the stomach or intestines, including bleeding or perforation (forming of a hole). These conditions can be fatal and gastrointestinal effects can occur without warning at any time while you are taking an NSAID. Older adults may have an even greater risk of these serious gastrointestinal side effects.

Do not use this medication if you are allergic to oxaprozin, or to aspirin or other NSAIDs.

Before taking oxaprozin, tell your doctor if you are allergic to any drugs, or if you have:

• a history of heart attack, stroke, or blood clot;
• heart disease, congestive heart failure, high blood pressure;
• a history of stomach ulcers or bleeding, bowel problems, diverticulosis;
• liver or kidney disease;
• asthma;
• polyps in your nose; or
• if you smoke.

If you have any of these conditions, you may need a dose adjustment or special tests to safely take this medication.

FDA pregnancy category C. This medication may be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. Taking oxaprozin during the last 3 months of pregnancy may harm the unborn baby. Do not take oxaprozin during pregnancy unless your doctor has told you to.

Oxaprozin can pass into breast milk and may harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Do not give this medicine to a child younger than 6 years old without the advice of a doctor.

Do not use any other over-the-counter cold, allergy, or pain medication without first asking your doctor or pharmacist. Many medicines available over the counter contain medicines similar to oxaprozin (such as aspirin, ibuprofen, ketoprofen, or naproxen). If you take certain products together you may accidentally take too much of this type of medication. Read the label of any other medicine you are using to see if it contains aspirin, ibuprofen, ketoprofen, or naproxen.

Do not drink alcohol while taking oxaprozin. Alcohol can increase the risk of stomach bleeding.

Cardiovascular Risk

• NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patient's with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see WARNINGS).
• Daypro Alta™ is contraindicated for treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

Gastrointestinal Risk

• NSAID's cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS).

General

Daypro Alta should not be used concomitantly with other oxaprozin-containing products, since all such products circulate in the plasma as the oxaprozin anion.

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

Hepatic Effects

Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including Daypro Alta. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing 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 fulminant 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 Alta. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.). Daypro Alta 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 clinical trials.

Hematological Effects

Anemia is sometimes seen in patients receiving NSAIDs, including Daypro Alta. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including Daypro Alta, should have their hemoglobin or hematocrit checked 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 Alta who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.

Preexisting Asthma

Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with 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 Alta 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 Alta, 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 Alta, 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 Alta, 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 Alta should be avoided because it may cause premature closure of the ductus arteriosus.

Laboratory Tests

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, Daypro Alta should be discontinued.

Drug Interactions

When Daypro Alta is administered with aspirin, its protein binding is reduced, although the clearance of free Daypro Alta is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of oxaprozin potassium and aspirin is not generally recommended because of the potential of increased adverse effects.

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% decrease in oral plasma clearance of methotrexate. A reduction in methotrexate dosage may be considered due to the potential for increased methotrexate toxicity associated with the increased exposure.

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

Clinical studies, as well as post-marketing observations, have shown that Daypro Alta 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 patients should be observed closely for signs of renal failure (see WARNINGS, Renal Effects), as well as to assure diuretic efficacy.

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

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

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 or the magnitude or duration of control. However, it is advisable to monitor patients' blood glucose in the beginning phase of glyburide and oxaprozin co-therapy.

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.

Subjects receiving 1200 mg oxaprozin once daily with 100 mg metoprolol twice daily exhibited statistically significant but transient increases in sitting and standing blood pressures after 14 days. Therefore, routine blood pressure monitoring should be considered in these patients when starting oxaprozin therapy.

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 maybe expected for several days following discontinuation of oxaprozin therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish oxaprozin from benzodiazepines.

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. No evidence of genetic toxicity or cell-transforming ability was found in test 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, or cell transformation testing in mouse fibroblast.

Oxaprozin administration was not associated with impairment of fertility in male and female rats at oral doses up to 200mg/kg/day (1180 mg/m2/day); the usual human dose is 17 mg/kg/day, or (629 mg/m2/day). However, testicular degeneration was observed in beagle dogs treated with 37.5 to 150 mg/kg/day (750 to 3000 mg/m2/day) 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.

Pregnancy

Pregnancy Category C

There are no adequate or well-controlled studies in pregnant women. 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 200mg/kg/day of oxaprozin (225 to 900 mg/m2/day). However, in rabbits, infrequent malformed fetuses were observed in dams treated with 7.5 to 30mg/kg/day of oxaprozin (the usual human dosage range). Animal reproduction studies are not always predictive of human response. Oxaprozin should be used during pregnancy only if the potential benefits justify the potential risk 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 Alta on labor and delivery in pregnant women are unknown.

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 Daypro Alta, 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 of Daypro Alta in pediatric patients have not been established.

Geriatric Use

Age was not shown to have an effect on the pharmacokinetics of Daypro Alta following 600, 1200 and 1800 rug doses or on the incidence of adverse reactions reported (see CLINICAL PHARMACOLOGY, Special Populations). In a controlled 6-month clinical trial of 803 patients (322 of whom received Daypro Alta), about 40% of whom were elderly, there was basically no difference detected in terms of the total number of subjects reporting adverse events with respect to age. As with any NSAID, the elderly are likely to tolerate adverse reactions less well than younger patients. Caution should be exercised in treating the elderly (65 years and older), and extra care should be taken when choosing a dose.

Oxaprozin is substantially excreted by the kidney, and the risk of toxic reactions to Daypro Alta 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).

Applies to oxaprozin: oral tablet

Along with its needed effects, oxaprozin (the active ingredient contained in Daypro Alta) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking oxaprozin:

• Skin rash

• Bloating
• bloody or black, tarry stools
• burning upper abdominal or stomach pain
• burning while urinating
• cloudy urine
• constipation
• decrease in urine output or decrease in urine-concentrating ability
• diarrhea
• difficult or painful urination
• frequent urination
• headache
• heartburn
• indigestion
• itching skin
• loss of appetite
• nausea or vomiting
• pale skin
• severe abdominal or stomach pain, cramping, or burning
• severe and continuing nausea
• swelling
• troubled breathing with exertion
• unusual bleeding or bruising
• unusual tiredness or weakness
• vomiting of blood or material that looks like coffee grounds
• weight loss

• Agitation
• bleeding gums
• blistering, peeling, or loosening of the skin
• blurred vision
• body aches or pain
• burning feeling in chest or stomach
• changes in blood pressure
• chest pain
• clay-colored stools
• coma
• confusion
• cough or hoarseness
• cracks in the skin
• dark urine
• depression
• difficult or labored breathing
• difficulty swallowing
• dilated neck veins
• dizziness
• ear congestion
• extreme fatigue
• fainting
• feeling of discomfort
• fever or chills
• fluid-filled skin blisters
• high fever
• hives or welts
• hostility
• increased sensitivity of the skin to sunlight
• increased thirst
• increased volume of pale, dilute urine
• inflammation of the joints
• irregular, fast or slow, or shallow breathing
• joint or muscle pain
• large, flat, blue or purplish patches in the skin
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• lethargy
• light-colored stools
• lightheadedness
• loss of heat from the body
• loss of voice
• lower back or side pain
• muscle aches
• muscle twitching
• noisy breathing
• pain or burning in the throat
• pain or tenderness around the eyes and cheekbones
• pale or blue lips, fingernails, or skin
• pinpoint red or purple spots on the skin
• pounding in the ears
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• rapid weight gain
• red skin lesions, often with a purple center
• red, irritated eyes
• redness or other discoloration of the skin
• redness, swelling, or soreness of tongue
• scaly skin
• seizures
• severe sunburn
• skin thinness
• slow, fast, irregular, pounding, or racing heartbeat or pulse
• sneezing
• sore throat
• sores, ulcers, or white spots on the lips or tongue or inside the mouth
• stuffy or runny nose
• stupor
• swelling of the face, fingers, feet, or lower legs
• swelling or inflammation of the mouth
• swollen lymph glands
• tenderness in the stomach area
• tightness in the chest
• unpleasant breath odor
• upper right abdominal or stomach pain
• yellow eyes or skin

Some side effects of oxaprozin may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Acid or sour stomach
• belching
• stomach discomfort

• Continuing ringing or buzzing or other unexplained noise in the ears
• excess air or gas in the stomach or intestines
• hearing loss
• passing gas
• relaxed and calm
• sleepiness or unusual drowsiness
• trouble sleeping

• Burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• burning, dry, or itching eyes
• change in taste
• decreased hearing
• discharge, excessive tearing
• dry mouth
• feeling of constant movement of self or surroundings
• general feeling of discomfort or illness
• lack or loss of strength
• redness, pain, swelling of the eye, eyelid, or inner lining of the eyelid
• sensation of spinning
• shakiness in the legs, arms, hands, feet
• trembling or shaking of the hands or feet

Applies to oxaprozin: oral tablet

General

The most frequently reported adverse effects were gastrointestinal (GI) in nature and included GI pain, anorexia, GI ulcers, heartburn, dyspepsia, nausea, vomiting, diarrhea, constipation, flatulence, and gross bleeding or perforation.[Ref]

Gastrointestinal

Common (1% to 10%): Abdominal pain/distress, anorexia, constipation, diarrhea, dyspepsia, flatulence, gastrointestinal (GI) ulcers, gross bleeding/perforation, heartburn, nausea, vomiting
Frequency not reported: Dry mouth, eructation, esophagitis, gastritis, glossitis, hematemesis, stomatitis, pancreatitis, hemorrhoid bleeding, rectal bleeding, melena[Ref]

Hepatic

Common (1% to 10%): Liver enzymes elevated
Frequency not reported: Jaundice, liver function abnormalities, hepatitis, liver failure[Ref]

Renal

Common (1% to 10%): Abnormal renal function
Frequency not reported: Acute interstitial nephritis, cystitis, renal insufficiency, acute renal failure, nephrotic syndrome, renal calculi[Ref]

Cardiovascular

Frequency not reported: Arrhythmia, blood pressure changes, congestive heart failure, hypertension, hypotension, myocardial infarction, palpitations, tachycardia, syncope, vasculitis[Ref]

Nervous system

Common (1% to 10%): CNS inhibition, somnolence, sedation, dizziness, headache
Frequency not reported: Taste disturbance, coma, convulsions, drowsiness, paresthesia, tremors[Ref]

Dermatologic

Common (1% to 10%): Pruritus, rash
Frequency not reported: Ecchymosis, purpura, alopecia, angioedema, urticaria, photosensitivity, pseudoporphyria, exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, sweating, toxic epidermal necrolysis[Ref]

Hematologic

Common (1% to 10%): Anemia, bleeding time increased
Frequency not reported: Agranulocytosis, aplastic anemia, eosinophilia, hemolytic anemia, lymphadenopathy, pancytopenia, thrombocytopenia, leukopenia[Ref]

Hypersensitivity

Frequency not reported: Hypersensitivity reactions[Ref]

Other

Common (1% to 10%): Edema, tinnitus
Frequency not reported: Death, sepsis, fever, infection, asthenia, malaise, meningitis, vertigo, weakness, hearing decreased[Ref]

Psychiatric

Common (1% to 10%): Depression, confusion, sleep disturbance, dream abnormalities
Frequency not reported: Anxiety, hallucinations, insomnia, nervousness[Ref]

Genitourinary

Common (1% to 10%): Dysuria, urinary frequency
Frequency not reported: Hematuria, menstrual flow increased, oliguria, polyuria, proteinuria, menstrual flow decreased[Ref]

Respiratory

Frequency not reported: Asthma, dyspnea, pulmonary infections, pneumonia, sinusitis, upper respiratory tract infection, respiratory depression[Ref]

Immunologic

Frequency not reported: Serum sickness[Ref]

Metabolic

Frequency not reported: Appetite changes, hyperglycemia, weight changes[Ref]

Ocular

Frequency not reported: Blurred vision, conjunctivitis[Ref]

Some side effects of Daypro Alta may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.