`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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
`
`Warnings and Precautions, Drug Reaction with Eosinophilia and Systemic
`
`Symptoms (DRESS) (5.10)
`04/2021
`
`
`
`Warnings and Precautions, Fetal Toxicity (5.11)
`04/2021
`
`
`
`
`
`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)
`
`
`
`
`
`
`• 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)
`
`
`• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS):
`
`Discontinue and evaluate clinically (5.10)
`
`• Fetal Toxicity: Limit use of NSAIDs, including ZORVOLEX, between
`
`
`about 20 to 30 weeks in pregnancy due to the risk of
`
`oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women
`
`
`at about 30 weeks gestation and later in pregnancy due to the risks of
`
`
`oligohydramnios/fetal dysfunction and premature closure of the fetal
`ductus arteriosus (5.11, 8.1)
`
`• Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with
`
`
`any signs or symptoms of anemia (5.12, 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 Zyla Life
`
`Sciences US Inc., at 1-800-518-1084 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
`
`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 04/2021
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4786646
`
`

`

`
`
`
`6
`
`
`7
`
`8
`
`
`10
`
`11
`
`12
`
`
`13
`
`
`Hematologic Toxicity
`5.12
`
`
`Masking of Inflammation and Fever
`5.13
`
`
`Laboratory Monitoring
`5.14
`
`
`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
`
`
`Mechanism of Action
`12.1
`
`
`
`12.3
`Pharmacokinetics
`
`
`NONCLINICAL TOXICOLOGY
`
`
`Carcinogenesis, Mutagenesis, and Impairment of
`13.1
`
`
`Fertility
`
`CLINICAL STUDIES
`14
`
`
`
`HOW SUPPLIED/STORAGE AND HANDLING
`16
`
`
`
`PATIENT COUNSELING INFORMATION
`17
`
`
`
` * Sections or subsections omitted from the full prescribing
`
`
` information are not listed.
`
`
`
`
`
`
`
`
`
`
`
`
`
` 2.3
`
`
`
`
`
`
`
`
`
`
`
`
`
` 1
`
` 2
`
`
` 3
`
` 4
`
` 5
`
`
`
`
`
`
`
`
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
` WARNING: RISK OF SERIOUS CARDIOVASCULAR AND
`
`
` GASTROINTESTINAL EVENTS
`
`
` INDICATIONS AND USAGE
` DOSAGE AND ADMINISTRATION
`
` 2.1
` General Dosing Instructions
`
`
`
` 2.2
`
` Dosage Adjustments in Patients with Hepatic
`
` Impairment
` Non-Interchangeability with Other Formulations of
`
` Diclofenac
` DOSAGE FORMS AND STRENGTHS
`
`
`
` CONTRAINDICATIONS
`
` WARNINGS AND PRECAUTIONS
`
` 5.1
`
` Cardiovascular Thrombotic Events
`
`
` 5.2
`
` Gastrointestinal Bleeding, Ulceration, andPerforation
`
` 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 AspirinSensitivity
` 5.9
`
`
`
` Serious Skin Reactions
` 5.10
` Drug Reaction with Eosinophilia and Systemic
`
`
` Symptoms
` Fetal Toxicity
`
`
`
`
`
`
` 5.11
`
`Reference ID: 4786646
`
`

`

` 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)].
`
`
`
`
`
` 1
`
` INDICATIONS AND USAGE
`
`
` 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: 4786646
`
`

`

` Dosage Adjustments in Patients with Hepatic Impairment Patients
` 2.2
`
`
`
`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: 4786646
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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: 4786646
`
`

`

` 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: 4786646
`
`

`

` 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: 4786646
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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: 4786646
`
`

`

`
`
`
`
`
` 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 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
`
`
`
`Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking
`
`
` NSAIDs such as ZORVOLEX. Some of these events have been fatal or life-threatening. DRESS
`typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling.
`Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis,
`
`or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is
`
`often present. Because this disorder is variable in its presentation, other organ systems not noted here
`may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or
`
`lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are
`
`present, discontinue ZORVOLEX and evaluate the patient immediately.
`
`
`
`
`
` 5.11 Fetal Toxicity
`
`
`
`
`
`Premature Closure of Fetal Ductus Arteriosus
`
` Avoid use of NSAIDS, including ZORVOLEX, in pregnant women at about 30 weeks of gestation
`
`and later. NSAIDs, including ZORVOLEX, increase the risk of premature closure of the fetal ductus
`
`
` arteriosus at approximately this gestational age.
`
` Oligohydramnios/Neonatal Renal Impairment
`
` Use of NSAIDs, including ZORVOLEX, at about 20 weeks gestation or later in pregnancy may cause
`
`
`
`
` fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment.
` These adverse outcomes are seen, on average, after days to weeks of treatment, although
`
`
` oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation.
` Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of
`
`
` prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation.
` In some postmarketing cases of impaired neonatal renal function, invasive procedures such as
`
`
`
` exchange transfusion or dialysis were required.
`
`
`
`If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit ZORVOLEX
`
`
`use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of
`
`
`amniotic fluid if ZORVOLEX treatment extends beyond 48 hours. Discontinue ZORVOLEX if
`
`oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations
`
`
`
`(8.1)].
`
`
`
`
`
` 5.12 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)].
`
`Reference ID: 4786646
`
`
`
`
`
`
`
`

`

` 5.13 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.
`
` 5.14 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)]
`
`
`
`
`
`
`
`
`
`
` 6.11 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.
`
`
`
`