Diclofenac Sodium

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Diclofenac Sodium Prescribing Information

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
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.
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: Gastrointestinal Bleeding, Ulceration, and Perforation
).
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 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG (see
CONTRAINDICATIONS
).
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 diclofenac in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If diclofenac is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.
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 to 6 months, and in about 2% to 4% of patients treated for one year. However, even short-term 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 use 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.
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 diclofenac sodium delayed-release tablets 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
PRECAUTIONS: Drug Interactions
).
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 to 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 to 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 than 90 days.
Physicians should measure transaminases at baseline and periodically in patients receiving long-term therapy with diclofenac, 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, reaction, abdominal pain, diarrhea, dark urine, etc.), diclofenac sodium delayed-release tablets 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, reaction, etc.), discontinue diclofenac sodium delayed-release tablets immediately, and perform a clinical evaluation of the patient.
To minimize the potential risk for an adverse liver related event in patients treated with diclofenac sodium delayed-release tablets, use the lowest effective dose for the shortest duration possible. Exercise caution when prescribing diclofenac sodium delayed-release tablets with concomitant drugs that are known to be potentially hepatotoxic (e.g., acetaminophen, antibiotics, anti-epileptics).
Hypertension
NSAIDs, including diclofenac sodium delayed-release tablets, 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, thiazides diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs (see
PRECAUTIONS: Drug Interactions
).
Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.
Heart Failure and Edema
The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalization 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
PRECAUTIONS: Drug Interactions
).
Avoid the use of diclofenac in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If diclofenac is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.
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 diclofenac sodium delayed-release tablets in patients with advanced renal disease. The renal effects of diclofenac sodium delayed-release tablets may hasten the progression of renal dysfunction in patients with pre-existing renal disease.
Correct volume status in dehydrated or hypovolemic patients prior to initiating diclofenac sodium delayed-release tablets. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of diclofenac sodium delayed-release tablets (see
PRECAUTIONS: Drug Interactions
).Avoid the use of diclofenac sodium delayed-release tablets in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If diclofenac sodium delayed-release tablets are 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.
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
,
WARNINGS: Exacerbation of Asthma Related to Aspirin Sensitivity
).
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, diclofenac sodium delayed-release tablets are contraindicated in patients with this form of aspirin sensitivity (see
CONTRAINDICATIONS
). When diclofenac sodium delayed-release tablets are used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.
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. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening.These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of diclofenac sodium delayed-release tablets at the first appearance of skin reaction or any other sign of hypersensitivity. Diclofenac sodium delayed-release tablets are contraindicated in patients with previous serious skin reactions to NSAIDs (see
CONTRAINDICATIONS
).
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 diclofenac sodium delayed-release tablets. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, reaction, 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 reaction is not evident. If such signs or symptoms are present, discontinue diclofenac sodium delayed-release tablets and evaluate the patient immediately.
Fetal Toxicity
Premature Closure of Fetal Ductus Arteriosus
:
Avoid use of NSAIDs, including diclofenac sodium delayed-release tablets, in pregnant women at about 30 weeks gestation and later. NSAIDs including diclofenac sodium delayed-release tablets, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.
Oligohydramnios/Neonatal Renal Impairment
:
Use of NSAIDs, including diclofenac sodium delayed-release tablets, 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 diclofenac sodium delayed-release tablets use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if diclofenac sodium delayed-release tablets treatment extends beyond 48 hours. Discontinue diclofenac sodium delayed-release tablets if oligohydramnios occurs and follow up according to clinical practice [
see
PRECAUTIONS; Pregnancy
].
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 diclofenac sodium delayed-release tablets, has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.
NSAIDs, including diclofenac sodium delayed-release tablets, 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
PRECAUTIONS: Drug Interactions
).
).
Diclofenac sodium delayed-release tablets are contraindicated in the setting of coronary artery bypass graft (CABG) surgery (see
CONTRAINDICATIONS
Diclofenac sodium delayed-release tablets are 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: Anaphylactic Reactions
,
Serious Skin Reactions
).
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: Anaphylactic Reaction
,
Exacerbation of Asthma Related to Aspirin Sensitivity
).
In the setting of coronary artery bypass graft (CABG) surgery (see
WARNINGS: Cardiovascular Thrombotic Events).
and
WARNINGS
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.
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: Gastrointestinal Bleeding, Ulceration, and Perforation
).
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 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG (see
CONTRAINDICATIONS
).
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 diclofenac in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If diclofenac is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.
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 to 6 months, and in about 2% to 4% of patients treated for one year. However, even short-term 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 use 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.
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 diclofenac sodium delayed-release tablets 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
PRECAUTIONS: Drug Interactions
).
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 to 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 to 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 than 90 days.
Physicians should measure transaminases at baseline and periodically in patients receiving long-term therapy with diclofenac, 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, reaction, abdominal pain, diarrhea, dark urine, etc.), diclofenac sodium delayed-release tablets 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, reaction, etc.), discontinue diclofenac sodium delayed-release tablets immediately, and perform a clinical evaluation of the patient.
To minimize the potential risk for an adverse liver related event in patients treated with diclofenac sodium delayed-release tablets, use the lowest effective dose for the shortest duration possible. Exercise caution when prescribing diclofenac sodium delayed-release tablets with concomitant drugs that are known to be potentially hepatotoxic (e.g., acetaminophen, antibiotics, anti-epileptics).
Hypertension
NSAIDs, including diclofenac sodium delayed-release tablets, 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, thiazides diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs (see
PRECAUTIONS: Drug Interactions
).
Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.
Heart Failure and Edema
The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalization 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
PRECAUTIONS: Drug Interactions
).
Avoid the use of diclofenac in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If diclofenac is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.
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 diclofenac sodium delayed-release tablets in patients with advanced renal disease. The renal effects of diclofenac sodium delayed-release tablets may hasten the progression of renal dysfunction in patients with pre-existing renal disease.
Correct volume status in dehydrated or hypovolemic patients prior to initiating diclofenac sodium delayed-release tablets. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of diclofenac sodium delayed-release tablets (see
PRECAUTIONS: Drug Interactions
).Avoid the use of diclofenac sodium delayed-release tablets in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If diclofenac sodium delayed-release tablets are 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.
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
,
WARNINGS: Exacerbation of Asthma Related to Aspirin Sensitivity
).
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, diclofenac sodium delayed-release tablets are contraindicated in patients with this form of aspirin sensitivity (see
CONTRAINDICATIONS
). When diclofenac sodium delayed-release tablets are used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.
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. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening.These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of diclofenac sodium delayed-release tablets at the first appearance of skin reaction or any other sign of hypersensitivity. Diclofenac sodium delayed-release tablets are contraindicated in patients with previous serious skin reactions to NSAIDs (see
CONTRAINDICATIONS
).
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 diclofenac sodium delayed-release tablets. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, reaction, 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 reaction is not evident. If such signs or symptoms are present, discontinue diclofenac sodium delayed-release tablets and evaluate the patient immediately.
Fetal Toxicity
Premature Closure of Fetal Ductus Arteriosus
:
Avoid use of NSAIDs, including diclofenac sodium delayed-release tablets, in pregnant women at about 30 weeks gestation and later. NSAIDs including diclofenac sodium delayed-release tablets, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.
Oligohydramnios/Neonatal Renal Impairment
:
Use of NSAIDs, including diclofenac sodium delayed-release tablets, 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 diclofenac sodium delayed-release tablets use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if diclofenac sodium delayed-release tablets treatment extends beyond 48 hours. Discontinue diclofenac sodium delayed-release tablets if oligohydramnios occurs and follow up according to clinical practice [
see
PRECAUTIONS; Pregnancy
].
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 diclofenac sodium delayed-release tablets, has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.
NSAIDs, including diclofenac sodium delayed-release tablets, 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
PRECAUTIONS: Drug Interactions
).
).

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
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.
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: Gastrointestinal Bleeding, Ulceration, and Perforation
).
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 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG (see
CONTRAINDICATIONS
).
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 diclofenac in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If diclofenac is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.
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 to 6 months, and in about 2% to 4% of patients treated for one year. However, even short-term 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 use 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.
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 diclofenac sodium delayed-release tablets 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
PRECAUTIONS: Drug Interactions
).
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 to 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 to 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 than 90 days.
Physicians should measure transaminases at baseline and periodically in patients receiving long-term therapy with diclofenac, 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, reaction, abdominal pain, diarrhea, dark urine, etc.), diclofenac sodium delayed-release tablets 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, reaction, etc.), discontinue diclofenac sodium delayed-release tablets immediately, and perform a clinical evaluation of the patient.
To minimize the potential risk for an adverse liver related event in patients treated with diclofenac sodium delayed-release tablets, use the lowest effective dose for the shortest duration possible. Exercise caution when prescribing diclofenac sodium delayed-release tablets with concomitant drugs that are known to be potentially hepatotoxic (e.g., acetaminophen, antibiotics, anti-epileptics).
Hypertension
NSAIDs, including diclofenac sodium delayed-release tablets, 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, thiazides diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs (see
PRECAUTIONS: Drug Interactions
).
Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.
Heart Failure and Edema
The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalization 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
PRECAUTIONS: Drug Interactions
).
Avoid the use of diclofenac in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If diclofenac is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.
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 diclofenac sodium delayed-release tablets in patients with advanced renal disease. The renal effects of diclofenac sodium delayed-release tablets may hasten the progression of renal dysfunction in patients with pre-existing renal disease.
Correct volume status in dehydrated or hypovolemic patients prior to initiating diclofenac sodium delayed-release tablets. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of diclofenac sodium delayed-release tablets (see
PRECAUTIONS: Drug Interactions
).Avoid the use of diclofenac sodium delayed-release tablets in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If diclofenac sodium delayed-release tablets are 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.
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
,
WARNINGS: Exacerbation of Asthma Related to Aspirin Sensitivity
).
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, diclofenac sodium delayed-release tablets are contraindicated in patients with this form of aspirin sensitivity (see
CONTRAINDICATIONS
). When diclofenac sodium delayed-release tablets are used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.
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. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening.These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of diclofenac sodium delayed-release tablets at the first appearance of skin reaction or any other sign of hypersensitivity. Diclofenac sodium delayed-release tablets are contraindicated in patients with previous serious skin reactions to NSAIDs (see
CONTRAINDICATIONS
).
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 diclofenac sodium delayed-release tablets. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, reaction, 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 reaction is not evident. If such signs or symptoms are present, discontinue diclofenac sodium delayed-release tablets and evaluate the patient immediately.
Fetal Toxicity
Premature Closure of Fetal Ductus Arteriosus
:
Avoid use of NSAIDs, including diclofenac sodium delayed-release tablets, in pregnant women at about 30 weeks gestation and later. NSAIDs including diclofenac sodium delayed-release tablets, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.
Oligohydramnios/Neonatal Renal Impairment
:
Use of NSAIDs, including diclofenac sodium delayed-release tablets, 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 diclofenac sodium delayed-release tablets use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if diclofenac sodium delayed-release tablets treatment extends beyond 48 hours. Discontinue diclofenac sodium delayed-release tablets if oligohydramnios occurs and follow up according to clinical practice [
see
PRECAUTIONS; Pregnancy
].
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 diclofenac sodium delayed-release tablets, has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.
NSAIDs, including diclofenac sodium delayed-release tablets, 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
PRECAUTIONS: Drug Interactions
).
).

Carefully consider the potential benefits and risks of diclofenac sodium delayed-release tablets and other treatment options before deciding to use diclofenac sodium delayed-release tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see

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 to 6 months, and in about 2% to 4% of patients treated for one year. However, even short-term 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 use 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.

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 diclofenac sodium delayed-release tablets 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
PRECAUTIONS: Drug Interactions
).

Diclofenac sodium delayed-release tablets are indicated:

For relief of the signs and symptoms of osteoarthritis
For relief of the signs and symptoms of rheumatoid arthritis
For acute or long-term use in the relief of signs and symptoms of ankylosing spondylitis

Gastrointestinal Bleeding, Ulceration, and Perforation

Risk Factors for GI Bleeding, Ulceration, and Perforation

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 diclofenac sodium delayed-release tablets 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
PRECAUTIONS: Drug Interactions
).

After observing the response to initial therapy with diclofenac sodium delayed-release tablets, the dose and frequency should be adjusted to suit an individual patient’s needs.

For the relief of osteoarthritis, the recommended dosage is 100 to 150 mg/day in divided doses (50 mg twice a day or three times a day, or 75 mg twice a day).

For the relief of rheumatoid arthritis, the recommended dosage is 150 to 200 mg/day in divided doses (50 mg three times a day or four times a day, or 75 mg twice a day).

For the relief of ankylosing spondylitis, the recommended dosage is 100 to 125 mg/day, administered as 25 mg four times a day, with an extra 25 mg dose at bedtime if necessary.

Different formulations of diclofenac (diclofenac sodium enteric-coated tablets; diclofenac sodium extended-release tablets; diclofenac potassium immediate-release tablets) are not necessarily bioequivalent even if the milligram strength is the same.

Diclofenac sodium delayed-release tablets are 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
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
,
WARNINGS: Exacerbation of Asthma Related to Aspirin Sensitivity
).
,
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. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening.These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of diclofenac sodium delayed-release tablets at the first appearance of skin reaction or any other sign of hypersensitivity. Diclofenac sodium delayed-release tablets are contraindicated in patients with previous serious skin reactions to NSAIDs (see
CONTRAINDICATIONS
).
).
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
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
,
WARNINGS: Exacerbation of Asthma Related to Aspirin Sensitivity
).
,
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, diclofenac sodium delayed-release tablets are contraindicated in patients with this form of aspirin sensitivity (see
CONTRAINDICATIONS
). When diclofenac sodium delayed-release tablets are used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.
).
In the setting of coronary artery bypass graft (CABG) surgery (see
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.
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: Gastrointestinal Bleeding, Ulceration, and Perforation
).
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 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG (see
CONTRAINDICATIONS
).
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 diclofenac in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If diclofenac is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.
).

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 practice.

In patients taking diclofenac sodium delayed-release tablets, or other NSAIDs, the most frequently reported adverse experiences occurring in approximately 1% to 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, reactions and tinnitus.

Additional adverse experiences 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

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, fixed drug eruption (FDE), urticaria

Special Senses

conjunctivitis, hearing impairment

To report

SUSPECTED ADVERSE REACTIONS

, contact Rising Pharma Holdings, Inc. at 1-844-874-7464 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects (see

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.

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: Gastrointestinal Bleeding, Ulceration, and Perforation

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 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG (see

CONTRAINDICATIONS

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 diclofenac in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If diclofenac is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

Gastrointestinal Bleeding, Ulceration, and Perforation

Risk Factors for GI Bleeding, Ulceration, and Perforation

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 diclofenac sodium delayed-release tablets 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
PRECAUTIONS: Drug Interactions
).

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 to 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 to 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 than 90 days.

Physicians should measure transaminases at baseline and periodically in patients receiving long-term therapy with diclofenac, 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, reaction, abdominal pain, diarrhea, dark urine, etc.), diclofenac sodium delayed-release tablets 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, reaction, etc.), discontinue diclofenac sodium delayed-release tablets immediately, and perform a clinical evaluation of the patient.

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

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 diclofenac sodium delayed-release tablets in patients with advanced renal disease. The renal effects of diclofenac sodium delayed-release tablets may hasten the progression of renal dysfunction in patients with pre-existing renal disease.

Correct volume status in dehydrated or hypovolemic patients prior to initiating diclofenac sodium delayed-release tablets. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of diclofenac sodium delayed-release tablets (see

PRECAUTIONS: Drug Interactions

).Avoid the use of diclofenac sodium delayed-release tablets in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If diclofenac sodium delayed-release tablets are 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.

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: Gastrointestinal Bleeding, Ulceration, and Perforation

, and

Hepatotoxicity

Diclofenac is 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 (see

CLINICAL PHARMACOLOGY

Mechanism of Action

Diclofenac has analgesic, anti-inflammatory, and antipyretic properties.

The mechanism of action of diclofenac sodium delayed-release tablets, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).

Diclofenac is a potent inhibitor of prostaglandin synthesis

in vitro

. Diclofenac concentrations reached during therapy have produced

in vivo

effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because diclofenac is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

Pharmacokinetics

Absorption

Diclofenac is 100% absorbed after oral administration compared to IV administration as measured by urine recovery. However, due to first-pass metabolism, only about 50% of the absorbed dose is systemically available (see Table 1). Food has no significant effect on the extent of diclofenac absorption. However, there is usually a delay in the onset of absorption of 1 to 4.5 hours and a reduction in peak plasma levels of <20%.

Table 1. Pharmacokinetic Parameters for Diclofenac
	Normal Healthy Adults (20-48 years)
PK Parameter	Mean	Coefficient of Variation (%)
Absolute Bioavailability (%) [N = 7]	55	40
Tmax (hr) [N = 56]	2.3	69
Oral Clearance (CL/F; mL/min) [N = 56]	582	23
Renal Clearance (% unchanged drug in urine)[N = 7]	<1	–
Apparent Volume of Distribution (V/F; L/kg) [N = 56]	1.4	58
Terminal Half-life (hr) [N = 56]	2.3	48

Distribution

The apparent volume of distribution (V/F) of diclofenac sodium is 1.4 L/kg.

Diclofenac is more than 99% bound to human serum proteins, primarily to albumin. Serum protein binding is constant over the concentration range (0.15 to 105 mcg/mL) achieved with recommended doses.

Diclofenac diffuses into and out of the synovial fluid. Diffusion into the joint occurs when plasma levels are higher than those in the synovial fluid, after which the process reverses and synovial fluid levels are higher than plasma levels. It is not known whether diffusion into the joint plays a role in the effectiveness of diclofenac.

Elimination

Metabolism

Five diclofenac metabolites have been identified in human plasma and urine. The metabolites include 4’-hydroxy-, 5-hydroxy-,3’-hydroxy-, 4’,5-dihydroxy- and 3’-hydroxy-4’-methoxy diclofenac. The major diclofenac metabolite, 4’-hydroxy-diclofenac, has very weak pharmacologic activity. The formation of 4’-hydroxy- diclofenac is primarily mediated by CYP2C9. Both diclofenac and its oxidative metabolites undergo glucuronidation or sulfation followed by biliary excretion. Acylglucuronidation mediated by UGT2B7 and oxidation mediated by CYP2C8 may also play a role in diclofenac metabolism. CYP3A4 is responsible for the formation of minor metabolites, 5-hydroxy- and 3’-hydroxy-diclofenac. In patients with renal dysfunction, peak concentrations of metabolites 4’-hydroxy- and 5-hydroxy-diclofenac were approximately 50% and 4% of the parent compound after single oral dosing compared to 27% and 1% in normal healthy subjects.

Excretion

Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites. Little or no free unchanged diclofenac is excreted in the urine. Approximately 65% of the dose is excreted in the urine and approximately 35% in the bile as conjugates of unchanged diclofenac plus metabolites. Because renal elimination is not a significant pathway of elimination for unchanged diclofenac, dosing adjustment in patients with mild to moderate renal dysfunction is not necessary. The terminal half-life of unchanged diclofenac is approximately 2 hours.

Special Populations

Pediatric

The pharmacokinetics of diclofenac sodium delayed-release tablets has not been investigated in pediatric patients.

Race

Pharmacokinetic differences due to race have not been identified.

Hepatic Impairment

Hepatic metabolism accounts for almost 100% of diclofenac sodium delayed-release tablets elimination, so patients with hepatic disease may require reduced doses of diclofenac sodium delayed-release tablets compared to patients with normal hepatic function.

Renal Impairment

Diclofenac pharmacokinetics has been investigated in subjects with renal insufficiency. No differences in the pharmacokinetics of diclofenac have been detected in studies of patients with renal impairment. In patients with renal impairment (inulin clearance 60 to 90, 30 to 60, and <30 mL/min; N=6 in each group), AUC values and elimination rate were comparable to those in healthy subjects.

Drug Interactions Studies

Voriconazole

When co-administered with voriconazole (inhibitor of CYP2C9, 2C19 and 3A4 enzyme), the C_maxand AUC of diclofenac increased by 114% and 78%, respectively (see

PRECAUTIONS: Drug Interactions

Aspirin

When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 2 for clinically significant drug interactions of NSAIDs with aspirin (see

PRECAUTIONS: Drug Interactions

ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

Cardiovascular Thrombotic Events (see
WARNINGS
)
GI Bleeding, Ulceration and Perforation (see
WARNINGS
)
Hepatotoxicity (see
WARNINGS
)
Hypertension (see
WARNINGS
)
Heart Failure and Edema (see
WARNINGS
)
Renal Toxicity and Hyperkalemia (see
WARNINGS
)
Anaphylactic Reactions (see
WARNINGS
)
Serious Skin Reactions (see
WARNINGS
)
Hematologic Toxicity (see
WARNINGS
)

Clinical Trials Experience

In patients taking diclofenac sodium delayed-release tablets, or other NSAIDs, the most frequently reported adverse experiences occurring in approximately 1% to 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, reactions and tinnitus.

Additional adverse experiences 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

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, fixed drug eruption (FDE), urticaria

Special Senses

conjunctivitis, hearing impairment

To report

SUSPECTED ADVERSE REACTIONS

, contact Rising Pharma Holdings, Inc. at 1-844-874-7464 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Report Adverse Event

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