FDA label 0ebcdcad-8eab-4d02-99fa-436b2ac366ca

WARNING Ketorolac tromethamine tablets, a non-steroidal anti-inflammatory drug (NSAID), are indicated for the short-term (up to 5 days in adults), management of moderately severe acute pain that requires analgesia at the opioid level and only as continuation treatment following IV or IM dosing of ketorolac tromethamine, if necessary. The total combined duration of use of ketorolac tromethamine should not exceed 5 days. Ketorolac tromethamine tablets are not indicated for use in pediatric patients and it is NOT indicated for minor or chronic painful conditions. Increasing the dose of ketorolac tromethamine tablets beyond a daily maximum of 40 mg in adults will not provide better efficacy but will increase the risk of developing serious adverse events. GASTROINTESTINAL RISK Ketorolac tromethamine can cause peptic ulcers, gastrointestinal bleeding and/or perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Therefore, ketorolac tromethamine is CONTRAINDICATED in patients with active peptic ulcer disease, in patients with recent gastrointestinal bleeding or perforation, and in patients with a history of peptic ulcer disease or gastrointestinal bleeding. Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS ). CARDIOVASCULAR RISK NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see WARNINGS and CLINICAL TRIALS ). Ketorolac tromethamine is CONTRAINDICATED for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS ). RENAL RISK Ketorolac tromethamine is CONTRAINDICATED in patients with advanced renal impairment and in patients at risk for renal failure due to volume depletion (see WARNINGS ). RISK OF BLEEDING Ketorolac tromethamine inhibits platelet function and is, therefore, CONTRAINDICATED in patients with suspected or confirmed cerebrovascular bleeding, patients with hemorrhagic diathesis, incomplete hemostasis and those at high risk of bleeding (see WARNINGS and PRECAUTIONS ). Ketorolac tromethamine is CONTRAINDICATED as prophylactic analgesic before any major surgery. RISK DURING LABOR AND DELIVERY The use of ketorolac tromethamine in labor and delivery is contraindicated because it may adversely affect fetal circulation and inhibit uterine contractions. The use of ketorolac tromethamine is contraindicated in nursing mothers because of the potential adverse effects of prostaglandin-inhibiting drugs on neonates. CONCOMITANT USE WITH NSAIDS Ketorolac tromethamine is CONTRAINDICATED in patients currently receiving aspirin or NSAIDs because of the cumulative risk of inducing serious NSAID-related side effects. SPECIAL POPULATIONS Dosage should be adjusted for patients 65 years or older, for patients under 50 kg (110 lbs) of body weight (see DOSAGE AND ADMINISTRATION ) and for patients with moderately elevated serum creatinine (see WARNINGS ).

WARNINGS (see also Boxed WARNING) The total combined duration of use of ketorolac tromethamine-IV/IM and ketorolac tromethamine tablets is not to exceed 5 days in adults. Ketorolac tromethamine tablets are not indicated for use in pediatric patients. The most serious risks associated with ketorolac tromethamine are: Gastrointestinal Effects – Risk of Ulceration, Bleeding and Perforation Ketorolac tromethamine is contraindicated in patients with previously documented peptic ulcers and/or GI bleeding. Ketorolac tromethamine 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 ketorolac tromethamine. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Minor upper gastrointestinal problems, such as dyspepsia, are common and may also occur at any time during NSAID therapy. The incidence and severity of gastrointestinal complications increases with increasing dose of, and duration of treatment with, ketorolac tromethamine. Do not use ketorolac tromethamine for more than 5 days. However, 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. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of ketorolac tromethamine until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered. NSAIDs should be given with care to patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn’s disease) as their condition may be exacerbated. Hemorrhage Because prostaglandins play an important role in hemostasis and NSAIDs affect platelet aggregation as well, use of ketorolac tromethamine in patients who have coagulation disorders should be undertaken very cautiously, and those patients should be carefully monitored. 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, physicians should administer such concomitant therapy only extremely cautiously. The concurrent use of ketorolac tromethamine and therapy that affects hemostasis, including prophylactic low-dose heparin (2500 to 5000 units q12h), warfarin and dextrans have not been studied extensively, but may also be associated with an increased risk of bleeding. Until data from such studies are available, physicians should carefully weigh the benefits against the risks and use such concomitant therapy in these patients only extremely cautiously. Patients receiving therapy that affects hemostasis should be monitored closely. In post-marketing experience, postoperative hematomas and other signs of wound bleeding have been reported in association with the perioperative use of IV or IM dosing of ketorolac tromethamine. Therefore, perioperative use of ketorolac tromethamine should be avoided and postoperative use be undertaken with caution when hemostasis is critical (see PRECAUTIONS ). Renal Effects 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 a 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. Ketorolac tromethamine and its metabolites are eliminated primarily by the kidneys, which, in patients with reduced creatinine clearance, will result in diminished clearance of the drug (see CLINICAL PHARMACOLOGY ). Therefore, ketorolac tromethamine should be used with caution in patients with impaired renal function (see DOSAGE AND ADMINISTRATION ) and such patients should be followed closely. With the use of ketorolac tromethamine, there have been reports of acute renal failure, interstitial nephritis and nephrotic syndrome. Impaired Renal Function Ketorolac tromethamine is contraindicated in patients with serum creatinine concentrations indicating advanced renal impairment (see CONTRAINDICATIONS ). Ketorolac tromethamine should be used with caution in patients with impaired renal function or a history of kidney disease because it is a potent inhibitor of prostaglandin synthesis. Because patients with underlying renal insufficiency are at increased risk of developing acute renal decompensation or failure, the risks and benefits should be assessed prior to giving ketorolac tromethamine to these patients. Anaphylactoid Reactions As with other NSAIDs, anaphylactoid reactions may occur in patients without a known previous exposure or hypersensitivity to ketorolac tromethamine. Ketorolac tromethamine 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 and PRECAUTIONS: Preexisting Asthma ). Anaphylactoid reactions, like anaphylaxis, may have a fatal outcome. Emergency help should be sought in cases where an anaphylactoid reaction occurs. Cardiovascular Effects 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 (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 does increase the risk of serious GI events (see Gastrointestinal Effects – Risk of Ulceration, Bleeding and Perforation ). 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 (see CONTRAINDICATIONS ). Hypertension NSAIDs, including ketorolac tromethamine, 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. NSAIDs, including ketorolac tromethamine, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy. Congestive Heart Failure and Edema Fluid retention, edema, retention of NaCl, oliguria, elevations of serum urea nitrogen and creatinine have been reported in clinical trials with ketorolac tromethamine. Therefore, ketorolac tromethamine should be used only very cautiously in patients with cardiac decompensation, hypertension or similar conditions. Skin Reactions NSAIDS, including ketorolac tromethamine, 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. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity. Pregnancy In late pregnancy, as with other NSAIDs, ketorolac tromethamine should be avoided because it may cause premature closure of the ductus arteriosus.

ADVERSE REACTIONS Adverse reaction rates increase with higher doses of ketorolac tromethamine. Practitioners should be alert for the severe complications of treatment with ketorolac tromethamine, such as G.I. ulceration, bleeding and perforation, postoperative bleeding, acute renal failure, anaphylactic and anaphylactoid reactions and liver failure (see Boxed WARNING, WARNINGS , PRECAUTIONS , and DOSAGE AND ADMINISTRATION ). These NSAID-related complications can be serious in certain patients for whom ketorolac tromethamine is indicated, especially when the drug is used inappropriately. In patients taking ketorolac tromethamine or other NSAIDs in clinical trials, the most frequently reported adverse experiences in approximately 1% to 10% of patients are: Gastrointestinal (GI) experiences including: Abdominal Pain * Constipation/Diarrhea Dyspepsia* Flatulence GI Fullness GI Ulcers (gastric/duodenal) Gross Bleeding/Perforation Heartburn Nausea* Stomatitis Vomiting Other experiences: Abnormal Renal Function Anemia Dizziness Drowsiness Edema Elevated Liver Enzymes Headaches* Hypertension Increased Bleeding Time Injection Site Pain Pruritus Purpura Rashes Tinnitus Sweating * Incidence greater than 10% Additional adverse experiences reported occasionally (<1% in patients taking ketorolac tromethamine or other NSAIDs in clinical trials) include: Body as a Whole: fever, infections, sepsis Cardiovascular: congestive heart failure, palpitation, pallor, tachycardia, syncope Dermatologic: alopecia, photosensitivity, urticaria Gastrointestinal: anorexia, dry mouth, eructation, esophagitis, excessive thirst, gastritis,glossitis, hematemesis, hepatitis, increased appetite, jaundice, melena, rectal bleeding Hemic and Lymphatic: ecchymosis, eosinophilia, epistaxis, leukopenia, thrombocytopenia Metabolic and Nutritional: weight change Nervous System: abnormal dreams, abnormal thinking, anxiety, asthenia, confusion, depression, euphoria, extrapyramidal symptoms, hallucinations, hyperkinesis, inability to concentrate, insomnia, nervousness, paresthesia, somnolence, stupor, tremors, vertigo, malaise Reproductive, female: infertility Respiratory: asthma, cough, dyspnea, pulmonary edema, rhinitis Special Senses: abnormal taste, abnormal vision, blurred vision, hearing loss Urogenital: cystitis, dysuria, hematuria, increased urinary frequency, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure, urinary retention Other rarely observed reactions (reported from post-marketing experience in patients taking ketorolac tromethamine or other NSAIDs) are: Body as a Whole: angioedema, death, hypersensitivity reactions such as anaphylaxis, anaphylactoid reaction, laryngeal edema, tongue edema (see WARNINGS ), myalgia Cardiovascular: arrhythmia, bradycardia, chest pain, flushing, hypotension, myocardial infarction, vasculitis Dermatologic: exfoliative dermatitis, erythema multiforme, Lyell’s syndrome, bullous reactions including Stevens-Johnson Syndrome and toxic epidermal necrolysis Gastrointestinal: acute pancreatitis, liver failure, ulcerative stomatitis, exacerbation of inflammatory bowel disease (ulcerative colitis, Crohn’s disease) Hemic and Lymphatic: agranulocytosis, aplastic anemia, hemolytic anemia, lymphadenopathy, pancytopenia, postoperative wound hemorrhage (rarely requiring blood transfusion — see Boxed WARNING, WARNINGS , and PRECAUTIONS ) Metabolic and Nutritional: hyperglycemia, hyperkalemia, hyponatremia Nervous System: aseptic meningitis, convulsions, coma, psychosis Respiratory: bronchospasm, respiratory depression, pneumonia Special Senses: conjunctivitis Urogenital: flank pain with or without hematuria and/or azotemia, hemolytic uremic syndrome Post-Marketing Surveillance Study: A large post-marketing observational, nonrandomized study, involving approximately 10,000 patients receiving ketorolac tromethamine IV or IM, demonstrated that the risk of clinically serious gastrointestinal (G.I.) bleeding was dose dependent (see Tables 3A and 3B). This was particularly true in elderly patients who received an average daily dose greater than 60 mg/day of ketorolac tromethamine IV or IM (see Table 3A). Table 3: Incidence of Clinically Serious G.I. Bleeding as Related to Age, Total Daily Dose and History of G.I. Perforation, Ulcer, Bleeding (PUB)after up to 5 Days of Treatment with Ketorolac Tromethamine IV/IM A. Adult Patients without History of PUB Age of Patients Total Daily Dose of Ketorolac Tromethamine IV/IM < 60 mg > 60 to 90 mg > 90 to 120 mg > 120 mg < 65 years of age 0.4% 0.4% 0.9% 4.6% > 65 years of age 1.2% 2.8% 2.2% 7.7% B. Adult Patients with History of PUB Age of Patients Total Daily Dose of Ketorolac Tromethamine IV/IM < 60 mg > 60 to 90 mg > 90 to 120 mg > 120 mg < 65 years of age 2.1% 4.6% 7.8% 15.4% > 65 years of age 4.7% 3.7% 2.8% 25%

<table ID="i9b2c8aeb-ffac-446b-8c1a-7479f8faacbf" border="0" width="869"> <tbody> <tr> <td>Gastrointestinal (GI) experiences including:</td> </tr> <tr> <td>Abdominal Pain<linkHtml href="#section-"> *</linkHtml> </td> <td>Constipation/Diarrhea</td> <td>Dyspepsia*</td> </tr> <tr> <td>Flatulence</td> <td>GI Fullness</td> <td>GI Ulcers (gastric/duodenal)</td> </tr> <tr> <td>Gross Bleeding/Perforation</td> <td>Heartburn</td> <td>Nausea*</td> </tr> <tr> <td>Stomatitis</td> <td>Vomiting</td> <td> </td> </tr> <tr> <td>Other experiences:</td> </tr> <tr> <td>Abnormal Renal Function</td> <td>Anemia</td> <td>Dizziness</td> </tr> <tr> <td>Drowsiness</td> <td>Edema</td> <td>Elevated Liver Enzymes</td> </tr> <tr> <td>Headaches*</td> <td>Hypertension</td> <td>Increased Bleeding Time</td> </tr> <tr> <td>Injection Site Pain</td> <td>Pruritus</td> <td>Purpura</td> </tr> <tr> <td>Rashes</td> <td>Tinnitus</td> <td>Sweating</td> </tr> </tbody> </table>

<table border="1" width="868" ID="i85037575-2a5a-43f8-88c1-f74d99cf7ebf"> <caption>Table 3: Incidence of Clinically Serious G.I. Bleeding as Related to Age, Total Daily Dose and History of G.I. Perforation, Ulcer, Bleeding (PUB)after up to 5 Days of Treatment with Ketorolac Tromethamine IV/IM</caption> <col width="17%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <tbody> <tr> <td> <content styleCode="bold">A. Adult Patients without History of PUB</content> </td> </tr> <tr> <td>Age of Patients </td> <td>Total Daily Dose of Ketorolac Tromethamine IV/IM</td> </tr> <tr> <td> <content styleCode="underline">&lt;</content> 60 mg</td> <td>&gt; 60 to 90 mg</td> <td>&gt; 90 to 120 mg</td> <td>&gt; 120 mg </td> </tr> <tr> <td>&lt; 65 years of age</td> <td>0.4%</td> <td>0.4%</td> <td>0.9%</td> <td>4.6%</td> </tr> <tr> <td> <content styleCode="underline">&gt;</content> 65 years of age</td> <td>1.2%</td> <td>2.8%</td> <td>2.2%</td> <td>7.7%</td> </tr> <tr> <td> <content styleCode="bold">B. Adult Patients with History of PUB</content> </td> </tr> <tr> <td>Age of Patients </td> <td>Total Daily Dose of Ketorolac Tromethamine IV/IM</td> </tr> <tr> <td> <content styleCode="underline">&lt;</content> 60 mg</td> <td>&gt; 60 to 90 mg</td> <td>&gt; 90 to 120 mg</td> <td>&gt; 120 mg</td> </tr> <tr> <td>&lt; 65 years of age</td> <td>2.1%</td> <td>4.6%</td> <td>7.8%</td> <td>15.4%</td> </tr> <tr> <td> <content styleCode="underline">&gt;</content> 65 years of age</td> <td>4.7%</td> <td>3.7%</td> <td>2.8%</td> <td>25%</td> </tr> </tbody> </table>