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warnings and cautions
5 WARNINGS AND PRECAUTIONS SPRIX should not be used concomitantly with IM/IV or oral ketorolac, aspirin, or other NSAIDs. ( 5.1 ) Ketorolac can cause serious GI adverse events including bleeding, ulceration, and perforation. SPRIX should be prescribed with caution in patients with a prior history of ulcer disease or GI bleeding. Elderly patients are at greater risk for serious GI events. ( 4 , 5.2 ) NSAIDs affect platelet aggregation and may cause bleeding complications. SPRIX should be used with caution in patients who have coagulation disorders or are on therapy that affects hemostasis. Do not use SPRIX in patients for whom hemostasis is critical. ( 4 , 5.3 ) Ketorolac can cause renal injury. SPRIX should not be used in patients with advanced renal disease or patients at risk for renal failure due to volume depletion, and should be used with caution in patients taking diuretics or ACE inhibitors. ( 4 , 5.4 , 12.4 ) Anaphylactoid reactions may occur in patients with or without a history of allergic reactions to aspirin or NSAIDs. SPRIX should be discontinued immediately in patients with allergic reactions. ( 4 , 5.5 , 5.7 , 5.11 ) Serious and potentially fatal cardiovascular thrombotic events, myocardial infarction, and stroke can occur with NSAID treatment. ( 5.6 ) Fluid retention and edema have been observed in patients taking NSAIDs. SPRIX should be used with caution in patients with cardiac decompensation or similar conditions. ( 5.4 , 5.6 ) NSAIDs can cause serious dermatologic adverse reactions such as exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, which can be fatal. SPRIX should be discontinued immediately in patients with skin reactions. ( 4 , 5.7 ) During pregnancy, use of SPRIX beyond 30 weeks gestation can cause premature closure of the ductus arteriosus, resulting in fetal harm. ( 5.8 ) 5.1 Limitations of Use The total duration of use of SPRIX alone or sequentially with other forms of ketorolac is not to exceed 5 days. SPRIX must not be used concomitantly with other forms of ketorolac or other NSAIDs [see Dosage and Administration ( 2.1 )]. 5.2 Gastrointestinal (GI) Effects - Risk of Ulceration, Bleeding, and Perforation SPRIX is contraindicated in patients with previously documented peptic ulcers and/or GI bleeding [see Contraindications ( 4 )] . Ketorolac tromethamine can cause serious 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 ketorolac. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Minor upper GI problems, such as dyspepsia, are common and may also occur at any time during NSAID therapy. The incidence and severity of GI complications increases with increasing dose of, and duration of treatment with, ketorolac. Even short-term therapy is not without risk. In addition to past history of ulcer disease, 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, the lowest effective dose should be used for the shortest possible duration. Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy, and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of SPRIX until a serious GI adverse event is ruled out. For high risk patients, consider alternate therapies that do not involve NSAIDs. Use great care when giving SPRIX to patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn's disease) as their condition may be exacerbated. 5.3 Hematological Effects Because prostaglandins play an important role in hemostasis and NSAIDs affect platelet aggregation as well, use caution with use of ketorolac tromethamine in patients who have coagulation disorders, and monitor these patients carefully. The effects of NSAIDs other than aspirin on platelet function are reversible. Patients on therapeutic doses of anticoagulants (e.g., heparin or dicumarol derivatives) have an increased risk of bleeding complications if given ketorolac tromethamine concurrently; therefore, administer such concomitant therapy only with extreme caution. The concurrent use of ketorolac tromethamine and therapy that affects hemostasis, including prophylactic low dose heparin (2500 to 5000 units q12h), warfarin and dextrans, has not been studied extensively, but may also be associated with an increased risk of bleeding. Until data from such studies are available, carefully weigh the benefits against the risks and use such concomitant therapy in these patients only with extreme caution. Monitor patients receiving therapy that affects hemostasis closely. In clinical trials, serious adverse events related to bleeding were more common in patients treated with SPRIX than placebo. In clinical trials and in postmarketing experience with ketorolac IV and IM dosing, postoperative hematomas and other signs of wound bleeding have been reported in association with peri-operative use. Therefore, use SPRIX with caution in the postoperative setting when hemostasis is critical. Anemia is sometimes seen in patients receiving NSAIDs. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Do not use SPRIX in patients for whom hemostasis is critical [see Contraindications ( 4 ), Drug Interactions ( 7.1 , 7.2 , 7.10 )]. 5.4 Renal Effects Ketorolac and its metabolites are eliminated primarily by the kidneys. Patients with reduced creatinine clearance will have diminished clearance of the drug [see Clinical Pharmacology ( 12.4 )]. SPRIX is contraindicated in patients with advanced renal impairment [see Contraindications ( 4 )]. In patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and renal blood flow, which may precipitate overt renal decompensation. Decreased intravascular volume such as when oral intake is poor increases the risks of renal toxicity with NSAIDs. Therefore, patients treated with SPRIX should be adequately hydrated. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Use SPRIX with caution in patients with impaired renal function, heart failure, liver dysfunction, those taking diuretics or ACE inhibitors, and the elderly. Assess the risks and benefits prior to giving SPRIX to these patients, and follow these patients closely during SPRIX therapy. Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury such as interstitial nephritis and nephrotic syndrome. 5.5 Anaphylactoid Reactions As with other NSAIDs, anaphylactoid reactions may occur in patients with or without a history of allergic reactions to aspirin or NSAIDs and in patients without known prior exposure to ketorolac. SPRIX should be discontinued immediately in patients with allergic reactions. SPRIX should not be given to 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 ), Warnings and Precautions ( 5.11 )]. Emergency help should be sought in cases where an anaphylactoid reaction occurs. 5.6 Cardiovascular Effects Cardiovascular (CV) 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 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, the lowest effective dose should be used 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. Patients should be informed about the signs and/or 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 increases the risk of serious GI events. 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 ), Warnings and Precautions ( 5.2 ), Drug Interactions ( 7.2 , 7.3 , 7.7 )]. Hypertension NSAIDs can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions ( 7.3 )]. Congestive Heart Failure and Edema Fluid retention, edema, retention of NaCl, oliguria, and elevations of serum urea nitrogen and creatinine have been reported in clinical trials with ketorolac. Therefore, only use SPRIX very cautiously in patients with cardiac decompensation or similar conditions. 5.7 Skin Reactions NSAIDs, including ketorolac, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin manifestations, and discontinue use of the drug at the first appearance of skin rash or any other sign of hypersensitivity [see Contraindications ( 4 )] . 5.8 Pregnancy Starting at 30 weeks gestation, SPRIX can cause fetal harm when administered to a pregnant woman due to an increased risk of premature closure of the ductus arteriosus. If SPRIX is used at or after 30 weeks gestation, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations ( 8.1 )] . 5.9 Hepatic Effects Use SPRIX with caution in patients with impaired hepatic function or a history of liver disease. Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs, including ketorolac. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice, fulminant hepatitis, liver necrosis, and hepatic failure, some of them with fatal outcomes, have been reported [see Warnings and Precautions ( 5.4 , 5.6 ),Clinical Pharmacology ( 12.4 )] . Evaluate patients with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, for evidence of the development of a more severe hepatic reaction while on therapy with SPRIX. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue SPRIX. 5.10 Inflammation and Fever The pharmacological activity of SPRIX in reducing inflammation and fever may diminish the utility of these diagnostic signs in detecting infections. 5.11 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, do not administer SPRIX to patients with this form of aspirin sensitivity, and use with caution in patients with preexisting asthma [see Contraindications ( 4 ), Warnings and Precautions ( 5.5 )] . 5.12 Eye Exposure Avoid contact of SPRIX with the eyes. If eye contact occurs, wash out the eye with water or saline, and consult a physician if irritation persists for more than an hour.