` HIGHLIGHTS OF PRESCRIBING INFORMATION
` These highlights do not include all the information needed to use
`
`
`
`
`
`
` VIMOVO safely and effectively. See full prescribing information for
` VIMOVO.
`
`
`VIMOVO (naproxen and esomeprazole magnesium) delayed release
`
`
`
`
`tablets, for oral use
`
`
`Initial US Approval: 2010
`
` WARNING: CARDIOVASCULAR AND GASTROINTESTINAL
` RISKS
`
`
`
`
`See full prescribing information for complete boxed warning
`
`Cardiovascular Risk
`
`
`• Naproxen, a component of VIMOVO, 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. (5.1)
`
`
`
`• VIMOVO is contraindicated for the treatment of peri-operative pain in
`
`
`
`
`the setting of coronary artery bypass graft (CABG) surgery. (4, 5.1)
`
`
`
`Gastrointestinal Risk
`
`
`
`
`
`• NSAIDs, including naproxen, a component of VIMOVO, 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 patients are at greater risk for serious
`
`
` gastrointestinal (GI) events. (5.4)
`
`
`-------------------------RECENT MAJOR CHANGES------------------------­
`
`
`
`Warnings and Precautions, Renal Effects (5.6)
` 03/2014
`
`
`
`Warnings and Precautions, Acute Interstitial Nephritis (5.16)
`12/2014
`
`
`
`Warnings and Precautions, Cyanocobalamin (vitamin B-12)
`
`
`12/2014
`Deficiency (5.17)
`
`-------------------------INDICATIONS AND USAGE------------------------­
`
`
`
`Relief of signs and symptoms of osteoarthritis, rheumatoid arthritis, and
`
`
`
`
`
`
`ankylosing spondylitis and to decrease the risk of developing gastric ulcers in
`
`
`
`
`patients at risk of developing NSAID associated gastric ulcers (1)
`
`
`------------------------DOSAGE AND ADMINISTRATION----------------­
`
`
`
`
`
`One tablet twice daily. Use the lowest effective dose. Should be avoided in
`
`moderate/severe renal insufficiency or in severe hepatic insufficiency.
`
`
`
`Consider dose reduction in mild/moderate hepatic insufficiency (2)
`
`
`----------------------DOSAGE FORMS AND STRENGTHS----------------­
`
`Delayed release tablets: 375 mg/20 mg or 500 mg/20 mg of naproxen and
`
`esomeprazole magnesium (3)
`
`
`----------------------------CONTRAINDICATIONS------------------------­
`
`• Known hypersensitivity to any component of VIMOVO or substituted
`
`
`benzimidazoles (4)
`
`
`• History of asthma, urticaria, or other allergic-type reactions after taking
`
`
`
`
`aspirin or other NSAIDs (4, 5.8, 5.9, 5.13)
`
` • Use during the peri-operative period in the setting of coronary artery
`
`
`bypass graft (CABG) surgery (4, 5.1)
`
`
`
`
`
`
`
`
`
`
`
`
`--------------------WARNINGS AND PRECAUTIONS---------------------­
`
`
`• Serious and potentially fatal cardiovascular (CV) thrombotic events,
`
`
`myocardial infarction, and stroke. Patients with known CV disease/risk
`
`factors may be at greater risk (5.1)
`
`
`• New onset or worsening of pre-existing hypertension. Blood pressure
`
`
`should be monitored closely during treatment with VIMOVO (5.2, 7.1, 7.6)
`
`
`
`
`
`• Congestive heart failure and edema. VIMOVO should be used with
`
`
`
`
`caution in patients with fluid retention or heart failure (5.3)
`
`
`
`• Serious gastrointestinal (GI) adverse events, which can be fatal. The risk
`
`
`
`
`
`is greater in patients with a prior history of ulcer disease or GI bleeding, and
`
`
`
`in patients at high risk for GI events, especially the elderly. VIMOVO should
`
`
`
`
`
`
`be used with caution in these patients (5.4, 8.5)
`
` • Symptomatic response to esomeprazole does not preclude the presence of
`
`gastric malignancy (5.4)
`
`
` • Atrophic gastritis has been noted on biopsy with long-term omeprazole
`
`therapy (5.4)
`• Treatment should be withdrawn when active and clinically significant
`
`
`
`bleeding from any source occurs (5.5)
`
`• Renal papillary necrosis and other renal injury with long-term use. Use
`
`VIMOVO with caution in the elderly, those with impaired renal function,
`
`
`
`
`
`
`
`
`hypovolemia, salt depletion, heart failure, liver dysfunction, and those taking
`
`
`
`
`
`
`
`Reference ID: 3675794
`
`
`
`
`
`
`
`diuretics, ACE-inhibitors or angiotensin II receptor antagonists. Acute
`
`
`
`
`
`interstitial nephritis has been observed in patients taking PPIs. Not
`recommended for patients with moderate or severe renal impairment (2, 5.6,
`
`
`
`
`5.7, 5.16, 7.1, 7.6, 8.7)
`
`• Anaphylactic reactions. Do not use VIMOVO in patients with the aspirin
`
`
`
`
`
`triad (5.8)
`• Serious skin adverse reactions such as exfoliative dermatitis, Stevens-
`
`
`Johnson syndrome, and toxic epidermal necrolysis, which can be fatal and
`
`can occur without warning. Discontinue VIMOVO at first appearance of skin
`
`rash or any other sign of hypersensitivity (5.9)
`• Elevated liver enzymes and, rarely, severe hepatic reactions. Discontinue
`
`
`
`use immediately if abnormal liver enzymes persist or worsen (5.11, 8.6, 12.3)
`
`
`
`• Should be avoided in patients with severe hepatic impairment (e.g., Child-
`
`
`
`Pugh C) (2, 5.11, 8.6, 12.3)
`
`• Cyanocobalamin (vitamin B-12) Deficiency: Daily long-term use (e.g.,
`
`
`
`longer than 3 years) may lead to malabsorption or a deficiency of
`
`cyanocobalamin. (5.17)
`
`
`• Proton pump inhibitor (PPI) therapy may be associated with increased risk
`
`
`of Clostridium difficile associated diarrhea. (5.18)
`
`
`
`
`
`• Avoid concomitant use of esomeprazole with clopidogrel (5.19)
`
`
`• Long-term and multiple daily dose PPI therapy is associated with an
`
`
`
`increased risk for osteoporosis-related fractures of the hip, wrist or spine
`
`(5.20)
`
`
`• Interactions with diagnostic investigations for Neuroendocrine Tumors:
`
`
`
`
`Increases in intragastric pH may result in hypergastrinemia,
`
`
`enterochromaffin-like cell hyperplasia, and increased Chromogranin A levels
`
`
`
`
`
`which may interfere with diagnostic investigations for neuroendocrine
`
`tumors. (5.22)
`
`
`
`• Hypomagnesemia has been reported rarely with prolonged treatment with
`
`
`PPIs (5.23)
`
`
`
`• Avoid concomitant use of VIMOVO with St John’s Wort or rifampin due
`
`
`to the potential reduction in esomeprazole levels. (5.24, 7.16)
`
`
`
`• Fetal toxicity: avoid drug starting at 30 weeks gestation (5.10, 8.1)
`
`
`
`---------------------------------ADVERSE REACTIONS-------------­
`
`
`Most common adverse reactions in clinical trials (>5%): erosive gastritis,
`
`dyspepsia, gastritis, diarrhea, gastric ulcer, upper abdominal pain, nausea
`
`(6.1)
`
`
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Horizon
`
`
`
`
`
`
`
`
`Pharma USA, Inc. at 1-866-479-6742 or FDA at 1-800-FDA-1088 or
`
`www.fda.gov/medwatch.
`
`
`----------------------------DRUG INTERACTIONS----------­
`
`
`• Concomitant use of NSAIDs may reduce the antihypertensive effect of
`
`
`
`ACE Inhibitors, angiotensin II receptor antagonists, diuretics, and beta-
`
`blockers (7.1, 7.6, 7.11)
`
`
`
`
`• As with all NSAIDs caution is advised when cyclosporin is co-
`
`
`
`administered because of the increased risk of nephrotoxicity. (7.4)
`
`• Tacrolimus: Concomitant administration of esomeprazole, a component of
`
`
`
`VIMOVO, and tacrolimus may increase the serum levels of tacrolimus. (7.5)
`
`
`
`• Concomitant use of NSAIDs increases lithium plasma levels (7.7)
`
`
`
`• Methotrexate: VIMOVO may increase serum levels of methotrexate (7.8)
`
`
`
`• Concomitant use of VIMOVO with warfarin may result in increased risk
`
`
`
`
`of bleeding complications. Monitor for increases in INR and prothrombin
`
`
`time (7.9)
`
`
`• Esomeprazole inhibits gastric acid secretion and may interfere with the
`
`
`
`
`absorption of drugs where gastric pH is an important determinant of
`
`
`bioavailability (e.g., ketoconazole, iron salts, erlotinib, digoxin, and
`
`
`
`
`mycophenolate mofetil). Patients treated with VIMOVO and digoxin may
`
`
`
`need to be monitored for increases in digoxin toxicity (7.14)
`
`
`• Clopidogrel: esomeprazole, a component of VIMOVO, decreases
`
`
`
`
`exposure to the active metabolite of clopidogrel. (7.16, 12.3)
`
`
`---------------------------USE IN SPECIFIC POPULATIONS------­
`
`
`
`
`• Hepatic Insufficiency: VIMOVO should be avoided in patients with
`
`
`
`severe hepatic insufficiency (2, 4, 5.11, 8.6, 12.3)
`
`
`• Renal Insufficiency: VIMOVO is not recommended in patients with
`
`
`
`moderate or severe renal insufficiency (2, 5.6, 5.7, 8.7, 12.3)
`
`
`SEE 17 FOR PATIENT COUNSELING INFORMATION and FDA-
`
`Approved Medication Guide
`
`
`Revised 12/2014
`
`
`
`DRL EXHIBIT 1030 PAGE 1
`
`

`

`
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`WARNING: CARDIOVASCULAR AND GASTROINTESTINAL RISKS
`
`
`1
`
`2
`
`3
`
`4
`
`5
`
`
`INDICATIONS AND USAGE
`
`DOSAGE AND ADMINISTRATION
`
`DOSAGE FORMS AND STRENGTHS
`
`CONTRAINDICATIONS
`
`WARNINGS AND PRECAUTIONS
`
`
`5.1 Cardiovascular Thrombotic Events
`
`
`
`
`5.2 Hypertension
`
`
`
`5.3 Congestive Heart Failure and Edema
`
`
`5.4 Gastrointestinal Effects — Risk of Ulceration, Bleeding, and
`
`
`
`
`
`Perforation
`
`
`
`5.5 Active Bleeding
`
`
`
`5.6 Renal Effects
`
`
`
`5.7 Advanced Renal Disease
`
`
`
`
`5.8 Anaphylactic Reactions
`
`
`
`5.9 Skin Reactions
`
`
`
`5.10 Fetal Toxicity
`
`
`
`5.11 Hepatic Effects
`
`
`
`5.12 Hematological Effects
`
`
`
`5.13 Pre-existing Asthma
`
`
`
`5.14 Concomitant NSAID Use
`
`
`5.15 Corticosteroid Treatment
`
`
`5.16 Acute Interstitial Nephritis
`
`
`
`5.17 Cyanocobalamin (vitamin B-12) Deficiency
`
`
`
`
`
`5.18 Clostridium difficile Associated Diarrhea
`
`
`
`
`
`5.19 Interaction with Clopidogrel
`
`
`
`
`
`5.20 Bone Fracture
`
`
`
`5.21 Masking of Inflammation and Fever
`
`
`
`5.22 Laboratory Tests
`
`
`
`5.23 Hypomagnesemia
`
`
`
`5.24 Concomitant use of St John's Wort or Rifampin with VIMOVO
`
`
`
`
`5.25 Concomitant use of VIMOVO with Methotrexate
`
`
`
`
`
`
`
`ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`
`6.2 Postmarketing Experience
`
`
`DRUG INTERACTIONS
`
`
`7.1 ACE-inhibitors/Angiotensin II Receptor Antagonists
`
`
`
`6
`
`
`7
`
`
`
`
`
`7.2 Aspirin
`
`
`7.3 Cholestyramine
`
`
`7.4 Cyclosporin
`
`
`7.5 Tacrolimus
`
`
`
`7.6 Diuretics
`
`
`7.7 Lithium
`
`
`7.8 Methotrexate
`
`
`
`7.9 Anticoagulants
`
`
`
`7.10 Selective Serotonin Reuptake Inhibitors (SSRIs)
`
`
`
`
`7.11 Other Information Concerning Drug Interactions
`
`
`
`
`
`7.12 Interactions With Investigations of Neuroendocrine Tumors
`
`
`
`
`
`7.13 Drug/Laboratory Test Interaction
`
`
`
`
`7.14 Interactions Related to Absorption
`
`
`
`
`7.15 Antiretroviral Agents
`
`
`
`7.16 Effects on Hepatic Metabolism/cytochrome P-450 pathways
`
`
`
`
`7.17 Other Pharmacokinetic-based Interactions
`
`
`
`USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`
`8.3 Nursing Mothers
`
`
`
`8.4 Pediatric Use
`
`
`
`8.5 Geriatric Use
`
`
`
`8.6 Hepatic Insufficiency
`
`
`8.7 Renal Insufficiency
`
`
`
`8.8 Females and Males of Reproductive Potential
`
`
`
`
`OVERDOSAGE
`
`DESCRIPTION
`
`CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`
`
`NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`
`13.2 Animal Toxicology and/or Pharmacology
`
`
`CLINICAL STUDIES
`
`HOW SUPPLIED/STORAGE AND HANDLING
`
`PATIENT COUNSELING INFORMATION
`
`
`
`8
`
`
`10
`
`11
`
`12
`
`
`13
`
`
`14
`
`16
`
`17
`
`*Sections or subsections omitted from the full prescribing information are
`
`
`
`not listed
`
`
`Reference ID: 3675794
`
`DRL EXHIBIT 1030 PAGE 2
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
`
`
`
`
`
`
`
` Cardiovascular Risk
`
` Non-Steroidal Anti-inflammatory Drugs (NSAIDs), a
`
`
` component of VIMOVO, may cause an increased risk
`cardiovascular
`
`
`of
` serious
` 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 and Precautions (5.1)].
`
` VIMOVO is contraindicated for the treatment of peri-
`
`
`
`operative pain in the setting of coronary artery bypass
`
`
`graft (CABG) surgery [see Contraindications (4), and
`
`Warnings and Precautions (5.1)].
`
`
`
`
`Gastrointestinal Risk
`
` including naproxen, a component of
` NSAIDs,
`
`
`
`
` VIMOVO, cause an
`increased
` risk of serious
`including bleeding,
`
`gastrointestinal adverse events
`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 are at greater risk for serious gastrointestinal
`
`
`
` events [see Warnings and Precautions (5.4)].
`
`
`
` 1
`
`
`
`
`
` 2
`
`
`
` INDICATIONS AND USAGE
`
`
`
` VIMOVO is a combination product that contains naproxen and esomeprazole. It is
`
` indicated for the relief of signs and symptoms of osteoarthritis, rheumatoid arthritis and
`
` ankylosing spondylitis and to decrease the risk of developing gastric ulcers in patients at
`
`
`
` risk of developing NSAID-associated gastric ulcers. VIMOVO is not recommended for
`
`
`
` initial treatment of acute pain because the absorption of naproxen is delayed compared to
`
` absorption from other naproxen-containing products. Controlled studies do not extend
`
`
`
`
` beyond 6 months.
`
` DOSAGE AND ADMINISTRATION
`
`
`
` Carefully consider the potential benefits and risks of VIMOVO and other treatment
`
` options before deciding to use VIMOVO. Use the lowest effective dose for the shortest
`
` duration consistent with individual patient treatment goals. VIMOVO does not allow for
`
` administration of a lower daily dose of esomeprazole. If a dose of esomeprazole lower
`
` than a total daily dose of 40 mg is more appropriate, a different treatment should be
`
`
`
`considered.
`
`Rheumatoid Arthritis, Osteoarthritis and Ankylosing Spondylitis
`
`The dosage is one tablet twice daily of VIMOVO 375 mg naproxen and 20 mg of
`
`esomeprazole or 500 mg naproxen and 20 mg of esomeprazole.
`
`
`
`The tablets are to be swallowed whole with liquid. Do not split, chew, crush or dissolve
`
`
`
`the tablet. VIMOVO is to be taken at least 30 minutes before meals.
`
`
`
` 3
`
`
`Reference ID: 3675794
`
`DRL EXHIBIT 1030 PAGE 3
`
`

`

`
`Geriatric Patients
`
`Studies indicate that although total plasma concentration of naproxen is unchanged, the
`
`unbound plasma fraction of naproxen is increased in the elderly. Use caution when high
`
`doses are required and some adjustment of dosage may be required in elderly patients. As
`
`with other drugs used in the elderly use the lowest effective dose [see Use in Specific
`
`
`
`Populations (8.5) and Clinical Pharmacology (12.3)].
`
`
`
`
`Patients With Moderate to Severe Renal Impairment
`
`
`
` Naproxen-containing products are not recommended for use in patients with moderate to
`
` severe or severe renal impairment (creatinine clearance <30 mL/min) [see Warnings and
`
`
`
` Precautions (5.6, 5.7) and Use in Specific Populations (8.7)].
`
`
`
`Hepatic Insufficiency
`
`
`
`Monitor patients with mild to moderate hepatic impairment closely and consider a
`
`possible dose reduction based on the naproxen component of VIMOVO.
`
`
`
`VIMOVO should be avoided in patients with severe hepatic impairment [see Warnings
`
`
`
`
`and Precautions (5.11), Use in Specific Populations (8.6) and Clinical Pharmacology
`(12.3)].
`
`
`
`Pediatric Patients
`
`
`
`The safety and efficacy of VIMOVO in children younger than 18 years has not been
`
`established. VIMOVO is therefore not recommended for use in children.
`
`
`
`
`DOSAGE FORMS AND STRENGTHS
`
`
`Oval, yellow, delayed release tablets for oral administration containing either:
`375 mg enteric coated naproxen and 20 mg esomeprazole (as magnesium
`
`•
`
`trihydrate) tablets printed with 375/20 in black, or
`500 mg enteric coated naproxen and 20 mg esomeprazole (as magnesium
`
`trihydrate) tablets printed with 500/20 in black.
`
`•
`
`
`
`
`3
`
`
`4
`
`
`
`
`
`
`
`CONTRAINDICATIONS
`
`
`VIMOVO is contraindicated in patients with known hypersensitivity to naproxen,
`
`
`esomeprazole magnesium, substituted benzimidazoles, or to any of the excipients.
`
`
`
`VIMOVO is contraindicated in 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
`and Precautions (5.8, 5.13)]. VIMOVO is also contraindicated in patients with known
`
`
`
`
`hypersensitivity to substituted benzimidazoles or to any component of the formulation
`
` Hypersensitivity reactions to esomeprazole may include
`including omeprazole.
`
`anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute interstitial nephritis,
`
`
`and urticaria [see Adverse Reactions (6)].
`
`
`
`
`VIMOVO is contraindicated for the treatment of peri-operative pain in the setting of
`
`coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)].
`
`
`
`
`
`
`
`
`Reference ID: 3675794
`
`
`
` 4
`
`
`DRL EXHIBIT 1030 PAGE 4
`
`

`

` 5
`
` 5.1
`
`
`
`
`5.2
`
`
`5.3
`
`
`5.4
`
` WARNINGS AND PRECAUTIONS
`
`
` 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,
`
`
` myocardial infarction, and stroke, which can be fatal. All NSAIDS, both COX-2 selective
`
`
` and nonselective, may have a similar risk. Patients with known CV disease or risk factors
`
` for CV disease may be at greater risk. To minimize the potential risk for an adverse CV
`
`
` event in patients treated with an NSAID, the lowest effective dose should be used for the
`
`
` shortest duration possible. Physicians and patients should remain alert for the
`
` development of such events, even in the absence of previous CV symptoms. Patients
`
`
` should be informed about the signs and/or 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.
`
`
`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 [see Contraindications (4)].
`
`
`
`
`Hypertension
`
`NSAIDs, including naproxen, a component of VIMOVO, 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 thiazides or loop diuretics may
`
`
`have impaired response to these therapies when taking NSAIDs. NSAIDs should be used
`
`with caution in patients with hypertension. Blood pressure (BP) should be monitored
`
`closely during the initiation of NSAID treatment and throughout the course of therapy
`
`
`[see Drug Interactions (7.1, 7.6)].
`
`
`
`Congestive Heart Failure and Edema
`
`Fluid retention, edema, and peripheral edema have been observed in some patients taking
`
`NSAIDs and should be used with caution in patients with fluid retention or heart failure.
`
`
`
`
`Gastrointestinal Effects — Risk of Ulceration, Bleeding, and Perforation
`
`
`including naproxen, a component of VIMOVO, can cause serious
`NSAIDs,
`
`
`gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and
`
`
`
`perforation of the stomach, small intestine, or large intestine, which can be fatal. While
`
`
`VIMOVO has been shown to significantly decrease the occurrence of gastric ulcers
`
`compared to naproxen alone, ulceration and associated complications can still occur.
`
`
`
`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 occur in approximately 1% of patients treated for 3–6
`
`
`months, and in about 2–4% of patients treated for one year. These trends continue with
`
`longer duration of use, increasing the likelihood of developing a serious GI event at some
`
`time during the course of therapy. However, even short-term therapy is not without risk.
`
`The utility of periodic laboratory monitoring has not been demonstrated, nor has it been
`
`adequately assessed.
`
`
`
`
`Reference ID: 3675794
`
`
`
` 5
`
`
`DRL EXHIBIT 1030 PAGE 5
`
`

`

`
`
`
`
`
`
` VIMOVO should be prescribed with caution in those with a prior history of ulcer disease
`
` or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or
`
` gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk of
`
`
` developing a GI bleed compared to patients with neither of these risk factors. Other
`
`
` factors that increase the risk for GI bleeding in patients treated with NSAIDs include
`
`
`
` concomitant use of oral corticosteroids or anticoagulants or antiplatelets (including low-
`
` dose aspirin), longer duration of NSAID therapy, smoking, use of alcohol, older age, and
`
` poor general health status. Most spontaneous reports of fatal GI events are in elderly or
`
`
`
`
` debilitated patients, and therefore special care should be taken in treating this population.
`
`
`
`
`To minimize the potential risk for an adverse GI event in patients treated with an NSAID
`
`
`or NSAID-containing product, the lowest effective dose should be used for the shortest
`
`
`possible duration. Patients and physicians should remain alert for signs and symptoms of
`
`
`GI ulceration and bleeding during NSAID therapy and promptly initiate additional
`
`
`evaluation and treatment if a serious GI adverse event is suspected. This should include
`
`discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk
`
`patients, alternate therapies that do not involve NSAIDs should be considered.
`
`
`Epidemiological studies of the case-control and cohort design have demonstrated an
`
`
`association between use of psychotropic drugs that interfere with serotonin reuptake and
`
`the occurrence of upper gastrointestinal bleeding. In two studies, concurrent use of an
`
`NSAID, COX-2 inhibitor, or aspirin potentiated the risk of bleeding [see Drug
`
`Interactions (7.2, 7.10)]. Although these studies focused on upper gastrointestinal
`
`
`
`
`bleeding, bleeding at other sites cannot be ruled out.
`
`
`NSAIDs should be given with care to patients with a history of inflammatory bowel
`
`
`disease (ulcerative colitis, Crohn’s disease) as their condition may be exacerbated.
`
`
`
`Gastrointestinal symptomatic response to therapy with VIMOVO does not preclude the
`
`
`presence of gastric malignancy.
`
`
`
`
`Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients
`
`
`
`
`treated long-term with omeprazole, of which esomeprazole is an enantiomer and a
`component of VIMOVO.
`
`
`Active Bleeding
`
`When active and clinically significant bleeding from any source occurs in patients
`
`receiving VIMOVO, the treatment should be withdrawn.
`
`
`
`Renal Effects
`
`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, hypovolemia, heart failure, liver dysfunction, salt depletion, those taking
`
`diuretics, ACE inhibitors, or angiotensin II receptor antagonists and the elderly.
`
`
`
`
`Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment
`
`
`state.
`
`
`
`5.5
`
`
`5.6
`
`
`
`
`Reference ID: 3675794
`
`
`
` 6
`
`
`DRL EXHIBIT 1030 PAGE 6
`
`

`

`
`5.9
`
`
`
` 5.7 Advanced Renal Disease
`
`
`
` No information is available from controlled clinical studies regarding the use of
`
`
` VIMOVO in patients with advanced renal disease. Therefore, treatment with VIMOVO is
` not recommended in these patients with advanced renal disease. If VIMOVO therapy
`
`
`
` must be initiated, close monitoring of the patient’s renal function is advisable [see
`
`
` Dosage and Administration (2), Use in Specific Populations (8.7) and Clinical
`
`
`
` Pharmacology (12.3)].
`
`
`
`5.8 Anaphylactic Reactions
`
`
`
`Anaphylactic reactions may occur in patients without known prior exposure to either
`
`
`
`component of VIMOVO. NSAIDs should not be given to patients with the aspirin triad.
`
`
`
`
`This symptom complex typically occurs in asthmatic patients who experience rhinitis
`
`with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after
`taking aspirin or other NSAIDs [see Contraindications (4)]. Emergency help should be
`
`
`
`
`
`
`sought in cases where an anaphylactic reaction occurs. Anaphylactic reactions, like
`
`anaphylaxis, may have a fatal outcome.
`
`
`Skin Reactions
`
`NSAIDs can cause serious skin adverse events such as exfoliative dermatitis, Stevens-
`
`
`Johnson syndrome, and toxic epidermal necrolysis, 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 use of the drug should be discontinued at
`
`the first appearance of skin rash or any other sign of hypersensitivity.
`
`
`
`5.10 Fetal Toxicity
`
`
`
`
`Starting at 30 weeks gestation, VIMOVO, as with other NSAID-containing products,
`
`
`
`should be avoided because it may cause premature closure of the ductus arteriosus [see
`Use in Specific Populations (8.1)].
`
`
`
`
`5.11 Hepatic Effects
`
`Borderline elevations of one or more liver tests may occur in up to 15% of patients taking
`
`NSAIDs including naproxen, a component of VIMOVO. Hepatic abnormalities may be
`
`
`the result of hypersensitivity rather than direct toxicity. These laboratory abnormalities
`
`may progress, may remain essentially unchanged, or may be transient with continued
`
`therapy. The SGPT (ALT) test is probably the most sensitive indicator of liver
`
`
`dysfunction. Notable elevations of ALT or AST (approximately three or more times the
`
`upper limit of normal) have been reported in approximately 1% of patients in clinical
`
`trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice
`and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal
`
`outcomes, have been reported.
`
`
`
`A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an
`
`abnormal liver test has occurred, should be evaluated for evidence of the development of
`
`more severe hepatic reaction while on therapy with VIMOVO.
`
`
`
`If clinical signs and symptoms consistent with liver disease develop, or if systemic
`
`
`manifestations occur (e.g., eosinophilia, rash, etc.), VIMOVO should be discontinued.
`
`
`
`Chronic alcoholic liver disease and probably other diseases with decreased or abnormal
`
`
`plasma proteins (albumin) reduce the total plasma concentration of naproxen, but the
`
`plasma concentration of unbound naproxen is increased. Caution is advised when high
`
` 7
`
`
`
`
`Reference ID: 3675794
`
`DRL EXHIBIT 1030 PAGE 7
`
`

`

`
`
` doses are required and some adjustment of dosage may be required in these patients. It is
`
` prudent to use the lowest effective dose for the shortest possible duration of adequate
`
` treatment.
`
`
`
`VIMOVO should be avoided in patients with severe hepatic impairment [see Dosage and
`
`
`
`Administration (2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
`
`
`
`
`5.12 Hematological Effects
`
`
`Anemia is sometimes seen in patients receiving NSAIDs. This may be due to fluid
`retention, occult or gross GI blood loss, or an incompletely described effect upon
`
`
`erythropoiesis. Patients on long-term treatment with NSAIDs should have their
`
`
`hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.
`
`
`NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in
`
`
`some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of
`
`
`
`shorter duration, and reversible. Patients receiving VIMOVO who may be adversely
`
`
`
`affected by alterations in platelet function, such as those with coagulation disorders or
`
`
`
`patients receiving anticoagulants or antiplatelets, should be carefully monitored.
`
`
`
`5.13 Pre-existing Asthma
`
`
`
`Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients
`
`with aspirin-sensitive asthma has been associated with severe bronchospasm, which can
`
`be fatal. Since cross reactivity, including bronchospasm, between aspirin and other
`
`
`NSAIDs has been reported in such aspirin-sensitive patients, VIMOVO should not be
`
`administered to patients with this form of aspirin sensitivity and should be used with
`
`caution in patients with pre-existing asthma.
`
`
`
`5.14 Concomitant NSAID Use
`
`VIMOVO contains naproxen as one of its active ingredients. It should not be used with
`
`
`
`other naproxen-containing products since they all circulate in the plasma as the naproxen
`
`anion.
`
`
`The concomitant use of VIMOVO with any dose of a non-aspirin NSAID should be
`
`
`avoided due to the potential for increased risk of adverse reactions.
`
`
`
`5.15 Corticosteroid Treatment
`
`
`
`VIMOVO cannot be expected to substitute for corticosteroids or to treat corticosteroid
`
`insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation.
`
`Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a
`
`decision is made to discontinue corticosteroids and the patient should be observed closely
`
`
`for any evidence of adverse effects, including adrenal insufficiency and exacerbation of
`
`symptoms of arthritis.
`
`
`
`
`5.16 Acute Interstitial Nephritis
`
`
`Acute interstitial nephritis has been observed in patients taking PPIs including VIMOVO.
`
`Acute interstitial nephritis may occur at any point during PPI therapy and is generally
`
`
`
`attributed to an idiopathic hypersensitivity reaction. Discontinue VIMOVO if acute
`
`interstitial nephritis develops [see Contraindications (4)].
`
`
`
`
` 8
`
`
`
`
`
`
`
`Reference ID: 3675794
`
`DRL EXHIBIT 1030 PAGE 8
`
`

`

`
` 5.17 Cyanocobalamin (vitamin B-12) Deficiency
`
`
`
`
`
` Daily treatment with any acid-suppressing medications over a long period of time
`
` (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (vitamin B-
`
`
`
`
`
` 12) caused by hypo-or achlorhydria. Rare reports of cyanocobalamin deficiency
`
`
`
`
`
` occurring with acid-suppressing therapy have been reported in the literature. This
`
`
` diagnosis should be considered if clinical symptoms consistent with cyanocobalamin
`
`
`deficiency are observed.
`
`
`5.18 Clostridium difficile Associated Diarrhea
`
`
`
`Published observational studies suggest that proton pump inhibitor (PPI) therapy like
`
`
`VIMOVO may be associated with an increased risk of Clostridium difficile associated
`
`
`
`diarrhea, especially in hospitalized patients. This diagnosis should be considered for
`
`diarrhea that does not improve [see Adverse Reactions (6.2)].
`
`
`
`
`Patients should use the lowest dose and shortest duration of PPI therapy appropriate to
`
`
`
`the condition being treated. [see Dosage and Administration (2)].
`
`
`
`
`
`
` 5.19
`
`
`
`
`Interaction with Clopidogrel
`
`
`
` Avoid concomitant use of esomeprazole with clopidogrel. Clopidogrel is a prodrug.
`Inhibition of platelet aggregation by clopidogrel is entirely due to an active metabolite.
`
` The metabolism of clopidogrel to its active metabolite can be impaired by use with
` concomitant medications, such as esomeprazole, that inhibit CYP2C19 activity.
`
`
`
` Concomitant use of clopidogrel with 40 mg esomeprazole reduces the pharmacological
` activity of clopidogrel. When using esomeprazole,