FDA label 46550da2-9d7e-4ab8-8efb-814ea15e6e25

WARNING Ketorolac tromethamine, a nonsteroidal anti-inflammatory drug (NSAID), is indicated for the short-term (up to 5 days) management of moderately severe acute pain that requires analgesia at the opioid level. It is NOT indicated for minor or chronic painful conditions. Ketorolac tromethamine is a potent NSAID analgesic, and its administration carries many risks. The resulting NSAID-related adverse events can be serious in certain patients for whom ketorolac tromethamine is indicated, especially when the drug is used inappropriately. Increasing the dose of ketorolac tromethamine beyond the label recommendations will not provide better efficacy but will result in increasing the risk of developing serious adverse events. Gastrointestinal Effects • Ketorolac tromethamine can cause peptic ulcers, gastrointestinal bleeding, and/or perforation. 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. Renal Effects • 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, and is CONTRAINDICATED intra-operatively when hemostasis is critical because of the increased risk of bleeding. Hypersensitivity • Hypersensitivity reactions, ranging from bronchospasm to anaphylactic shock, have occurred and appropriate counteractive measures must be available when administering the first dose of ketorolac tromethamine injection (see CONTRAINDICATIONS and WARNINGS ). Ketorolac tromethamine is CONTRAINDICATED in patients with previously demonstrated hypersensitivity to ketorolac tromethamine or allergic manifestations to aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). Intrathecal or Epidural Administration • Ketorolac tromethamine is CONTRAINDICATED for intrathecal or epidural administration due to its alcohol content. Labor, Delivery and Nursing • The use of ketorolac tromethamine in labor and delivery is CONTRAINDICATED because it may adversely affect fetal circulation and the uterus. • 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 ASA or NSAIDs because of the cumulative risk of inducing serious NSAID-related side effects. DOSAGE AND ADMINISTRATION Ketorolac Tromethamine Tablets • Ketorolac tromethamine tablets are indicated only as continuation therapy to ketorolac tromethamine injection, and the combined duration of use of ketorolac tromethamine injection and ketorolac tromethamine tablets is not to exceed 5 (five) days, because of the increased risk of serious adverse events. • The recommended total daily dose of ketorolac tromethamine tablets (maximum 40 mg) is significantly lower than for ketorolac tromethamine injection (maximum 120 mg) (see DOSAGE AND ADMINISTRATION and Transition from ketorolac tromethamine injection to ketorolac tromethamine tablets). 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 ). Doses of ketorolac tromethamine injection are not to exceed 60 mg (total dose per day) in these patients.

WARNINGS (see also Boxed WARNING) ► The combined use of ketorolac tromethamine injection and tablets is not to exceed 5 days. The most serious risks associated with ketorolac tromethamine are: • Gastrointestinal Ulcerations, Bleeding and Perforation: Ketorolac tromethamine is CONTRAINDICATED in patients with previously documented peptic ulcers and/or G.I. bleeding. Serious gastrointestinal toxicity, such as bleeding, ulceration, and perforation, can occur at any time, with or without warning symptoms, in patients treated with ketorolac tromethamine. Studies to date with NSAIDs have not identified any subset of patients not at risk of developing peptic ulceration and bleeding. Elderly or debilitated patients seem to tolerate ulceration or bleeding less well than other individuals, and most spontaneous reports of fatal G.I. events are in this population. Postmarketing experience with parenterally administered ketorolac tromethamine suggests that there may be a greater risk of gastrointestinal ulcerations, bleeding and perforation in the elderly. The incidence and severity of gastrointestinal complications increases with increasing dose of, and duration of treatment with ketorolac tromethamine. In a non-randomized, in-hospital postmarketing surveillance study, comparing parenteral ketorolac tromethamine to parenteral opioids, higher rates of clinically serious G.I. bleeding were seen in patients <65 years of age who received an average total daily dose of more than 90 mg of ketorolac tromethamine injection per day (see CLINICAL PHARMACOLOGY – Postmarketing Surveillance Study) The same study showed that elderly (≥65 years of age), and debilitated patients are more susceptible to gastrointestinal complications. A history of peptic ulcer disease was revealed as another risk factor that increases the possibility of developing serious gastrointestinal complications during ketorolac tromethamine therapy (see Tables 3A and B). • Impaired Renal Function: 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. Renal toxicity with ketorolac tromethamine has been seen in patients with conditions leading to a reduction in blood volume and/or renal blood flow, where renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients, administration of ketorolac tromethamine may cause a dose-dependent reduction in renal prostaglandin formation and may precipitate acute renal failure. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, heart failure, liver dysfunction, those taking diuretics and the elderly. Discontinuation of ketorolac tromethamine therapy is usually followed by recovery to the pretreatment state. Renal Effects: 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, nephritis, and nephrotic syndrome. Because patients with underlying renal insufficiency are at increased risk of developing acute renal failure, the risks and benefits should be assessed prior to giving ketorolac tromethamine to these patients. Hence, in patients with moderately elevated serum creatinine, it is recommended that the daily dose of ketorolac tromethamine injection be reduced by half, not to exceed 60 mg/day. Ketorolac tromethamine is CONTRAINDICATED IN PATIENTS WITH SERUM CREATININE CONCENTRATIONS INDICATING ADVANCED RENAL IMPAIRMENT (see CONTRAINDICATIONS). Hypovolemia should be corrected before treatment with ketorolac tromethamine is initiated. • Fluid Retention 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. • 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 prophylactic low-dose heparin (2500-5000 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. In patients who receive anticoagulants for any reason, there is an increased risk of intramuscular hematoma formation from administered ketorolac tromethamine IM (see PRECAUTIONS – Drug Interactions ). Patients receiving therapy that affects hemostasis should be monitored closely. In postmarking experience, postoperative hematomas and other signs of wound bleeding have been reported in association with the perioperative use of ketorolac tromethamine injection. Therefore, perioperative use of ketorolac tromethamine should be avoided and postoperative use be undertaken with caution when hemostasis is critical (see WARNINGS and PRECAUTIONS ). • Anaphylactoid Reactions: Anaphylactoid reactions may occur in patients without a known previous exposure or hypersensitivity to aspirin, ketorolac tromethamine, or other NSAIDs, or in individuals with a history of angioedema, bronchospastic reactivity (e.g., asthma), and nasal polyps. Anaphylactoid reactions, like anaphylaxis, may have a fatal outcome.

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. The adverse reactions listed below were reported in clinical trials as probably related to ketorolac tromethamine. • Incidence Greater Than 1% [Percentage of incidence in parentheses for those events reported in 3% or more patients] Body as a Whole: edema (4%). Cardiovascular: hypertension. Dermatologic: pruritus, rash. Gastrointestinal: nausea (12%), dyspepsia (12%), gastrointestinal pain (13%), diarrhea (7%), constipation, flatulence, gastrointestinal fullness, vomiting, stomatitis. Hemic and Lymphatic: purpura. Nervous System: headache (17%), drowsiness (6%), dizziness (7%), sweating. Injection-site pain was reported by 2% of patients in multi-dose studies. • Incidence 1% or Less Body as a Whole: weight gain, fever, infections, asthenia. Cardiovascular: palpitation, pallor, syncope. Dermatologic: urticaria. Gastrointestinal: gastritis, rectal bleeding, eructation, anorexia, increased appetite. Hemic and Lymphatic: epistaxis, anemia, eosinophilia. Nervous System: tremors, abnormal dreams, hallucinations, euphoria, extrapyramidal symptoms, vertigo, paresthesia, depression, insomnia, nervousness, excessive thirst, dry mouth, abnormal thinking, inability to concentrate, hyperkinesis, stupor. Respiratory: dyspnea, pulmonary edema, rhinitis, cough. Special Senses: abnormal taste, abnormal vision, blurred vision, tinnitus, hearing loss. Urogenital: hematuria, proteinuria, oliguria, urinary retention, polyuria, increased urinary frequency. The following adverse events were reported from postmarketing experience. Body as a Whole: hypersensitivity reactions such as anaphylaxis, anaphylactoid reaction, laryngeal edema, tongue edema (see Boxed WARNING, WARNINGS ), myalgia. Cardiovascular: hypotension and flushing. Dermatologic: Lyell’s syndrome, Stevens-Johnson syndrome, exfoliative dermatitis, maculo-papular rash, urticaria. Gastrointestinal: peptic ulceration, G.I. hemorrhage, G.I. perforation (see Boxed WARNING, WARNINGS), melena, acute pancreatitis. Hemic and Lymphatic: postoperative wound hemorrhage (rarely requiring blood transfusion - see Boxed WARNING, WARNINGS and PRECAUTIONS ), thrombocytopenia, leukopenia. Hepatic: hepatitis, liver failure, cholestatic jaundice. Nervous System: convulsions, psychosis, aseptic meningitis. Respiratory: asthma, bronchospasm. Urogenital: acute renal failure (see Boxed WARNING, WARNINGS ), flank pain with or without hematuria and/or azotemia, nephritis, hyponatremia, hyperkalemia, hemolytic uremic syndrome.