FDA Label for Naproxen

How Supplied

500 MG: WHITE TO OFF-WHITE, CAPSULE-SHAPED TABLETS WITH 140 DEBOSSED ON ONE SIDE AND SCORED ON

OTHER SIDE. PACKAGED IN LIGHT-RESISTANT BOTTLES OF 100 AND 500.

NDC 68071-4381-4 BOTTLES OF 4

NDC 68071-4381-6 BOTTLES OF 6

NDC 68071-4381-2 BOTTLES OF 20

STORE AT 20°-25°C (68°-77°F) EXCURSIONS PERMITTED TO 15°-30°C (59°-86°F) IN WELL-CLOSED CONTAINERS

[SEE USP CONTROLLED ROOM TEMPERATURE]. DISPENSE IN LIGHT-RESISTANT CONTAINERS.

RX ONLY

Spl Medguide

CARDIOVAS CULAR THROMBOTIC EVENTS

CLINICAL TRIALS OF SEVERAL COX-2 SELECTIVE AND NON-SELECTIVE NSAIDS OF UP TO THREE YEARS DURATION HAVE SHOWN AN INCREASED RISK OF SERIOUS CARDIOVASCULAR (CV) THROMBOTIC EVENTS, MYOCARDIAL INFARCTION, 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. SOMEOBSERVATIONAL 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 (SEE WARNINGS; GASTROINTESTINAL BLEEDING, ULCERATION, AND PERFORATION).

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 (SEE CONTRAINDICATIONS).

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 NAPROXEN IN PATIENTS WITH A RECENT MI UNLESS THE BENEFITS ARE EXPECTED TO OUTWEIGH THE RISK OF RECURRENT CV THROMBOTIC EVENTS. IF NAPROXEN IS USED IN PATIENTS WITH A RECENT MI, MONITOR PATIENTS FOR SIGNS OF CARDIAC ISCHEMIA.

GASTROINTESTINAL 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 3-6 MONTHS, AND IN ABOUT 2%-

4% OF PATIENTS TREATED FOR ONE YEAR. HOWEVER, EVEN SHORT-TERM NSAID THERAPY IS NOT WITHOUT RISK. RISK FACTORS FOR GI BLEEDING, ULCERATION, AND PERFORATION PATIENTS WITH A PRIOR HISTORY OF PEPTIC ULCER DISEASE AND/OR GI BLEEDING WHO USED NSAIDS HAD A GREATER

THAN 10-FOLD INCREASED RISK FOR DEVELOPING A GI BLEED COMPARED TO PATIENTS WITHOUT THESE RISK FACTORS. OTHER FACTORS THAT INCREASE THE RISK OF GI BLEEDING IN PATIENTS TREATED WITH NSAIDS INCLUDE LONGER DURATION OF NSAID THERAPY; CONCOMITANT USE OF ORAL CORTICOSTEROIDS, ASPIRIN, ANTICOAGULANTS, OR SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIS); SMOKING; USE OF ALCOHOL; OLDER AGE; AND POOR GENERAL HEALTH STATUS. MOST POSTMARKETING REPORTS OF FATAL GI EVENTS OCCURRED IN ELDERLY OR DEBILITATED PATIENTS.

ADDITIONALLY, PATIENTS WITH ADVANCED LIVER DISEASE AND/OR COAGULOPATHY ARE AT INCREASED RISK FOR GI BLEEDING.

STRATEGIES TO MINIMIZE THE GI RISKS IN NSAID-TREATED PATIENTS:

• USE THE LOWEST EFFECTIVE DOSAGE FOR THE SHORTEST POSSIBLE DURATION.
• AVOID ADMINISTRATION OF MORE THAN ONE NSAID AT A TIME.
• AVOID USE IN PATIENTS AT HIGHER RISK UNLESS BENEFITS ARE EXPECTED TO OUTWEIGH THE INCREASED RISK OF
• BLEEDING. FOR SUCH PATIENTS, AS WELL AS THOSE WITH ACTIVE GI BLEEDING, CONSIDER ALTERNATE THERAPIES OTHER THAN NSAIDS.
• REMAIN ALERT FOR SIGNS AND SYMPTOMS OF GI ULCERATION AND BLEEDING DURING NSAID THERAPY.
• IF A SERIOUS GI ADVERSE EVENT IS SUSPECTED, PROMPTLY INITIATE EVALUATION AND TREATMENT, AND DISCONTINUE NAPROXEN 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 PRECAUTIONS; DRUG INTERACTIONS).

HEPATOTOXICITY

ELEVATIONS OF ALT OR AST (THREE OR MORE TIMES THE UPPER LIMIT OF NORMAL [ULN]) HAVE BEEN REPORTED IN APPROXIMATELY 1% OF 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 TAKING 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 "FLULIKE" SYMPTOMS). IF CLINICAL SIGNS AND SYMPTOMS CONSISTENT WITH LIVER DISEASE DEVELOP, OR IF SYSTEMIC MANIFESTATIONS OCCUR (E.G., EOSINOPHILIA, RASH, ETC.), DISCONTINUE NAPROXEN IMMEDIATELY, AND PERFORM A CLINICAL EVALUATION OF THE PATIENT.

HYPERTENSION

NSAIDS, INCLUDING NAPROXEN, CAN LEAD TO ONSET OF NEW HYPERTENSION 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, THIAZIDES OR LOOP DIURETICS MAY HAVE IMPAIRED RESPONSE TO THESE THERAPIES WHEN TAKING NSAIDS (SEE PRECAUTIONS; DRUG INTERACTIONS).

MONITOR BLOOD PRESSURE (BP) DURING THE INITIATION OF NSAID TREATMENT AND THROUGHOUT THE COURSE OF THERAPY.

HEART FAILURE AND EDEMA

THE COXIB AND TRADITIONAL NSAID TRIALISTS’ COLLABORATION META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS DEMONSTRATED AN APPROXIMATELY TWO-FOLD INCREASE IN HOSPITALIZATION 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]) (SEE PRECAUTIONS; DRUG INTERACTIONS).

AVOID THE USE OF NAPROXEN IN PATIENTS WITH SEVERE HEART FAILURE UNLESS THE BENEFITS ARE EXPECTED TO OUTWEIGH THE RISK OF WORSENING HEART FAILURE. IF NAPROXEN IS USED IN PATIENTS WITH SEVERE HEART FAILURE, MONITOR PATIENTS FOR SIGNS OF WORSENING HEART FAILURE.

RENAL TOXICITY AND HYPERKALEMIA

RENAL TOXICITY

LONG-TERM ADMINISTRATION OF NSAIDS HAS RESULTED IN RENAL PAPILLARY NECROSIS AND OTHER RENAL INJURY.

RENAL TOXICITY HAS ALSO BEEN SEEN IN PATIENTS IN WHOM RENAL PROSTAGLANDINS HAVE A COMPENSATORY ROLE IN THE MAINTENANCE OF RENAL PERFUSION. IN THESE PATIENTS, ADMINISTRATION OF AN NSAID MAY CAUSE A DOSEDEPENDENT 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, HYPOVOLEMIA, HEART FAILURE, LIVER DYSFUNCTION, SALT DEPLETION, 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 NAPROXEN IN PATIENTS WITH ADVANCED RENAL DISEASE. THE RENAL EFFECTS OF NAPROXEN MAY HASTEN THE PROGRESSION OF RENAL DYSFUNCTION IN PATIENTS WITH PREEXISTING RENAL DISEASE.

CORRECT VOLUME STATUS IN DEHYDRATED OR HYPOVOLEMIC PATIENTS PRIOR TO INITIATING NAPROXEN. MONITOR RENAL FUNCTION IN PATIENTS WITH RENAL OR HEPATIC IMPAIRMENT, HEART FAILURE, DEHYDRATION, OR HYPOVOLEMIA DURING USE OF NAPROXEN (SEE PRECAUTIONS; DRUG INTERACTIONS). AVOID THE USE OF NAPROXEN IN PATIENTS WITH ADVANCED RENAL DISEASE UNLESS THE BENEFITS ARE EXPECTED TO OUTWEIGH THE RISK OF WORSENING RENAL FUNCTION. IF NAPROXEN 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.

ANAPHYLACTOID REACTIONS

NAPROXEN HAS BEEN ASSOCIATED WITH ANAPHYLACTIC REACTIONS IN PATIENTS WITH AND WITHOUT KNOWN HYPERSENSITIVITY TO NAPROXEN AND IN PATIENTS WITH ASPIRIN-SENSITIVE ASTHMA (SEE

CONTRAINDICATIONS, WARNINGS; EXACERBATION OF ASTHMA RELATED TO ASPIRIN SENSITIVITY).

EXACERBATION OF ASTHMA RELATED TO ASPIRIN SENSITIVITY

A SUBPOPULATION OF PATIENTS WITH ASTHMA MAY HAVE ASPIRIN-SENSITIVE ASTHMA WHICH MAY INCLUDE CHRONIC RHINOSINUSITIS COMPLICATED BY NASAL POLYPS; SEVERE, POTENTIALLY FATAL BRONCHOSPASM; AND/OR INTOLERANCE TO ASPIRIN AND OTHER NSAIDS. BECAUSE CROSS-REACTIVITY BETWEEN ASPIRIN AND OTHER NSAIDS HAS BEEN REPORTED IN SUCH ASPIRIN-SENSITIVE PATIENTS, NAPROXEN TABLETS ARE CONTRAINDICATED IN PATIENTS WITH THIS FORM OF ASPIRIN SENSITIVITY (SEE CONTRAINDICATIONS). WHEN NAPROXEN TABLETS ARE USED IN PATIENTS WITH PREEXISTING ASTHMA (WITHOUT KNOWN ASPIRIN SENSITIVITY), MONITOR PATIENTS FOR CHANGES IN THE SIGNS AND SYMPTOMS OF ASTHMA.

SERIOUS SKIN REACTIONS

NSAIDS, INCLUDING NAPROXEN, CAN CAUSE SERIOUS SKIN ADVERSE EVENTS SUCH AS EXFOLIATIVE DERMATITIS, STEVENS- JOHNSON SYNDROME (SJS), AND TOXIC EPIDERMAL NECROLYSIS (TEN), WHICH CAN BE FATAL. THESE SERIOUS EVENTS MAY OCCUR WITHOUT WARNING. PATIENTS SHOULD BE INFORMED ABOUT THE SIGNS AND SYMPTOMS OF SERIOUS SKIN MANIFESTATIONS AND TO DISCONTINUE THE USE OF NAPROXEN AT THE FIRST APPEARANCE OF SKIN RASH OR ANY OTHER SIGN OF HYPERSENSITIVITY. NAPROXEN TABLETS ARE CONTRAINDICATED IN PATIENTS WITH PREVIOUS

SERIOUS SKIN REACTIONS TO NSAIDS (SEE CONTRAINDICATIONS).

PREMATURE CLOSURE OF FETAL DUCTUS ARTERIOSUS

NAPROXEN MAY CAUSE PREMATURE CLOSURE OF THE FETAL DUCTUS ARTERIOSUS. AVOID USE OF NSAIDS, INCLUDING NAPROXEN, IN PREGNANT WOMEN STARTING AT 30 WEEKS OF GESTATION (THIRD TRIMESTER) (SEE PRECAUTIONS; PREGNANCY).

HEMATOLOGIC TOXICITY

ANEMIA HAS OCCURRED IN NSAID-TREATED PATIENTS. THIS MAY BE DUE TO OCCULT OR GROSS BLOOD LOSS, FLUID RETENTION, OR AN INCOMPLETELY DESCRIBED EFFECT ON ERYTHROPOIESIS. IF A PATIENT TREATED WITH NAPROXEN HAS ANY SIGNS OR SYMPTOMS OF ANEMIA, MONITOR HEMOGLOBIN OR HEMATOCRIT.

NSAIDS, INCLUDING NAPROXEN, MAY INCREASE THE RISK OF BLEEDING EVENTS. CO-MORBID CONDITIONS SUCH AS COAGULATION DISORDERS, OR CONCOMITANT USE OF WARFARIN AND OTHER ANTICOAGULANTS, ANTIPLATELET AGENTS (E.G., ASPIRIN), SEROTONIN REUPTAKE INHIBITORS (SSRIS) AND SEROTONIN NOREPINEPHRINE REUPTAKE INHIBITORS (SNRIS) MAY INCREASE THIS RISK. MONITOR THESE PATIENTS FOR SIGNS OF BLEEDING (SEE PRECAUTIONS; DRUG

INTERACTIONS).