`
`
`
`
`ZORVOLEX
`
`diclofenac
`
`
`
`
`
`Trade Name:
`
`
`Generic or
`Proper Name:
`
`Sponsor:
`
`Approval Date:
`
`Indication:
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`204592Orig1s002
`
`Iroko Pharmaceuticals LLC
`
`08/22/2014
`
`ZORVOLEX is an NSAID indicated for management of mild to
`moderate acute pain and osteoarthritis pain.
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`NDA 204592/S-002
`
`
`
`
`CONTENTS
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`
`x
`
`x
`
`x
`x
`
`x
`x
`x
`
`
`x
`
`
`x
`
`
`x
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`APPLICATION NUMBER:
`NDA 204592/S-002
`NDA 204592/S-002
`
`
`APPLICA TI0N NUMBER:
`
`APPROVAL LETTER
`APPROVAL LETTER
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`NDA 204592/S-002
`
`NDA 204592/S-004
`
`
`
`
`
`
`
`Food and Drug Administration
`
`Silver Spring MD 20993
`
`SUPPLEMENT APPROVAL
`
`
`Iroko Pharmaceuticals LLC
`One Kew Place
`150 Rouse Boulevard
`Philadelphia, PA 19112
`
`Attention:
`
`Paul M. Kirsch
`VP, Regulatory Affairs & Quality
`
`
`Please refer to your Supplemental New Drug Applications (sNDAs) dated and received October
`31, 2014, (S-002) and April 25, 2014, (S-004) submitted pursuant to section 505(b)(2) of the
`Federal Food, Drug, and Cosmetic Act (FDCA) for Zorvolex (diclofenac) capsules, 18 mg and
`35 mg.
`
`We acknowledge receipt of your amendments for S-002, dated December 27, 2013, and January
`29 and 31, and February 6, 2014.
`
`Reference is also made to your email dated August 21, 2014, which included the final agreed-
`upon labeling.
`
`These “Prior Approval” supplemental new drug applications propose the following:
`
`
`S-002: Addition of a new indication for the management of osteoarthritis pain.
`
`
`
`
`S-004: Changes to the medication guide, in response to our supplement request letter
`dated April 10, 2014.
`
`
`APPROVAL & LABELING
`
`We have completed our review of these supplemental applications, as amended. They are
`approved, effective on the date of this letter, for use as recommended in the enclosed, agreed-
`upon labeling text.
`
`WAIVER OF HIGHLIGHTS SECTION
`
`Please note that we have previously granted a waiver of the requirements of 21 CFR
`201.57(d)(8) regarding the length of Highlights of prescribing information.
`
`
`Reference ID: 3615072
`
`

`

`NDA 204592/S-002
`NDA 204592/S-004
`Page 2
`
`
`CONTENT OF LABELING
`
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
`automated drug registration and listing system (eLIST), as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`of labeling must be identical to the enclosed labeling (text for the package insert and Medication
`Guide), with the addition of any labeling changes in pending “Changes Being Effected” (CBE)
`supplements, as well as annual reportable changes not included in the enclosed labeling.
`
`Information on submitting SPL files using eList may be found in the guidance for industry titled
`“SPL Standard for Content of Labeling Technical Qs and As at
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf
`
`
`The SPL will be accessible from publicly available labeling repositories.
`
`
`Also within 14 days, amend all pending supplemental applications that includes labeling changes
`for this NDA, including CBE supplements for which FDA has not yet issued an action letter,
`with the content of labeling [21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the
`changes approved in this supplemental application, as well as annual reportable changes and
`annotate each change. To facilitate review of your submission, provide a highlighted or marked-
`up copy that shows all changes, as well as a clean Microsoft Word version. The marked-up copy
`should provide appropriate annotations, including supplement number(s) and annual report
`date(s).
`
`MARKET PACKAGE
`
`
`Please submit one market package of the drug product when it is available to the following
`address:
`
`
`Swati Patwardhan
`
`Food and Drug Administration
`
`Center for Drug Evaluation and Research
`
`White Oak Building 22, Room: 3170
`
`10903 New Hampshire Avenue
`
`Silver Spring, MD
`
`Use zip code 20903 if shipping via United States Postal Service (USPS).
`
`Use zip code 20993 if sending via any carrier other than USPS (e.g., UPS, DHL, FedEx).
`
`
`
`
`
`Reference ID: 3615072
`
`

`

`
`
`NDA 204592/S-002
`NDA 204592/S-004
`Page 3
`
`
` REQUIRED PEDIATRIC ASSESSMENTS
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
`active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
`administration are required to contain an assessment of the safety and effectiveness of the
`product for the claimed indication(s) in pediatric patients unless this requirement is waived,
`deferred, or inapplicable.
`
`We are waiving the pediatric study requirement for this application because necessary studies are
`impossible or highly impracticable due to the extremely limited incidence of osteoarthritis in the
`pediatric population.
`
`
`PROMOTIONAL MATERIALS
`
`You may request advisory comments on proposed introductory advertising and promotional
`labeling. To do so, submit the following, in triplicate, (1) a cover letter requesting advisory
`comments, (2) the proposed materials in draft or mock-up form with annotated references, and
`(3) the package insert(s) to:
`
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion (OPDP)
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`You must submit final promotional materials and package insert(s), accompanied by a Form
`
`FDA 2253, at the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. Form
`
`FDA 2253 is available at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.
`Information and Instructions for completing the form can be found at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. For
`more information about submission of promotional materials to the Office of Prescription Drug
`Promotion (OPDP), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`All promotional materials that include representations about your drug product must be promptly
`revised to be consistent with the labeling changes approved in this supplement, including any
`new safety information [21 CFR 314.70(a)(4)]. The revisions in your promotional materials
`should include prominent disclosure of the important new safety information that appears in the
`revised package labeling. Within 7 days of receipt of this letter, submit your statement of intent
`to comply with 21 CFR 314.70(a)(4) to the address above or by fax to 301-847-8444.
`
`
`REPORTING REQUIREMENTS
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`Reference ID: 3615072
`
`

`

`
`
`Sincerely,
`
` {See appended electronic signature page}
`
`Sharon Hertz, MD
`Deputy Director
`Division of Anesthesia, Analgesia,
`and Addiction Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
`
`NDA 204592/S-002
`NDA 204592/S-004
`Page 4
`
`
`
`If you have any questions, call Swati Patwardhan, Regulatory Project Manager, at (301) 796-
`4085.
`
`
`
`ENCLOSURE:
`Content of Labeling
`
`
`Reference ID: 3615072
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SHARON H HERTZ
`08/22/2014
`
`Reference ID: 3615072
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`APPLICATION NUMBER:
`NDA 204592/S-002
`NDA 204592/S-002
`
`
`APPLICA TI0N NUMBER:
`
`
`LABELING
`LABELING
`
`
`
`
`
`
`
`

`

`factors for CV disease may be at greater risk. Use the lowest effective dose
`for the shortest duration possible. (5.1)
`
` Serious gastrointestinal (GI) adverse events including bleeding, ulceration,
`
`and perforation, which can be fatal. Prescribe ZORVOLEX with caution in
`
`
`patients with a prior history of ulcer disease or GI bleeding. Use the lowest
`
`effective dose for the shortest duration possible. (5.2)
`
` Elevation of one or more liver tests and severe hepatic reactions. Measure
`
`transaminases (ALT and AST) periodically in patients receiving long-term
`
`
`therapy with ZORVOLEX. Discontinue ZORVOLEX immediately if
`abnormal liver tests persist or worsen. (5.3)
`
`
` New onset or worsening of hypertension. Monitor blood pressure closely
`
`
`during treatment with ZORVOLEX. (5.4)
`
`
` Fluid retention and edema. Use ZORVOLEX with caution in patients with
`fluid retention or heart failure. (5.5)
`
` Renal papillary necrosis and other renal injury with long-term use. Use
`
`ZORVOLEX with caution in patients at greatest risk of this reaction,
`including the elderly, those with impaired renal function, heart failure, liver
`dysfunction, and those taking diuretics and ACE inhibitors. (5.6)
`
` Anaphylactoid reactions in patients with the aspirin triad or in patients
`without prior exposure to ZORVOLEX. Discontinue immediately if an
`anaphylactoid reaction occurs. (5.7)
`
` Serious skin adverse events such as exfoliative dermatitis, Stevens -
`Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can
`be fatal. Discontinue ZORVOLEX if rash or other signs of local skin
`reaction occur. (5.8)
`
`
`
`ADVERSE REACTIONS
`
`Most common adverse reactions in controlled clinical trials (incidence ≥2% in
`
`ZORVOLEX 18 mg or 35 mg group) include, edema, nausea, headache,
`
`
`dizziness, vomiting, constipation, pruritus, diarrhea, flatulence, pain in
`extremity, abdominal pain, sinusitis, alanine aminotransferase increased, blood
`creatinine increased, hypertension, and dyspepsia. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Iroko
`
`Pharmaceuticals, LLC at 1-877-757-0676 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`
`
`
`DRUG INTERACTIONS
`
`
` Concomitant use of ZORVOLEX and aspirin is not generally
`
`recommended because of the potential of increased adverse effects
`including increased GI bleeding. (7.1)
`
` Concomitant use of ZORVOLEX and anticoagulants have a risk of serious
`
`GI bleeding higher than users of either drug alone. (7.2)
`
`
`USE IN SPECIFIC POPULATIONS
`
`
` Pregnancy: Based on animal data, may cause fetal harm. Starting at
`30 weeks gestation, ZORVOLEX should be avoided as premature closure
`of the ductus arteriosus in the fetus may occur. (5.9, 8.1)
`
` Nursing Mothers: Based on available data, diclofenac may be present in
`
`human milk. Exercise caution when ZORVOLEX is administered to a
`
`nursing woman. (8.3)
`
`
` Hepatic insufficiency: Patients with hepatic disease may require reduced
`
`doses of ZORVOLEX. Start treatment at the lowest dose. Discontinue use
`if efficacy is not achieved with the lowest dose. (2.2, 12.3)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`Guide.
`
`Revised: 08/2014
`
`
`
`
`
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use
`ZORVOLEX® safely and effectively. See full prescribing information for
`
`
`ZORVOLEX.
`
`
`
`ZORVOLEX (diclofenac) capsules, for oral use
`
`Initial U.S. Approval: 1988
`
`
`
`
`
`WARNING: RISK OF SERIOUS CARDIOVASCULAR AND
`
`GASTROINTESTINAL EVENTS
`
`See full prescribing information for complete boxed warning.
`
`Cardiovascular Risk
`
`
`• Nonsteroidal anti-inflammatory drugs (NSAIDs) may cause an
`
`
`increased risk of serious cardiovascular thrombotic events, myocardial
`infarction, and stroke, which can be fatal. This risk may increase with
`
`
`duration of use. Patients with cardiovascular disease or risk factors
`
`
`for cardiovascular disease may be at greater risk. (5.1)
`
`• ZORVOLEX is contraindicated for the treatment of perioperative
`pain in the setting of coronary artery bypass graft (CABG) surgery. (4)
`Gastrointestinal Risk
`
`• NSAIDs cause an increased risk of serious gastrointestinal adverse
`
`
`events including bleeding, ulceration, and perforation of the stomach
`or intestines, which can be fatal. These events can occur at any time
`
`
`during use and without warning symptoms. Elderly patients are at
`
`
`greater risk for serious gastrointestinal events. (5.2)
`
`
`
`
`
`
`
`
`INDICATIONS AND USAGE
`
`
`ZORVOLEX is an NSAID indicated for management of mild to moderate acute
`pain and osteoarthritis pain. (1)
`
`
`DOSAGE AND ADMINISTRATION
`
`
`
` The dosage for acute pain is 18 mg or 35 mg orally three times a day. (1.2)
`
`
` The dosage for osteoarthritis pain is 35 mg orally three times a day. (1.2)
`
` Use lowest effective dosage for shortest duration consistent with individual
`patient treatment goals. (1.2)
`
` ZORVOLEX capsules are not interchangeable with other formulations of
`oral diclofenac even if the milligram strength is the same. (2.3)
`
`RECENT MAJOR CHANGES
`
`
`Indications and Usage, Osteoarthritis Pain (1 2)
`
`
`
`
`
`8/2014
`
`
`DOSAGE FORMS AND STRENGTHS
`
`
`Capsules: 18 mg or 35 mg (3)
`
`
`CONTRAINDICATIONS
`
`
` Known hypersensitivity to diclofenac or any components of the drug
`product. (4)
`
` History of asthma, urticaria, or other allergic-type reactions after taking
`
`
`aspirin or other NSAIDs. (4)
`
` Perioperative pain in the setting of coronary artery bypass graft (CABG)
`surgery. (4)
`
`
`
`WARNINGS AND PRECAUTIONS
`
`
` Serious and potentially fatal cardiovascular (CV) thrombotic events,
`
`myocardial infarction, and stroke. Patients with known CV disease or risk
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3615450
`
`

`

` 
` 
`Clinical Trials Experience
`
`6.1
` 
`DRUG INTERACTIONS
` 
` 
`7.1
`Aspirin
`
` 
` 
`7.2
`Anticoagulants
`
` 
` 
`7.3
`ACE-inhibitors
`
` 
` 
`7.4
`Diuretics
`
` 
` 
`7.5
`Lithium
`
` 
` 
`7.6
`Methotrexate
`
` 
` 
`7.7
`Cyclosporine
`
` 
`7.8
`Inhibitors or Substrates of Cytochrome P450 2C9 Other
`
`
` 
`Considerations
`
` 
`USE IN SPECIFIC POPULATIONS
` 
` 
`8.1
`Pregnancy
`
` 
` 
`8.2
`Labor and Delivery
`
` 
` 
`8.3
`Nursing Mothers
`
` 
` 
`8.4
`Pediatric Use
`
` 
` 
`8.5
`Geriatric Use
`
` 
`OVERDOSAGE
` 
`DESCRIPTION
` 
`CLINICAL PHARMACOLOGY
` 
` 
`12.1
`Mechanism of Action
`
` 
` 
`12.3
`Pharmacokinetics
`
` 
`NONCLINICAL TOXICOLOGY
` 
`Carcinogenesis, Mutagenesis, and Impairment of
`
`13.1
` 
`Fertility
`
` 
`CLINICAL STUDIES
` 
`HOW SUPPLIED/STORAGE AND HANDLING
` 
`PATIENT COUNSELING INFORMATION
`
` 
`7
`
` 
`8
`
` 
`10
` 
`11
` 
`12
`
` 
`13
`
` 
`14
` 
`16
` 
`17
`
`
`
` * Sections or subsections omitted from the full prescribing
`information are not listed.
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
` 
`1
`
` 
`2
`
` 
`2.3
`
` WARNING: RISK OF SERIOUS CARDIOVASCULAR AND
`
` 
`GASTROINTESTINAL EVENTS
` 
`INDICATIONS AND USAGE
` 
` 
`1.1
`Acute Pain
`
` 
` 
`1.2
`Osteoarthritis Pain
`
` 
`DOSAGE AND ADMINISTRATION
`
` 
` 
`Initial Dosing
`
`2.1
` 
`2.2
`Dosage Adjustments in Patients with Hepatic
`
` 
`Impairment
`
`Non-Interchangeability with Other Formulations of
`
` 
`Diclofenac
`
` 
`DOSAGE FORMS AND STRENGTHS
` 
`CONTRAINDICATIONS
` 
`WARNINGS AND PRECAUTIONS
` 
` 
`Cardiovascular Thrombotic Events
`
`5.1
` 
`5.2
`Gastrointestinal (GI) Effects – Risk of GI Ulceration,
`
` 
`Bleeding, and Perforation
`
` 
` 
`Hepatic Effects
`
`5.3
` 
` 
`Hypertension
`
`5.4
` 
` 
`Congestive Heart Failure and Edema
`
`5.5
` 
` 
`Renal Effects
`
`5.6
` 
` 
`Anaphylactoid Reactions
`
`5.7
` 
` 
`Adverse Skin Reactions
`
`5.8
` 
` 
`Fetal Toxicity
`
`5.9
` 
` 
`Corticosteroid-Responsive Illness
`
`5.10
` 
` 
`Masking of Inflammation and Fever
`
`5.11
` 
` 
`Hematological Effects
`
`5.12
` 
` 
`Use in Patients with Preexisting Asthma
`
`5.13
` 
` 
`Monitoring
`
`5.14
` 
`ADVERSE REACTIONS
`
` 
`3
` 
`4
` 
`5
`
` 
`6
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3615450
`
`
`
`

`

`
`
`FULL PRESCRIBING INFORMATION
`
`
`WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL
`EVENTS
`
`Cardiovascular Risk
`
`• NSAIDs may cause an increased risk of serious cardiovascular thrombotic events,
`myocardial infarction, and stroke, which can be fatal. This risk may increase with
`duration of use. Patients with cardiovascular disease or risk factors for
`cardiovascular disease may be at greater risk. [see Warnings and Precautions (5.1)]
`
`• ZORVOLEX is contraindicated for the treatment of perioperative pain in the
`setting of coronary artery bypass graft (CABG) surgery. [see Contraindications (4)]
` Gastrointestinal Risk
`
`
`• NSAIDs cause an increased risk of serious gastrointestinal adverse events including
`bleeding, ulceration, and perforation of the stomach or intestines, which can be
`fatal. These events can occur at any time during use and without warning
`symptoms. Elderly patients are at greater risk for serious gastrointestinal events.
`[see Warnings and Precautions (5.2)]
`
`
`INDICATIONS AND USAGE
`1
`
` 1.1 Acute Pain
`
`ZORVOLEX is indicated for management of mild to moderate acute pain.
`1.2 Osteoarthritis Pain
`
`
`ZORVOLEX is indicated for management of osteoarthritis pain.
`2
`DOSAGE AND ADMINISTRATION
`2.1
`Initial Dosing
`
`The effectiveness of ZORVOLEX when taken with food has not been studied in clinical
`studies. Taking ZORVOLEX with food may cause a reduction in effectiveness compared to
`
` taking ZORVOLEX on an empty stomach [see Clinical Pharmacology (12.3)]. Use the
`lowest effective dose for the shortest duration consistent with individual patient treatment
`goals [see Warnings and Precautions (5.1, 5.2)].
`
`
`Acute Pain
`For management of mild to moderate acute pain, the dosage is 18 mg or 35 mg orally three
`
`times daily.
`
`Osteoarthritis Pain
`For management of osteoarthritis pain, the dosage is 35 mg orally three times daily.
`
`
`
`Reference ID: 3615450
`
`

`

`
`
`2.2 Dosage Adjustments in Patients with Hepatic Impairment
`
`Patients with hepatic disease may require reduced doses of ZORVOLEX compared to
`
` patients with normal hepatic function [see Clinical Pharmacology (12.3)]. As with other
`diclofenac products, start treatment at the lowest dose. If efficacy is not achieved with the
`lowest dose, discontinue use.
`
` 2.3 Non-Interchangeability with Other Formulations of Diclofenac
`
`
`
`ZORVOLEX capsules are not interchangeable with other formulations of oral diclofenac
`even if the milligram strength is the same. ZORVOLEX capsules contain diclofenac free acid
`whereas other diclofenac products contain a salt of diclofenac, i.e., diclofenac potassium or
`sodium. A 35 mg dose of ZORVOLEX is approximately equal to 37.6 mg of sodium
`diclofenac or 39.5 mg of potassium diclofenac. Therefore, do not substitute similar dosing
`strengths of other diclofenac products without taking this into consideration.
`3
`DOSAGE FORMS AND STRENGTHS
`
`ZORVOLEX (diclofenac) capsules 18 mg - blue body and light green cap (imprinted IP-203
`on the body and 18 mg on the cap in white ink).
`
`ZORVOLEX (diclofenac) capsules 35 mg - blue body and green cap (imprinted IP-204 on
`the body and 35 mg on the cap in white ink).
`4
`CONTRAINDICATIONS
`
`ZORVOLEX is contraindicated in patients with:
`
`
` known hypersensitivity (e.g., anaphylactoid reactions and serious skin reactions) to
`diclofenac or any components of the drug product [see Warnings and Precautions
`
` (5.7, 5.8)].
`
`
` a history of asthma, urticaria, or other 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 (5.7, 5.13)].
`
`
` perioperative pain 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 studies 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
`
`
`
`Reference ID: 3615450
`
`

`

`
`
`CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in
`patients treated with an NSAID, use the lowest effective dose 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. Inform patients about the signs and/or
`symptoms of serious CV events and the steps to take if they occur.
`
`Two large, controlled, clinical studies 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)].
`
`
`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 diclofenac, does increase the risk of serious GI events [see Warnings and
`Precautions (5.2), Drug Interactions (7.1)].
`5.2 Gastrointestinal (GI) Effects – Risk of GI Ulceration, Bleeding, and
`Perforation
`
`NSAIDs, including ZORVOLEX, can cause serious gastrointestinal (GI) adverse events
`including inflammation, bleeding, ulceration, and perforation of the 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 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
`NSAID therapy is not without risk.
`
`Prescribe NSAIDs, including ZORVOLEX, with extreme caution in patients 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 for 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, 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, use
`the lowest effective dose 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, alternative therapies that do not include NSAIDs
`should be considered.
`
`
`
`Reference ID: 3615450
`
`

`

`
`
`5.3 Hepatic Effects
`
`Elevations of one or more liver tests may occur during therapy with ZORVOLEX. These
`laboratory abnormalities may progress, may remain unchanged, or may be transient with
`continued therapy. Borderline elevations (greater than the upper limit of normal [ULN] to
`3 times the ULN range) of transaminases have been observed in approximately 15% of
`diclofenac-treated patients. Of the markers of hepatic function, ALT (SGPT) is
`recommended for the monitoring of liver injury.
`
`
`In clinical trials of diclofenac-containing products, meaningful elevations (i.e., more than
`3 times the ULN) of AST (SGOT) (ALT was not measured in all studies) were observed in
`about 2% of approximately 5,700 patients at some time during diclofenac treatment.
`
`In a large, open-label, controlled diclofenac sodium trial of 3,700 patients treated for
`2-6 months, patients were monitored first at 8 weeks and 1,200 patients were monitored
`again at 24 weeks. Meaningful elevations of ALT and/or AST occurred in about 4% of
`patients and included marked elevations (greater than 8 times the ULN) in about 1% of the
`3,700 patients. In that open-label study, a higher incidence of borderline (less than 3 times
`the ULN), moderate (3-8 times the ULN), and marked (greater than 8 times the ULN)
`elevations of ALT or AST was observed in patients receiving diclofenac when compared to
`other NSAIDs. Elevations in transaminases were seen more frequently in patients with
`osteoarthritis than in those with rheumatoid arthritis.
`
`
`Almost all meaningful elevations in transaminases were detected before patients became
`
`symptomatic. Abnormal tests occurred during the first 2 months of therapy with diclofenac
`in 42 of the 51 patients in all trials who developed marked transaminase elevations.
`
`In postmarketing reports, cases of drug-induced hepatotoxicity have been reported in the first
`month, and in some cases, the first 2 months of therapy, but can occur at any time during
`treatment with diclofenac. Postmarketing surveillance has reported cases of severe hepatic
`reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice,
`and liver failure. Some of these reported cases resulted in fatalities or liver transplantation.
`
`Physicians should measure transaminases periodically in patients receiving long-term therapy
`with ZORVOLEX, because severe hepatotoxicity may develop without a prodrome of
`distinguishing symptoms. The optimum times for making the first and subsequent
`transaminase measurements are not known. Based on clinical trial data and postmarketing
`experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment
`with diclofenac. However, severe hepatic reactions can occur at any time during treatment
`with diclofenac. If abnormal liver tests persist or worsen, if clinical signs and/or symptoms
`
`consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia,
`rash, abdominal pain, diarrhea, dark urine, etc.), discontinue ZORVOLEX immediately.
`
`To minimize the possibility that hepatic injury will become severe between transaminase
`measurements, inform patients of the warning signs and symptoms of hepatotoxicity (e.g.,
`nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and
`
`
`
`Reference ID: 3615450
`
`

`

`
`
`"flulike" symptoms), and the appropriate action patients should take if these signs and
`symptoms appear.
`
`To minimize the potential risk for an adverse liver related event in patients treated with
`ZORVOLEX, use the lowest effective dose for the shortest duration possible. Exercise
`caution when prescribing ZORVOLEX with concomitant drugs that are known to be
`potentially hepatotoxic (e.g., acetaminophen, certain antibiotics, and anti-epileptics).
`
`5.4 Hypertension
`
`NSAIDs, including ZORVOLEX, can lead to new onset or worsening of pre-existing
`hypertension, either of which may contribute to the increased incidence of CV events. Use
`NSAIDs, including ZORVOLEX, with caution in patients with hypertension. Monitor blood
`pressure (BP) closely during the initiation of NSAID treatment and throughout the course of
`therapy.
`
`Patients taking ACE inhibitors, thiazides or loop diuretics may have impaired response to
`these therapies when taking NSAIDs.
`5.5 Congestive Heart Failure and Edema
`
`Fluid retention and edema have been observed in some patients taking NSAIDs. Use
`
`ZORVOLEX with caution in patients with fluid retention or heart failure.
`5.6 Renal Effects
`
`Use caution when initiating treatment with ZORVOLEX in patients with considerable
`dehydration.
`
`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, heart failure, liver
`dysfunction, those taking diuretics and ACE inhibitors, 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
`ZORVOLEX in patients with advanced renal disease. Therefore, treatment with
`ZORVOLEX is not recommended in patients with advanced renal disease. If ZORVOLEX
`therapy must be initiated, monitor the patient's renal function closely.
`
` 5.7 Anaphylactoid Reactions
`
`As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior
`exposure to ZORVOLEX. ZORVOLEX is contraindicated in patients with the aspirin triad.
`This symptom complex typically occurs in asthmatic patients who experience rhinitis with or
`
`
`
`Reference ID: 3615450
`
`

`

`
`
`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 anaphylactoid reaction occurs.
`5.8 Adverse Skin Reactions
`
`NSAIDs, including ZORVOLEX, can cause serious skin adverse reactions such as
`exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis
`(TEN), which can be fatal. These serious events may occur without warning. Patients
`should be informed about the signs and symptoms of serious skin manifestations, and to
`discontinue ZORVOLEX at the first appearance of skin rash or any other sign of
`hypersensitivity [see Contraindications (4)].
`
`
`5.9 Fetal Toxicity
`
`Starting at 30 weeks gestation, ZORVOLEX and other NSAIDs, should be avoided by
`pregnant women as premature closure of the ductus arteriosus in the fetus may occur. If this
`drug is used during this time period in pregnancy, the patient should be apprised of the
`potential hazard to a fetus [see Use in Specific Populations (8.1)].
`
`5.10 Corticosteroid-Responsive Illness
`
`ZORVOLEX cannot be expected to substitute for corticosteroids or to treat corticosteroid
`insufficiency. Abrupt discontinuation of corticosteroids may lead to exacerbation of
`corticosteroid-responsive illness. Patients on prolonged corticosteroid therapy should have
`
`their therapy tapered slowly if a decision is made to discontinue corticosteroids.
`5.11 Masking of Inflammation and Fever
`
`The pharmacological activity of ZORVOLEX in reducing inflammation, and possibly fever,
`may diminish the utility of diagnostic signs in detecting infectious complications of
`presumed noninfectious, painful conditions.
`5.12 Hematological Effects
`
`Anemia may occur in patients receiving NSAIDs, including ZORVOLEX. This may be due
`to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon
`erythropoiesis. In patients on long-term therapy with NSAIDs, including ZORVOLEX,
`
`check hemoglobin or hematocrit if they exhibit any signs or symptoms of anemia or blood
`loss.
`
`NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding tim