Naprelan

Tablets are indicated for the treatment of: • rheumatoid arthritis (RA) • osteoarthritis (OA) • ankylosing spondylitis (AS) • tendinitis, bursitis • acute gout • primary dysmenorrhea (PD) • the relief of mild to moderate pain . NAPRELAN is a nonsteroidal anti-inflammatory drug indicated for the treatment of: • rheumatoid arthritis (RA) • osteoarthritis (OA) • ankylosing spondylitis (AS) • tendinitis, bursitis • acute gout • primary dysmenorrhea (PD) • the relief of mild to moderate pain

Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals RA, OA, and AS: The dosage is two 375 mg or 500 mg tablets once daily, or one 750 mg tablet once daily. Management of Pain, PD, and Acute Tendinitis and Bursitis: The dosage is two 500 mg tablets once daily. For patients requiring greater analgesic benefit, two 750 mg tablets or three 500 mg tablets may be used for a limited period. Thereafter, the total daily dose should not exceed two 500 mg tablets For the treatment of Acute Gout: The dosage is two to three 500 mg tablets once daily on the first day, followed by two 500 mg tablets once daily, until the attack has subsided.

2.1General Dosing Instructions Carefully

consider the potential benefits and risks of NAPRELAN and other treatment options before deciding to use NAPRELAN. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals . After observing the response to initial therapy with NAPRELAN, the dose and frequency should be adjusted to suit an individual patient’s needs.

2.2Rheumatoid Arthritis, Osteoarthritis, and Ankylosing Spondylitis

The recommended starting dose of NAPRELAN Tablets in adults is two NAPRELAN 375 mg tablets (750 mg) once daily, one NAPRELAN 750 mg (750 mg) once daily, or two NAPRELAN 500 mg tablets (1,000 mg) once daily. Patients already taking naproxen 250 mg, 375 mg, or 500 mg twice daily (morning and evening) may have their total daily dose replaced with NAPRELAN Tablets as a single daily dose. During long-term administration, the dose of NAPRELAN Tablets may be adjusted up or down depending on the clinical response of the patient.

In patients who tolerate lower doses of NAPRELAN Tablets well, the dose may be increased to two NAPRELAN 750 mg tablets (1,500 mg), or three NAPRELAN 500 mg tablets (1,500 mg) once daily for limited periods when a higher level of anti-inflammatory/analgesic activity is required. When treating patients, especially at the higher dose levels, the physician should observe sufficient increased clinical benefit to offset the potential increased risk . The lowest effective dose should be sought and used in every patient. Symptomatic improvement in arthritis usually begins within one week; however, treatment for two weeks may be required to achieve a therapeutic benefit.

2.3Management of Pain, Primary Dysmenorrhea, and Acute

Tendinitis and Bursitis The recommended starting dose is two NAPRELAN 500 mg tablets (1,000 mg) once daily. For patients requiring greater analgesic benefit, two NAPRELAN 750 mg tablets (1,500 mg) or three NAPRELAN 500 mg tablets (1,500 mg) may be used for a limited period. Thereafter, the total daily dose should not exceed two NAPRELAN 500 mg tablets (1,000 mg).

2.4Acute Gout The

recommended dose on the first day is two to three NAPRELAN 500 mg tablets (1,000 to 1,500 mg) once daily, followed by two NAPRELAN 500 mg tablets (1,000 mg) once daily, until the attack has subsided.

2.5Dosage Adjustments in Patients with Hepatic Impairment

A lower dose should be considered in patients with renal or hepatic impairment or in elderly patients . Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly it is prudent to use the lowest effective dose.

2.1General Dosing Instructions Carefully

consider the potential benefits and risks of NAPRELAN and other treatment options before deciding to use NAPRELAN. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals . After observing the response to initial therapy with NAPRELAN, the dose and frequency should be adjusted to suit an individual patient’s needs.

2.2Rheumatoid Arthritis, Osteoarthritis, and Ankylosing Spondylitis

The recommended starting dose of NAPRELAN Tablets in adults is two NAPRELAN 375 mg tablets (750 mg) once daily, one NAPRELAN 750 mg (750 mg) once daily, or two NAPRELAN 500 mg tablets (1,000 mg) once daily. Patients already taking naproxen 250 mg, 375 mg, or 500 mg twice daily (morning and evening) may have their total daily dose replaced with NAPRELAN Tablets as a single daily dose. During long-term administration, the dose of NAPRELAN Tablets may be adjusted up or down depending on the clinical response of the patient.

In patients who tolerate lower doses of NAPRELAN Tablets well, the dose may be increased to two NAPRELAN 750 mg tablets (1,500 mg), or three NAPRELAN 500 mg tablets (1,500 mg) once daily for limited periods when a higher level of anti-inflammatory/analgesic activity is required. When treating patients, especially at the higher dose levels, the physician should observe sufficient increased clinical benefit to offset the potential increased risk . The lowest effective dose should be sought and used in every patient. Symptomatic improvement in arthritis usually begins within one week; however, treatment for two weeks may be required to achieve a therapeutic benefit.

2.3Management of Pain, Primary Dysmenorrhea, and Acute

Tendinitis and Bursitis The recommended starting dose is two NAPRELAN 500 mg tablets (1,000 mg) once daily. For patients requiring greater analgesic benefit, two NAPRELAN 750 mg tablets (1,500 mg) or three NAPRELAN 500 mg tablets (1,500 mg) may be used for a limited period. Thereafter, the total daily dose should not exceed two NAPRELAN 500 mg tablets (1,000 mg).

2.4Acute Gout The

recommended dose on the first day is two to three NAPRELAN 500 mg tablets (1,000 to 1,500 mg) once daily, followed by two NAPRELAN 500 mg tablets (1,000 mg) once daily, until the attack has subsided.

2.5Dosage Adjustments in Patients with Hepatic Impairment

A lower dose should be considered in patients with renal or hepatic impairment or in elderly patients . Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly it is prudent to use the lowest effective dose.

Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure ( 5.4 , 7 ) Heart Failure and Edema: Avoid use of NAPRELAN in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of NAPRELAN in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs Exacerbation of Asthma Related to Aspirin Sensitivity: NAPRELAN is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) Serious Skin Reactions: Discontinue NAPRELAN at first appearance of skin rash or other signs of hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) : Discontinue and evaluate clinically. Fetal Toxicity: Limit use of NSAIDs, including NAPRELAN, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus (5.11, 8.1). Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia (5.12, 7 )

5.1Cardiovascular 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 naproxen, 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 NAPRELAN in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events.

If NAPRELAN is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

5.2Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs,

including naproxen, 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. 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 NAPRELAN 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 .

5.3Hepatotoxicity 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 naproxen.

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 NAPRELAN immediately, and perform a clinical evaluation of the patient.

5.4Hypertension NSAIDs,

including NAPRELAN, can lead to new onset or worsening of pre-existing 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.

5.5Heart 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 naproxen 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 NAPRELAN in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If NAPRELAN is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

5.6Renal 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 NAPRELAN in patients with advanced renal disease.

The renal effects of NAPRELAN may hasten the progression of renal dysfunction in patients with preexisting renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating NAPRELAN. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of NAPRELAN . Avoid the use of NAPRELAN in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If NAPRELAN 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.

5.7Anaphylactic Reactions Naproxen

has been associated with anaphylactic reactions in patients with and without known hypersensitivity to naproxen and in patients with aspirin-sensitive asthma . Seek emergency help if an anaphylactic reaction occurs.

5.8Exacerbation 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, NAPRELAN is contraindicated in patients with this form of aspirin sensitivity . When NAPRELAN is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.

5.9Serious Skin Reactions NSAIDs,

including naproxen can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening.

These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of NAPRELAN at the first appearance of skin rash or any other sign of hypersensitivity. NAPRELAN is contraindicated in patients with previous serious skin reactions to NSAIDs .

5.10Drug Reaction with Eosinophilia and Systemic Symptoms

(DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as NAPRELAN. 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 NAPRELAN and evaluate the patient immediately.

5.11Fetal Toxicity Premature Closure of Fetal

Ductus Arteriosus Avoid use of NSAIDs, including NAPRELAN, in pregnant women at about 30 weeks gestation and later. NSAIDs, including NAPRELAN, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including NAPRELAN, 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 NAPRELAN use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if NAPRELAN treatment extends beyond 48 hours.

Discontinue NAPRELAN if oligohydramnios occurs and follow up according to clinical practice .

5.12Hematologic 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 NAPRELAN has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including NAPRELAN, may increase the risk of bleeding events.

Co-morbid conditions such as coagulation disorders, 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 .

5.13Masking of Inflammation and Fever The

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

5.14Laboratory 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 .

5.1Cardiovascular 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 naproxen, 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 NAPRELAN in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events.

If NAPRELAN is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

5.2Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs,

including naproxen, 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. 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 NAPRELAN 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 .

5.3Hepatotoxicity 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 naproxen.

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 NAPRELAN immediately, and perform a clinical evaluation of the patient.

5.4Hypertension NSAIDs,

including NAPRELAN, can lead to new onset or worsening of pre-existing 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.

5.5Heart 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 naproxen 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 NAPRELAN in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If NAPRELAN is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

5.6Renal 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 NAPRELAN in patients with advanced renal disease.

The renal effects of NAPRELAN may hasten the progression of renal dysfunction in patients with preexisting renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating NAPRELAN. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of NAPRELAN . Avoid the use of NAPRELAN in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If NAPRELAN 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.

5.7Anaphylactic Reactions Naproxen

has been associated with anaphylactic reactions in patients with and without known hypersensitivity to naproxen and in patients with aspirin-sensitive asthma . Seek emergency help if an anaphylactic reaction occurs.

5.8Exacerbation 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, NAPRELAN is contraindicated in patients with this form of aspirin sensitivity . When NAPRELAN is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.

5.9Serious Skin Reactions NSAIDs,

including naproxen can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening.

These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of NAPRELAN at the first appearance of skin rash or any other sign of hypersensitivity. NAPRELAN is contraindicated in patients with previous serious skin reactions to NSAIDs .

5.11Fetal Toxicity Premature Closure of Fetal

Ductus Arteriosus Avoid use of NSAIDs, including NAPRELAN, in pregnant women at about 30 weeks gestation and later. NSAIDs, including NAPRELAN, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including NAPRELAN, 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 NAPRELAN use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if NAPRELAN treatment extends beyond 48 hours.

Discontinue NAPRELAN if oligohydramnios occurs and follow up according to clinical practice .

5.12Hematologic 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 NAPRELAN has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including NAPRELAN, may increase the risk of bleeding events.

Co-morbid conditions such as coagulation disorders, 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 .

5.13Masking of Inflammation and Fever The

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

5.14Laboratory 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 .

4 CONTRAINDICATIONS NAPRELAN is contraindicated in the following patients: Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to naproxen 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 Known hypersensitivity to naproxen or any components of the drug product History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs In the setting of CABG surgery

8.1Pregnancy Risk Summary Use of NSAIDs,

including NAPRELAN, 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 NAPRELAN use between about 20 and 30 weeks of gestation, and avoid NAPRELAN use at about 30 weeks of gestation and later in pregnancy . Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including NAPRELAN, 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 in rats, rabbit, and mice no evidence of teratogenicity or fetal harm when naproxen was administered during the period of organogenesis at doses 0.13, 0.26, and 0.6 times the maximum recommended human daily dose of 1,500 mg/day, respectively. 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 naproxen, 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 NAPRELAN, can cause premature closure of the fetal ductus arteriosus . 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 NAPRELAN treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue NAPRELAN and follow up according to clinical practice . Labor or Delivery There are no studies on the effects of NAPRELAN during labor or delivery.

In animal studies, NSAIDS, including naproxen sodium, inhibit prostaglandin synthesis, cause delayed parturition, increase incidence of dystocia and increase the incidence of stillbirth. Data Human Data There is some evidence to suggest that when inhibitors of prostaglandin synthesis are used to delay preterm labor, there is an increased risk of neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus, and intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction, and abnormal prostaglandin E levels in preterm infants.

Because of the known effect of drugs of this class on the human fetal cardiovascular system (closure of the ductus arteriosus), use during third trimester should be avoided. 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 Reproduction studies have been performed in rats at 20 mg/kg/day (0.13 times the maximum recommended human daily dose of 1,500 mg/day based on body surface area comparison) rabbits at 20 mg/kg/day (0.26 times the maximum recommended human daily dose, based on body surface area comparison), and mice at 170 mg/kg/day (0.6 times the maximum recommended human daily dose based on body surface area comparison) with no evidence of impaired fertility or harm to the fetus due to the drug. 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 naproxen sodium resulted in increased pre- and post-implantation loss.

8.2Lactation Risk Summary The

naproxen anion has been found in the milk of lactating women at a concentration of approximately 1% of that found in the plasma. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NAPRELAN and any potential adverse effects on the breastfed infant from the NAPRELAN or from the underlying maternal condition.

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 The most frequent adverse events were headache (15%), followed by dyspepsia (14%), and flu syndrome (10%). To report SUSPECTED ADVERSE REACTIONS, contact TWi Pharmaceuticals, Inc. at 1-844-518-2989 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical 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. As with all drugs in this class, the frequency and severity of adverse events depends on several factors: the dose of the drug and duration of treatment; the age, the sex, physical condition of the patient; any concurrent medical diagnoses or individual risk factors. The following adverse reactions are divided into three parts based on frequency and whether or not the possibility exists of a causal relationship between drug usage and these adverse events.

In those reactions listed as “Probable Causal Relationship” there is at least one case for each adverse reaction where there is evidence to suggest that there is a causal relationship between drug usage and the reported event. The adverse reactions reported were based on the results from two double-blind controlled clinical trials of three months duration with an additional nine month open-label extension. A total of 542 patients received NAPRELAN Tablets either in the double-blind period or in the nine month open-label extension.

Of these 542 patients, 232 received NAPRELAN Tablets, 167 were initially treated with Naprosyn ® and 143 were initially treated with placebo. Adverse reactions reported by patients who received NAPRELAN Tablets are shown by body system. Those adverse reactions observed with naproxen but not reported in controlled trials with NAPRELAN Tablets are italicized . The most frequent adverse events from the double-blind and open-label clinical trials were headache (15%), followed by dyspepsia (14%), and flu syndrome (10%).

The incidence of other adverse events occurring in 3% to 9% of the patients are marked with an asterisk. Those reactions occurring in less than 3% of the patients are unmarked. Incidence greater than 1% (probable causal relationship) Body as a Whole—Pain (back)*, pain*, infection*, fever, injury (accident), asthenia, pain chest, headache (15%), flu syndrome (10%).

Gastrointestinal—Nausea*, diarrhea*, constipation*, abdominal pain*, flatulence, gastritis, vomiting, dysphagia, dyspepsia (14%), heartburn* , stomatitis . Hematologic—Anemia, ecchymosis. Respiratory—Pharyngitis*, rhinitis*, sinusitis*, bronchitis, cough increased. Renal—Urinary tract infection*, cystitis.

Dermatologic—Skin rash*, skin eruptions* , ecchymoses* , purpura . Metabolic and Nutrition—Peripheral edema, hyperglycemia. Central Nervous System—Dizziness, paresthesia, insomnia, drowsiness* , lightheadedness . Cardiovascular—Hypertension, edema* , dyspnea* , palpitations . Musculoskeletal—Cramps (leg), myalgia, arthralgia, joint disorder, tendon disorder. Special Senses— Tinnitus* , hearing disturbances , visual disturbances . General— Thirst . Incidence less than 1% (probable causal relationship) Body as a Whole—Abscess, monilia, neck rigid, pain neck, abdomen enlarged, carcinoma, cellulitis, edema general, LE syndrome, malaise, mucous membrane disorder, allergic reaction, pain pelvic.

Gastrointestinal—Anorexia, cholecystitis, cholelithiasis, eructation, GI hemorrhage, rectal hemorrhage, stomatitis aphthous, stomatitis ulcer, ulcer mouth, ulcer stomach, periodontal abscess, cardiospasm, colitis, esophagitis, gastroenteritis, GI disorder, rectal disorder, tooth disorder, hepatosplenomegaly, liver function abnormality, melena, ulcer esophagus, hematemesis , jaundice , pancreatitis , necrosis . Renal—Dysmenorrhea, dysuria, kidney function abnormality, nocturia, prostate disorder, pyelonephritis, carcinoma breast, urinary incontinence, kidney calculus, kidney failure, menorrhagia, metrorrhagia, neoplasm breast, nephrosclerosis, hematuria, pain kidney, pyuria, urine abnormal, urinary frequency, urinary retention, uterine spasm, vaginitis, glomerular nephritis , hyperkalemia , interstitial nephritis , nephrotic syndrome , renal disease , renal failure , renal papillary necrosis . Hematologic—Leukopenia, bleeding time increased, eosinophilia, abnormal RBC, abnormal WBC, thrombocytopenia, agranulocytosis , granulocytopenia . Central Nervous System—Depression, anxiety, hypertonia, nervousness, neuralgia, neuritis, vertigo, amnesia, confusion, co-ordination, abnormal diplopia, emotional lability, hematoma subdural, paralysis, dream abnormalities , inability to concentrate , muscle weakness . Dermatologic: Angiodermatitis, herpes simplex, dry skin, sweating, ulcer skin, acne, alopecia, dermatitis contact, eczema, herpes zoster, nail disorder, skin necrosis, subcutaneous nodule, pruritus, urticaria, neoplasm skin, photosensitive dermatitis , photosensitivity reactions resembling porphyria cutaneous tarda , epidermolysis bullosa . Special Senses—Amblyopia, scleritis, cataract, conjunctivitis, deaf, ear disorder, keratoconjunctivitis, lacrimation disorder, otitis media, pain eye. Cardiovascular—Angina pectoris, coronary artery disease, myocardial infarction, deep thrombophlebitis, vasodilation, vascular anomaly, arrhythmia, bundle branch block, abnormal ECG, heart failure right, hemorrhage, migraine, aortic stenosis, syncope, tachycardia, congestive heart failure . Respiratory—Asthma, dyspnea, lung edema, laryngitis, lung disorder, epistaxis, pneumonia, respiratory distress, respiratory disorder, eosinophilic pneumonitis . Musculoskeletal—Myasthenia, bone disorder, spontaneous bone fracture, fibrotendinitis, bone pain, ptosis, spasm general, bursitis. Metabolic and Nutrition—Creatinine increase, glucosuria, hypercholesteremia, albuminuria, alkalosis, BUN increased, dehydration, edema, glucose tolerance decrease, hyperuricemia, hypokalemia, SGOT increase, SGPT increase, weight decrease.

General— Anaphylactoid reactions , angioneurotic edema , menstrual disorders , hypoglycemia , pyrexia (chills and fevers) . Incidence less than 1% (causal relationship unknown) Other adverse reactions listed in the naproxen package label, but not reported by those who received NAPRELAN Tablets are shown in italics. These observations are being listed as alerting information to the physician. Hematologic— Aplastic anemia , hemolytic anemia . Central Nervous System— Aseptic meningitis , cognitive dysfunction . Dermatologic— Epidermal necrolysis , erythema multiforme , Stevens-Johnson syndrome . Gastrointestinal— Non-peptic GI ulceration , ulcerative stomatitis . Cardiovascular— Vasculitis .

6.2Postmarketing Experience The

following adverse reactions have been identified during postapproval use of naproxen. 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. Skin and Appendages: Exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE).

6.1Clinical 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. As with all drugs in this class, the frequency and severity of adverse events depends on several factors: the dose of the drug and duration of treatment; the age, the sex, physical condition of the patient; any concurrent medical diagnoses or individual risk factors. The following adverse reactions are divided into three parts based on frequency and whether or not the possibility exists of a causal relationship between drug usage and these adverse events.

In those reactions listed as “Probable Causal Relationship” there is at least one case for each adverse reaction where there is evidence to suggest that there is a causal relationship between drug usage and the reported event. The adverse reactions reported were based on the results from two double-blind controlled clinical trials of three months duration with an additional nine month open-label extension. A total of 542 patients received NAPRELAN Tablets either in the double-blind period or in the nine month open-label extension.

Of these 542 patients, 232 received NAPRELAN Tablets, 167 were initially treated with Naprosyn ® and 143 were initially treated with placebo. Adverse reactions reported by patients who received NAPRELAN Tablets are shown by body system. Those adverse reactions observed with naproxen but not reported in controlled trials with NAPRELAN Tablets are italicized . The most frequent adverse events from the double-blind and open-label clinical trials were headache (15%), followed by dyspepsia (14%), and flu syndrome (10%).

The incidence of other adverse events occurring in 3% to 9% of the patients are marked with an asterisk. Those reactions occurring in less than 3% of the patients are unmarked. Incidence greater than 1% (probable causal relationship) Body as a Whole—Pain (back)*, pain*, infection*, fever, injury (accident), asthenia, pain chest, headache (15%), flu syndrome (10%).

Gastrointestinal—Nausea*, diarrhea*, constipation*, abdominal pain*, flatulence, gastritis, vomiting, dysphagia, dyspepsia (14%), heartburn* , stomatitis . Hematologic—Anemia, ecchymosis. Respiratory—Pharyngitis*, rhinitis*, sinusitis*, bronchitis, cough increased. Renal—Urinary tract infection*, cystitis.

Dermatologic—Skin rash*, skin eruptions* , ecchymoses* , purpura . Metabolic and Nutrition—Peripheral edema, hyperglycemia. Central Nervous System—Dizziness, paresthesia, insomnia, drowsiness* , lightheadedness . Cardiovascular—Hypertension, edema* , dyspnea* , palpitations . Musculoskeletal—Cramps (leg), myalgia, arthralgia, joint disorder, tendon disorder. Special Senses— Tinnitus* , hearing disturbances , visual disturbances . General— Thirst . Incidence less than 1% (probable causal relationship) Body as a Whole—Abscess, monilia, neck rigid, pain neck, abdomen enlarged, carcinoma, cellulitis, edema general, LE syndrome, malaise, mucous membrane disorder, allergic reaction, pain pelvic.

Gastrointestinal—Anorexia, cholecystitis, cholelithiasis, eructation, GI hemorrhage, rectal hemorrhage, stomatitis aphthous, stomatitis ulcer, ulcer mouth, ulcer stomach, periodontal abscess, cardiospasm, colitis, esophagitis, gastroenteritis, GI disorder, rectal disorder, tooth disorder, hepatosplenomegaly, liver function abnormality, melena, ulcer esophagus, hematemesis , jaundice , pancreatitis , necrosis . Renal—Dysmenorrhea, dysuria, kidney function abnormality, nocturia, prostate disorder, pyelonephritis, carcinoma breast, urinary incontinence, kidney calculus, kidney failure, menorrhagia, metrorrhagia, neoplasm breast, nephrosclerosis, hematuria, pain kidney, pyuria, urine abnormal, urinary frequency, urinary retention, uterine spasm, vaginitis, glomerular nephritis , hyperkalemia , interstitial nephritis , nephrotic syndrome , renal disease , renal failure , renal papillary necrosis . Hematologic—Leukopenia, bleeding time increased, eosinophilia, abnormal RBC, abnormal WBC, thrombocytopenia, agranulocytosis , granulocytopenia . Central Nervous System—Depression, anxiety, hypertonia, nervousness, neuralgia, neuritis, vertigo, amnesia, confusion, co-ordination, abnormal diplopia, emotional lability, hematoma subdural, paralysis, dream abnormalities , inability to concentrate , muscle weakness . Dermatologic: Angiodermatitis, herpes simplex, dry skin, sweating, ulcer skin, acne, alopecia, dermatitis contact, eczema, herpes zoster, nail disorder, skin necrosis, subcutaneous nodule, pruritus, urticaria, neoplasm skin, photosensitive dermatitis , photosensitivity reactions resembling porphyria cutaneous tarda , epidermolysis bullosa . Special Senses—Amblyopia, scleritis, cataract, conjunctivitis, deaf, ear disorder, keratoconjunctivitis, lacrimation disorder, otitis media, pain eye. Cardiovascular—Angina pectoris, coronary artery disease, myocardial infarction, deep thrombophlebitis, vasodilation, vascular anomaly, arrhythmia, bundle branch block, abnormal ECG, heart failure right, hemorrhage, migraine, aortic stenosis, syncope, tachycardia, congestive heart failure . Respiratory—Asthma, dyspnea, lung edema, laryngitis, lung disorder, epistaxis, pneumonia, respiratory distress, respiratory disorder, eosinophilic pneumonitis . Musculoskeletal—Myasthenia, bone disorder, spontaneous bone fracture, fibrotendinitis, bone pain, ptosis, spasm general, bursitis. Metabolic and Nutrition—Creatinine increase, glucosuria, hypercholesteremia, albuminuria, alkalosis, BUN increased, dehydration, edema, glucose tolerance decrease, hyperuricemia, hypokalemia, SGOT increase, SGPT increase, weight decrease.

General— Anaphylactoid reactions , angioneurotic edema , menstrual disorders , hypoglycemia , pyrexia (chills and fevers) . Incidence less than 1% (causal relationship unknown) Other adverse reactions listed in the naproxen package label, but not reported by those who received NAPRELAN Tablets are shown in italics. These observations are being listed as alerting information to the physician. Hematologic— Aplastic anemia , hemolytic anemia . Central Nervous System— Aseptic meningitis , cognitive dysfunction . Dermatologic— Epidermal necrolysis , erythema multiforme , Stevens-Johnson syndrome . Gastrointestinal— Non-peptic GI ulceration , ulcerative stomatitis . Cardiovascular— Vasculitis .