Ketorolac

INDICATIONS AND USAGE Carefully consider the potential benefits and risks of ketorolac tromethamine and other treatment options before deciding to use ketorolac. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS ). Acute Pain in Adult Patients Ketorolac tromethamine is indicated for the short-term (≤5 days) management of moderately severe acute pain that requires analgesia at the opioid level, usually in a postoperative setting. Therapy should always be initiated with intravenous or intramuscular dosing of ketorolac tromethamine, and oral ketorolac tromethamine is to be used only as continuation treatment, if necessary. The total combined duration of use of ketorolac tromethamine injection and oral ketorolac tromethamine is not to exceed 5 days of use because of the potential of increasing the frequency and severity of adverse reactions associated with the recommended doses (see WARNINGS , PRECAUTIONS , DOSAGE AND ADMINISTRATION , and ADVERSE REACTIONS ). Patients should be switched to alternative analgesics as soon as possible, but ketorolac tromethamine therapy is not to exceed 5 days. Ketorolac tromethamine injection has been used concomitantly with morphine and meperidine and has shown an opioid-sparing effect. For breakthrough pain, it is recommended to supplement the lower end of the ketorolac tromethamine injection dosage range with low doses of narcotics prn, unless otherwise contraindicated. Ketorolac tromethamine injection and narcotics should not be administered in the same syringe (see DOSAGE AND ADMINISTRATION – Pharmaceutical Information for Ketorolac Tromethamine Injection ).

CLINICAL PHARMACOLOGY Pharmacodynamics Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits analgesic activity in animal models. The mechanism of action of ketorolac, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition. The biological activity of ketorolac tromethamine is associated with the S-form. Ketorolac tromethamine possesses no sedative or anxiolytic properties. The peak analgesic effect of ketorolac tromethamine occurs within 2 to 3 hours and is not statistically significantly different over the recommended dosage range of ketorolac tromethamine. The greatest difference between large and small doses of ketorolac tromethamine by either route is in the duration of analgesia. Pharmacokinetics Ketorolac tromethamine is a racemic mixture of [-]S- and [+]R-enantiomeric forms, with the S‑form having analgesic activity. Comparison of Intravenous, Intramuscular and Oral Pharmacokinetics The pharmacokinetics of ketorolac tromethamine, following intravenous, intramuscular and oral doses of ketorolac tromethamine are compared in Table 1 . In adults, the extent of bioavailability following administration of the ORAL and INTRAMUSCULAR forms of ketorolac tromethamine was equal to that following an intravenous bolus. Table 1: Table of Approximate Average Pharmacokinetic Parameters (Mean±SD) Following Oral, Intramuscular and Intravenous Doses of Ketorolac Tromethamine Oral † Intramuscular* Intravenous Bolus ‡ Pharmacokinetic Parameters (units) 10 mg 15 mg 30 mg 60 mg 15 mg 30 mg Bioavailability (extent) 100% T max 1 (min) 44±34 33±21** 44±29 33±21** 1.1±0.7** 2.9±1.8 C max 2 (mcg/mL) [Single-dose] 0.87±0.22 1.14±0.32** 2.42±0.68 4.55±1.27** 2.47±0.51** 4.65±0.96 C max (mcg/mL) [steady state qid] 1.05±0.26** 1.56±0.44** 3.11±0.87** N/A †† 3.09±1.17** 6.85±2.61 C min 3 (mcg/mL) [steady state qid] 0.29±0.07** 0.47±0.13** 0.93±0.26** N/A 0.61±0.21** 1.04±0.35 C avg 4 (mcg/mL) [steady state qid] 0.59±0.2** 0.94±0.29** 1.88±0.59** N/A 1.09±0.3** 2.17±0.59 V β 5 (L/kg) ———— 0.175±0.039 ———— 0.210±0.044 % Dose metabolized = <50 % Dose excreted in urine = 91 % Dose excreted in feces = 6 % Plasma protein binding = 99 1 Time-to-peak plasma concentration 2 Peak plasma concentration 3 Trough plasma concentration 4 Average plasma concentration 5 Volume of distribution † Derived from PO pharmacokinetic studies in 77 normal fasted volunteers * Derived from intramuscular pharmacokinetic studies in 54 normal volunteers ‡ Derived from intravenous pharmacokinetic studies in 24 normal volunteers †† Not applicable because 60 mg is only recommended as a single dose ** Mean value was simulated from observed plasma concentration data and standard deviation was simulated from percent coefficient of variation for observed C max and T max data Linear Kinetics In adults, following administration of single ORAL, INTRAMUSCULAR or INTRAVENOUS doses of ketorolac tromethamine in the recommended

DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of ketorolac tromethamine and other treatment options before deciding to use ketorolac tromethamine. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals. In adults, the combined duration of use of intravenous or intramuscular dosing of ketorolac tromethamine and oral ketorolac tromethamine is not to exceed 5 days. In adults, the use of oral ketorolac tromethamine is only indicated as continuation therapy to intravenous or intramuscular dosing of ketorolac tromethamine. See package insert for ketorolac tromethamine tablets for transition from intravenous or intramuscular dosing of ketorolac tromethamine (single- or multiple-dose) to multiple-dose oral ketorolac tromethamine. Note: Oral formulation should not be given as an initial dose. Use minimum effective dose for the individual patient. Total duration of treatment in adult patients: the combined duration of use of intravenous or intramuscular dosing of ketorolac tromethamine and oral ketorolac tromethamine is not to exceed 5 days. KETOROLAC TROMETHAMINE INJECTION Ketorolac tromethamine injection may be used as a single or multiple dose on a regular or "prn" schedule for the management of moderately severe, acute pain that requires analgesia at the opioid level, usually in a postoperative setting. Hypovolemia should be corrected prior to the administration of ketorolac tromethamine (see WARNINGS – Renal Effects ). Patients should be switched to alternative analgesics as soon as possible, but ketorolac tromethamine therapy is not to exceed 5 days. When administering ketorolac tromethamine injection, the intravenous bolus must be given over no less than 15 seconds. The intramuscular administration should be given slowly and deeply into the muscle. The analgesic effect begins in ~30 minutes with maximum effect in 1 to 2 hours after dosing intravenous or intramuscular. Duration of analgesic effect is usually 4 to 6 hours. Single-Dose Treatment: The following regimen should be limited to single administration use only Intramuscular Dosing Patients <65 years of age: One dose of 60 mg. Patients ≥65 years of age, renally impaired and/or less than 50 kg (110 lbs) of body weight: One dose of 30 mg. Intravenous Dosing Patients <65 years of age: One dose of 30 mg. Patients ≥65 years of age, renally impaired and/or less than 50 kg (110 lbs) of body weight: One dose of 15 mg. Multiple-Dose Treatment (Intravenous or Intramuscular) Patients <65 years of age: The recommended dose is 30 mg ketorolac tromethamine injection every 6 hours. The maximum daily dose for these populations should not exceed 120 mg. For patients ≥65 years of age, renally impaired patients (see WARNINGS ), and patients less than 50 kg (110 lbs): The recommended dose is 15 mg ketorolac tromethamine injection every 6 hours. The maximum daily dose for these populations should not exceed 60 mg. For breakthrough pain, do not increase the dose or the frequency of ketorolac tromethamine. Consideration should be given to supplementing these regimens with low doses of opioids "prn" unless otherwise contraindicated. Pharmaceutical Information for Ketorolac Tromethamine Injection Ketorolac tromethamine injection should not be mixed in a small volume (e.g., in a syringe) with morphine sulfate, meperidine hydrochloride, promethazine hydrochloride or hydroxyzine hydrochloride; this will result in precipitation of ketorolac from solution. NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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 postmarketing 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, post operative 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 Postmarketing Surveillance Study A large postmarketing observational, nonrandomized study, involving approximately 10,000 patients receiving ketorolac tromethamine, demonstrated that the risk of clinically serious gastrointestinal (GI) bleeding was dose-dependent (see Tables 3A an

WARNINGS (See also Boxed WARNING .) The total combined duration of use of oral ketorolac tromethamine and intravenous or intramuscular dosing of ketorolac tromethamine is not to exceed 5 days in adults. Ketorolac tromethamine is 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 gastrointestinal (GI) bleeding. 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 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 five 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 (2500-5000 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 postmarketing experience, postoperative hematomas and other signs of wound bleeding have been reported in association with the peri-operative use of intravenous or intramuscular dosing of ketorolac tromethamine. Therefore, peri-operative use of ketorolac tromethamine should be avoided and postoperative use be undertaken with caution when hemostasis is critical (see PRECAUT

CONTRAINDICATIONS (see also Boxed WARNING ) Ketorolac Tromethamine is contraindicated in patients with previously demonstrated hypersensitivity to ketorolac tromethamine. 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. Ketorolac tromethamine should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS – Anaphylactoid Reactions , and PRECAUTIONS – Pre-existing Asthma ). Ketorolac tromethamine is contraindicated as prophylactic analgesic before any major surgery. In the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS ). Ketorolac tromethamine is contraindicated in patients with advanced renal impairment or in patients at risk for renal failure due to volume depletion (see WARNINGS for correction of volume depletion). Ketorolac tromethamine is contraindicated in labor and delivery because, through its prostaglandin synthesis inhibitory effect, it may adversely affect fetal circulation and inhibit uterine musculature, thus increasing the risk of uterine hemorrhage. Ketorolac tromethamine inhibits platelet function and is, therefore, contraindicated in patients with suspected or confirmed cerebrovascular bleeding, hemorrhagic diathesis, incomplete hemostasis and those at high risk of bleeding (see WARNINGS and PRECAUTIONS ). Ketorolac tromethamine is contraindicated in patients currently receiving aspirin or NSAIDs because of the cumulative risks of inducing serious NSAID-related adverse events. The concomitant use of ketorolac tromethamine and probenecid is contraindicated. The concomitant use of ketorolac tromethamine and pentoxifylline is contraindicated. Ketorolac tromethamine injection is contraindicated for neuraxial (epidural or intrathecal) administration due to its alcohol content.

OVERDOSAGE Symptoms and Signs Symptoms following acute NSAIDs overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose. Treatment Patients should be managed by symptomatic and supportive care following a NSAIDs overdose. There are no specific antidotes. Emesis and/or activated charcoal (60 g to 100 g in adults, 1 g/kg to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large oral overdose (5 to 10 times the usual dose). Forced diuresis, alkalization of urine, hemodialysis or hemoperfusion may not be useful due to high protein binding. Single overdoses of ketorolac tromethamine have been variously associated with abdominal pain, nausea, vomiting, hyperventilation, peptic ulcers and/or erosive gastritis and renal dysfunction which have resolved after discontinuation of dosing.