Diclofenac Potassium

Cardiovascular Thrombotic Events

Clinical trials of several COX-2 selective and nonselective NSAIDs of up to 3 years duration have shown an increased risk of serious cardiovascular thrombotic events, including myocardial infarction (MI) and stroke.

• Incidence of serious cardiovascular thrombotic events greater in patients with known cardiovascular disease or risk factors.
• Increased risk has been observed as early as the first weeks of treatment (based on observational studies).
• Higher doses have been linked to increased cardiovascular thrombotic risk.
• To minimize risk, use the lowest effective dose for the shortest time possible.
• Evidence regarding use of aspirin to mitigate risk has not been consistent; aspirin coadministered with diclofenac may increase the risk of serious GI adverse events.

NSAIDs are contraindicated in the setting of coronary artery bypass graft (CABG) surgery. Based on findings from 2 large studies evaluating a COX-2 selective NSAID, use in the first 10–14 days after CABG resulted in an increased incidence of MI and stroke.

Post-MI Patients

Among patients treated with NSAIDs in the post-MI period, there was an increase in the risk of reinfarction, cardiovascular-related death, and all-cause mortality beginning in the first week of treatment, according to observational studies.

• Incidence of death in the first year in the NSAID cohort: 20 per 100 person years
• Incidence of death in the first year in the non-NSAID cohort: 12 per 100 person years
• The relative risk of death in NSAID users persisted over at least the next 4 years of follow up.

Avoid the use of diclofenac potassium in patients with recent MI unless the benefits are expected to outweigh the risk of recurrent cardiovascular thrombotic events. Monitor for signs of cardiac ischemia if used in patients with recent MI.

Hypertension

• NSAIDs can lead to new onset hypertension or worsening of pre-existing hypertension.
• Impaired responses to thiazides and loop diuretics possible when taken with NSAIDs.
• Use with caution in patients with hypertension; monitor BP.

Heart Failure and Edema

• Meta-analysis of randomized controlled trials showed ~2-fold increase in hospitalizations for heart failure in patients treated with COX-2 selective and nonselective NSAIDs compared with placebo.
• NSAID use was also associated with increased risk of MI, hospitalization for heart failure and death in a Danish National Registry study of patients with heart failure.
• Fluid retention and edema have been observed in some patients treated with NSAIDs.
• Diclofenac may blunt the cardiovascular effects of diuretics, ACE inhibitors, ARBs.
• Avoid use in patients with severe heart failure unless benefits outweigh risk of worsening heart failure.
• Monitor for signs of worsening heart failure if diclofenac potassium is used in patients with severe heart failure.

Gastrointestinal (GI) Effects

• NSAIDs can cause serious GI adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine.
• These can occur at any time, with or without warning symptoms (only 1 in 5 patients who develop a serious upper GI adverse event on NSAIDs is symptomatic).
• Incidence of upper GI ulcers, gross bleeding, or perforation with NSAIDs: ~1% of patients treated for 3-6 months and 2-4% of patients treated for 1 year.
• Prior history of ulcer disease or GI bleeding: prescribe with caution; these patients have a >10-fold increased risk for developing GI bleed vs those without these risk factors.
• Other factors that increase risk of GI bleed in patients treated with NSAIDs: concomitant oral corticosteroids, anticoagulants; longer duration of NSAID use; smoking; alcohol; older age; and poor general health status.
• Use the lowest effective dose for the shortest possible duration to minimize the potential for GI adverse events.
• If a serious GI adverse event occurs, discontinue NSAID therapy.
  Alternative therapies should be explored for patients considered at high risk for GI effects.

Hepatic Effects

• In clinical trials of diclofenac-containing products, meaningful elevations (eg, >3xULN of aspartate aminotransferase (AST) were observed in about 2% of approximately 5,700 patients at some time during diclofenac treatment.
• 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.
• Transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac.
• For patients with symptoms/signs suggesting liver dysfunction, or in whom abnormal liver test has occurred: evaluate for more severe hepatic reaction.
• Discontinue diclofenac potassium if abnormal liver tests persist or worsen, if clinical signs/symptoms of liver disease develop, or if systemic manifestations (eg, eosinophilia, rash) occur. 

Renal Effects

• Long-term NSAID use has been associated with 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 NSAIDs may cause a dose-dependent reduction in prostaglandin formation and, secondarily in renal blood flow, which may result in overt renal decompensation.
• Patients with impaired renal function, heart failure, liver dysfunction, on diuretics or ACE inhibitors, those who are volume-depleted and the elderly are at greatest risk of this reaction.
• Discontinuing NSAID therapy usually leads to recovery.
• Correct volume status in dehydrated or hypovolemic patients prior to initiating diclofenac potassium. 
• Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of diclofenac potassium. 
• Avoid the use of diclofenac potassium in patients with advanced renal disease unless the benefits are expected to outweigh the risk 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.
• 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 potassium is contraindicated in patients with this form of aspirin sensitivity. 
• When diclofenac potassium is 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 can cause serious skin adverse events including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis.
• Discontinue treatment at the first appearance of skin rash or any other sign of hypersensitivity.

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 potassium. 
• Some of these events have been fatal or life-threatening. 
• DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. 
• Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. 
• Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. Discontinue diclofenac potassium if such signs or symptoms are present; evaluate the patient immediately. 

Hematological Effects

• Anemia is sometimes seen in patients receiving NSAIDs.
• Check hemoglobin/hematocrit if patients exhibit signs/symptoms of anemia during long-term treatment.
• Patients who may be adversely affected by alterations in platelet function (eg, those with coagulation disorders or receiving anticoagulants) should be carefully monitored.

Cardiovascular Thrombotic Events

Clinical trials of several COX-2 selective and nonselective NSAIDs of up to 3 years duration have shown an increased risk of serious cardiovascular thrombotic events, including myocardial infarction (MI) and stroke.

• Incidence of serious cardiovascular thrombotic events greater in patients with known cardiovascular disease or risk factors.
• Increased risk has been observed as early as the first weeks of treatment (based on observational studies).
• Higher doses have been linked to increased cardiovascular thrombotic risk.
• To minimize risk, use the lowest effective dose for the shortest time possible.
• Evidence regarding use of aspirin to mitigate risk has not been consistent; aspirin coadministered with diclofenac may increase the risk of serious GI adverse events.

NSAIDs are contraindicated in the setting of coronary artery bypass graft (CABG) surgery. Based on findings from 2 large studies evaluating a COX-2 selective NSAID, use in the first 10–14 days after CABG resulted in an increased incidence of MI and stroke.

Post-MI Patients

Among patients treated with NSAIDs in the post-MI period, there was an increase in the risk of reinfarction, cardiovascular-related death, and all-cause mortality beginning in the first week of treatment, according to observational studies.

• Incidence of death in the first year in the NSAID cohort: 20 per 100 person years
• Incidence of death in the first year in the non-NSAID cohort: 12 per 100 person years
• The relative risk of death in NSAID users persisted over at least the next 4 years of follow up.

Avoid the use of diclofenac potassium in patients with recent MI unless the benefits are expected to outweigh the risk of recurrent cardiovascular thrombotic events. Monitor for signs of cardiac ischemia if used in patients with recent MI.

Hypertension

• NSAIDs can lead to new onset hypertension or worsening of pre-existing hypertension.
• Impaired responses to thiazides and loop diuretics possible when taken with NSAIDs.
• Use with caution in patients with hypertension; monitor BP.

Heart Failure and Edema

• Meta-analysis of randomized controlled trials showed ~2-fold increase in hospitalizations for heart failure in patients treated with COX-2 selective and nonselective NSAIDs compared with placebo.
• NSAID use was also associated with increased risk of MI, hospitalization for heart failure and death in a Danish National Registry study of patients with heart failure.
• Fluid retention and edema have been observed in some patients treated with NSAIDs.
• Diclofenac may blunt the cardiovascular effects of diuretics, ACE inhibitors, ARBs.
• Avoid use in patients with severe heart failure unless benefits outweigh risk of worsening heart failure.
• Monitor for signs of worsening heart failure if diclofenac potassium is used in patients with severe heart failure.

Gastrointestinal (GI) Effects

• NSAIDs can cause serious GI adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine.
• These can occur at any time, with or without warning symptoms (only 1 in 5 patients who develop a serious upper GI adverse event on NSAIDs is symptomatic).
• Incidence of upper GI ulcers, gross bleeding, or perforation with NSAIDs: ~1% of patients treated for 3-6 months and 2-4% of patients treated for 1 year.
• Prior history of ulcer disease or GI bleeding: prescribe with caution; these patients have a >10-fold increased risk for developing GI bleed vs those without these risk factors.
• Other factors that increase risk of GI bleed in patients treated with NSAIDs: concomitant oral corticosteroids, anticoagulants; longer duration of NSAID use; smoking; alcohol; older age; and poor general health status.
• Use the lowest effective dose for the shortest possible duration to minimize the potential for GI adverse events.
• If a serious GI adverse event occurs, discontinue NSAID therapy.
  Alternative therapies should be explored for patients considered at high risk for GI effects.

Hepatic Effects

• In clinical trials of diclofenac-containing products, meaningful elevations (eg, >3xULN of aspartate aminotransferase (AST) were observed in about 2% of approximately 5,700 patients at some time during diclofenac treatment.
• 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.
• Transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac.
• For patients with symptoms/signs suggesting liver dysfunction, or in whom abnormal liver test has occurred: evaluate for more severe hepatic reaction.
• Discontinue diclofenac potassium if abnormal liver tests persist or worsen, if clinical signs/symptoms of liver disease develop, or if systemic manifestations (eg, eosinophilia, rash) occur. 

Renal Effects

• Long-term NSAID use has been associated with 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 NSAIDs may cause a dose-dependent reduction in prostaglandin formation and, secondarily in renal blood flow, which may result in overt renal decompensation.
• Patients with impaired renal function, heart failure, liver dysfunction, on diuretics or ACE inhibitors, those who are volume-depleted and the elderly are at greatest risk of this reaction.
• Discontinuing NSAID therapy usually leads to recovery.
• Correct volume status in dehydrated or hypovolemic patients prior to initiating diclofenac potassium. 
• Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of diclofenac potassium. 
• Avoid the use of diclofenac potassium in patients with advanced renal disease unless the benefits are expected to outweigh the risk 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.
• 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 potassium is contraindicated in patients with this form of aspirin sensitivity. 
• When diclofenac potassium is 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 can cause serious skin adverse events including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis.
• Discontinue treatment at the first appearance of skin rash or any other sign of hypersensitivity.

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 potassium. 
• Some of these events have been fatal or life-threatening. 
• DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. 
• Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. 
• Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. Discontinue diclofenac potassium if such signs or symptoms are present; evaluate the patient immediately. 

Hematological Effects

• Anemia is sometimes seen in patients receiving NSAIDs.
• Check hemoglobin/hematocrit if patients exhibit signs/symptoms of anemia during long-term treatment.
• Patients who may be adversely affected by alterations in platelet function (eg, those with coagulation disorders or receiving anticoagulants) should be carefully monitored.

Cardiovascular Thrombotic Events

Clinical trials of several COX-2 selective and nonselective NSAIDs of up to 3 years duration have shown an increased risk of serious cardiovascular thrombotic events, including myocardial infarction (MI) and stroke.

• Incidence of serious cardiovascular thrombotic events greater in patients with known cardiovascular disease or risk factors.
• Increased risk has been observed as early as the first weeks of treatment (based on observational studies).
• Higher doses have been linked to increased cardiovascular thrombotic risk.
• To minimize risk, use the lowest effective dose for the shortest time possible.
• Evidence regarding use of aspirin to mitigate risk has not been consistent; aspirin coadministered with diclofenac may increase the risk of serious GI adverse events.

NSAIDs are contraindicated in the setting of coronary artery bypass graft (CABG) surgery. Based on findings from 2 large studies evaluating a COX-2 selective NSAID, use in the first 10–14 days after CABG resulted in an increased incidence of MI and stroke.

Post-MI Patients

Among patients treated with NSAIDs in the post-MI period, there was an increase in the risk of reinfarction, cardiovascular-related death, and all-cause mortality beginning in the first week of treatment, according to observational studies.

• Incidence of death in the first year in the NSAID cohort: 20 per 100 person years
• Incidence of death in the first year in the non-NSAID cohort: 12 per 100 person years
• The relative risk of death in NSAID users persisted over at least the next 4 years of follow up.

Avoid the use of diclofenac potassium in patients with recent MI unless the benefits are expected to outweigh the risk of recurrent cardiovascular thrombotic events. Monitor for signs of cardiac ischemia if used in patients with recent MI.

Hypertension

• NSAIDs can lead to new onset hypertension or worsening of pre-existing hypertension.
• Impaired responses to thiazides and loop diuretics possible when taken with NSAIDs.
• Use with caution in patients with hypertension; monitor BP.

Heart Failure and Edema

• Meta-analysis of randomized controlled trials showed ~2-fold increase in hospitalizations for heart failure in patients treated with COX-2 selective and nonselective NSAIDs compared with placebo.
• NSAID use was also associated with increased risk of MI, hospitalization for heart failure and death in a Danish National Registry study of patients with heart failure.
• Fluid retention and edema have been observed in some patients treated with NSAIDs.
• Diclofenac may blunt the cardiovascular effects of diuretics, ACE inhibitors, ARBs.
• Avoid use in patients with severe heart failure unless benefits outweigh risk of worsening heart failure.
• Monitor for signs of worsening heart failure if diclofenac potassium is used in patients with severe heart failure.

Gastrointestinal (GI) Effects

• NSAIDs can cause serious GI adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine.
• These can occur at any time, with or without warning symptoms (only 1 in 5 patients who develop a serious upper GI adverse event on NSAIDs is symptomatic).
• Incidence of upper GI ulcers, gross bleeding, or perforation with NSAIDs: ~1% of patients treated for 3-6 months and 2-4% of patients treated for 1 year.
• Prior history of ulcer disease or GI bleeding: prescribe with caution; these patients have a >10-fold increased risk for developing GI bleed vs those without these risk factors.
• Other factors that increase risk of GI bleed in patients treated with NSAIDs: concomitant oral corticosteroids, anticoagulants; longer duration of NSAID use; smoking; alcohol; older age; and poor general health status.
• Use the lowest effective dose for the shortest possible duration to minimize the potential for GI adverse events.
• If a serious GI adverse event occurs, discontinue NSAID therapy.
  Alternative therapies should be explored for patients considered at high risk for GI effects.

Hepatic Effects

• In clinical trials of diclofenac-containing products, meaningful elevations (eg, >3xULN of aspartate aminotransferase (AST) were observed in about 2% of approximately 5,700 patients at some time during diclofenac treatment.
• 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.
• Transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac.
• For patients with symptoms/signs suggesting liver dysfunction, or in whom abnormal liver test has occurred: evaluate for more severe hepatic reaction.
• Discontinue diclofenac potassium if abnormal liver tests persist or worsen, if clinical signs/symptoms of liver disease develop, or if systemic manifestations (eg, eosinophilia, rash) occur. 

Renal Effects

• Long-term NSAID use has been associated with 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 NSAIDs may cause a dose-dependent reduction in prostaglandin formation and, secondarily in renal blood flow, which may result in overt renal decompensation.
• Patients with impaired renal function, heart failure, liver dysfunction, on diuretics or ACE inhibitors, those who are volume-depleted and the elderly are at greatest risk of this reaction.
• Discontinuing NSAID therapy usually leads to recovery.
• Correct volume status in dehydrated or hypovolemic patients prior to initiating diclofenac potassium. 
• Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of diclofenac potassium. 
• Avoid the use of diclofenac potassium in patients with advanced renal disease unless the benefits are expected to outweigh the risk 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.
• 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 potassium is contraindicated in patients with this form of aspirin sensitivity. 
• When diclofenac potassium is 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 can cause serious skin adverse events including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis.
• Discontinue treatment at the first appearance of skin rash or any other sign of hypersensitivity.

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 potassium. 
• Some of these events have been fatal or life-threatening. 
• DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. 
• Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. 
• Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. Discontinue diclofenac potassium if such signs or symptoms are present; evaluate the patient immediately. 

Hematological Effects

• Anemia is sometimes seen in patients receiving NSAIDs.
• Check hemoglobin/hematocrit if patients exhibit signs/symptoms of anemia during long-term treatment.
• Patients who may be adversely affected by alterations in platelet function (eg, those with coagulation disorders or receiving anticoagulants) should be carefully monitored.