Daypro
FDA Label NDC 0025-1381

Cardiovascular Thrombotic Events

• Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.1)].
• DAYPRO is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1)].

Gastrointestinal Bleeding, Ulceration, and Perforation

• NSAIDs cause an increased risk of serious gastrointestinal (GI) 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 and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2)].

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 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)].

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

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-times 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, antiplatelet drugs (such as 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 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 [see Drug Interactions (7)].

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 in patients with advanced renal disease. The renal effects of DAYPRO 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. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of DAYPRO [see Drug Interactions (7)]. Avoid the use of DAYPRO in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If DAYPRO 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.

Premature Closure of Fetal Ductus Arteriosus

Avoid use of NSAIDs, including DAYPRO, in pregnant women at about 30 weeks gestation and later. NSAIDs, including DAYPRO, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.

Oligohydramnios/Neonatal Renal Impairment

Use of NSAIDs, including DAYPRO, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required.

If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit DAYPRO use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if DAYPRO treatment extends beyond 48 hours. Discontinue DAYPRO if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)].

Risk Summary

Use of NSAIDs, including DAYPRO, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of DAYPRO use between about 20 and 30 weeks of gestation, and avoid DAYPRO use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data).

Premature Closure of Fetal Ductus Arteriosus

Use of NSAIDs, including DAYPRO, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal Renal Impairment

Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment.

Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. 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, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses.

The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Premature Closure of Fetal Ductus Arteriosus:

Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including DAYPRO, can cause premature closure of the fetal ductus arteriosus (see Data).

Oligohydramnios/Neonatal Renal Impairment:

If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If DAYPRO treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue DAYPRO and follow up according to clinical practice (see Data).

Labor or Delivery

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

Data

Human Data

Premature Closure of Fetal Ductus Arteriosus:

Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus.

Oligohydramnios/Neonatal Renal Impairment:

Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis.

Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain.

Animal data

Teratology studies with oxaprozin 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 maximum recommended human daily dose of 1800 mg based on a body surface area comparison, 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 maximum recommended human daily dose of 1800 mg based on a body surface area comparison).

Risk Summary

Lactation studies have not been conducted with DAYPRO. It is not known whether DAYPRO is excreted in human milk. DAYPRO 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 and any potential adverse effects on the breastfed infant from the DAYPRO or from the underlying maternal condition.

Infertility

Females

Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including DAYPRO, 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, 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 [see Nonclinical Toxicology (13.1)]

General Pharmacokinetic Characteristics

In dose proportionality studies utilizing 600 mg, 1200 mg, 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. Decreased clearance of the unbound drug was related predominantly to a decrease in the volume of distribution of the unbound drug and not an increase in the elimination half-life. This phenomenon is considered to have minimal impact on drug accumulation upon multiple dosing. The pharmacokinetic parameters of oxaprozin in healthy subjects receiving a single dose or multiple once-daily doses of 1200 mg are presented in Table 3.

Table 3. Oxaprozin Pharmacokinetic Parameters [Mean (%CV)] (1200 mg)

	Healthy Adults (19–78 years)
	Total Drug		Unbound Drug
	Single N=35	Multiple N=12	Single N=35	Multiple N=12
Tmax = time to reach the maximum plasma concentration of oxaprozin.
Tmax (hr)	3.09 (39)	2.44 (40)	3.03 (48)	2.33 (35)
Oral Clearance (L/hr/70 kg)	0.150 (24)	0.301 (29)	136 (24)	102 (45)
Apparent Volume of Distribution at Steady State (Vd/F; L/70 kg)	11.7 (13)	16.7 (14)	6230 (28)	2420 (38)
Elimination Half-life (hr)	54.9 (49)	41.4 (27)	27.8 (34)	19.5 (15)

Absorption

DAYPRO is 95% absorbed after oral administration. Food may reduce the rate of absorption of oxaprozin, but the extent of absorption is unchanged. Antacids do not significantly affect the extent and rate of DAYPRO absorption.

Distribution

The apparent volume of distribution (Vd/F) of total oxaprozin is approximately 11 to 17 L/70 kg. Oxaprozin 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 multiple 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 penetrates into synovial tissues of rheumatoid arthritis patients with oxaprozin concentrations 2-fold and 3-fold greater than in plasma and synovial fluid, respectively. 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.

Elimination

Metabolism

Several oxaprozin metabolites have been identified in human urine or feces.

Oxaprozin is primarily metabolized in the liver, by both microsomal oxidation (65%) and glucuronic acid conjugation (35%). Ester and ether glucuronide are the major conjugated metabolites of oxaprozin. On chronic dosing, metabolites do not accumulate in the plasma of patients with normal renal function. Concentrations of the metabolites in plasma are very low.

Oxaprozin's metabolites do not have significant pharmacologic activity. The major ester and ether glucuronide conjugated metabolites have been evaluated along with oxaprozin in receptor binding studies and in vivo animal models and have demonstrated no activity. A small amount (<5%) of active phenolic metabolites are produced, but the contribution to overall activity is limited.

Excretion

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 metabolites. Biliary excretion of unchanged oxaprozin is a minor pathway, and enterohepatic recycling of oxaprozin is insignificant. Upon chronic dosing, the accumulation half-life is approximately 22 hours. The elimination half-life is approximately twice the accumulation half-life due to increased binding and decreased clearance at lower concentrations.

Specific Populations

Geriatric: A multiple dose study comparing the pharmacokinetics of oxaprozin (1200 mg once daily) in 20 young (21 to 44 years) adults and 20 elderly (64 to 83 years) adults did not show any statistically significant differences between age groups.

Pediatric: A population pharmacokinetic study indicated no clinically important age dependent changes in the apparent clearance of unbound oxaprozin between adult rheumatoid arthritis patients (N=40) and juvenile rheumatoid arthritis (JRA) patients (≥6 years, N=44) when adjustments were made for differences in body weight between these patient groups. The extent of protein binding of oxaprozin at various therapeutic total plasma concentrations was also similar between the adult and pediatric patient groups. Pharmacokinetic model-based estimates of daily exposure (AUC_0–24) to unbound oxaprozin in JRA patients relative to adult rheumatoid arthritis patients suggest dose to body weight range relationships, as shown in Table 4.

Table 4. Dose to Body Weight Range to Achieve Similar Steady-State Exposure (AUC_0–24hr) to Unbound Oxaprozin in JRA Patients Relative to 70 kg Adult Rheumatoid Arthritis Patients Administered Oxaprozin 1200 mg Once Daily

Model-based nomogram derived from unbound oxaprozin steady-state plasma concentrations in JRA patients weighing 22.1 – 42.7 kg or ≥45.0 kg administered oxaprozin 600 mg or 1200 mg once daily for 14 days, respectively.

Dose (mg)	Body Weight Range (kg)
600	22 –31
900	32 –54
1200	≥ 55

Race: Pharmacokinetic differences due to race have not been identified.

Hepatic Impairment: Approximately 95% of oxaprozin is metabolized by the liver. However, patients with well-compensated cirrhosis do not require reduced doses of oxaprozin as compared to patients with normal hepatic function. Nevertheless, monitor patients with severe hepatic dysfunction for adverse reactions.

Renal Impairment: Oxaprozin's renal clearance decreased proportionally with creatinine clearance (CrCL), but since only approximately 5% of oxaprozin dose is excreted unchanged in the urine, the decrease in total body clearance becomes clinically important only in those subjects with highly decreased CrCL. Oxaprozin is not significantly removed from the blood in patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis (CAPD) due to its high protein binding. Oxaprozin plasma protein binding may decrease in patients with severe renal deficiency. Dosage adjustment may be necessary in patients with renal insufficiency [see Warnings and Precautions (5.6)].

Cardiac Failure: Well-compensated cardiac failure does not affect the plasma protein binding or the pharmacokinetics of oxaprozin.

Drug Interaction Studies

ACE inhibitors (enalapril): Oxaprozin has been shown to alter the pharmacokinetics of enalapril (significant decrease in dose-adjusted AUC_0–24 and C_max) and its active metabolite enalaprilat (significant increase in dose-adjusted AUC_0–24) [see Drug Interactions (7)].

Aspirin: When oxaprozin was administered with aspirin, the protein binding of oxaprozin was reduced, although the clearance of free oxaprozin was not altered. The clinical significance of this interaction is not known. An in vitro study showed that oxaprozin significantly interfered with the anti-platelet activity of aspirin [see Drug Interactions (7)].

Beta-blockers (metoprolol): Subjects receiving 1200 mg DAYPRO once daily with 100 mg metoprolol twice daily exhibited statistically significant but transient increases in sitting and standing blood pressures after 14 days [see Drug Interactions (7)].

Glyburide: Oxaprozin altered the pharmacokinetics of glyburide; however, 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 [see Drug Interactions (7)].

H₂-receptor antagonists (cimetidine, ranitidine): The total 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.

Lithium: Oxaprozin has produced an elevation in plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20% [see Drug Interactions (7)].

Methotrexate: Coadministration of oxaprozin with methotrexate resulted in approximately 36% reduction in apparent oral clearance of methotrexate [see Drug Interactions (7)].

Other drugs: The coadministration of oxaprozin and antacids, acetaminophen, or conjugated estrogens resulted in no statistically significant changes in pharmacokinetic parameters in single- and/or multiple-dose studies. The interaction of oxaprozin with cardiac glycosides has not been studied.

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 [see Warnings and Precautions (5.1)].

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 [see Warnings and Precautions (5.2)].

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 and seek immediate medical therapy [see Warnings and Precautions (5.3)].

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 [see Warnings and Precautions (5.5)].

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 [see Contraindications (4) and Warnings and Precautions (5.7)].

Serious Skin Reactions, including DRESS

Advise patients to stop taking DAYPRO immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9, 5.10)].

Female Fertility

Advise females of reproductive potential who desire pregnancy that NSAIDs, including DAYPRO, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3)].

Fetal Toxicity

Inform pregnant women to avoid use of DAYPRO and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with DAYPRO is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)].

Avoid Concomitant Use of NSAIDs

Inform patients that the concomitant use of DAYPRO 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 [see Warnings and Precautions (5.2) and Drug Interactions (7)]. 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 until they talk to their healthcare provider [see Drug Interactions (7)].

This product's labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com.



Logo (Daypro 02)

LAB-0189-13.0

DAYPRO is indicated:

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

Carefully consider the potential benefits and risks of DAYPRO and other treatment options before deciding to use DAYPRO. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)].

For OA, the dosage is 1200 mg (two 600 mg caplets) given orally once a day [see Dosage and Administration (2.5)].

For RA, the dosage is 1200 mg (two 600 mg caplets) given orally once a day [see Dosage and Administration (2.5)].

For JRA, in patients 6 to 16 years of age, the recommended dosage given orally once per day should be based on body weight of the patient as given in Table 1 [see Dosage and Administration (2.5)].

After observing the response to initial therapy with DAYPRO, the dose and frequency should be adjusted to suit an individual patient's needs. In osteoarthritis and rheumatoid arthritis and juvenile rheumatoid arthritis, the dosage should be individualized to the lowest effective dose of DAYPRO to minimize adverse effects. The maximum recommended total daily dose of DAYPRO in adults is 1800 mg (26 mg/kg, whichever is lower) in divided doses. In children, doses greater than 1200 mg have not been studied.

Patients with low body weight should initiate therapy with 600 mg once daily. Patients with severe renal impairment or on dialysis should also initiate therapy with 600 mg once daily. If there is insufficient relief of symptoms in such patients, the dose may be cautiously increased to 1200 mg, but only with close monitoring [see Clinical Pharmacology (12.3)].

In adults, in cases where a quick onset of action is important, the pharmacokinetics of oxaprozin allows therapy to be started with a one-time loading dose of 1200 mg to 1800 mg (not to exceed 26 mg/kg). Doses larger than 1200 mg/day on a chronic basis should be reserved for patients who weigh more than 50 kg, have normal renal and hepatic function, are at low risk of peptic ulcer, and whose severity of disease justifies maximal therapy. Physicians should ensure that patients are tolerating doses in the 600 mg to 1200 mg/day range without gastroenterologic, renal, hepatic, or dermatologic adverse effects before advancing to the larger doses. Most patients will tolerate once-a-day dosing with DAYPRO, although divided doses may be tried in patients unable to tolerate single doses.

DAYPRO (oxaprozin) caplets: 600 mg caplets, white, capsule-shaped, scored, film-coated, with DAYPRO debossed on one side and 1381 on the other side.

DAYPRO is contraindicated in the following patients:

• Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to oxaprozin or any components of the drug product [see Warnings and Precautions (5.7, 5.9)]
• 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 [see Warnings and Precautions (5.7, 5.8)]
• In the setting of CABG surgery [see Warnings and Precautions (5.1)]

Clinical trials of several cyclooxygenase-2 (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 [see Warnings and Precautions (5.2)].

NSAIDs, including DAYPRO, 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 to 6 months, and in about 2% to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.

Elevations of alanine aminotransferase (ALT) or aspartate aminotransferase (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.

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), discontinue DAYPRO immediately, and perform a clinical evaluation of the patient.

NSAIDs, including DAYPRO, 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 [see Drug Interactions (7)].

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

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]) [see Drug Interactions (7)].

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

Oxaprozin has been associated with anaphylactic reactions in patients with and without known hypersensitivity to oxaprozin and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)].

Seek emergency help if an anaphylactic reaction occurs.

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 is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When DAYPRO is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.

NSAIDs, including oxaprozin, 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 at the first appearance of skin rash or any other sign of hypersensitivity. DAYPRO is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)].

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as DAYPRO. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue DAYPRO and evaluate the patient immediately.

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

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

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

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 complete blood count (CBC) and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)].

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.

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

• Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)]
• GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)]
• Hepatotoxicity [see Warnings and Precautions (5.3)]
• Hypertension [see Warnings and Precautions (5.4)]
• Heart Failure and Edema [see Warnings and Precautions (5.5)]
• Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)]
• Anaphylactic Reactions [see Warnings and Precautions (5.7)]
• Serious Skin Reactions [see Warnings and Precautions (5.9)]
• Hematologic Toxicity [see Warnings and Precautions (5.12)]

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 DAYPRO in multidose, controlled, and open-label clinical trials. Rates for events from clinical trial experience are based on 2253 patients who took 1200 mg to 1800 mg DAYPRO per day in clinical trials. Of these, 1721 patients were treated for at least 1 month, 971 patients for at least 3 months, and 366 patients for more than 1 year.

Incidence Greater than 1%: In clinical trials of DAYPRO 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 Greater 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.

The following adverse reactions have been identified during post approval use of DAYPRO. 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.

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

Laboratory Test Interactions

False-positive urine immunoassay screening tests for benzodiazepines have been reported in patients taking DAYPRO. This is due to lack of specificity of the screening tests. False-positive test results may be expected for several days following discontinuation of DAYPRO therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish DAYPRO from benzodiazepines.

Safety and effectiveness of DAYPRO in pediatric patients below the age of 6 years of age have not been established. The effectiveness of DAYPRO for the treatment of the signs and symptoms of juvenile rheumatoid arthritis (JRA) in pediatric patients aged 6 to 16 years is supported by evidence from adequate and well controlled studies in adult rheumatoid arthritis patients, and is based on an extrapolation of the demonstrated efficacy of DAYPRO in adults with rheumatoid arthritis and the similarity in the course of the disease and the drug's mechanism of effect between these two patient populations. Use of DAYPRO in JRA patients 6 to 16 years of age is also supported by the following pediatric studies.

The pharmacokinetic profile and tolerability of oxaprozin were assessed in JRA patients relative to adult rheumatoid arthritis patients in a 14 day multiple dose pharmacokinetic study. Apparent clearance of unbound oxaprozin in JRA patients was reduced compared to adult rheumatoid arthritis patients, but this reduction could be accounted for by differences in body weight [see Clinical Pharmacology (12.3)]. No pharmacokinetic data are available for pediatric patients under 6 years. Adverse events were reported by approximately 45% of JRA patients versus an approximate 30% incidence of adverse events in the adult rheumatoid arthritis patient cohort. Most of the adverse events were related to the gastrointestinal tract and were mild to moderate.

In a 3 month open label study, 10 to 20 mg/kg/day of oxaprozin were administered to 59 JRA patients. Adverse events were reported by 58% of JRA patients. Most of those reported were generally mild to moderate, tolerated by the patients, and did not interfere with continuing treatment. Gastrointestinal symptoms were the most frequently reported adverse effects and occurred at a higher incidence than those historically seen in controlled studies in adults. Fifty-two patients completed 3 months of treatment with a mean daily dose of 20 mg/kg. Of 30 patients who continued treatment (19 to 48 week range total treatment duration), nine (30%) experienced rash on sun-exposed areas of the skin and 5 of those discontinued treatment. Controlled clinical trials with oxaprozin in pediatric patients have not been conducted.

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 [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.14)].

No adjustment of the dose of DAYPRO 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 [see Clinical Pharmacology (12.3)].

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.

DAYPRO is substantially excreted by the kidney, and the risk of toxic reactions to DAYPRO 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 and Precautions (5.6)].

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 (5.1, 5.2, 5.4, 5.6)].

Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 grams to 100 grams in adults, 1 gram 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 (1-800-222-1222).

DAYPRO (oxaprozin) caplet is a nonsteroidal anti-inflammatory drug, available as caplets of 600 mg for oral administration. The chemical name is 4,5-diphenyl-2-oxazole-propionic acid. The molecular weight is 293. Its molecular formula is C₁₈H₁₅NO₃, and it has the following chemical structure.

Chemical Structure (Daypro 01)

Oxaprozin is a white to off-white powder with a slight odor and a melting point of 162°C to 163°C. It is slightly soluble in alcohol and insoluble in water, with an octanol/water partition coefficient of 4.8 at physiologic pH (7.4). The pK_a in water is 4.3.

The inactive ingredients in DAYPRO include: microcrystalline cellulose, hypromellose, methylcellulose, magnesium stearate, polacrilin potassium, starch, polyethylene glycol and titanium dioxide. DAYPRO 600-mg caplets are white, capsule-shaped, scored, film-coated, with DAYPRO debossed on one side and 1381 on the other side.

Oxaprozin has analgesic, anti-inflammatory, and antipyretic properties.

The mechanism of action of DAYPRO, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).

Oxaprozin is a potent inhibitor of prostaglandin synthesis in vitro. Oxaprozin concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because oxaprozin is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

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 male or female rats treated with up to 216 mg/kg via the diet (1.2-times the maximum daily human dose of 1800 mg based on body surface area). The significance of this species-specific finding to man is unknown.

Mutagenesis

Oxaprozin was 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 a 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.

DAYPRO was evaluated for the management of the signs and symptoms of osteoarthritis in a total of 616 patients in active controlled clinical trials against aspirin (N=464), piroxicam (N=102), and other NSAIDs. DAYPRO was given both in variable (600 to 1200 mg/day) and in fixed (1200 mg/day) dosing schedules in either single or divided doses. In these trials, oxaprozin was found to be comparable to 2600 to 3200 mg/day doses of aspirin or 20 mg/day doses of piroxicam. Oxaprozin was effective both in once daily and in divided dosing schedules. In controlled clinical trials several days of oxaprozin therapy were needed for the drug to reach its full effects [see Dosage and Administration (2.5)].

DAYPRO was evaluated for managing the signs and symptoms of rheumatoid arthritis in placebo and active controlled clinical trials in a total of 646 patients. DAYPRO was given in single or divided daily doses of 600 to 1800 mg/day and was found to be comparable to 2600 to 3900 mg/day of aspirin. At these doses there was a trend (over all trials) for oxaprozin to be more effective and cause fewer gastrointestinal side effects than aspirin.

DAYPRO was given as a once-a-day dose of 1200 mg in most of the clinical trials, but larger doses (up to 26 mg/kg or 1800 mg/day) were used in selected patients. In some patients, DAYPRO may be better tolerated in divided doses. Due to its long half-life, several days of DAYPRO therapy were needed for the drug to reach its full effect [see Dosage and Administration (2.5)].

DAYPRO (oxaprozin) 600 mg caplets are white, capsule-shaped, scored, film-coated, with DAYPRO debossed on one side and 1381 on the other side, supplied as:

Storage

Keep bottles tightly closed. Store at room temperature 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container with a child-resistant closure. Protect the unit dose from light.

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 and periodically during the course of ongoing therapy.

ALWAYS DISPENSE WITH MEDICATION GUIDE

NDC 0025-1381-31

Pfizer

Daypro^®
oxaprozin caplets

600 mg

100 Caplets
Rx only

Principal Display Panel (600 mg Caplet Bottle Label)