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Zorvolex

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Zorvolex

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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].

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as diclofenac, does increase the risk of serious GI events [see Gastrointestinal (GI) Effects – Risk of GI Ulceration, Bleeding, and Perforation, DRUG INTERACTIONS].

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.

Hepatic Effects

Elevations of one or more liver tests may occur during therapy with ZORVOLEX. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continued therapy. Borderline elevations (greater than the upper limit of normal [ULN] to 3 times the ULN range) of transaminases have been observed in approximately 15% of diclofenac-treated patients. Of the markers of hepatic function, ALT (SGPT) is recommended for the monitoring of liver injury.

In clinical trials of diclofenac-containing products, meaningful elevations (i.e., more than 3 times the ULN) of AST (SGOT) (ALT was not measured in all studies) were observed in about 2% of approximately 5,700 patients at some time during diclofenac treatment.

In a large, open-label, controlled diclofenac sodium trial of 3,700 patients treated for 2-6 months, patients were monitored first at 8 weeks and 1,200 patients were monitored again at 24 weeks. Meaningful elevations of ALT and/or AST occurred in about 4% of patients and included marked elevations (greater than 8 times the ULN) in about 1% of the 3,700 patients. In that open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3-8 times the ULN), and marked (greater than 8 times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared to other NSAIDs. Elevations in transaminases were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis.

Almost all meaningful elevations in transaminases were detected before patients became symptomatic. Abnormal tests occurred during the first 2 months of therapy with diclofenac in 42 of the 51 patients in all trials who developed marked transaminase elevations.

In postmarketing reports, cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the first 2 months of therapy, but can occur at any time during treatment with diclofenac. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation.

Physicians should measure transaminases periodically in patients receiving long-term therapy with ZORVOLEX, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms. The optimum times for making the first and subsequent transaminase measurements are not known. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac. However, severe hepatic reactions can occur at any time during treatment with diclofenac. If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), discontinue ZORVOLEX immediately.

To minimize the possibility that hepatic injury will become severe between transaminase measurements, inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flulike” symptoms), and the appropriate action patients should take if these signs and symptoms appear.

To minimize the potential risk for an adverse liver related event in patients treated with ZORVOLEX, use the lowest effective dose for the shortest duration possible. Exercise caution when prescribing ZORVOLEX with concomitant drugs that are known to be potentially hepatotoxic (e.g., acetaminophen, certain antibiotics, and anti-epileptics).

Hypertension

NSAIDs, including ZORVOLEX, can lead to new onset or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Use NSAIDs, including ZORVOLEX, with caution in patients with hypertension. Monitor blood pressure (BP) closely during the initiation of NSAID treatment and throughout the course of therapy.

Patients taking ACE inhibitors, thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs.

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.

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.

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].

Emergency help should be sought in cases where an anaphylactoid reaction occurs.

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].

Fetal Toxicity

Starting at 30 weeks gestation, ZORVOLEX and other NSAIDs, should be avoided by pregnant women as premature closure of the ductus arteriosus in the fetus may occur. If this drug is used during this time period in pregnancy, the patient should be apprised of the potential hazard to a fetus [see Use In Specific Populations].

Corticosteroid-Responsive Illness

ZORVOLEX cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to exacerbation of corticosteroid-responsive illness. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.

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.

Hematological Effects

Anemia may occur in patients receiving NSAIDs, including ZORVOLEX. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. In patients on long-term therapy with NSAIDs, including ZORVOLEX, check hemoglobin or hematocrit if they exhibit any signs or symptoms of anemia or blood loss.

NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding 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.

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].

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 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.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (NSAID Medication Guide).

Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy.

Cardiovascular Effects

Advise patients to be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and to ask for medical advice when observing any indicative sign or symptoms. Inform patients of the importance of this follow-up [see WARNINGS AND PRECAUTIONS].

Gastrointestinal Effects

Advise patients to be alert for the signs and symptoms of ulcerations and bleeding, and to ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Inform patients of the importance of this follow-up [see WARNINGS AND PRECAUTIONS].

Hepatotoxicity

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop therapy and seek immediate medical therapy [see WARNINGS AND PRECAUTIONS].

Adverse Skin Reactions

Advise patients to be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and to ask for medical advice when observing any indicative signs or symptoms. Advise patients to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible [see WARNINGS AND PRECAUTIONS].

Weight Gain and Edema

Advise patients to promptly report to their physicians signs or symptoms of unexplained weight gain or edema during treatment with ZORVOLEX [see WARNINGS AND PRECAUTIONS].

Anaphylactoid Reactions

Inform patients of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see WARNINGS AND PRECAUTIONS].

Effects During Pregnancy

Advise female patients to inform their prescriber if pregnant or planning to become pregnant [see Use In Specific Populations, WARNINGS AND PRECAUTIONS].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, And Impairment Of Fertility

Carcinogenesis

Long-term carcinogenicity studies in rats given diclofenac sodium up to 2 mg/kg/day (0.2-fold the maximum recommended human dose [MRHD] of ZORVOLEX based on body surface area comparison) have revealed no significant increase in tumor incidence. A 2-year carcinogenicity study conducted in mice employing diclofenac sodium at doses up to 0.3 mg/kg/day (0.014-fold the MRHD based on body surface area comparison) in males and 1 mg/kg/day (0.04-fold the MRHD based on body surface area comparison) in females did not reveal any oncogenic potential.

Mutagenesis

Diclofenac sodium did not show mutagenic activity in in vitro point mutation assays in mammalian (mouse lymphoma) and microbial (yeast, Ames) test systems and was nonmutagenic in several mammalian in vitro and in vivo tests, including dominant lethal and male germinal epithelial chromosomal aberration studies in Chinese hamsters.

Impairment of Fertility

Diclofenac sodium administered to male and female rats at 4 mg/kg/day (0.4-fold the MRHD based on body surface area comparison) did not affect fertility.

Use In Specific Populations

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 potential hazard to the fetus. Prior to 30 weeks gestation, ZORVOLEX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In animals, no evidence of teratogenicity was observed in mouse, rat, or rabbit reproductive studies at doses of diclofenac equivalent to approximately 1 to 2 times the maximum recommended human dose (MRHD) of ZORVOLEX, 105 mg/day.

Data

Animal data

Reproductive studies have been performed in mice given diclofenac sodium (up to 20 mg/kg/day, equivalent to the maximum recommended human dose [MRHD] based on a body surface area comparison), and in rats and rabbits given diclofenac sodium (up to 10 mg/kg/day; 1 [rats] and 2 [rabbits] times the MRHD on a mg/m² basis, respectively) and have revealed no evidence of teratogenicity despite the induction of maternal toxicity and fetal toxicity. In rats, maternally toxic doses were associated with dystocia, prolonged gestation, reduced fetal weights and growth, and reduced fetal survival. Diclofenac has been shown to cross the placental barrier in mice, rats, and humans.

Labor And Delivery

The effects of ZORVOLEX on labor and delivery in pregnant women are unknown. In rat studies maternal exposure to NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, increased the incidence of dystocia, delayed parturition, and decreased pup survival.

Nursing Mothers

Based on available data, diclofenac may be present in human milk. One woman treated orally with a diclofenac salt, 150 mg/day, had a milk diclofenac level of 100 mcg/L, equivalent to an infant dose of about 0.03 mg/kg/day. Diclofenac was not detectable in breast milk in 12 women using diclofenac (after either 100 mg/day orally for 7 days or a single 50 mg intramuscular dose administered in the immediate postpartum period). Exercise caution when ZORVOLEX is administered to a nursing woman.

Pediatric Use

The safety and effectiveness of ZORVOLEX in pediatric patients has not been established.

Geriatric Use

As with any NSAID, caution should be exercised in treating the elderly (65 years and older). In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy.

Diclofenac metabolites are known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Older age increases the risk for GI bleeding. Most spontaneous reports of fatal GI events are in elderly or debilitated patients, and therefore special care should be taken in treating this population [see WARNINGS AND PRECAUTIONS].

Last reviewed on RxList: 9/4/2014
This monograph has been modified to include the generic and brand name in many instances.

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