`
`
` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`204592Orig1s000
`LABELING
`
`
`
`

`

`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. Blood pressure should be
`monitored closely during treatment with ZORVOLEX. (5.4)
` Fluid retention and edema. ZORVOLEX should be used with caution in
`patients with fluid retention or heart failure. (5.5)
` Renal papillary necrosis and other renal injury with long-term use.
`ZORVOLEX should be used 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)
`
`
`
`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 with a dose of ZORVOLEX 18 mg
`three times a day and if efficacy is not achieved, discontinue use. (2.3,
`12.3)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`Revised: 10/2013
`
`
`
`ADVERSE REACTIONS
`Most common adverse reactions in clinical trials (incidence ≥2% in
`ZORVOLEX 18 mg or 35 mg group) include, edema, nausea, headache,
`dizziness, vomiting, constipation, pruritus, flatulence, pain in extremity, 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)
`
`
`
`
`
`
`
`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 treatment of mild to moderate acute
`pain in adults. (1)
`
`
`DOSAGE AND ADMINISTRATION
` The dosage is 18 mg or 35 mg orally three times a day. (2.1)
` Use lowest effective dosage for shortest duration consistent with individual
`patient treatment goals. (2 1)
` ZORVOLEX capsules are not interchangeable with other formulations of
`oral diclofenac even if the milligram strength is the same. (2.2)
`
`
`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
`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
`
`
`
`Reference ID: 3392875
`
`

`

`8 
`
`10 
`11 
`12 
`
`13 
`
`14 
`16 
`17 
`
`7.3 
`7.4 
`7.5 
`7.6 
`7.7 
`7.8 
`
`11 
`ACE-inhibitors
`11 
`Diuretics
`12 
`Lithium
`12 
`Methotrexate
`12 
`Cyclosporine
`Inhibitors or Substrates of Cytochrome P450 2C9 Other
`12 
`Considerations
`12 
`USE IN SPECIFIC POPULATIONS
`8.1 
`12 
`Pregnancy
`8.2 
`13 
`Labor and Delivery
`8.3 
`13 
`Nursing Mothers
`8.4 
`13 
`Pediatric Use
`8.5 
`13 
`Geriatric Use
`14 
`OVERDOSAGE
`14 
`DESCRIPTION
`15 
`CLINICAL PHARMACOLOGY
`12.1 
`15 
`Mechanism of Action
`12.3 
`15 
`Pharmacokinetics
`17 
`NONCLINICAL TOXICOLOGY
`13.1 
`Carcinogenesis, Mutagenesis, and Impairment of
`Fertility
`CLINICAL STUDIES
`HOW SUPPLIED/STORAGE AND HANDLING
`PATIENT COUNSELING INFORMATION
`17.1 
`Cardiovascular Effects
`17.2 
`Gastrointestinal Effects
`17.3 
`Hepatotoxicity
`17.4 
`Adverse Skin Reactions
`17.5 
`Weight Gain and Edema
`17.6 
`Anaphylactoid Reactions
`17.7 
`Effects During Pregnancy
`
`17 
`18 
`19 
`19 
`20 
`20 
`20 
`20 
`20 
`20 
`21 
`
` *
`
` Sections or subsections omitted from the full prescribing
`information are not listed.
`
`3 
`3 
`3 
`3 
`
`3 
`
`3 
`4 
`4 
`4 
`4 
`
`5 
`5 
`6 
`7 
`7 
`7 
`7 
`8 
`8 
`8 
`8 
`8 
`8 
`9 
`9 
`11 
`11 
`11 
`
`1 
`2 
`
`3 
`4 
`5 
`
`2.3 
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: RISK OF SERIOUS CARDIOVASCULAR AND
`GASTROINTESTINAL EVENTS
`INDICATIONS AND USAGE
`DOSAGE AND ADMINISTRATION
`2.1 
`Initial Dosing
`2.2 
`Non-Interchangeability with Other Formulations of
`Diclofenac
`Dosage Adjustments in Patients with Hepatic
`Impairment
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
`5.1 
`Cardiovascular Thrombotic Events
`5.2 
`Gastrointestinal (GI) Effects – Risk of GI Ulceration,
`Bleeding, and Perforation
`5.3 
`Hepatic Effects
`5.4 
`Hypertension
`5.5 
`Congestive Heart Failure and Edema
`5.6 
`Renal Effects
`5.7 
`Anaphylactoid Reactions
`5.8 
`Adverse Skin Reactions
`5.9 
`Pregnancy
`5.10 
`Corticosteroid Treatment
`5.11 
`Masking of Inflammation and Fever
`5.12 
`Hematological Effects
`5.13 
`Use in Patients with Preexisting Asthma
`5.14 
`Monitoring
`ADVERSE REACTIONS
`6.1 
`Clinical Trials Experience
`DRUG INTERACTIONS
`7.1 
`Aspirin
`7.2 
`Anticoagulants
`
`6 
`
`7 
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3392875
`
`

`

`
`
`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
`
`ZORVOLEX is indicated for treatment of mild to moderate acute pain in adults.
`2
`DOSAGE AND ADMINISTRATION
`2.1
`Initial Dosing
`
`For treatment of mild to moderate acute pain, the dosage is 18 mg or 35 mg three times daily.
`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)].
`
`2.2 Non-Interchangeability with Other Formulations of Diclofenac
`
`ZORVOLEX (diclofenac) capsules do not result in an equivalent systemic exposure to
`diclofenac as other formulations of oral diclofenac. Other formulations contain a salt of
`diclofenac, i.e. diclofenac potassium or sodium, while ZORVOLEX contains the free acid.
`Therefore, do not substitute similar dosing strengths of other diclofenac products for
`ZORVOLEX.
`
`2.3 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
`
`
`
`Reference ID: 3392875
`
`

`

`
`
`diclofenac products, treatment should be started at the lowest dose. Start treatment with a
`dose of ZORVOLEX 18 mg three times a day and if efficacy is not achieved, discontinue
`use.
`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 the following:
`
` 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
`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
`
`
`
`Reference ID: 3392875
`
`

`

`
`
`an NSAID, such as diclofenac, does increase the risk of serious GI events [see Warnings and
`Precautions (5.2)].
`
`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.
`
`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.
`
`
`
`Reference ID: 3392875
`
`

`

`
`
`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
`"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, 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
`
`
`
`Reference ID: 3392875
`
`

`

`
`
`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
`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)].
`
`
`
`Reference ID: 3392875
`
`

`

`
`
`5.9 Pregnancy
`
`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 Treatment
`
`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. ZORVOLEX is not indicated for long-term treatment.
`
`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. Carefully monitor patients treated with ZORVOLEX who may be
`adversely affected by alterations in platelet function, such as those with coagulation disorders
`or patients receiving anticoagulants.
`
`5.13 Use in Patients with Preexisting 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, ZORVOLEX is contraindicated in patients with
`this form of aspirin sensitivity and should be used with caution in all patients with
`preexisting asthma [see Contraindications (4)].
`
`5.14 Monitoring
`
`Because serious GI tract ulcerations and bleeding can occur without warning symptoms,
`physicians should monitor for signs or symptoms of GI bleeding. For patients on long-term
`
`
`
`Reference ID: 3392875
`
`

`

`
`
`treatment with NSAIDs, periodically check a CBC and a chemistry profile including liver
`function tests. Discontinue ZORVOLEX if abnormal liver tests or renal tests persist or
`worsen. ZORVOLEX is not indicated for long-term treatment.
`6
`ADVERSE REACTIONS
`
`The following serious adverse reactions are discussed elsewhere in the labeling:
`
`• Cardiovascular thrombotic events [see Boxed Warning and Warnings and Precautions
`(5.1)]
`• Gastrointestinal effects [see Boxed Warning and Warnings and Precautions (5.2)]
`• Hepatic effects [see Warnings and Precautions (5.3)]
`• Hypertension [see Warnings and Precautions (5.4)]
`• Congestive heart failure and edema [see Warnings and Precautions (5.5)]
`• Renal effects [see Warnings and Precautions (5.6)]
`• Anaphylactoid reactions [see Warnings and Precautions (5.7)]
`• Serious skin reactions [see Warnings and Precautions (5.8)]
`
`6.1 Clinical Trials Experience
`
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`observed in the clinical trials of a drug cannot be directly compared to rates in the clinical
`trials of another drug and may not reflect the rates observed in clinical practice.
`
`Two-hundred sixteen (216) patients received ZORVOLEX in the completed, 48-hour,
`double-blind, placebo-controlled, clinical trial of acute pain following bunionectomy. The
`most frequent adverse reactions in this study are summarized below.
`
`
`
`
`
`
`
`Reference ID: 3392875
`
`

`

`
`
`Table 1
`
`Adverse Reactions
`
`Summary of Adverse Reactions (≥2% in ZORVOLEX 18 mg or
`35 mg group) – Phase 3 Study in Patients With Postsurgical Pain
`
`ZORVOLEX 18 mg or 35 mg
`three times daily*
`Placebo*
`N = 216
`N = 106
`33%
`32%
`Edema
`27%
`37%
`Nausea
`13%
`15%
`Headache
`10%
`16%
`Dizziness
`9%
`12%
`Vomiting
`8%
`4%
`Constipation
`7%
`6%
`Pruritus
`3%
`2%
`Flatulence
`3%
`1%
`Pain in Extremity
`2%
`1%
`Dyspepsia
`*One tablet of hydrocodone/acetaminophen 10 mg/325 mg was permitted every 4 to 6 hours as rescue
`medication for pain management. There was a greater use of concomitant opioid rescue medication
`in placebo-treated patients than in ZORVOLEX-treated patients. About 82% of patients in the
`ZORVOLEX 35 mg group, 85% of the patients in the ZORVOLEX 18 mg group, and 97% of
`patients in the placebo group took rescue medication for pain management during the study.
`
`Adverse reactions reported for diclofenac and other NSAIDs:
`
`In patients taking other NSAIDs, the most frequently reported adverse reactions occurring in
`approximately 1%-10% of patients are:
`
`Gastrointestinal experiences including: abdominal pain, constipation, diarrhea, dyspepsia,
`flatulence, gross bleeding/perforation, heartburn, nausea, GI ulcers (gastric/duodenal) and
`vomiting.
`
`Abnormal renal function, anemia, dizziness, edema, elevated liver enzymes, headaches,
`increased bleeding time, pruritus, rashes and tinnitus.
`
`Additional adverse reactions reported occasionally include:
`
`Body as a Whole: fever, infection, sepsis
`Cardiovascular System: congestive heart failure, hypertension, tachycardia, syncope
`Digestive System: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, gastrointestinal
`bleeding, glossitis, hematemesis, hepatitis, jaundice
`Hemic and Lymphatic System: ecchymosis, eosinophilia, leukopenia, melena, purpura,
`rectal bleeding, stomatitis, thrombocytopenia
`Metabolic and Nutritional: weight changes
`Nervous System: anxiety, asthenia, confusion, depression, dream abnormalities, drowsiness,
`insomnia, malaise, nervousness, paresthesia, somnolence, tremors, vertigo
`Respiratory System: asthma, dyspnea
`Skin and Appendages: alopecia, photosensitivity, sweating increased
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`Special Senses: blurred vision
`Urogenital System: cystitis, dysuria, hematuria, interstitial nephritis, oliguria/polyuria,
`proteinuria, renal failure
`
`Other adverse reactions, which occur rarely are:
`
`Body as a Whole: anaphylactic reactions, appetite changes, death
`Cardiovascular System: arrhythmia, hypotension, myocardial infarction, palpitations,
`vasculitis
`Digestive System: colitis, eructation, fulminant hepatitis with and without jaundice, liver
`failure, liver necrosis, pancreatitis
`Hemic and Lymphatic System: agranulocytosis, hemolytic anemia, aplastic anemia,
`lymphadenopathy, pancytopenia
`Metabolic and Nutritional: hyperglycemia
`Nervous System: convulsions, coma, hallucinations, meningitis
`Respiratory System: respiratory depression, pneumonia
`Skin and Appendages: angioedema, toxic epidermal necrolysis, erythema multiforme,
`exfoliative dermatitis, Stevens-Johnson syndrome, urticaria
`Special Senses: conjunctivitis, hearing impairment
`
` 7
`
`DRUG INTERACTIONS
`
`7.1 Aspirin
`
`When administered with aspirin, the protein binding of ZORVOLEX is reduced. The clinical
`significance of this interaction is not known; however, as with other NSAIDs, concomitant
`administration of ZORVOLEX and aspirin is not generally recommended because of the
`potential of increased GI adverse reactions [see Warnings and Precautions (5.2)].
`
`7.2 Anticoagulants
`
`The effects of anticoagulants, such as warfarin and NSAIDs on GI bleeding, are synergistic,
`such that users of both drugs together have a risk of serious GI bleeding higher than that with
`use of either drug alone [see Warnings and Precautions (5.2)].
`
`7.3 ACE-inhibitors
`
`NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE)
`inhibitors.
`
`This interaction should be given consideration in patients taking NSAIDs concomitantly with
`ACE-inhibitors.
`
`7.4 Diuretics
`
`Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce
`the natriuretic effect of furosemide and thiazides in some patients. This response has been
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`attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with
`ZORVOLEX and these diuretics, observe patients closely for signs of renal failure [see
`Warnings and Precautions (5.6)], as well as to assure diuretic efficacy.
`
`7.5 Lithium
`
`NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium
`clearance. The mean minimum lithium concentration increased 15% and the renal clearance
`was decreased by approximately 20%. These effects have been attributed to inhibition of
`renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are
`administered concurrently, observe patients carefully for signs of lithium toxicity.
`
`7.6 Methotrexate
`
`NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit
`kidney slices. This indicates that NSAIDs may enhance the toxicity of methotrexate. Use
`caution when NSAIDs are administered concomitantly with methotrexate.
`
`7.7 Cyclosporine
`
`NSAIDs may affect renal prostaglandins and increase the toxicity of cyclosporine.
`Therefore, concomitant therapy with NSAIDs may increase cyclosporine's nephrotoxicity.
`Use caution when NSAIDs are administered concomitantly with cyclosporine.
`
`7.8
`
`Inhibitors or Substrates of Cytochrome P450 2C9 Other
`Considerations
`
`Diclofenac is metabolized predominantly by cytochrome P450 2C9. Co-administration of
`diclofenac with another drug known to be metabolized by, or which inhibits, cytochrome
`P450 2C9 may unpredictably affect the pharmacokinetics of diclofenac or the co-
`administered drug. Caution should be used to evaluate each patient's medical history when
`consideration is given to prescribing diclofenac [see Clinical Pharmacology (12.3)].
`8
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`
`Pregnancy Category C prior to 30 weeks gestation;
`
`Category D starting at 30 weeks gestation.
`
`Risk Summary
`
`There are no adequate and well controlled studies of ZORVOLEX in pregnant women.
`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.
`ZORVOLEX can cause fetal harm when administered starting at 30 weeks gestation. If the
`drug is used during this time period in pregnancy, the patient should be apprised of the
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`potential hazard to the fetus. Prior to 30 weeks gestation, ZORVOLEX should be used
`during pregnancy only if the potential benefit justifies the potential r