2150900
`
`~ ~imovci~P
`
`jnaproxen/esooeprazoemagnesIm)
`
`375lzn.eaulZO mu delayed-release
`
`rauIet~
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`needed tu use VfMOVO safely and
`all
`the information
`da nat include
`These highlights
`effectively. See full prescribinginformation
`for V/MOVO.
`
`VIMOVOeI
`
`(naproxen and esomeprazole magnesium) DELAYED-RELEASE TABLETS
`Initial US Approval: 2010
`
`WARNING: CARDIOVASCULAR AND GASTROINTESTINAL RISKS
`See lull prescribinginformation
`
`for complete boxed warning
`
`Cardiovascular Risk
`of VIMOVO, may cause an increased risk of serious cardio-
`~ Naproxen,
`a component
`aad stroke, which can be fatal.
`infarction,
`thrombotic
`vascular
`events, myocardial
`disease or
`This risk may increase with duration of use. Patients with cardiovascular
`risk. (5.1)
`risk factors for cardiovascular disease may be at greater
`pain in the setting of
`of perioperative
`(4, 5.1)
`
`~ VIMOVO is contraindicated
`for the treatment
`coronary artery bypass graft (CABG) surgery.
`Risk
`Gastrointestinal
`of VIMOVO, cause an increased risk of
`~ NSAIDs,
`a component
`napraxen,
`including
`and perfo-
`bleeding, ulceration,
`adverse
`events
`serious gastrointestinal
`including
`ration of the stomach or intestines, which can be fatal. These events can occur at
`symptoms. Elderly patients are at greater
`any time during use aad without warning
`(Gl) events. (5.4)
`risk for serious gastrointestinal
`
`- RECENT MAJOR CHANGES-
`(5.17)
`Interaction with Clopidogrel
`and Precautions, Clostridium difficile associated diarrhea
`
`and Precautions,
`
`(5.16)
`use of VIMOVO with Methotrexate
`
`Warnings
`
`Warnings
`
`Warnings
`
`10/2012
`
`09/2012
`
`(5.23)
`
`01/2012
`
`11/2011
`
`~
`
`~
`
`~
`
`~
`
`~
`
`~
`
`~
`
`~
`
`~
`
`~
`
`~
`
`~
`
`~
`
`Atrophic gastritis has been noted on biopsy with long-term omeprazole
`
`therapy (5.4)
`
`from any
`
`bleeding
`
`should be withdrawn when active and clinically significant
`Treatment
`source occurs (5.5)
`long-term use. Llse VIMOVO with
`necrosis
`and other
`injury with
`renal
`Renal papillary
`salt depletion,
`those with impaired
`function,
`renal
`hypovolemia,
`caution in the elderly,
`and those taking diuretics, or ACE-inhibitors. Not recom-
`liver dysfunction,
`heart failure,
`(2, 5.6, 5.7, 7.1, 7.6, 8.7)
`mended for patients with moderate or severe renal
`impairment
`reactions. Do not use VIMOVO in patients with the aspirin triad (5.8)
`Anaphylactic
`Serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson
`syndrome,
`and can occur without warning.
`can be fatal
`necrolysis, which
`and toxic epidermal
`of skin rash or any other sign of hypersensitivity
`Discontinue VIMOVO at first appearance
`(5 9)
`
`rarely, severe hepatic reactions. Discontinue use immediately
`and,
`Elevated liver enzymes
`liver enzymes persist or worsen (5.11,8.6, 12.3)
`if abnormal
`
`in patients with severe hepatic
`
`impairment
`
`(e.g., Child-Pugh C) (2,
`
`Should be avoided
`5.11, 8.6, 1 2.3)
`therapy may be associated with
`PPI
`(5,16)
`diarrhea,
`Avoid concomitant use of esomeprazole with clapidogrel
`
`increased
`
`risk of Clostridium difficile associated
`
`risk for
`
`Hypomagnesemia
`
`and Precautions, Concomitant
`and Precautions, Bone Fracture (5.18)
`
`Warnings
`
`Relief
`
`ankylosing
`risk of
`at
`
`- INDICATIONS AND USAGE-
`arthritis,
`and
`of osteoarthritis,
`rheumatoid
`of signs
`symptoms
`and
`gastric ulcers
`in patients
`and to decrease
`the risk of developing
`spondylitis
`developing NSAID associated gastric ulcers (1).
`- - - - - - - - - - - - - - - - - DOSAGE AND ADMINISTRATION
`twice daily. Use the lowest effective dose. Should be avoided in moderate/severe
`One tablet
`dose reduction
`insufficiency. Consider
`severe
`in mild/
`or
`hepatic
`insufficiency
`renal
`in
`(2).
`moderate hepatic insufficiency
`DOSAGE FORMS AND STRENGTHS- - - - - - - - - - - - - - - --
`tablets: 375 mg/20 mg or 500 mg/20 mg of naproxen
`and esomeprazole
`
`Delayed-release
`magnesium {3)
`
`Known hypersensitivity
`
`- CONTRAINDICATIONS
`of VIMOVO or substituted
`to any component
`
`benzimidazoles
`
`(4)
`
`reactions after taking aspirin or other
`
`History of asthma, urticaria, or other allergic-type
`NSAIDs (4, 5.8, 5.9, 5.13)
`Use during the peri-operative
`surgery (4, 5.1)
`(4, 5.10, 8.1)
`Late pregnancy
`
`period in the setting of coronary artery bypass graft (CABG)
`
`WARNINGS AND PRECAUTIONS-
`'erious and potentially fatal cardiovascular
`(CV) thrombotic
`infarction,
`events, myocardial
`risk (5.1)
`factors may be at greater
`and stroke. Patients with known CV disease/risk
`
`~
`
`~
`
`~
`
`~
`
`New onset
`monitored
`
`Blood pressure
`hypertension.
`of pre-existing
`or worsening
`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)
`
`should
`
`be
`
`events, which can be fatal. The risk is greater
`Serious gastrointestinal
`(Gl) adverse
`in
`and in patients at high risk for
`patients with a prior history of ulcer disease or Gl bleeding,
`Gl events, especially the elderly. VIMOVO should be used with caution in these patients
`(5.4, 8.5)
`
`Symptomatic
`malignancy
`
`response
`(5.4)
`
`to esomeprazole
`
`does not preclude
`
`the presence
`
`of gastric
`
`(5.17)
`daily dose PPI therapy is associated with an increased
`Long-term and multiple
`fractures of the hip, wrist or spine (5.18)
`osteoporosis-related
`Increases in intra-
`for Neuroendocrine Tumors:
`Interactions with diagnostic investigations
`enterochromaffin-like
`cell hyperplasia,
`and
`in hypergastrinemia,
`gastric pH may result
`for
`investigations
`A levels which may interfere with diagnostic
`increased Chromogranin
`(5.20)
`tumors.
`neuroendocrine
`has been reported rarely with prolonged treatment with PPls (5.21)
`use of VIMOVO with St John's Wort or rifampin
`due to the potential
`Avoid concomitant
`levels. (5.22, 7.16)
`reduction in esomeprazole
`
`- ADVERSE REACTIONS-
`trials (&5%):erosive gastritis, dyspepsia, gastritis,
`Most common adverse reactions in clinical
`pain, nausea (6.1)
`diarrhea, gastric ulcer, upper abdominal
`Ta report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca
`FDA at1-800-FDA-1088 or www.fda.gov/medwatch.
`
`at 1-800-236-9933 ar
`
`- DRUG INTERACTIONS-
`'oncomitant
`use of NSAIDs may reduce the antihypertensive
`(7.1,7.6, 7.11)
`and beta-blockers
`diuretics,
`As with all NSAIDs caution is advised when cyclosporin is coadministered
`(7.4)
`increased risk of nephrotoxicity
`
`~
`
`effect of ACE Inhibitors,
`
`because of the
`
`of VIMOVO, and
`
`a component
`of esomeprazole,
`Tacrolimus: Concomitant
`administration
`(7.5)
`tacrolimus may increase the serum levels of tacrolimus
`lithium plasma levels (7.7)
`use of NSAIDs increases
`Concomitant
`~ Methotrexate: VIMOVO may increase serum levels of methotrexate {7.8)
`in increased
`risk of bleeding
`~
`use of VIMOVO with warfarin may result
`Concomitant
`time (7,9)
`for increases
`in INR and prothrombin
`complications. Monitor
`gastric acid secretion and may interfere with the absorption
`of
`Esomeprazole
`inhibits
`(eg, ketoconazole,
`of bioavailability
`determinant
`drugs where gastric pH is an important
`iron salts, erlotinib, and digoxin). Patients treated with VIMOVO and digoxin may need to
`in digoxin toxicity (7.14)
`be monitored for increases
`of VIMOVO, decreases exposure to the active
`
`~
`
`~
`
`~
`
`~
`
`esomeprazole,
`Clopidogrel:
`metabolite of clopidogrel.
`
`a component
`(7.16, 12.3)
`
`USE IN SPECIFIC POPULATIONS-
`'regnancy Category C: VIMOVO should not be used in late pregnancy {4,5.10, 8.1)
`severe
`hepatic
`in patients with
`Insufficiency: VIMOVO should
`be avoided
`Hepatic
`(2, 4, 5.11,8.6, 12.3)
`insufficiency
`Insufficiency: VIMOVO is not recommended
`(2, 5.6, 5.7, 8,7, 12.3)
`insufficiency
`
`~
`
`~
`
`Renal
`renal
`
`in patients with moderate or severe
`
`SEE17 FOR PATIENT COUNSELING INFORMATION and FDA-Approved Medication Guide
`
`Revised 10/2012
`
`Page 1 Dr. Reddy's Exh. 1034
`
`

`

`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`FULL PRESCRIBING INFORMATION
`
`VIMOVO (naproxen/esomeprazole
`
`magnesium)
`
`375/20 ~ 500/20 delayed-release
`
`tablets
`
`WARNING: CARDIOVASCULAR AND GASTROINTESTINAL RISKS
`
`Cardiovascular Risk
`
`INDICATIONS AND USAGE
`
`DOSAGE AND ADMINISTRATION
`
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATION S
`
`of VIMOVO, may cause an
`~ Non-Steroidal Anti-inflammatory
`Drugs (NSAIDs), a component
`increased risk af serious cardiovascular
`infarction,
`events, myocardial
`thrombotic
`and
`of use. Patients with
`stroke, which can be fatal. This risk may increase with duration
`disease may be at greater
`disease or risk factors for cardiovascular
`risk
`cardiovascular
`(5.1)].
`[see Warnings and Precautions
`the treatment
`pain in the setting
`~ VIMOVO is contraindicated
`of perioperative
`for
`coronary artery bypass graft (CABG) surgery [see Cantraindicatians(4),
`and Warnings and
`Precautions (5.1)].
`
`af
`
`Gastrointestinal
`Risk
`of VIMOVO, cause an increased risk of serious
`~ NSAIDs,
`a component
`including naproxen,
`of the
`adverse
`events
`and perforation
`ulceration,
`bleeding,
`gastrointestinal
`including
`stomach or intestines, which can de fatal. These events can accur at any time during use
`risk for serious gastro-
`are at greater
`symptoms. Elderly patients
`and without warning
`(5.4)].
`events [see Warnings and Precautions
`
`intestinal
`
`ng, and Perforation
`
`1
`
`INDICATIONS AND USAGE
`that contains naproxen and esomeprazole.
`product
`VIMOVO is a combination
`
`It is indicated for the
`and to
`
`and Fever
`
`VIMOVO
`
`Tu
`
`mors
`
`P-450 Pa
`
`thways
`
`individual
`
`esomeprazole.
`
`2
`DOSAGE AND ADMINISTRATION
`and risks of VIMOVO and other
`treatment
`benefits
`consider
`the potential
`Carefully
`deciding to use VIMOVO. Use the lowest effective dose for the shortest duration
`of a lower daily dose of
`treatment goals. VIMOVO does not allow for administration
`patient
`lower than a total daily dose of 40 mg is more appropriate,
`If a dose of esomeprazole
`should be considered.
`treatment
`a different
`and Anky[osing Spondylitis
`Rheumatoid Arthritis, Osteoarthritis
`twice daily of VIMOVO 375 mg naproxen
`and 20 mg of esomeprazole
`The dosage is one tablet
`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.
`
`options before
`consistent with
`
`or
`
`elderly
`
`Pharmacalogy
`
`Geriatric Patients
`the unbound
`is unchanged,
`total plasma concentration
`of naproxen
`Studies
`indicate that although
`plasma fraction of naproxen is increased in the elderly, Use caution when high doses are required and
`in elderly patients. As with other drugs used in the
`of dosage may be required
`some adjustment
`(8.5) and Clinical
`in Specific Populations
`[see Use
`dose
`effective
`use the
`lowest
`(12.3)].
`Patients With Moderate to Severe Renal
`Impairment
`for use in patients with moderate to severe or
`products are not recommended
`Naproxen-containing
`clearance &30 mL/min)
`(5.6,
`and Precautions
`(8.7)].
`
`(creatinine
`severe renal
`impairment
`5.7) and Use in Specific Populations
`
`[see Warnings
`
`Hepatic Insufficiency
`Monitor patients with mild to moderate
`hepatic impairment
`reduction based on the naproxen component of VIMOVO.
`
`closely and consider a possible dose
`
`be avoided
`VIMOVO should
`in patients with
`(5.11),Use in Specific Papulations
`Precautions
`
`[see Warnings
`severe hepatic
`impairment
`(12.3)].
`(8.6) and Clinical Pharmacology
`
`and
`
`relief of signs and symptoms
`decrease the risk of developing
`
`of osteoarthritis,
`
`gastric ulcers
`recommended
`
`rheumatoid
`
`in patients
`
`for
`
`initial
`
`gastric ulcers. VIMOVO is not
`to absorption
`compared
`of naproxen
`is delayed
`absorption
`products. Controlled studies do not extend beyond 6 months.
`
`treatment
`
`from other
`
`spondylitis
`arthritis and ankylosing
`at risk of developing NSAID-associated
`the
`pain because
`of acute
`naproxen-containing
`
`1 2 3 4 5
`
`6
`
`7
`
`WARNINGS AND PRECAUTIONS
`5.1 Cardiovascular Thrombotic Events
`5.2 Hypertension
`5.3 Congestive Heart Failure and Edema
`Effects —Risk of Ulceration, Bleedi
`5.4 Gastrointestinal
`5.5 Active Bleeding
`5.6 Renal Effects
`5.7 Advanced Renal Disease
`5.8 Anaphylactic Reactions
`5.9 Skin Reactions
`5.10 Pregnancy
`5.11 Hepatic Effects
`5.12 Hematological Effects
`5.13 Pre-existing Asthma
`5.14 Concomitant NSAID Use
`5.15 Corticosteroid Treatment
`5,16 Clostridium difficile associated diarrhea
`5.17 interaction with Clopidogrel
`5.18 Bone Fracture
`5.19 Masking of Inflammation
`5.20 Laboratory Tests
`5.21 Hypomagnesemia
`5.22 Concomitant use of St John's Wort or Rifampin with
`5.23 Concomitant use of VIMOVO with Methotrexate
`ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing
`Experience
`DRUG INTERACTIONS
`7.1 ACE-inhibitors
`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
`(SSRls)
`Inhibitors
`7.11 Other
`Information Concerning Drug Interactions
`7.12 interactions With Investigations
`of Neuroendocrine
`7.13 Drug/Laboratory
`Test Interaction
`7.14 interactions Related to Absorption
`7.15 Antiretroviral Agents
`7.16 Effects on Hepatic Metabolism/Cytochrome
`7.17 Other Pharmacokinetic-based
`Interactions
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.2 Labor and Delivery
`8.3 Nursing Mothers
`8.4
`Pediatric Use
`8.5 Geriatric Use
`8.6 Hepatic Insufficiency
`8,7 Renal
`Insufficiency
`
`OVER DOSAGE
`
`DESCRIPTION
`
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis,
`Impairment
`13.2 Animal Toxicology and/or Pharmacology
`CLINICAL STUDIES
`
`HOW SUPPLIED/STORAGE
`AND HANDLING
`
`of Fertility
`
`B
`
`10
`11
`12
`
`13
`
`14
`16
`
`PATIENT COUNSELING INFORMATION
`
`17
`Sections or subsections
`
`omitted tram the full prescrrbmg
`
`intormation
`
`are not hsted
`
`Pediatric Patients
`The safety and efficacy of VIMOVO in children younger
`for use in children.
`VIMOVO is therefore not recommended
`
`than 18 years has not been established,
`
`3
`DOSAGE FORMS AND STRENGTHS
`tablets for oral administration
`Oval, yellow, delayed-release
`~ 375 mg enteric coated naproxen
`printed with 375/20 in black, or
`
`and 20 mg esomeprazole
`
`containing
`
`either:
`
`(as magnesium trihydrate)
`
`tablets
`
`~ 500 mg enteric coated naproxen
`printed with 500/20 in black
`
`and 20 mg esomeprazole
`
`(as magnesium trihydrate)
`
`tablets
`
`4
`CONTRAINDICATION 5
`VIMOVO is contraindicated
`hypersensitivity
`in patients with
`or to any of the excipients.
`
`magnesium,
`
`substituted
`
`benzimidazoles,
`
`known
`
`to naproxen,
`
`esomeprazole
`
`VIMOVO is contraindicated
`
`reported
`
`in such patients
`
`reactions
`
`reactions,
`
`eg,
`
`in patients who have experienced asthma, urticaria, ar allergic-type
`reactions to NSAIDs have been
`rarely fatal, anaphylactic-like
`after taking aspirin or other NSAIDs. Severe,
`(5.8, 5.13)], Hypersensitivity
`and Precautions
`have been reported with esomeprazole use.
`
`angioedema
`
`and anaphylactic
`
`[see Warnings
`reaction/shock,
`
`for the treatment
`VIMOVO is contraindicated
`(CABG) surgery [see Warnings
`
`bypass graft
`
`of peri-operative
`
`and Precautions
`
`stages
`the
`VIMOVO is contraindicated
`in patients
`late
`in
`(8.1)].
`(5.10) and Use in Specific Populations
`
`Precautions
`
`pain in the setting of coronary artery
`(5.1)],
`of pregnancy
`
`[see Warnings
`
`and
`
`Page 2 Dr. Reddy's Exh. 1034
`
`

`

`VIMOVO (naproxen/esomeprazole
`
`tablets
`
`375/20 ~ 500/20 delayed-release
`magnesium)
`5.7 Advanced Renal Disease
`is available from controlled clinical studies
`No information
`recommended
`renal disease. Therefore,
`treatment with VIMOVO is not
`If VIMOVO therapy must be initiated, close monitoring
`of the
`renal disease,
`in Specific
`(2), Use
`[see Dosage
`and Administration
`is advisable
`function
`renal
`(12.3)].
`(8.7) and Clinical Pharmacology
`Populations
`5.8 Anaphylactic Reactions
`reactions may occur in patients without known prior exposure to either component
`of
`Anaphylactic
`not be given to patients with the aspirin triad. This symptom complex
`VIMOVO. NSAIDs should
`rhinitis with or without nasal polyps, or who
`typically occurs in asthmatic patients who experience
`[see
`or other NSAIDs
`after
`bronchospasm
`aspirin
`severe,
`fatal
`taking
`exhibit
`potentially
`in cases where an anaphylactic
`reaction
`(4)]. Emergency help should be sought
`Contraindications
`like anaphylaxis, may have a fatal outcome.
`occurs. Anaphylactic
`reactions,
`5.9 Skin Reactions
`Stevens-Johnson
`such as exfoliative
`dermatitis,
`NSAIDs can cause serious
`skin adverse
`events
`events may occur
`necrolysis, which can be fatal. These serious
`and toxic epidermal
`of serious
`about
`the signs
`skin
`should
`and symptoms
`Patients
`be informed
`without warning.
`at the first appearance of skin rash or any
`and use of the drug should be discontinued
`manifestations
`other sign of hypersensitivity.
`5.10 Pregnancy
`Pregnancy Category C
`a component
`as with other NSAIDs, naproxen,
`In late pregnancy,
`closure of the ductus arteriosus
`because it may cause premature
`(8.1)].
`Use in Specific Populations
`5.11 Hepatic Effects
`elevations of one or more liver tests may occur in up to 15% of patients
`taking NSAIDs
`Borderline
`of VIMOVO. Hepatic abnormalities may be the result of hyper-
`a component
`naproxen,
`toxicity. These laboratory
`abnormalities may progress, may remain
`than direct
`or may be transient with continued therapy. The SGPT (ALT) test is probably
`essentially unchanged,
`of ALT or AST (approximately
`elevations
`the most sensitive
`indicator of liver dysfunction. Notable
`limit of normal) have been reported in approximately1% of patients
`three or more times the upper
`rare cases of severe hepatic reactions,
`jaundice and
`including
`trials with NSAIDs.
`In addition,
`clinical
`some of them with fatal outcomes,
`liver necrosis and hepatic failure,
`
`with
`
`advanced
`
`patients with advanced
`patient's
`
`regarding
`
`the use of VIMOVO in patients
`these
`
`&n
`
`syndrome,
`
`including
`
`sensitivity
`
`rather
`
`fatal
`
`fulminant
`
`hepatitis,
`
`been reported.
`
`of VIMOVO,
`should
`[see Contraindications
`
`be avoided
`
`(4), and
`
`in
`
`have
`
`A patient with symptoms
`test has occurred,
`should
`reaction while on therapy with VIMOVO.
`
`be evaluated
`
`and/or
`
`or in whom an abnormal
`liver dysfunction,
`signs suggesting
`of more severe hepatic
`for evidence of the development
`
`liver
`
`the increased risk of serious
`
`taking NSAIDs
`
`Effects —Risk of Ulceration, Bleeding, and Perforation
`
`5
`WARNINGS AND PRECAUTIONS
`5.1 Cardiovascular Thrombotic Events
`trials of several COX-2 selective and nonselective NSAIDs of up to three years duration
`have
`Clinical
`infarction,
`(CV) thrombotic
`events, myocardial
`cardiovascular
`risk of serious
`shown an increased
`and stroke, which can be fatal. All NSAIDS, both COX-2 selective and nonselective, may have a
`risk. Patients with known CV disease or risk factors for CV disease may be at greater
`risk. To
`similar
`the lowest
`treated with an NSAID,
`risk for an adverse CV event
`in patients
`the potential
`minimize
`be used for the shortest duration
`possible. Physicians
`and patients
`should
`effective dose should
`even in the absence of previous CV symptoms.
`remain alert for the development
`of such events,
`of serious CV events and the steps to
`Patients should be informed about
`the signs and/or
`symptoms
`take if they occur.
`There is no consistent evidence that concurrent use of aspirin mitigates
`events associated with NSAID use.
`CV thrombotic
`of pain in the first
`trials of a COX-2 selective NSAID for the treatment
`Two large, controlled,
`clinical
`10-14 days following CABG surgery found
`incidence
`of myocardial
`infarction
`and
`an increased
`(4)].
`stroke [see Contraindications
`5.2 Hypertension
`or
`of VIMOVO, can lead to onset of new hypertension
`a component
`NSAIDs,
`naproxen,
`including
`either of which may contribute to the increased incidence of
`of pre-existing
`hypertension,
`worsening
`CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies
`Blood
`be used with caution in patients with hypertension.
`should
`when taking NSAIDs. NSAIDs
`closely during the initiation of NSAID treatment
`and throughout
`(BP) should be monitored
`pressure
`(7.1, 7.6)].
`the course of therapy [see Drug Interactions
`5.3 Congestive Heart Failure and Edema
`edema have been observed in some patients
`edema, and peripheral
`Fluid retention,
`and should be used with caution in patients with fluid retention or heart failure.
`5.4 Gastrointestinal
`can cause serious gastrointestinal
`of VIMOVO,
`a component
`(Gl)
`naproxen,
`NSAIDs,
`including
`of the stomach,
`small
`and perforation
`adverse events
`ulceration,
`inflammation,
`bleeding,
`including
`intestine, which can be fatal. While VIMOVO has been shown to significantly
`or large
`intestine,
`and associated
`decrease the occurrence of gastric ulcers compared to naproxen
`alone, ulceration
`can still occur.
`complications
`These serious adverse events can occur at any time, with or without warning
`in patients
`symptoms,
`treated with NSAIDs. Only one in five patients who develop a serious upper Gl adverse
`event on
`caused by NSAIDs
`NSAID therapy is symptomatic. Upper Gl ulcers, gross bleeding, or perforation
`treated for 3-6 months,
`and in about 2%-4% of patients
`1% of patients
`occur in approximately
`increasing the likelihood of
`treated for one year. These trends continue with longer duration
`of use,
`a serious Gl event at some time during the course of therapy. However, even short-term
`developing
`has not been demonstrated,
`risk. The utility of periodic laboratory monitoring
`therapy is not without
`assessed.
`nor has it been adequately
`VIMOVO should be prescribed with caution in those with a prior history of ulcer disease or gastro-
`intestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal
`bleeding
`than 10-fold increased risk of developing
`a Gl bleed compared to
`who use NSAIDs have a greater
`patients with neither of these risk factors. Other factors that increase the risk for Gl bleeding in patients
`or antiplatelets
`treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants
`smoking, use of alcohol, older age,
`low-dose aspirin),
`of NSAID therapy,
`longer duration
`(including
`reports of fatal Gl events are in elderly or debilitated
`and poor general health status. Most spontaneous
`and therefore special care should be taken in treating this population.
`patients,
`treated with an NSAID or NSAID-
`risk for an adverse Gl event
`in patients
`the potential
`the lowest effective dose should be used for the shortest possible duration.
`product,
`containing
`of Gl ulceration
`should remain alert for signs and symptoms
`and bleeding
`Patients
`and physicians
`if a serious Gl
`and treatment
`evaluation
`additional
`initiate
`and promptly
`during NSAID therapy
`of the NSAID until a serious Gl
`is suspected. This should
`include discontinuation
`adverse
`event
`that do not
`involve NSAIDs
`alternate
`is ruled out. For high risk patients,
`therapies
`adverse
`event
`should be considered.
`an association
`studies of the case-control
`and cohort design have demonstrated
`Epidemiological
`and the occurrence of
`interfere with serotonin
`that
`reuptake
`use of psychotropic
`between
`drugs
`use of an NSAID, COX-2 inhibitor,
`or
`concurrent
`In two studies,
`upper gastrointestinal
`bleeding.
`(7.2, 7.10)].Although
`these studies
`[see Drug Interactions
`the risk of bleeding
`aspirin potentiated
`bleeding at other sites cannot be ruled out.
`focused on upper gastrointestinal
`bleeding,
`bowel disease
`care to patients with
`of inflammatory
`a history
`should
`be given with
`colitis, Crohn's disease) as their condition may be exacerbated.
`response to therapy with VIMOVO does not preclude the presence of
`
`To minimize
`
`NSAIDs
`
`(ulcerative
`
`Gastrointestinal
`symptomatic
`gastric malignancy.
`treated long-
`Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients
`of VIMOVO.
`and a component
`is an enantiomer
`of which esomeprazole
`term with omeprazole,
`5.5 Active Bleeding
`When active and clinically significant bleeding from any source occurs in patients
`the treatment
`should be withdrawn,
`5.6 Renal Effects
`of NSAIDs has resulted in renal papillary necrosis and other renal
`Long-term administration
`injury.
`have a compensatory
`role
`toxicity has also been seen in patients
`in whom renal prostaglandins
`Renal
`of an NSAID may cause a
`In these patients,
`administration
`of renal perfusion.
`in the maintenance
`in renal blood flow, which
`and, secondarily,
`dose-dependent
`reduction
`formation
`in prostaglandin
`risk of this reaction are those with
`Patients at greatest
`renal decompensation.
`may precipitate overt
`those taking
`salt depletion,
`heart
`liver dysfunction,
`renal
`function,
`failure,
`hypovolemia,
`impaired
`of NSAID therapy is usually followed by
`and the elderly. Discontinuation
`diuretics and ACE inhibitors,
`state.
`recovery to the pretreatment
`
`receiving VIMOVO,
`
`consistent with liver disease develop, or if systemic manifestations
`If clinical signs and symptoms
`rash, etc), VIMOVO should be discontinued.
`occur (eg, eosinophilia,
`other diseases with decreased or abnormal
`Chronic alcoholic liver disease and probably
`plasma
`of naproxen, but the plasma concentration
`reduce the total plasma concentration
`proteins
`high doses are required
`and some
`is increased. Caution
`is advised when
`naproxen
`to use the lowest effective dose
`of dosage may be required in these patients.
`adjustment
`for the shortest possible duration of adequate treatment.
`
`(albumin)
`
`of unbound
`
`It is prudent
`
`[see Dosage
`severe
`impairment
`hepatic
`(12.3)].
`(8.6), and Clinical Pharmacology
`
`and
`
`be avoided
`in patients with
`VIMOVO should
`(2), Use in Specific Populations
`Administration
`5.12 Hematological Effects
`receiving NSAIDs. This may be due to fluid retention, occult or
`seen in patients
`Anemia is sometimes
`described effect upon erythropoiesis.
`Patients on long-term
`gross Gl blood loss, or an incompletely
`or hematocrit checked if they exhibit any signs
`treatment with NSAIDs should have their hemoglobin
`of anemia.
`
`or symptoms
`
`and
`
`have been shown
`
`to prolong
`
`or
`
`in some
`time
`bleeding
`aggregation
`less, of shorter duration,
`function
`their effect on platelet
`is quantitatively
`receiving VIMOVO who may be adversely affected by alterations
`in platelet
`and reversible. Patients
`disorders
`those with
`or patients
`anticoagulants
`receiving
`coagulation
`as
`should be carefully monitored.
`antiplatelets,
`5.13 Pre-existing Asthma
`asthma. The use of aspirin in patients with aspirin-
`Patients with asthma may have aspirin-sensitive
`asthma has been associated with severe bronchospasm, which can be fatal. Since cross
`sensitive
`in such
`aspirin and other NSAIDs has been reported
`between
`bronchospasm,
`including
`to patients with this form of aspirin
`patients, VIMOVO should not be administered
`aspirin-sensitive
`asthma.
`sensitivity and should be used with caution in patients with pre-existing
`5.14 Concomitant NSAID Use
`not be used with other
`as one of its active
`It should
`ingredients.
`VIMOVO contains
`naproxen
`since they all circulate in the plasma as the naproxen anion.
`products
`The concomitant use of VIMOVO with any dose of a non-aspirin NSAID should be avoided due to the
`for increased risk of adverse reactions.
`potential
`5.15 Corticosteroid Treatment
`for corticosteroids or to treat corticosteroid insufficiency.
`VIMOVO cannot be expected to substitute
`of corticosteroids may lead to disease exacerbation. Patients on prolonged
`Abrupt discontinuation
`corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue
`effects,
`closely for any evidence
`of adverse
`be observed
`corticosteroids
`should
`and the patient
`and exacerbation of symptoms
`of arthritis.
`
`NSAIDs
`
`inhibit
`
`platelet
`
`patients. Unlike aspirin,
`
`function,
`
`such
`
`reactivity,
`
`naproxen-containing
`
`including
`
`adrenal
`
`insufficiency
`
`Page 3 Dr. Reddy's Exh. 1034
`
`

`

`VIMOVD (naproxen/esomeprazole
`
`magnes
`
`ium) 375/20 ~ 500/20 delayed-release
`
`tablets
`
`4
`
`Table1: Adverse Reactions Occurring in Patients &2% Study1 and Study 2 (Endoscopic Studies)
`
`VIMOVO
`500 mg/20 mg twice daily
`(n =428)
`0/
`
`EC-Naproxen
`500 mg twice daily
`(n =426)
`0/
`
`38
`
`27
`
`14
`
`5 2
`
`9 5
`
`4
`
`4 3 8 3 2
`
`12
`
`3
`
`7
`
`2
`
`4
`
`5
`
`4
`
`19
`
`18
`
`17
`
`6
`
`6
`
`6
`
`5
`
`4
`
`4
`
`4
`
`3
`
`2
`
`2
`
`2
`
`&1
`
`&1
`
`&1
`
`5
`
`Preferred Term
`
`(sorted by SOC)
`
`Gastrointestinal Disorders
`
`Gastritis Erosive
`
`Dyspepsia
`
`Gastritis
`
`Diarrhea
`
`Gastric Ulcer
`
`Abdominal
`
`Pain Upper
`
`Nausea
`
`Hiatus Hernia
`
`Abdominal Distension
`
`Flatulence
`
`Esophagitis
`
`Constipation
`
`Abdominal
`
`Pain
`
`Erosive Duodenitis
`
`Abdominal
`
`Pain Lower
`
`Duodenitis
`
`Gastritis Hemorrhagic
`
`the utility
`
`Gastroesophageal
`
`Reflux Disease
`
`Duodenal Ulcer
`
`Erosive Esophagitis
`
`Infections and Infestations
`
`Upper Respiratory Tract Infection
`
`with
`
`Bronchitis
`
`Urinary Tract Infection
`
`Sinusitis
`
`Nasopharyngitis
`
`2
`
`2
`
`2
`
`&1
`
`Musculoskeletal
`
`and Connective Tissue Disorders
`
`Arthralgia
`
`Nervous System Disorders
`
`Headache
`
`Dysgeusia
`
`Respiratory, Thoracic and Mediastinal Disorders
`
`Cough
`
`1
`
`3
`
`2
`
`2
`
`2
`
`1
`
`2
`
`2
`
`2
`
`1
`
`3
`
`discontinuations
`taking VIMOVO had fewer premature
`due to
`In Study 1 and Study 2, patients
`(7.9% vs 12.5%
`enteric-coated
`to patients
`alone
`reactions
`adverse
`naproxen
`compared
`taking
`respectively). The most common reasons for discontinuations
`due to adverse events in the VIMOVO
`pain (1.2%, n=5), duodenal
`ulcer (0.7%, n=3) and erosive
`group were upper abdominal
`treatment
`(0.7%, n=3). Among patients
`receiving enteric-coated naproxen,
`the most common reasons
`gastritis
`ulcer 5.4% (n=23), dyspepsia
`2.8%
`events were duodenal
`due to adverse
`for discontinuations
`pain 1.2% (n=5). The proportion
`treatment
`of patients discontinuing
`(n=12), and upper abdominal
`due to any upper gastrointestinal
`adverse events
`in patients treated with
`(including duodenal ulcers)
`VIMOVO was 4% compared to 12% for patients
`taking enteric-coated naproxen.
`of causality, occurring in &2% of patients
`regardless
`The table below lists all adverse reactions,
`of the knee (Study 3 and Study 4).
`2 clinical studies conducted in patients with osteoarthritis
`Table 2: Adverse Reactions Occurring in Patients &2% (Study 3 and Study 4)
`Placebo
`
`Preferred Term
`
`from
`
`(n=246)
`0/
`
`12
`
`4 3 1
`
`VIMOVO
`500 mg/20 mg twice daily
`(n =490)
`0/
`
`(sorted by SOC)
`
`Gastrointestinal Disorders
`
`Dyspepsia
`
`Diarrhea
`
`Abdominal
`
`Pain Upper
`
`Constipation
`
`Nausea
`
`Nervous System Disorders
`
`Dizziness
`
`Headache
`
`General Disorders
`and Administration
`
`Peripheral Edema
`
`Site Conditions
`
`Respiratory, Thoracic and Mediastinal Disorders
`
`Cough
`
`Infections and Infestations
`
`Sinusitis
`
`8
`
`6
`
`4
`
`4
`
`4
`
`3
`
`3
`
`3
`
`1
`
`'5.16 Clostridium difficile associated diarrhea
`that PPI therapy like VIMOVO may be associated with an
`studies
`observational
`Published
`suggest
`risk of C/ostridium difficile associated diarrhea,
`patients. This
`especially in hospitalized
`increased
`'iagnosis
`[see Adverse Reactions (6.2)].
`should be considered for diarrhea that does not
`improve
`to the condition
`should use the lowest dose and shortest duration of PPI therapy appropriate
`Patients
`being treated. [see Dosage and Administration
`(2)].
`5.17 Interaction with Clopidogrel
`is a prodrug.
`use of esomeprazole
`concomitant
`Inhibition
`clopidogrel. Clopidogrel
`Avoid
`due to an active metabolite. The metabolism of
`of platelet
`is entirely
`by clopidogrel
`aggregation
`such as
`by use with concomitant medications,
`to its active metabolite
`can be impaired
`clopidogrel
`40 mg
`inhibit CYP2C19 activity. Concomitant
`of
`use
`clopidogrel
`that
`esomeprazole,
`with
`esomeprazole,
`activity of clopidogrel. When using
`reduces
`a
`esomeprazole
`the pharmacological
`(7.16) and
`therapy [see Drug Interactions
`of VIMOVO, consider alternative
`anti-platelet
`, component
`(12.3)]
`I Pharmacokinetics
`,'5.18 Bone Fracture
`that proton pump inhibitor
`(PPI) therapy may be
`studies
`observational
`! Several published
`suggest
`'ssociated with an increased risk for osteoporosis-related
`fractures of the hip, wrist, or spine. The
`daily doses,
`defined as multiple
`risk of fracture was increased in patients who received high-dose,
`use the lowest dose and shortest
`(a year or longer). Patients
`should
`and long-term PPI therapy
`to the condition being treated. Patients at risk for osteoporosis-
`duration of PPI therapy appropriate
`[see Dosage
`should be managed according to the established treatment guidelines.
`, related fractures
`(2) and Adverse Reactions (6.2)].
`and Administration
`is approved for use twice a day and does not allow for admin-
`VIMOVO (a combination
`PPI/NSAID)
`istration of a lower daily dose of the PPI. [see Dosage and Administration
`(2)].
`5.19 Masking of Inflammation
`and Fever
`activity of VIMOVO in reducing fever and inflammation may diminish
`The pharmacological
`of presumed
`noninfectious,
`of these diagnostic
`noninflammatory
`signs in detecting complications
`painful conditions.
`5.20 Laboratory Tests
`and bleeding can occur without warning
`Because serious Gl tract ulcerations
`physicians
`symptoms,
`of Gl bleeding. Patients on long-term treatment with NSAIDs
`for signs or symptoms
`should monitor
`should have their CBC and a chemistry profile checked periodically.
`