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warnings and cautions
5. WARNINGS AND PRECAUTIONS Serious and potentially fatal cardiovascular (CV) thrombotic events, myocardial infarction, and stroke can occur with NSAID treatment. The lowest possible dose of Zipsor should be used in patients with known CV disease or risk factors for CV disease. ( 5.1 ) NSAIDs, including diclofenac, can cause serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation. Zipsor should be prescribed with caution in those with a prior history of ulcer disease or gastrointestinal bleeding. ( 5.2 ) Elevation of one or more liver tests may occur during therapy with diclofenac. Zipsor should be discontinued immediately if abnormal liver tests persist or worsen. ( 5.3 ) Hypertension can occur with NSAID treatment. Blood pressure should be monitored closely during treatment with Zipsor. ( 5.4 ) Fluid retention and edema have been observed in some patients taking NSAIDs. Zipsor should be used with caution in patients with fluid retention or heart failure. ( 5.5 ) Long-term administration of NSAIDs can result in renal papillary necrosis and other renal injury. Zipsor should be used with caution in patients at greatest risk of this reaction, including the elderly, those with impaired renal function, heart failure, liver dysfunction, and those taking diuretics and ACE inhibitors. ( 5.6 ) Anaphylactoid reactions may occur in patients with the aspirin triad or in patients without prior exposure to Zipsor and should be discontinued immediately if an anaphylactoid reaction occurs. ( 5.7 ) NSAIDs can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Zipsor should be discontinued if rash or other signs of local skin reaction occur. ( 5.8 ) 5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Inform patients about the signs and/or symptoms of serious CV events and the steps to take if they occur. Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke [see Contraindications ( 4 )]. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as diclofenac, does increase the risk of serious GI events [see Warnings and Precautions ( 5.2 )]. 5.2 Gastrointestinal (GI) Effects – Risk of GI Ulceration, Bleeding, and Perforation NSAIDs, including diclofenac, can cause serious gastrointestinal (GI) adverse events including, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term NSAID therapy is not without risk. Prescribe NSAIDs, including Zipsor, with extreme caution in patients with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or GI bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients, and therefore special care should be taken in treating this population. To minimize the potential risk for an adverse GI event in patients treated with an NSAID, use the lowest effective dose for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during Zipsor therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of Zipsor until a serious GI adverse event is ruled out. For high risk patients, alternative therapies that do not include NSAIDs should be considered. 5.3 Hepatic Effects Borderline elevations (less than 3 times the upper limit of the normal [ULN] range) or greater elevations of transaminases occurred in about 15% of diclofenac-treated patients in clinical trials of indications other than acute pain. Of the markers of hepatic function, ALT (SGPT) is recommended for the monitoring of liver injury. In clinical trials of a diclofenac - misoprostol combination product, meaningful elevations (i.e., more than 3 times the ULN) of AST (SGOT) occurred in about 2% of approximately 5,700 patients at some time during diclofenac treatment (ALT was not measured in all studies). In an open-label, controlled trial of 3,700 patients treated for 2–6 months, patients were monitored first at 8 weeks and 1,200 patients were monitored again at 24 weeks. Meaningful elevations of ALT and/or AST occurred in about 4% of the 3,700 patients and included marked elevations (>8 times the ULN) in about 1% of the 3,700 patients. In this open-label study, a higher incidence of borderline (less than 3 times the ULN), moderate (3–8 times the ULN), and marked (>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 NSAID therapy. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation. In a European retrospective population-based, case-controlled study, 10 cases of diclofenac associated drug-induced liver injury with current use compared with non-use of diclofenac were associated with a statistically significant 4-fold adjusted odds ratio of liver injury. In this particular study, based on an overall number of 10 cases of liver injury associated with diclofenac, the adjusted odds ratio increased further with female gender, doses of 150 mg or more, and duration of use for more then 90 days. Physicians should measure transaminases (ALT and AST) 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, rash, abdominal pain, diarrhea, dark urine, etc.), discontinue Zipsor immediately. To minimize the possibility that hepatic injury will become severe between transaminase measurements, inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms), and the appropriate action patients should take if these signs and symptoms appear. To minimize the potential risk for an adverse liver-related event in patients treated with Zipsor, use the lowest effective dose for the shortest duration possible. Exercise caution when prescribing Zipsor with concomitant drugs that are known to be potentially hepatotoxic (e.g., acetaminophen, certain antibiotics, antiepileptics). Caution patients to avoid taking unprescribed acetaminophen while using Zipsor. 5.4 Hypertension NSAIDs, including diclofenac, can lead to new onset or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Use NSAIDs, including Zipsor, with caution in patients with hypertension. Monitor blood pressure (BP) closely during the initiation of NSAID treatment and throughout the course of therapy. Patients taking ACE inhibitors, thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. 5.5 Congestive Heart Failure and Edema Fluid retention and edema have been observed in some patients taking NSAIDs. Use Zipsor with caution in patients with fluid retention or heart failure. 5.6 Renal Effects Use caution when initiating treatment with Zipsor in patients with considerable dehydration. Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of Zipsor in patients with advanced renal disease. Therefore, treatment with Zipsor is not recommended in patients with advanced renal disease. If Zipsor therapy must be initiated, close monitoring of the patient's renal function is advisable. 5.7 Anaphylactoid Reactions As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to Zipsor. Zipsor is contraindicated in patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs [see Contraindications ( 4 )]. 5.8 Adverse Skin Reactions NSAIDs, including diclofenac, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations, and to discontinue Zipsor at the first appearance of skin rash or any other sign of hypersensitivity [see Contraindications ( 4 )]. 5.9 Pregnancy Starting at 30 weeks gestation, Zipsor, as with other NSAIDs, should be avoided by pregnant women as premature closure of the ductus arteriosus in the fetus may occur. 5.10 Corticosteroid Treatment Zipsor cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to exacerbation of corticosteroid-responsive illness. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. 5.11 Masking of Inflammation and Fever The pharmacological activity of diclofenac in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infectious complications of presumed noninfectious, painful conditions. 5.12 Hematological Effects Anemia may occur in patients receiving NSAIDs. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. In patients on long-term therapy with NSAIDs, including diclofenac, check hemoglobin or hematocrit if they exhibit any signs or symptoms of anemia or blood loss. Zipsor is not indicated for long-term treatment. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Carefully monitor patients treated with Zipsor who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants. 5.13 Use in Patients with Preexisting Asthma Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, Zipsor is contraindicated in patients with this form of aspirin sensitivity and should be used with caution in all patients with preexisting asthma [see Contraindications ( 4 )]. 5.14 Monitoring Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. For patients on long-term treatment with NSAIDs, periodically check a CBC and a chemistry profile. Discontinue Zipsor if abnormal liver tests or renal tests persist or worsen. Zipsor is not indicated for long-term treatment.