NAPRELAN ® (naproxen sodium) CONTROLLED-RELEASE TABLETS

Equivalent to 375mg, 500mg and 750mg naproxen
NAPRELAN^® Controlled-Release Tablets, 375mg, 500mg and 750mg

Cardiovascular Risk

• NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk. (See WARNINGS).
• Naproxen as NAPRELAN^® is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (SeeWARNINGS).

Gastrointestinal Risk

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

NAPRELAN^{® *} Tablets contain naproxen sodium, a member of the arylacetic acid group of nonsteroidal anti-inflammatory drugs (NSAIDs). NAPRELAN^® Tablets use the proprietary IPDAS^{® **} (Intestinal Protective Drug Absorption System) technology. It is a rapidly disintegrating tablet system combining an immediate release component and a sustained release component of microparticles that are widely dispersed, allowing absorption of the active ingredient throughout the gastrointestinal (GI) tract, maintaining blood levels over 24 hours. The chemical name for naproxen sodium is 2-naphthaleneacetic acid, 6-methoxy-a-methyl-sodium salt, (S)- with the following structural formula:

Naproxen sodium is an odorless crystalline powder, white to creamy in color. It is soluble in methanol and water. NAPRELAN^® Tablets contain 412.5 mg, 550 mg, or 825 mg of naproxen sodium, equivalent to 375 mg, 500 mg, and 750 mg of naproxen and 37.5, mg 50 mg, and 75 mg sodium respectively. Each NAPRELAN^® Tablet also contains the following inactive ingredients: ammoniomethacrylate copolymer Type A, ammoniomethacrylate copolymer Type B, citric acid, crospovidone, magnesium stearate, methacrylic acid copolymer Type A, microcrystalline cellulose, povidone, and talc. The tablet coating contains hydroxypropyl methylcellulose, polyethylene glycol, and titanium dioxide.

Naproxen is a nonsteroidal anti-inflammatory drug (NSAID), with analgesic and antipyretic properties. As with other NSAIDs, its mode of action is not fully understood; however, its ability to inhibit prostaglandin synthesis may be involved in the anti-inflammatory effect.

Carefully consider the potential benefits and risks of NAPRELAN^® Tablets and other treatment options before deciding to use NAPRELAN^® Tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).

NAPRELAN^® Tablets are indicated for the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, tendinitis, bursitis and acute gout. It is also indicated in the relief of mild to moderate pain and the treatment of primary dysmenorrhea.

NAPRELAN^® is contraindicated in patients with known hypersensitivity to naproxen.

NAPRELAN^® should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS- Anaphylactoid Reactions, and PRECAUTIONS- Preexisting Asthma).

NAPRELAN^® is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.

1. NAPRELAN^®, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pan, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects).
2. NAPRELAN^®, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects: Risk of Ulceration, Bleeding and Perforation).
3. NAPRELAN^®, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalization and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.
4. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.
5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
6. Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS).
7. In late pregnancy, as with other NSAIDs, NAPRELAN^® should be avoided because it may cause premature closure of the ductus arteriosus.

Naproxen may decrease platelet aggregation and prolong bleeding time. This effect should be kept in mind when bleeding times are determined.

The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-dinitrobenzene used in this assay. Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artificially altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.

Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).

A two year study was performed in rats to evaluate the carcinogenic potential of naproxen at doses of 8 mg/kg/day, 16 mg/kg/day, and 24 mg/kg/day (50 mg/m², 100 mg/m², and 150 mg/m²). The maximum dose used was 0.28 times the systemic exposure to humans at the recommended dose. No evidence of tumorigenicity was found.

No pediatric studies have performed with NAPRELAN^® Tablets, thus safety of NAPRELAN^® Tablets in pediatric populations has not been established.

Clinical studies of NAPRELAN^® Tablets did not include a sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for the elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Aging may affect the pharmacokinetics of naproxen. 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. Elderly or debilitated patients seem to tolerate GI ulcerations and bleeding less well than other individuals taking NSAIDs (see WARNINGS, RISK of GI Ulceration, Bleeding And Perforation With NSAID Therapy). Additionally, elderly patients may be more sensitive to dose-dependent reduction in renal prostaglandin formation while taking NSAIDs (see WARNINGS, Renal Effects).

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% - 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.

Significant naproxen overdosage may be characterized by drowsiness, heartburn, indigestion, nausea or vomiting. Because naproxen sodium may be rapidly absorbed, high and early blood levels should be anticipated. A few patients have experienced seizures, but it is not clear whether or not these were drug-related. It is not known what dose of the drug would be life threatening. The oral LD₅₀ of the drug is 500 mg/kg in rats, 1200 mg/kg in mice, 4000 mg/kg in hamsters and greater than 1000 mg/kg in dogs. In animals 0.5 g/kg of activated charcoal was effective in reducing plasma levels of naproxen.

Patients should be managed by symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. Hemodialysis does not decrease the plasma concentration of naproxen because of the high degree of its protein binding. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic carthartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose. Forced diuresis, alkalinization of urine or hemoperfusion may not be useful due to high protein binding.

Carefully consider the potential benefits and risks of NAPRELAN^® and other treatment options before deciding to use NAPRELAN^®. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).

After observing the response to initial therapy with NAPRELAN^®, the dose and frequency should be adjusted to suit an individual patient's needs.

For the relief of:

Rheumatoid 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 (1000 mg) once a daily. Patients already taking naproxen 250 mg, 375 mg, or 500mg 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 (1500 mg), or three NAPRELAN^® 500 mg tablets (1500 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 (see CLINICAL PHARMACOLOGY). 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.

A lower dose should be considered in patients with renal or hepatic impairment or in elderly patients (see PRECAUTIONS). Studies indicate that although total plasma contcentration 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.

NAPRELAN^® (naproxen sodium) Controlled-Release Tablets are available as follows:

• NAPRELAN^® 375: white, capsule-shaped tablet with “N” on one side and “375” on the reverse; in bottles of 100; NDC 68453-375-10. Each tablet contains 412.5 mg naproxen sodium equivalent to 375 mg naproxen.
• NAPRELAN^® 500: white, capsule-shaped tablet with “N” on one side and “500” on the reverse; in bottles of 75; NDC 68453-850-75. Each tablet contains 550 mg naproxen sodium equivalent to 500 mg naproxen.
• NAPRELAN^® 750: white-capsule-shaped tablet with “N” on one side and “750” on the reverse; in bottles of 30; 68453-777-03; in bottles of 60; NDC 68453-777-06. Each tablet contains 825 mg naproxen sodium equivalent to 750 mg naproxen.
• NAPRELAN^® DOSE CARD: contains six 750 mg white-capsule-shaped tablets with “N” on one side and “750” on the reverse (3 days of therapy) and fourteen 500 mg white, capsule-shaped tablets with "N" on one side and "500" on the reverse (7 days of therapy) in a single blister card; NDC 68453-900-02.

Rx Only

US Patent 5,637,320

Store at controlled room temperature, 20° - 25° C (68° - 77° F).

Dispense in a well-closed container.

______________________________________________________________

^*Registered Trademark of Elan Corporation plc

^**Registered Trademark of Elan Pharma Int. Ltd.

^***Naprosyn^® is a registered trademark of Syntex Puerto Rico, Inc.

Manufactured for: Victory Pharma, Inc., San Diego, CA 92130

Manufactured by: Elan Pharma International Ltd., Athlone, Ireland

PI3750107

Rev 8/09

Medication Guide for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

(See the end of this Medication Guide for a list of prescription NSAID medicines.)

NAPRELAN^®
(naproxen sodium)
CONTROLLED-RELEASE TABLETS

What is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

NSAID medicines may increase the chance of a heart attack or stroke that can lead to death._

This chance increases:

• with longer use of NSAID medicines
• in people who have heart disease

NSAID medicines should never be used right before or after a heart surgery called a “coronary artery bypass graft (CABG).”

NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment. Ulcers and bleeding:

• can happen without warning symptoms
• may cause death

The chance of a person getting an ulcer or bleeding increases with:

• taking medicines called “corticosteroids” and “anti-coagulants”
• longer use
• smoking
• drinking alcohol
• older age
• having poor health

NSAID medicines should only be used:

• exactly as prescribed
• at the lowest dose possible for your treatment
• for the shortest time needed

________________________________________________

What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as:

• different types of arthritis
• menstrual cramps and other types of short-term pain

Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?

Do not take an NSAID medicine:

• if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine.
• for pain right before or after heart bypass surgery.

Tell your healthcare provider:

• about all your medical conditions
• about all of the medicines you take. NSAIDs and some other medicines can interact with each other and cause serious side effects. Keep a list of your medicines to show to your healthcare provider and pharmacist.
• if you are pregnant. NSAID medicines should not be used by pregnant women late in their pregnancy.
• if you are breastfeeding. Talk to your doctor.

What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?

Serious side effects include:

• heart attack
• stroke
• high blood pressure
• heart failure from body swelling (fluid retention)
• kidney problems including kidney failure
• bleeding and ulcers in the stomach and intestine
• low red blood cells (anemia)
• life-threatening skin reactions
• life-threatening allergic reactions
• liver problems including liver failure
• asthma attacks in people who have asthma

Other side effects include:

• stomach pain
• constipation
• diarrhea
• gas
• heartburn
• nausea
• vomiting
• dizziness

Get emergency help right away if you have any of the following symptoms:

• shortness of breath or trouble breathing
• chest pain
• weakness in one part or side of your body
• slurred speach
• swelling of the face or throat

Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms:

• nausea
• more tired or weaker than usual
• itching
• your skin or eyes look yellow
• stomach pain
• flu-like symptoms
• vomit blood
• there is blood in your bowel movement or it is black and sticky like tar
• unusual weight gain
• skin rash or blisters with fever
• swelling of the arms and legs, hands and feet

These are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more information about NSAID medicines. Call your doctor for medial advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

• Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.
• Some of these NSAID medicines are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

NAPRELAN 750MG LABEL IMAGE     NAPRELAN 750MG LABEL IMAGE