HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
`
` These highlights do not include all the information needed to use
`
`
` NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS safely and
`
`
`
`
`effectively. See
`for NAPROSYN, EC­
`full prescribing
`information
`
`NAPROSYN and ANAPROX DS.
`
`
` NAPROSYN (naproxen) tablets,
`
`
`
`EC-NAPROSYN (naproxen delayed-release tablets),
`
`
`
`ANAPROX DS (naproxen sodium tablets), for oral use
`
`
`
`
`Initial U.S. Approval: 1976
`
`
`
`
`
`
`
`
`
` WARNING: RISK OF SERIOUS CARDIOVASCULAR AND
`
`
` GASTROINTESTINAL EVENTS
`
` See full prescribing information for complete boxed warning.
`
`
`
`
` • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of
`
` serious cardiovascular thrombotic events, including myocardial infarction and
`
` stroke, which can be fatal. This risk may occur early in treatment and may
`
`
`
`
`
`
`
`
` increase with duration of use. (5.1)
`
`
`
`
` • NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS are contraindicated
`
` in the setting of coronary artery bypass graft (CABG) surgery. (4, 5.1)
`
`
`
`
`
`
`
` • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events
`
` including bleeding, ulceration, and perforation of the stomach or intestines, which
`
`
`
`
` can be fatal. These events can occur at any time during use and without warning
`
`
`
`
`
`
` symptoms. Elderly patients and patients with a prior history of peptic ulcer
`
`
`
`
`
`
`
`
`
` disease and/or GI bleeding are at greater risk for serious GI events. (5.2)
`
`
`
`
`
`
`
`
`
`
`
`---------------------RECENT MAJOR CHANGES-------------------------­
`
`
`Boxed Warning
`05/2016
`
`
`
`Warnings and Precautions (5.1, 5.5)
` 05/2016
`
`---------------------INDICATIONS AND USAGE--------------------------­
`
`
`
`
` NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS are non-steroidal anti-
`
` inflammatory drugs indicated for:
`
`
`
`
`
`
`the relief of the signs and symptoms of:
`
`
`rheumatoid arthritis
`
`•
`
`
`osteoarthritis
`
`•
`
`
`ankylosing spondylitis
`•
`
`
`
`
`polyarticular juvenile idiopathic arthritis
`•
`
`
`
`
`
`
`
`
`NAPROSYN Tablets and ANAPROX DS are also indicated for:
`
`
`
`the relief of signs and symptoms of:
`
`
`tendonitis
`•
`
`
`bursitis
`•
`
`
`acute gout
`•
`
`
`
`
`the manage ment of:
`
`
`pain
`•
`
`
`•
`primary dysmenorrhea
`------------------DOSAGE AND ADMINISTRATION--------------------­
`
`
`
` Use the lowest effective dosage for shortest duration consistent with individual patient
`
`
` treatment goals. (2.1)
`
`
`
`
`
` Rheumatoid Arthritis, Osteoarthritis, and Ankylosing Spondylitis
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Management of Pain, Primary Dysmenorrhea, and Acute Tendonitis and Bursitis
`
`
`
` Recommended starting dose 550 mg of naproxen sodium as ANAPROX DS followed by 550
`
`
`
` mg every 12 hours or 275 mg every 6 to 8 hours as required. The initial total daily dose
`
` should not exceed 1375 mg of naproxen sodium. Thereafter, the total daily dose should not
`
`
` exceed 1100 mg of naproxen sodium. ANAPROX DS is recommended for the management
`
`
`
`
`
` of acute painful conditions when prompt onset of pain relief is desired.
`
`
`Acute Gout
`
`Recommended starting dose 750 mg of NAPROSYN Tablets followed by 250 mg every 8
`
`
`
`
`
`hours until the attack has subsided. ANAPROX DS may also be used at a starting dose of 825
`
`
`
`
`
`
`
`mg followed by 275 mg every 8 hours. EC-NAPROSYN is not recommended because of the
`
`
`
`
`
`
`
`delay in absorption.
`
`----------------DOSAGE FORMS AND STRENGTHS--------------------­
`
`
` NAPROSYN (naproxen) tablets: 500 mg
`
` EC-NAPROSYN (naproxen) delayed-release tablets: 375 mg and 500 mg
`
`
`
`
`
`ANAPROX DS (naproxen sodium) tablets: 550 mg (contains 50 mg of sodium)
`
`--------------------------CONTRAINDICATIONS---------------------------­
`
`
` • Known hypersensitivity to naproxen or any components of the drug product (4)
`
`
`
` • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other
`
`
`
` NSAIDs (4)
`
` • In the setting of CABG surgery (4)
`
`
`---------------------WARNINGS AND PRECAUTIONS-------------------
` 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. (5.3)
`
`
`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 NAPROSYN Tablets, EC-NAPROSYN and
`
`
`
`
`
`ANAPROX DS in patients with severe heart failure unless benefits are expected to outweigh
`
`
`
`
`risk of worsening heart failure. (5.5)
`
`
`
`
`Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart
`
`
`
`
`
`failure, dehydration, or hypovolemia. Avoid use of NAPROSYN Tablets, EC-NAPROSYN
`
`
`
`
`
`and ANAPROX DS in patients with advanced renal disease unless benefits are expected to
`
`
`
`outweigh risk of worsening renal function. (5.6)
`
`
`
`Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs. (5.7)
`
`
`
`
`
`Exacerbation of Asthma Related to Aspirin Sensitivity: NAPROSYN Tablets, EC­
`
`
`
`
`NAPROSYN and ANAPROX DS are contraindicated in patients with aspirin-sensitive
`
`
`
`
`asthma. Monitor patients with preexisting asthma (without aspirin sensitivity). (5.8)
`
`
`Serious Skin Reactions: Discontinue NAPROSYN Tablets, EC-NAPROSYN and ANAPROX
`
`
`
`DS at first appearance of skin rash or other signs of hypersensitivity. (5.9)
`
`
`
`
`
`Premature Closure of Fetal Ductus Arteriosus: Avoid use in pregnant women starting at 30
`
`
`
`
`
`
`weeks gestation. (5.10, 8.1)
`
`
`Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or
`
`
`
`
`
`
`
`
`
`
`
`
`symptoms of anemia. (5.11,7)
`
`---------------------------ADVERSE REACTIONS--------------------------­
`
`
` Most common adverse reactions to naproxen were dyspepsia, abdominal pain, nausea,
`
`
` headache, rash, ecchymosis, and edema. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Canton Laboratories
`
`
`
`LLC.at1-844-302-5227 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`--------------------------DRUG INTERACTIONS--------------------------­
`
`
` Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs):
`Monitor patients for bleeding who are concomitantly taking NAPROSYN Tablets, EC­
`
`
`
`
`
`NAPROSYN or ANAPROX DS with drugs that interfere with hemostasis. Concomitant use
`
`
`
`
`
`of NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS and analgesic doses of aspirin
`
`
`
`
`is not generally recommended. (7)
`
`
`ACE inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers: Concomitant use
`
`
`
`
`
`with NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS may diminish the
`
`
`
`
`antihypertensive effect of these drugs. Monitor blood pressure. (7)
`
`
`ACE Inhibitors and ARBs: Concomitant use with NAPROSYN Tablets, EC-NAPROSYN or
`
`
`
`ANAPROX DS in elderly, volume depleted, or those with renal impairment may result in
`
`
`
`
`
`deterioration of renal function. In such high risk patients, monitor for signs of worsening renal
`
`
`
`
`
`
`
`function. (7)
`
`
`Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor
`
`
`
`patients to assure diuretic efficacy including antihypertensive effects. (7)
`
`
`
`Digoxin: Concomitant use with NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS
`
`
`
`
`can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin
`
`
`
`
`levels. (7)
`
`
`
`---------------------USE IN SPECIFIC POPULATIONS------------------­
` Pregnancy: Use of NSAIDs during the third trimester of pregnancy increases the risk of
`
`
`
`
`
`
`
`
`
`
`
`
`premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs in pregnant women
`
`
`
`
`
`
`starting at 30 weeks gestation. (5.10, 8.1)
`
`
`Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of
`
`
`
`
`
`
`NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS in women who have difficulties
`
`
`conceiving. (8.3)
`
`
`
`Renal Impairment: Naproxen-containing products are not recommended for use in patients
`
`with moderate to severe and severe renal impairment (creatinine clearance <30 mL/min). (8.7)
`
`
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`Guide.
`
`Revised: [03/2017]
`
`
`
` NAPROSYN Tablets
`
`
`
`
`
` ANAPROX DS
`
`
`
` EC-NAPROSYN
`
`
`
`
`
` 250 mg (one-half tablet)
`
` 500 mg
` 275 mg (one-half tablet)
`
` 550 mg
`
` 375 mg
` or 500 mg
`
`
`
`
` twice daily
`
`
`
` twice daily
`
`
`
` twice daily
`
`
`
` To maintain the integrity of the enteric coating, the EC-NAPROSYN tablet should not be
`
`
`
`
`
` broken, crushed or chewed during ingestion.
`
`The dose may be adjusted up or down depending on the clinical response of the patient.
`
`
`
`
`In patients who tolerate lower doses well, the dose may be increased to naproxen 1500
`
`mg/day for up to 6 months.
`
`
`
`
`
`
`Polyarticular Juvenile Idiopathic Arthritis
`
`
`
`NAPROSYN Tablets may not allow for the flexible dose titration needed in pediatric patients
`
`
`
`
`
`
`
`with polyarticular juvenile idiopathic arthritis. A liquid formulation may be more appropriate.
`
`
`
`
`
`
`
`Recommended total daily dose of naproxen is approximately 10 mg/kg given in 2 divided
`
`
`
`
`
`
`
`
`
`
`
`doses. Dosing with NAPROSYN Tablets is not appropriate for children weighing less than 50
`
`
`
`
`
`
`kilograms.
`
`
`
`
`Reference ID: 4068238
`
`
`
`
`1
`
`
`
`MYLAN PHARMS. INC. EXHIBIT 1020 PAGE 1
`
`

`

`
`
`
`
`6
`
`
`7
`
`8
`
`
`13
`
`
`ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`
`
`6.2
`Postmarketing Experience
`
`
`
`DRUG INTERACTIONS
`
`USE IN SPECIFIC POPULATIONS
`
`8.1
`Pregnancy
`
`
`
`8.2
`Lactation
`
`
`
`8.3
`Females and Males of Reproductive Potential
`
`
`
`
`8.4
`Pediatric Use
`
`
`
`8.5 Geriatric Use
`
`
`
`8.6 Hepatic Impairment
`
`
`
`8.7 Renal Impairment
`
`
`
`10 OVERDOSAGE
`
`
`11
`DESCRIPTION
`
`
`12
`CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`
`12.3 Pharmacokinetics
`
`
`
`NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`
`CLINICAL STUDIES
`14
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`17
`PATIENT COUNSELING INFORMATION
`
`
`
` *Sections or subsections omitted from the full prescribing
`
`
` information are not listed.
`
`
`
`
`
`
`
`
`
`
`
`
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
` WARNING: RISK OF SERIOUS CARDIOVASCULAR AND
`GASTROINTESTINAL EVENTS
`
`INDICATIONS AND USAGE
`1
`
`
`2
`DOSAGE AND ADMINISTRATION
`
`
` 2.1 General Dosing Instructions
`
`
`
`
`2.2 Rheumatoid Arthritis, Osteoarthritis and Ankylosing Spondylitis
`
`
`
`2.3
`
` Polyarticular Juvenile Idiopathic Arthritis
`
`
`
` 2.4 Management of Pain, Primary Dysmenorrhea, and Acute Tendonitis
`
`
`and Bursitis
`
`
`2.5 Acute Gout
`
`
`
`2.6 Non-Interchangeability with Other Formulations of Naproxen
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`CONTRAINDICATIONS
`4
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
` 5.1 Cardiovascular Thrombotic Events
`
`
`
`
` 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation
`
`
`
`
`5.3 Hepatotoxicity
`
`
`
`5.4 Hypertension
`
`
`
`5.5 Heart Failure and Edema
`
`
`
`5.6 Renal Toxicity and Hyperkalemia
`
`
`
`5.7 Anaphylactic Reactions
`
`
`
`5.8
`
` Exacerbation of Asthma Related to Aspirin Sensitivity
`
`
`
`
`5.9
`
` Serious Skin Reactions
`
`
`
`5.10 Premature Closure of Fetal Ductus Arteriosus
`
`
`
`5.11 Hematologic Toxicity
`
`
`
`
` 5.12 Masking of Inflammation and Fever
`
`
`
`5.13 Long-Term Use and Laboratory Monitoring
`
`
`
`
`
`
`
`
`Reference ID: 4068238
`
`
`
`
` 2
`
`MYLAN PHARMS. INC. EXHIBIT 1020 PAGE 2
`
`

`

`
`
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`
` WARNING: RISK OF SERIOUS CARDIOVASCULAR AND
`
`
` GASTROINTESTINAL EVENTS
`
`
`
`
`
` Cardiovascular Thrombotic Events
`
`
`
`
`
`
` • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular
` thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may
`
`
`
`
` occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.1)].
`
`
`
`
`
`
`
`
` • NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS are contraindicated in the setting of
`
`
`
`
`
`
` coronary artery bypass graft (CABG) surgery [see Contraindications (4), Warnings and Precautions
`
`
`
`(5.1)].
`
`
`
`
`
`Gastrointestinal Bleeding, Ulceration, and Perforation
`
`
`
` • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding,
`
`
`
`
`
` ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at
`
`
`
` any time during use and without warning symptoms. Elderly patients and patients with a prior
`
`
`
`
` history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see
`
`
` Warnings and Precautions (5.2)].
`
`
`
`
`
` INDICATIONS AND USAGE
`
`1
`
` NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS are indicated for:
`
` the relief of the signs and symptoms of:
`
`
`
`
`
`
`
`
`
`
`
`
`
`rheumatoid arthritis
`
`
`•
`
`osteoarthritis
`
`
`•
`
`ankylosing spondylitis
`
`•
`
`• Polyarticular Juvenile Idiopathic Arthritis
`
`
`
`
`
`
`NAPROSYN Tablets and ANAPROX DS are also indicated for:
`
`
`
`
`
`the relief of signs and symptoms of:
`
`
`
`
`•
`
`•
`
`pain
`
`primary dysmenorrhea
`
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1
`General Dosing Instructions
`
`
`
`
` Carefully consider the potential benefits and risks of NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS and
`
`other treatment options before deciding to use NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS. Use the lowest
`
`
`effective dose for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)].
`
`
`
`After observing the response to initial therapy with NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS, the dose and
`
`
`frequency should be adjusted to suit an individual patient’s needs.
`
`
`
`
`
`Reference ID: 4068238
`
`
`3
`
`
`
`•
`
`•
`
`•
`
`tendonitis
`
`bursitis
`
`acute gout
`
`
`
`the management of:
`
`
`
`
`MYLAN PHARMS. INC. EXHIBIT 1020 PAGE 3
`
`

`

`
` To maintain the integrity of the enteric coating, the EC-NAPROSYN tablet should not be broken, crushed or chewed during
`
` ingestion.
`
`
`
`
`
` Naproxen-containing products such as NAPROSYN, EC-NAPROSYN and ANAPROX DS, and other naproxen products
`
`
`
` should not be used concomitantly since they all circulate in the plasma as the naproxen anion.
`
`
`
` Rheumatoid Arthritis, Osteoarthritis and Ankylosing Spondylitis
` 2.2
`
`
`
`
` The recommended dosages of NAPROSYN Tablets, ANAPROX DS, and EC-NAPROSYN are shown in Table 1.
`
` Table 1: Recommended dosages for NAPROSYN Tablets, ANAPROX DS, and EC-NAPROSYN
`
`
` twice daily
`250 mg (one half tablet)
`
`
`
` NAPROSYN
`
` 500 mg
` 275 mg (one half tablet)
`
`
` 550 mg (naproxen 500 mg with 50 mg sodium)
`
`
` 375 mg
` or 500 mg
`
`
`ANAPROX DS
`
`
`EC-NAPROSYN
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` twice daily
`
`
` twice daily
`
` twice daily
`
`
`
`
`
` During long-term administration, the dose of naproxen may be adjusted up or down depending on the clinical response of the
`
` patient. A lower daily dose may suffice for long-term administration. The morning and evening doses do not have to be equal
`
` in size and the administration of the drug more frequently than twice daily is not necessary.
`
`
`
`
`
` The morning and evening doses do not have to be equal in size and administration of the drug more frequently than twice
`
`
`
`
` daily does not generally make a difference in response.
`
`
`
`
`
`
` In patients who tolerate lower doses well, the dose may be increased to naproxen 1500 mg/day for limited periods of up to 6
` months when a higher level of anti-inflammatory/analgesic activity is required. When treating such patients with naproxen
`
`
`
`
` 1500 mg/day, the physician should observe sufficient increased clinical benefits to offset the potential increased risk.
`
`
` 2.3
` Polyarticular Juvenile Idiopathic Arthritis
`
`
`
`
`
`
`
`
`
`
`
` Naproxen solid-oral dosage forms may not allow for the flexible dose titration needed in pediatric patients with polyarticular
`
`
`
`
`
` juvenile idiopathic arthritis. A liquid formulation may be more appropriate for weight-based dosing and due to the need for
`
`
`
`
`
`
`
`
` dose flexibility in children.
`
`
`
` In pediatric patients, doses of 5 mg/kg/day produced plasma levels of naproxen similar to those seen in adults taking 500 mg of
`
`
`
`
`
`
`
` naproxen [see Clinical Pharmacology (12)]. The recommended total daily dose of naproxen is approximately 10 mg/kg given in
`
`
`
`
`
`
`2 divided doses. Dosing with NAPROSYN Tablets is not appropriate for children weighing less than 50 kilograms.
`
`
`
`
`Management of Pain, Primary Dysmenorrhea, and Acute Tendonitis and Bursitis
`2.4
`
`
`
`
`
`
`The recommended starting dose of ANAPROX DS (naproxen sodium) tablets is 550 mg followed by 550 mg every 12 hours
`
`
`
`
`or 275 mg (one half of a 550 mg tablet) every 6 to 8 hours as required. The initial total daily dose should not exceed 1375 mg
`
`
`
`(two and one-half tablets) of naproxen sodium. Thereafter, the total daily dose should not exceed 1100 mg of naproxen
`
`
`
`sodium. Because the sodium salt of naproxen is more rapidly absorbed, ANAPROX DS is recommended for the management
`
`
`
`
`
`
`of acute painful conditions when prompt onset of pain relief is desired. NAPROSYN Tablets may also be used. The
`
`
`
`
`
`recommended starting dose of NAPROSYN Tablets is 500 mg followed by 250 mg (one half of a 500 mg NAPROSYN
`
`
`
`tablet) every 6-8 hours as required.. The total daily dose should not exceed 1250 mg of naproxen.
`
`
`EC-NAPROSYN is not recommended for initial treatment of acute pain because absorption of naproxen is delayed compared
`
`to other naproxen-containing products [see Clinical Pharmacology (12)].
`
`
`
`
`2.5
`Acute Gout
`
`
`
`
`
`
`The recommended starting dose is 750 mg (one and one-half tablets) of NAPROSYN Tablets followed by 250 mg (one-half
`
`
`
`
`
`
`
`
`
`tablet) every 8 hours until the attack has subsided. ANAPROX DS may also be used at a starting dose of 825 mg (one and
`
`
`
`
`
`
`one-half tablets) followed by 275 mg (one-half tablet) every 8 hours. EC-NAPROSYN is not recommended because of the
`delay in absorption.
`
`
`
`
`
`Reference ID: 4068238
`
`
`4
`
`
`MYLAN PHARMS. INC. EXHIBIT 1020 PAGE 4
`
`

`

`
`
`Non-Interchangeability with Other Formulations of Naproxen
`2.6
`
`
`Different dose strengths and formulations (e.g., tablets, suspension) of naproxen are not interchangeable. This difference
`
`
`should be taken into consideration when changing strengths or formulations.
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`NAPROSYN (naproxen) tablets: 500 mg: yellow, capsule-shaped, engraved with NPR LE 500 on one side and scored on
`
`
`
`
`
`the other.
`
`EC-NAPROSYN (naproxen) delayed-release tablets: 375 mg: white, oval biconvex coated tablets imprinted with NPR EC
`
`
`
`
`375 on one side.
`
`EC-NAPROSYN (naproxen) delayed-release tablets: 500 mg: white, oblong coated tablets imprinted with NPR EC 500 on
`
`
`
`
`one side.
`
`ANAPROX DS (naproxen sodium) tablets: 550 mg: dark blue, oblong-shaped, engraved with NPS 550 on one side and
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`scored on both sides.
`
`
`4 CONTRAINDICATIONS
`
`
`
`
`
`
`
`NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS are contraindicated in the following patients:
`
`• Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to naproxen or any components of the
`
`
`
`
`drug product [see Warnings and Precautions (5.7, 5.9)]
`
`
`
`
`
`
`
`
`
`
`
`• History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes
`
`fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)]
`
` In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)]
`
`
`
`
`
`•
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1
`Cardiovascular Thrombotic Events
`
`
`
`Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased
`
`
`risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal.
`
`
`
`
`Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in
`
`
`
`serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known
`
`
`
`
`CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute
`
`
`
`
`
`
`
`incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that
`
`
`
`this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV
`
`
`
`thrombotic risk has been observed most consistently at higher doses.
`
`
`
`To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the
`
`
`shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the
`
`entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of
`
`
`
`serious CV events and the steps to take if they occur.
`
`
`
`
`There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events
`
`
`associated with NSAID use. The concurrent use of aspirin and an NSAID, such as naproxen, increases the risk of serious
`
`
`
`
`gastrointestinal (GI) events [see Warnings and Precautions (5.2)].
`
`
`
`Status Post Coronary Artery Bypass Graft (CABG) Surgery
`
`
`
`Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following
`
`
`
`
`CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting
`
`
`
`
`
`
`of CABG [see Contraindications (4)].
`
`
`Post-MI Patients
`
`
`
`
`
`
`
`Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the
`
`
`
`
`
`post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of
`
`
`
`
`
`
`treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated
`
`
`
`Reference ID: 4068238
`
`
`5
`
`
`MYLAN PHARMS. INC. EXHIBIT 1020 PAGE 5
`
`

`

`
` 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 NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS in patients with a recent MI unless the
`
` benefits are expected to outweigh the risk of recurrent CV thrombotic events. If NAPROSYN Tablets, EC-NAPROSYN and
`
`
`
` ANAPROX DS are used in patients with a recent MI, monitor patients for signs of cardiac ischemia.
`
`
`
`
`
`
` 5.2
` 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 NAPROSYN
`•
`
`
`
`Tablets, EC-NAPROSYN, or ANAPROX DS until a serious GI adverse event is ruled out.
`
`
`
`
`
`
`In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence
`
`of GI bleeding [see Drug Interactions (7)].
`
`
`
`
`Hepatotoxicity
`5.3
`
`
`
`
`
`
`
`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 NAPROSYN Tablets, EC­
`
`
`
`
`
`NAPROSYN, or ANAPROX DS immediately, and perform a clinical evaluation of the patient.
`
`
`
`Hypertension
`5.4
`
`
`
`
`NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, can lead to new onset of 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, thiazide diuretics, or loop diuretics may have impaired response to
`
`
`these therapies when taking NSAIDs [see Drug Interactions (7)].
`
`
`
`•
`
`
`
`Reference ID: 4068238
`
`
`6
`
`
`MYLAN PHARMS. INC. EXHIBIT 1020 PAGE 6
`
`

`

`
`
`
`
`
`
`
` Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.
`
`Heart Failure and Edema
`5.5
`
`
`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]) [see Drug Interactions (7)].
`
`
`Avoid the use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS in patients with severe heart failure unless the
`
`
`
`
`
`
`
`benefits are expected to outweigh the risk of worsening heart failure. If NAPROSYN Tablets, EC-NAPROSYN, or
`
`
`
`
`ANAPROX DS is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.
`
`
`
`
`
`
`
`
`
`Since each ANAPROX DS tablet contains 50 mg of sodium (about 2 mEq per each 500 mg of naproxen), this should be
`
`
`
`considered in patients whose overall intake of sodium must be severely restricted.
`
`
`
`
`
`Renal Toxicity and Hyperkalemia
`5.6
`
`
`
`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 NAPROSYN Tablets, EC-NAPROSYN, or
`
`
`
`
`
`ANAPROX DS in patients with advanced renal disease. The renal effects of NAPROSYN Tablets, EC-NAPROSYN, or
`
`
`
`
`
`ANAPROX DS may hasten the progression of renal dysfunction in patients with preexisting renal disease.
`
`
`
`
`
`
`Correct volume status in dehydrated or hypovolemic patients prior to initiating NAPROSYN Tablets, EC-NAPROSYN, or
`
`
`
`ANAPROX DS. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or
`
`
`
`
`
`hypovolemia during use of NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS [see Drug Interactions (7)]. Avoid
`
`
`
`
`
`
`
`
`
`the use of NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS in patients with advanced renal disease unless the
`
`
`
`
`
`benefits are expected to outweigh the risk of worsening renal function. If NAPROSYN Tablets, EC-NAPROSYN, or
`
`
`
`
`
`
`
`
`ANAPROX DS is used in patients with advanced renal disease, monitor patients for signs of worsening renal function.
`
`
`Hyperkalemia
`
`
`
`
`Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some
`
`
`
`
`
`
`patients without renal impairment. In patients with normal renal function, these effects have been attributed to a
`
`hyporeninemic-hypoaldosteronism state.
`
`
`
`Anaphylactic Reactions
`5.7
`
`
`
`
`
`
`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 (4) and Warnings and Precautions (5.8)].
`
`
`
`
`
`Seek emergency help if an anaphylactic reaction occurs.
`
`
`
`Exacerbation of Asthma Related to Aspirin Sensitivity
`5.8
`
`
`
`
`
`
`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.
`
`
`
`Reference ID: 4068238
`
`
`7
`
`
`MYLAN PHARMS. INC. EXHIBIT 1020 PAGE 7
`
`

`

`
`
`
` Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients,
`
` NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS are contraindicated in patients with this form of aspirin
`
`
`
`
`
`
`
`
`sensitivity [see Contraindications (4)]. When NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS is used in patients
`
`
`
`
`
`
`with preexisti