Daypro ALTA

Dosage Forms And Strengths

DAYPRO ALTA (oxaprozin potassium) tablets: 600 mg tablets, blue, capsule-shaped, film-coated, with Searle 1391 printed on one side.

Storage And Handling

DAYPRO ALTA 600 mg tablets are blue, capsule-shaped, film-coated, with Searle 1391 printed on one side.

Store at room temperature 20ºC to 25ºC (68ºF to 77ºF); excursions permitted between 15ºC to 30ºC (59ºF to 86ºF) (see USP Controlled Room Temperature). Dispense in a tightly-closed container. Protect from moisture.

Manufacture by: Pfizer Inc., 235 East 42nd Street, New York, NY, 10017. Revised May 2016

DAYPRO ALTA is indicated:

• For relief of the signs and symptoms of osteoarthritis
• For relief of the signs and symptoms of rheumatoid arthritis

General Dosing Instructions

Carefully consider the potential benefits and risks of DAYPRO ALTA and other treatment options before deciding to use DAYPRO ALTA. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals.

After observing the response to initial therapy with DAYPRO ALTA, the dose and frequency should be adjusted to suit an individual patient’s needs.

Divided doses may be tried in patients unable to tolerate single doses. For osteoarthritis patients of low body weight or with milder disease, an initial dose of one 600 mg tablet once a day may be appropriate. The maximum total daily dose is 1200 mg.

Osteoarthritis

For OA, the dosage is 1200 mg (two 600 mg tablets) given orally once a day.

Rheumatoid Arthritis

For RA, the dosage is 1200 mg (two 600 mg tablets) given orally once a day.

DAYPRO ALTA is contraindicated in the following patients:

• Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to oxaprozin potassium or any components of the drug product
• History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients
• In the setting of coronary artery bypass graft (CABG) surgery

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Cardiovascular Thrombotic Events

Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.

To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as oxaprozin, increases the risk of serious gastrointestinal (GI) events.

Status Post Coronary Artery Bypass Graft (CABG) Surgery

Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG.

Post-MI Patients

Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.

Avoid the use of DAYPRO ALTA in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If DAYPRO ALTA is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

Gastrointestinal Bleeding, Ulceration, And Perforation

NSAIDs, including DAYPRO ALTA cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.

Risk Factors For GI Bleeding, Ulceration, And Perforation

Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding.

Strategies To Minimize The GI Risks In NSAID-Treated Patients:

• Use the lowest effective dosage for the shortest possible duration.
• Avoid administration of more than one NSAID at a time.
• Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs.
• Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.
• If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue DAYPRO ALTA until a serious GI adverse event is ruled out.
• In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding.

Hepatotoxicity

Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported.

Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including oxaprozin potassium.

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue DAYPRO ALTA immediately, and perform a clinical evaluation of the patient.

Hypertension

NSAIDs, including DAYPRO ALTA, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs.

Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.

Heart Failure And Edema

The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.

Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of oxaprozin may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]).

Avoid the use of DAYPRO ALTA in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If DAYPRO ALTA is used in patients with severe heart failure, monitor patients for signs of worsening heart failure

Renal Toxicity And Hyperkalemia

Renal Toxicity

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 an NSAID 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, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, 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 DAYPRO ALTA in patients with advanced renal disease. The renal effects of DAYPRO ALTA may hasten the progression of renal dysfunction in patients with preexisting renal disease.

Correct volume status in dehydrated or hypovolemic patients prior to initiating DAYPRO ALTA. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of DAYPRO ALTA. Avoid the use of DAYPRO ALTA in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If DAYPRO ALTA is used in patients with advanced renal disease, monitor patients for signs of worsening renal function.

Hyperkalemia

Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.

Anaphylactic Reactions

Oxaprozin potassium has been associated with anaphylactic reactions in patients with and without known hypersensitivity to oxaprozin and in patients with aspirin-sensitive asthma.

Seek emergency help if an anaphylactic reaction occurs.

Exacerbation Of Asthma Related To Aspirin Sensitivity

A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, DAYPRO ALTA is contraindicated in patients with this form of aspirin sensitivity. When DAYPRO ALTA is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.

Serious Skin Reactions

NSAIDs, including oxaprozin potassium, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of DAYPRO ALTA at the first appearance of skin rash or any other sign of hypersensitivity. DAYPRO ALTA is contraindicated in patients with previous serious skin reactions to NSAIDs.

Premature Closure Of Fetal Ductus Arteriosus

Oxaprozin may cause premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including DAYPRO ALTA, in pregnant women starting at 30 weeks of gestation (third trimester).

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 DAYPRO ALTA has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.

NSAIDs, including DAYPRO ALTA, 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.

Masking Of Inflammation And Fever

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

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.

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.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with DAYPRO ALTA and periodically during the course of ongoing therapy.

Cardiovascular Thrombotic Events

Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately.

Gastrointestinal Bleeding, Ulceration, And Perforation

Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding.

Hepatotoxicity

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop DAYPRO ALTA and seek immediate medical therapy.

Heart Failure And Edema

Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur.

Anaphylactic Reactions

Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur.

Serious Skin Reactions

Advise patients to stop DAYPRO ALTA immediately if they develop any type of rash and to contact their healthcare provider as soon as possible.

Female Fertility

Advise females of reproductive potential who desire pregnancy that NSAIDs, including DAYPRO ALTA, may be associated with a reversible delay in ovulation.

Fetal Toxicity

Inform pregnant women to avoid use of DAYPRO ALTA and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus.

Avoid Concomitant Use Of NSAIDs

Inform patients that the concomitant use of DAYPRO ALTA with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia.

Use Of NSAIDS And Low-Dose Aspirin

Inform patients not to use low-dose aspirin concomitantly with DAYPRO ALTA until they talk to their healthcare provider.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

In carcinogenicity studies in rats and mice, 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 treated with up to 216 mg/kg via the diet (1.2-times the maximum recommended human daily dose of 1800 mg based on body surface. The significance of this species-specific finding to man is unknown.

Mutagenesis

Oxaprozin did not genotoxic in 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.

Impairment Of Fertility

Oxaprozin administration was not associated with impairment of fertility in male and female rats at oral doses up to 200 mg/kg/day (1.1-times the maximum recommended human daily dose [MRHD] of 1800 mg based on body surface area comparison). However, testicular degeneration was observed in beagle dogs treated with 37.5 mg/kg/day (0.7-times the MRHD based on body surface area) of oxaprozin for 42 days or 6 months, a finding not confirmed in other species. The clinical relevance of this finding is not known.

Use In Specific Populations

Pregnancy

Risk Summary

Use of NSAIDs, including DAYPRO ALTA, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including DAYPRO ALTA, in pregnant women starting at 30 weeks of gestation (third trimester).

There are no adequate and well-controlled studies of DAYPRO ALTA in pregnant women.

Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2-4% for major malformations, and 15-20% for pregnancy loss. In animal reproduction studies, oral administration of oxaprozin to pregnant rabbits at doses 0.1-times the maximum daily human dose (based on body surface area) resulted in evidence of teratogenicity; however, oral administration of oxaprozin to pregnant mice and rats during organogenesis at doses equivalent to the maximum recommended human dose revealed no evidence of teratogenicity or embryotoxicity. In rat reproduction studies in which oxaprozin was administered through late gestation failure to deliver and a reduction in live birth index was observed at doses equivalent to the maximum recommended human dose. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as oxaprozin potassium, resulted in increased pre- and post-implantation loss.

Clinical Considerations

Labor or Delivery

There are no studies on the effects of DAYPRO ALTA during labor or delivery. In animal studies, NSAIDS, including oxaprozin potassium, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.

Data

Animal data

Teratology studies with oxaprozin potassium were performed in mice, rats, and rabbits in pregnant animals administered oral doses up to 200 mg/kg/day, 200 mg/kg/day, and 30 mg/kg/day, respectively, during the period of organogenesis. In rabbits, malformations were observed at doses greater than or equal to 7.5 mg/kg/day of oxaprozin (0.1-times the maximum recommended human daily dose [MRHD] of 1800 mg based on body surface area). However, in mice and rats, no drug-related developmental abnormalities or embryo-fetal toxicity were observed at doses up to 50 and 200 mg/kg/day of oxaprozin, respectively (0.1-times and 1.1-times the MRHD based on body surface area, respectively).

In fertility/reproductive studies in rats, 200 mg/kg/day oxaprozin was orally administered to female rats for 14 days prior to mating through lactation day (LD) 2, or from gestation day (GD) 15 through LD 2 and the females were mated with males treated with 200 mg/kg/day oxaprozin for 60 days prior to mating. Oxaprozin administration resulted in failure to deliver and a reduction in live birth index at 200 mg/kg/day (1.1-times the MRHD based on body surface area comparison).

Lactation

Risk Summary

Lactation studies have not been conducted with Daypro Alta. It is not known whether Daypro Alta is excreted in human milk. Daypro Alta should be administered to lactating women only if clearly indicated. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for DAYPRO ALTA and any potential adverse effects on the breastfed infant from the DAYPRO ALTA or from the underlying maternal condition.

Females And Males Of Reproductive Potential

Infertility

Females

Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including DAYPRO ALTA, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including DAYPRO ALTA, in women who have difficulties conceiving or who are undergoing investigation of infertility.

Males

Testicular degeneration was observed in beagle dogs treated with 37.5 mg/kg/day (0.7-times the maximum recommended human daily dose based on body surface area) of oxaprozin for 42 days or 6 months.

Pediatric Use

DAYPRO ALTA has not been investigated in patients <16 years of age. Safety and effectiveness of DAYPRO ALTA in pediatric patients 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.

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. 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.

SIDE EFFECTS

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

• Cardiovascular Thrombotic Events
• GI Bleeding, Ulceration and Perforation
• Hepatotoxicity
• Hypertension
• Heart Failure and Edema
• Renal Toxicity and Hyperkalemia
• Anaphylactic Reactions
• Serious Skin Reactions
• Hematologic Toxicity

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.

In patients taking DAYPRO ALTA (oxaprozin potassium tablets), oxaprozin, or other NSAIDs , the following are the most frequently reported adverse experiences occurring in approximately 1-10% of patients :

Gastrointestinal experiences including: abdominal pain, anorexia, constipation, diarrhea, dyspepsia, flatulence, gross gastrointestinal bleeding/perforation, GI ulcers (gastric/duodenal), heartburn, nausea, vomiting.

Non-gastrointestinal experiences including: abnormal renal function, anemia, confusion, depression, disturbance of sleep, dizziness, dysuria or frequency, edema, elevated liver enzymes, headaches, increased bleeding time, pruritus, rashes, sedation, somnolence, tinnitus.

Additional Adverse Experiences Reported In Less Than 1% Of Patients:

Body as a whole: anaphylactic reactions, appetite changes, death, fever, infection, sepsis, serum sickness.

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

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

Hemic and lymphatic system: agranulocytosis, aplastic anemia, ecchymosis, eosinophilia, hemolytic anemia, leukopenia, lymphadenopathy, melena, pancytopenia, purpura, thrombocytopenia.

Metabolic and nutritional: 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, pneumonia, pulmonary infections, respiratory depression, sinusitis, symptoms of upper respiratory tract infection.

Skin and appendages: alopecia. angioedema, increased sweating, photosensitivity, pseudoporphyria, exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’ssyndrome), urticaria.

Special senses: blurred vision, conjunctivitis, hearing impairment.

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

DRUG INTERACTIONS

See Table 1 for clinically significant drug interactions with oxaprozin potassium.

Table 1: Clinically Significant Drug Interactions with Oxaprozin Potassium

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.

Risk Summary

Use of NSAIDs, including DAYPRO ALTA, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including DAYPRO ALTA, in pregnant women starting at 30 weeks of gestation (third trimester).

There are no adequate and well-controlled studies of DAYPRO ALTA in pregnant women.

Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2-4% for major malformations, and 15-20% for pregnancy loss. In animal reproduction studies, oral administration of oxaprozin to pregnant rabbits at doses 0.1-times the maximum daily human dose (based on body surface area) resulted in evidence of teratogenicity; however, oral administration of oxaprozin to pregnant mice and rats during organogenesis at doses equivalent to the maximum recommended human dose revealed no evidence of teratogenicity or embryotoxicity. In rat reproduction studies in which oxaprozin was administered through late gestation failure to deliver and a reduction in live birth index was observed at doses equivalent to the maximum recommended human dose. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as oxaprozin potassium, resulted in increased pre- and post-implantation loss.

Clinical Considerations

Labor or Delivery

There are no studies on the effects of DAYPRO ALTA during labor or delivery. In animal studies, NSAIDS, including oxaprozin potassium, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.

Data

Animal data

Teratology studies with oxaprozin potassium were performed in mice, rats, and rabbits in pregnant animals administered oral doses up to 200 mg/kg/day, 200 mg/kg/day, and 30 mg/kg/day, respectively, during the period of organogenesis. In rabbits, malformations were observed at doses greater than or equal to 7.5 mg/kg/day of oxaprozin (0.1-times the maximum recommended human daily dose [MRHD] of 1800 mg based on body surface area). However, in mice and rats, no drug-related developmental abnormalities or embryo-fetal toxicity were observed at doses up to 50 and 200 mg/kg/day of oxaprozin, respectively (0.1-times and 1.1-times the MRHD based on body surface area, respectively).

In fertility/reproductive studies in rats, 200 mg/kg/day oxaprozin was orally administered to female rats for 14 days prior to mating through lactation day (LD) 2, or from gestation day (GD) 15 through LD 2 and the females were mated with males treated with 200 mg/kg/day oxaprozin for 60 days prior to mating. Oxaprozin administration resulted in failure to deliver and a reduction in live birth index at 200 mg/kg/day (1.1-times the MRHD based on body surface area comparison).

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

• Cardiovascular Thrombotic Events
• GI Bleeding, Ulceration and Perforation
• Hepatotoxicity
• Hypertension
• Heart Failure and Edema
• Renal Toxicity and Hyperkalemia
• Anaphylactic Reactions
• Serious Skin Reactions
• Hematologic Toxicity

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.

In patients taking DAYPRO ALTA (oxaprozin potassium tablets), oxaprozin, or other NSAIDs , the following are the most frequently reported adverse experiences occurring in approximately 1-10% of patients :

Gastrointestinal experiences including: abdominal pain, anorexia, constipation, diarrhea, dyspepsia, flatulence, gross gastrointestinal bleeding/perforation, GI ulcers (gastric/duodenal), heartburn, nausea, vomiting.

Non-gastrointestinal experiences including: abnormal renal function, anemia, confusion, depression, disturbance of sleep, dizziness, dysuria or frequency, edema, elevated liver enzymes, headaches, increased bleeding time, pruritus, rashes, sedation, somnolence, tinnitus.

Additional Adverse Experiences Reported In Less Than 1% Of Patients:

Body as a whole: anaphylactic reactions, appetite changes, death, fever, infection, sepsis, serum sickness.

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

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

Hemic and lymphatic system: agranulocytosis, aplastic anemia, ecchymosis, eosinophilia, hemolytic anemia, leukopenia, lymphadenopathy, melena, pancytopenia, purpura, thrombocytopenia.

Metabolic and nutritional: 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, pneumonia, pulmonary infections, respiratory depression, sinusitis, symptoms of upper respiratory tract infection.

Skin and appendages: alopecia. angioedema, increased sweating, photosensitivity, pseudoporphyria, exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’ssyndrome), urticaria.

Special senses: blurred vision, conjunctivitis, hearing impairment.

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

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.

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).

General Pharmacokinetic Characteristics

In dose proportionality studies utilizing 600, 1200 and 1800 mg doses, the pharmacokinetics of oxaprozin in healthy subjects demonstrated nonlinear kinetics of both the total and unbound drug in opposite directions, i.e., dose exposure related increase in the clearance of total drug and decrease in the clearance of the unbound drug. Concentration dependent changes in the protein binding also resulted in changes in the oxaprozin volume of distribution, which increased for the total drug but decreased for the unbound drug. The pharmacokinetic parameters of oxaprozin in healthy subjects receiving a single dose or multiple once-daily doses of 1200 mg are presented in Table 2.

Table 2. Oxaprozin Pharmacokinetic Parameters with DAYPRO ALTA Dosing (1200 mg) [Mean (%CV)]

Absorption

After oral administration, DAYPRO ALTA dissociates into free oxaprozin which is 95% absorbed. Peak plasma concentration occurs at about 1 hour and 45 minutes after single dose administration (see Table 2). When DAYPRO ALTA is administered with food, the peak concentration of oxaprozin is delayed by about 45 minutes, but the extent of absorption is unchanged. Antacids do not significantly affect the extent and rate of oxaprozin absorption.

Distribution

The apparent volume of distribution (Vd/F) of total oxaprozin is approximately 10-16 L/70 kg. Oxaprozin potassium is 99% bound to plasma proteins, primarily to albumin. At therapeutic drug concentrations, the plasma protein binding of oxaprozin is saturable, resulting in a higher proportion of the free drug as the total drug concentration is increased. With increases in single doses or following repetitive once-daily dosing, the apparent volume of distribution and clearance of total drug increased, while that of unbound drug decreased due to the effects of nonlinear protein binding. 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.

Metabolism

Several oxaprozin metabolites excreted in human urine or feces are considered not to have significant pharmacologic activity. Oxaprozin is primarily metabolized by the liver, by both microsomal oxidation (65%) and glucuronic acid conjugation (35%). Ester and ether glucuronides are the major conjugated metabolites of oxaprozin. A small amount (<5%) of active phenolic metabolites is produced, but the contribution to overall activity is limited.

Excretion

Sixty-five percent (65%) of the dose is excreted into the urine and 35% in the feces as metabolites. Renal elimination of oxaprozin metabolites is a major pathway of elimination. Biliary excretion of unchanged oxaprozin is a minor pathway. After multiple doses of DAYPRO ALTA (1200mg QD), post-steady state mean elimination half-lives of total oxaprozin and protein unbound oxaprozin were 38.0 and 16.4 hrs, respectively (see Table 2).