` Heart Failure and Edema: Avoid use of ZORVOLEX in patients with
`
`severe heart failure unless benefits are expected to outweigh risk of
`
`worsening heart failure (5.5)
`
` Renal Toxicity: Monitor renal function in patients with renal or hepatic
`impairment, heart failure, dehydration, or hypovolemia. Avoid use of
`ZORVOLEX in patients with advanced renal disease unless benefits are
`expected to outweigh risk of worsening renal function (5.6)
`
` Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction
`occurs (5.7)
`
` Exacerbation of Asthma Related to Aspirin Sensitivity: ZORVOLEX is
`contraindicated in patients with aspirin-sensitive asthma. Monitor patients
`with preexisting asthma (without aspirin sensitivity) (5.8)
`
` Serious Skin Reactions: Discontinue ZORVOLEX at first appearance of
`
`skin rash or other signs of hypersensitivity (5.9)
`
` Premature Closure of Fetal Ductus Arteriosus: Avoid use in pregnant
`women starting at 30 weeks gestation (5.10, 8.1)
`
`
` Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with
`any signs or symptoms of anemia (5.11, 7)
`
`
`
`ADVERSE REACTIONS
`
`Most common adverse reactions (incidence ≥2%) are 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
`
`
` Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs):
`
`
`Monitor patients for bleeding who are concomitantly taking ZORVOLEX
`with drugs that interfere with hemostasis. Concomitant use of ZORVOLEX
`and analgesic doses of aspirin is not generally recommended (7)
`
` ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers:
`
`Concomitant use with ZORVOLEX may diminish the antihypertensive
`effect of these drugs. Monitor blood pressure (7)
`
` ACE Inhibitors and ARBs: Concomitant use with ZORVOLEX in elderly,
`volume depleted, or those with renal impairment may result in deterioration
`of renal function. In such high risk patients, monitor for signs of worsening
`
`
`
`renal function (7)
`
` Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide
`
`diuretics. Monitor patients to assure diuretic efficacy including
`antihypertensive effects (7)
`
` Digoxin: Concomitant use with ZORVOLEX can increase serum
`
`
`concentration and prolong half-life of digoxin. Monitor serum digoxin
`
`levels (7)
`
`
`USE IN SPECIFIC POPULATIONS
`
`Pregnancy: Use of NSAIDs during the third trimester of pregnancy increases
`the risk of premature closure of the fetal ductus arteriosus. Avoid use of
`NSAIDs in pregnant women starting at 30 weeks gestation (5.10, 8.1)
`Infertility: NSAIDs are associated with reversible infertility. Consider
`withdrawal of ZORVOLEX in women who have difficulties conceiving (8.3)
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`Guide.
`
`
`
`Revised 5/2016
`
`
`
`
`
`
`
`
`
`
`
`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.
`
`
` Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased
`
`risk of serious cardiovascular thrombotic events, including myocardial
`
`
`infarction and stroke, which can be fatal. This risk may occur early in
`treatment and may increase with duration of use (5.1)
`
` ZORVOLEX is contraindicated in the setting of coronary artery
`
`bypass graft (CABG) surgery (4, 5.1)
`
`
` NSAIDs cause an increased risk of serious gastrointestinal (GI)
`adverse events including bleeding, ulceration, and perforation of the
`
`stomach or intestines, which can be fatal. These events can occur at
`any time during use and without warning symptoms. Elderly patients
`
`
`and patients with a prior history of peptic ulcer disease and/or GI
`
`bleeding are at greater risk for serious GI events (5.2)
`
`
` RECENT MAJOR CHANGES
`
`5/2016
`Boxed Warning
`
`
`
`
`
`
`
`
`
`
`
`Warnings and Precautions, Cardiovascular Thrombotic Events (5.1) 5/2016
`Warnings and Precautions, Heart Failure and Edema (5.5)
` 5/2016
`
`
`
`
`
`
`INDICATIONS AND USAGE
`ZORVOLEX is a nonsteroidal anti-inflammatory drug indicated for
`
`
` management of mild to moderate acute pain (1)
`
` management of osteoarthritis pain.(1)
`
`DOSAGE AND ADMINISTRATION
`
`
`
` Use the lowest effective dosage for shortest duration consistent with
`individual patient treatment goals. (2)
`
` The dosage for acute pain is 18 mg or 35 mg orally three times a day. (2)
`
`
` The dosage for osteoarthritis pain is 35 mg orally three times a day. (2)
`
`DOSAGE FORMS AND STRENGTHS
`
`
`ZORVOLEX (diclofenac) capsules: 18 mg and 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)
`
` In the setting of CABG surgery (4)
`
`
`
`WARNINGS AND PRECAUTIONS
`
` Hepatotoxicity: Inform patients of warning signs and symptoms of
`hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if
`clinical signs and symptoms of liver disease develop (5.3)
`
`
` Hypertension: Patients taking some antihypertensive medications may have
`impaired response to these therapies when taking NSAIDs. Monitor blood
`pressure (5.4, 7)
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3928107
`
`

`

` 
` 
`Masking of Inflammation and Fever
`5.12
` 
` 
`Laboratory Monitoring
`5.13
` 
`ADVERSE REACTIONS
` 
` 
`Clinical Trials Experience
`6.1
` 
`DRUG INTERACTIONS
` 
`USE IN SPECIFIC POPULATIONS
` 
` 
`8.1
`Pregnancy
` 
` 
`8.2
`Lactation
` 
` 
`8.3
`Females and Males of Reproductive Potential
` 
` 
`8.4
`Pediatric Use
` 
` 
`8.5
`Geriatric Use
` 
`OVERDOSAGE
` 
`DESCRIPTION
` 
`CLINICAL PHARMACOLOGY
` 
` 
`12.1
`Mechanism of Action
` 
` 
`12.3
`Pharmacokinetics
` 
`NONCLINICAL TOXICOLOGY
` 
` 
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.1
` 
`CLINICAL STUDIES
` 
`HOW SUPPLIED/STORAGE AND HANDLING
` 
`PATIENT COUNSELING INFORMATION
`
` 
`6
`
` 
`7
` 
`8
`
` 
`10
` 
`11
` 
`12
`
` 
`13
`
` 
`14
` 
`16
` 
`17
`
`
`
` * Sections or subsections omitted from the full prescribing
`information are not listed.
`
` 
`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
`
` 
` 
`General Dosing Instructions
`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 Bleeding, Ulceration, and Perforation
` 
` 
`5.3
`Hepatotoxicity
` 
` 
`5.4
`Hypertension
` 
` 
`5.5
`Heart Failure and Edema
` 
` 
`5.6
`Renal Toxicity and Hyperkalemia
`
` 
` 
`5.7
`Anaphylactic Reactions
` 
` 
`5.8
`Exacerbation of Asthma Related to Aspirin Sensitivity
` 
` 
`5.9
`Serious Skin Reactions
` 
` 
`5.10
`Premature Closure of Fetal Ductus Arteriosus
` 
` 
`5.11
`Hematologic Toxicity
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3928107
`
`
`
`

`

`
`
`FULL PRESCRIBING INFORMATION
`WARNING: RISK OF SERIOUS CARDIOVASCULAR AND
`GASTROINTESTINAL EVENTS
`Cardiovascular Thrombotic Events
`
`• Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious
`
`
`cardiovascular thrombotic events, including myocardial infarction and stroke,
`
`
`which can be fatal. This risk may occur early in treatment and may increase with
`
`duration of use [see Warnings and Precautions (5.1)].
`
`
`• ZORVOLEX is contraindicated in the setting of coronary artery bypass graft
`
`(CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.1)].
`
`
`
`Gastrointestinal Bleeding, Ulceration, and Perforation
`
`• NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events
`
`including bleeding, ulceration, and perforation of the stomach or intestines, which
`
`
`can be fatal. These events can occur at any time during use and without warning
`symptoms. Elderly patients and patients with a prior history of peptic ulcer disease
`and/or GI bleeding are at greater risk for serious GI events [see Warnings and
`
`Precautions (5.2)].
`
`
`
`
`INDICATIONS AND USAGE
`1
`ZORVOLEX is indicated for:
`
`• Management of mild to moderate acute pain
`
`
`• Management of osteoarthritis pain
`
`
`2 DOSAGE AND ADMINISTRATION
`
` 2.1 General Dosing Instructions
`
`Carefully consider the potential benefits and risks of ZORVOLEX and other treatment
`
`options before deciding to use ZORVOLEX. Use the lowest effective dosage for the shortest
`duration consistent with individual patient treatment goals [see Warnings and Precautions
`
`
`
`(5)].
`
`
`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)].
`
`
`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: 3928107
`
`

`

`
`
`
`
`
` Dosage Adjustments in Patients with Hepatic Impairment
`2.2
`
`
`
`
` Patients with hepatic disease may require reduced doses of ZORVOLEX compared to
` patients with normal hepatic function [see Clinical Pharmacology (12)]. As with other
`
`
` diclofenac products, start treatment at the lowest dose. If efficacy is not achieved with the
`
` lowest dose, discontinue use.
`
`Non-Interchangeability with Other Formulations of Diclofenac
`2.3
`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 the following patients:
`
`
`
` Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to
`diclofenac or any components of the drug product [see Warnings and Precautions (5.7,
`5.9)]
`
`
` History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other
`
`NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported
`in such patients [see Warnings and Precautions (5.7, 5.8)]
`
`In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and
`Precautions (5.1)]
`
`
`5 WARNINGS AND PRECAUTIONS
`
` 5.1 Cardiovascular Thrombotic Events
`Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years
`duration have shown an increased risk of serious cardiovascular (CV) thrombotic events,
`including myocardial infarction (MI) and stroke, which can be fatal. Based on available data,
`
`
`it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative
`
`
`
`increase in serious CV thrombotic events over baseline conferred by NSAID use appears to
`be similar in those with and without known CV disease or risk factors for CV disease.
`
`
`However, patients with known CV disease or risk factors had a higher absolute incidence of
`
`
`excess serious CV thrombotic events, due to their increased baseline rate. Some observational
`studies found that this increased risk of serious CV thrombotic events began as early as the
`first weeks of treatment. The increase in CV thrombotic risk has been observed most
`consistently at higher doses.
`
`
`
`
`
`
`Reference ID: 3928107
`
`

`

`
`
` To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the
`
`
` lowest effective dose for the shortest duration possible. Physicians and patients should remain
` alert for the development of such events, throughout the entire treatment course, even in the
`
`
`
` absence of previous CV symptoms. Patients should be informed about the symptoms of
` serious CV events and the steps to take if they occur.
`
`
` There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of
`
`
`
`
`
`
` serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and
` an NSAID, such as diclofenac, increases the risk of serious gastrointestinal (GI) events [see
`
`
`
`Warnings and Precautions (5.2)].
`
` Status Post Coronary Artery Bypass Graft (CABG) Surgery
`
`
`Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in
`
`the first 10–14 days following CABG surgery found an increased incidence of myocardial
`
`infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see
`Contraindications (4)].
`
`
`Post-MI Patients
`
`Observational studies conducted in the Danish National Registry have demonstrated that
`
`patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction,
`CV-related death, and all-cause mortality beginning in the first week of treatment. In this
`
`
`same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in
`
`
`NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed
`patients. Although the absolute rate of death declined somewhat after the first year post-MI,
`
`the increased relative risk of death in NSAID users persisted over at least the next four years
`of follow-up.
`
`Avoid the use of ZORVOLEX in patients with a recent MI unless the benefits are expected to
`
`
`outweigh the risk of recurrent CV thrombotic events. If ZORVOLEX is used in patients with
`a recent MI, monitor patients for signs of cardiac ischemia.
`
`
`
`5.2 Gastrointestinal Bleeding, Ulceration, and Perforation
`NSAIDs, including diclofenac, cause serious gastrointestinal (GI) adverse events including
`inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small
`intestine, or large intestine, which can be fatal. These serious adverse events can occur at any
`
`
`
`
`time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five
`patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic.
`
`
`Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately
`
`
`1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year.
`
`However, even short-term NSAID therapy is not without risk.
`
`
`Risk Factors for GI Bleeding, Ulceration, and Perforation
`
`
`Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had
`
`a greater than 10-fold increased risk for developing a GI bleed compared to patients without
`
`
`these risk factors. Other factors that increase the risk of GI bleeding in patients treated with
`NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids,
`aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of
`
`
`
`alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI
`
`
`
`
`events occurred in elderly or debilitated patients. Additionally, patients with advanced liver
`
`
`disease and/or coagulopathy are at increased risk for GI bleeding.
`
`
`
`Reference ID: 3928107
`
`

`

`
`
`
`Strategies to Minimize the GI Risks in NSAID-treated patients:
`
`
`
`
`
` Use the lowest effective dosage for the shortest possible duration.
`
` Avoid administration of more than one NSAID at a time.
`
`
`
` Avoid use in patients at higher risk unless benefits are expected to outweigh the
`increased risk of bleeding. For such patients, as well as those with active GI bleeding,
`
`consider alternate therapies other than NSAIDs.
`
`
`
`
` Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID
`
`
`
`therapy.
`
`
` If a serious GI adverse event is suspected, promptly initiate evaluation and treatment,
`
`
`and discontinue ZORVOLEX until a serious GI adverse event is ruled out.
`
`
` In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor
`patients more closely for evidence of GI bleeding [see Drug Interactions (7)].
`
`
`5.3 Hepatotoxicity
`In clinical trials of diclofenac-containing products, meaningful elevations (i.e., more than
`
`
`
`3 times the ULN) of AST (SGOT) were observed in about 2% of approximately 5,700
`
`patients at some time during diclofenac treatment (ALT was not measured in all studies).
`
`
`In a large, open-label, controlled trial of 3,700 patients treated with oral diclofenac sodium
`
`
`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.
`
`In a European retrospective population-based, case-controlled study, 10 cases of diclofenac
`associated drug-induced liver injury with current use compared with non-use of diclofenac
`
`
`were associated with a statistically significant 4-fold adjusted odds ratio of liver injury. In
`
`
`
`
`this particular study, based on an overall number of 10 cases of liver injury associated with
`
`
`diclofenac, the adjusted odds ratio increased further with female gender, doses of 150 mg or
`
`more, and duration of use for more then 90 days.
`
`
`
`
`
`Reference ID: 3928107
`
`

`

`
`
`Physicians should measure transaminases at baseline and 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.), ZORVOLEX should be discontinued immediately.
`
`
`
`Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue,
`lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like"
`symptoms). If clinical signs and symptoms consistent with liver disease develop, or if
`
`
`systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue ZORVOLEX
`
`immediately, and perform a clinical evaluation of the patient.
`
`
`
`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, antibiotics, and anti-epileptics).
`
`
`
`5.4 Hypertension
`NSAIDs, including ZORVOLEX, can lead to new onset of hypertension or worsening of
`
`
`preexisting hypertension, either of which may contribute to the increased incidence of CV
`events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or
`
`loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug
`
`Interactions (7)].
`
`
`
`Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the
`
`course of therapy.
`
`5.5 Heart Failure and Edema
`
`The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized
`controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart
`
`failure in COX-2 selective-treated patients and nonselective NSAID-treated patients
`
`
`
`compared to placebo-treated patients. In a Danish National Registry study of patients with
`
`heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.
`
`Additionally, fluid retention and edema have been observed in some patients treated with
`
`NSAIDs. Use of diclofenac may blunt the CV effects of several therapeutic agents used to
`treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor
`blockers [ARBs]) [see Drug Interactions (7)].
`
`
`
`Avoid the use of ZORVOLEX in patients with severe heart failure unless the benefits are
`
`
`expected to outweigh the risk of worsening heart failure. If ZORVOLEX is used in patients
`
`with severe heart failure, monitor patients for signs of worsening heart failure.
`
`
`
`
`Reference ID: 3928107
`
`

`

`
`
`5.6 Renal Toxicity and Hyperkalemia
` Renal Toxicity
`
`
`Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal
`injury.
`
`Renal toxicity has also been seen in patients in whom renal prostaglandins have a
`compensatory role in the maintenance of renal perfusion. In these patients, administration of
`
`an NSAID may cause a dose-dependent reduction in prostaglandin formation and,
`secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients
`
`at greatest risk of this reaction are those with impaired renal function, dehydration,
`
`hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or
`
`
`ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to
`
`the pretreatment state.
`
`
`
`
`No information is available from controlled clinical studies regarding the use of ZORVOLEX
`
`
`in patients with advanced renal disease. The renal effects of ZORVOLEX may hasten the
`
`
`
`progression of renal dysfunction in patients with preexisting renal disease.
`
`Correct volume status in dehydrated or hypovolemic patients prior to initiating ZORVOLEX.
`Monitor renal function in patients with renal or hepatic impairment, heart failure,
`dehydration, or hypovolemia during use of ZORVOLEX [see Drug Interactions (7)]. Avoid
`
`
`
`
`the use of ZORVOLEX in patients with advanced renal disease unless the benefits are
`
`
`expected to outweigh the risk of worsening renal function. If ZORVOLEX is used in patients
`
`with advanced renal disease, monitor patients for signs of worsening renal function.
`
`
`Hyperkalemia
`Increases in serum potassium concentration, including hyperkalemia, have been reported with
`
`use of NSAIDs, even in some patients without renal impairment. In patients with normal
`
`
`renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism
`
`
`state.
`
`
` 5.7 Anaphylactic Reactions
`
`
` Diclofenac has been associated with anaphylactic reactions in patients with and without
` known hypersensitivity to diclofenac and in patients with aspirin-sensitive asthma [see
`
`
`
` Contraindications (4) and Warnings and Precautions (5.8)].
`
`
`Seek emergency help if an anaphylactic reaction occurs.
`
`5.8 Exacerbation of Asthma Related to Aspirin Sensitivity
`A subpopulation of patients with asthma may have aspirin-sensitive asthma which may
`
`
`
`include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal
`bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity
`
`between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients,
`
`ZORVOLEX is contraindicated in patients with this form of aspirin sensitivity [see
`
`
`
`Contraindications (4)]. When ZORVOLEX is used in patients with preexisting asthma
`
`(without known aspirin sensitivity), monitor patients for changes in the signs and symptoms
`
`of asthma.
`
`
`
`
`
`Reference ID: 3928107
`
`

`

`
`
`5.9 Serious Skin Reactions
`
`
` NSAIDs, including diclofenac, 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. Inform patients about the signs
` and symptoms of serious skin reactions, and to discontinue the use of ZORVOLEX at the
`
`first appearance of skin rash or any other sign of hypersensitivity. ZORVOLEX is
`
` contraindicated in patients with previous serious skin reactions to NSAIDs [see
`
` Contraindications (4)].
`
`5.10 Premature Closure of Fetal Ductus Arteriosus
`Diclofenac may cause premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs,
`including ZORVOLEX, in pregnant women starting at 30 weeks of gestation (third trimester)
`[see Use in Specific Populations (8.1)].
`
`
`
` 5.11 Hematologic Toxicity
`
`Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood
`
`loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated
`
`with ZORVOLEX has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.
`
`NSAIDs, including ZORVOLEX, may increase the risk of bleeding events. Co-morbid
`
`conditions, such as coagulation disorders, concomitant use of warfarin, other anticoagulants,
`antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin
`
`norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for
`signs of bleeding [see Drug Interactions (7)].
`
`
` 5.12 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 infections.
`
`
`
`
`5.13 Laboratory Monitoring
`Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning
`
`symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC
`
`and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)].
`
`
`
`6 ADVERSE REACTIONS
`The following adverse reactions are discussed in greater detail in other sections of the
`labeling:
`
`
`
`
` Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)]
`
` GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)]
`
` Hepatotoxicity [see Warnings and Precautions (5.3)]
`
` Hypertension [see Warnings and Precautions (5.4)]
`
` Heart Failure and Edema [see Warnings and Precautions (5.5)]
`
`
` Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)]
`
` Anaphylactic Reactions [see Warnings and Precautions (5.7)]
`
` Serious Skin Reactions [see Warnings and Precautions (5.9)]
`
` Hematologic Toxicity [see Warnings and Precautions (5.11)]
`
`
`
`
`Reference ID: 3928107
`
`

`

`
`
`
` 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.
`
`
`
`
`
` Adverse Reactions in Patients with Acute Pain
`
`
`
`Adverse Reactions
`
`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 in Table 1.
`
`Summary of Adverse Reactions (≥2% in ZORVOLEX 18 mg or 35 mg
`Table 1
`
`
`
`group) – Phase 3 Study in Patients With Postsurgical Pain
`
`
`
`
`
` ZORVOLEX 18 mg or 35 mg
`three times daily*
`Placebo*
`
`N = 216
`N = 106
`
`32%
`Edema
`33%
`37%
`Nausea
`27%
`15%
`Headache
`13%
`16%
`Dizziness
`10%
`12%
`Vomiting
`9%
`
`4%
`Constipation
`8%
`
`6%
`Pruritus
`7%
`
`
`2%
`Flatulence
`3%
`
`1%
`Pain in Extremity
`3%
`
`
`1%
`Dyspepsia
`2%
`
`*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 in Patients with Osteoarthritis Pain
`
`Two-hundred two (202) patients received ZORVOLEX in the completed, 12-week, double-
`blind, placebo-controlled, clinical trial of osteoarthritis pain of the knee or hip. The most
`
`frequent adverse reactions in this study are summarized in Table 2.
`Summary of Adverse Reactions (≥2%) – 12-week Phase 3 Study in
`Table 2
`
`Patients With Osteoarthritis Pain*
` ZORVOLEX 35 mg
`
`N=202
`
`7%
`
`6%
`
`4%
`
`3%
`
`3%
`
`
`
` Adverse Reactions
`
`Nausea
`Diarrhea
`
`Headache
`Abdominal Pain Upper
`Sinusitis
`
`
`
`Reference ID: 3928107
`
` Placebo
`
`N=103
`2%
`
`3%
`3%
`1%
`1%
`
`

`

`
`
`Vomiting
`1%
`
` 3%
` Alanine Aminotransferase Increased
`
`
` 0
`
` 2%
`Blood Creatinine Increased
`
` 0
`
` 2%
`Dyspepsia
`1%
`
` 2%
`Flatulence
`0
`
` 2%
`Hypertension
`
`
` 2%
` 1%
` * Adverse reactions that occurred in >2% of patients treated with ZORVOLEX and occurred more frequently
`
`than in patients treated with placebo
`
`
`
` Six-hundred one (601) patients received ZORVOLEX 35 mg either twice or three times daily
`
`
`
`
` in a 52-week, open-label, clinical trial in osteoarthritis pain of the knee or hip. Of those, 360
` (60%) patients completed the trial. The most frequent adverse reactions in this study are
`
`
`
` summarized in Table 3.
`
`
`
`
`
`
`Table 3
`
`
`
`Summary of Adverse Reactions (≥2%) – 52-week Open-label Study in
`
`Patients with Osteoarthritis Pain
`
`
`Adverse Reactions
`
`
`Upper respiratory tract infection
`Headache
`Urinary tract infection
`Diarrhea
`Nasopharyngitis
`Nausea
`Constipation
`Sinusitis
`Osteoarthritis
`Cough
`
`Alanine aminotransferase increased
`Back pain
`Dyspepsia
`
`Procedural pain
`Bronchitis
`Hypertension
`Abdominal pain upper
`Influenza
`Arthralgia
`Contusion
`Vomiting
`
`Abdominal discomfort
`Aspartate aminotransferase increased
`Dizziness
`Fall
`
`Abdominal pain
`
`
`
`
`Reference ID: 3928107
`
`ZORVOLEX 35 mg
`
`N=601
`
`8%
`8%
`
`7%
`
`6%
`6%
`6%
`5%
`5%
`5%
`