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.

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 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 known prior exposure 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 - pre-existing asthma ). emergency help should be sought in cases where an anaphylactoid reaction occurs.

on of use of intravenous or intramuscular dosing of ketorolac tromethamine and oral ketorolac tromethamine is not to exceed 5 days.

tulence gi fullness gi ulcers (gastric/duodenal) gross bleeding/perforation heartburn nausea* stomatitis vomiting other experiences: * incidence greater than 10% abnormal renal function anemia dizziness drowsiness edema elevated liver enzymes headaches* hypertension increased bleeding time injection site pain pruritus purpura rashes tinnitus sweating 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 and 3b ). this was particularly true in elderly patients who received an average daily dose greater than 60 mg/day of ketorolac tromethamine (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 injection a. adult patients without history of pub age of patients total daily dose of ketorolac tromethamine injection ≤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 injection ≤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% 25.0%

tal risks of nsaid use in women in the first or second trimesters of pregnancy are inconclusive. reproduction studies have been performed during organogenesis using daily oral doses of ketorolac tromethamine at 3.6 mg/kg (0.37 times the human auc) in rabbits and at 10 mg/kg (1.0 times the human auc) in rats. results of these studies did not reveal evidence of teratogenicity to the fetus. however, animal reproduction studies are not always predictive of human response. oral doses of ketorolac tromethamine at 1.5 mg/kg (0.14 times the human auc), administered after gestation day 17, caused dystocia and higher pup mortality in rats. based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. in animal studies, administration of prostaglandin synthesis inhibitors such as ketorolac, resulted in increased pre- and post-implantation loss. prostaglandins also have been shown to have an important role in fetal kidney development. in published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. the estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. clinical considerations fetal/neonatal adverse reactions premature closure of fetal ductus arteriosus: avoid use of nsaids in women at about 30 weeks gestation and later in pregnancy, because nsaids, including ketorolac tromethamine, can cause premature closure of the fetal ductus arteriosus (see warnings; fetal toxicity ). oligohydramnios/neonatal renal impairment: if an nsaid is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. if ketorolac tromethamine treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. if oligohydramnios occurs, discontinue ketorolac tromethamine and follow up according to clinical practice (see warnings; fetal toxicity ). data human data there are no adequate and well-controlled studies of ketorolac tromethamine in pregnant women. ketorolac tromethamine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. premature closure of fetal ductus arteriosus: published literature reports that the use of nsaids at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. oligohydramnios/neonatal renal impairment: published studies and postmarketing reports describe maternal nsaid use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. these adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after nsaid initiation. in many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. there have been a limited number of case reports of maternal nsaid use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. these limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal nsaid use. because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to nsaids through maternal use is uncertain.

armacokinetics 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 % dose metabolized = <50 % dose excreted in feces = 6 1 time-to-peak plasma concentration % dose excreted in urine = 91 % plasma protein binding = 99 2 peak plasma concentration † derived from po pharmacokinetic studies in 77 normal fasted volunteers 3 trough plasma concentration * derived from intramuscular pharmacokinetic studies in 54 normal volunteers 4 average plasma concentration ‡ derived from intravenous pharmacokinetic studies in 24 normal volunteers 5 volume of distribution †† 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 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 linear kinetics in adults, following administration of single oral, intramuscular or intravenous doses of ketorolac tromethamine in the recommended dosage ranges, the clearance of the racemate does not change. this implies that the pharmacokinetics of ketorolac tromethamine in adults, following single or multiple intramuscular, intravenous, or recommended oral doses of ketorolac tromethamine, are linear. at the higher recommended doses, there is a proportional increase in the concentrations of free and bound racemate. distribution the mean apparent volume (v β ) of ketorolac tromethamine following complete distribution was approximately 13 liters. this parameter was determined from single-dose data. the ketorolac tromethamine racemate has been shown to be highly protein bound (99%). nevertheless, plasma concentrations as high as 10 mcg/ml will only occupy approximately 5% of the albumin binding sites. thus, the unbound fraction for each enantiomer will be constant over the therapeutic range. a decrease in serum albumin, however, will result in increased free drug concentrations. ketorolac tromethamine is excreted in human milk (see precautions – nursing mothers ). metabolism ketorolac tromethamine is largely metabolized in the liver. the metabolic products are hydroxylated and conjugated forms of the parent drug. the products of metabolism, and some unchanged drug, are excreted in the urine. excretion the principal route of elimination of ketorolac and its metabolites is renal. about 92% of a given dose is found in the urine, approximately 40% as metabolites and 60% as unchanged ketorolac. approximately 6% of a dose is excreted in the feces. a single-dose study with 10 mg ketorolac tromethamine (n = 9) demonstrated that the s-enantiomer is cleared approximately two times faster than the r-enantiomer and that the clearance was independent of the route of administration. this means that the ratio of s/r plasma concentrations decreases with time after each dose. there is little or no inversion of the r- to s- form in humans. the clearance of the racemate in normal subjects, elderly individuals and in hepatically and renally impaired patients is outlined in table 2 (see clinical pharmacology – kinetics in special populations ). the half-life of the ketorolac tromethamine s-enantiomer was approximately 2.5 hours (sd ± 0.4) compared with 5 hours (sd ± 1.7) for the r-enantiomer. in other studies, the half-life for the racemate has been reported to lie within the range of 5 to 6 hours. accumulation ketorolac tromethamine administered as an intravenous bolus, every 6 hours, for 5 days, to healthy subjects (n = 13), showed no significant difference in c max on day 1 and day 5. trough levels averaged 0.29 mcg/ml (sd ± 0.13) on day 1 and 0.55 mcg/ml (sd ± 0.23) on day 6. steady state was approached after the fourth dose. accumulation of ketorolac tromethamine has not been studied in special populations (geriatric, pediatric, renal failure patients, or hepatic disease patients).

an nsaid and periodically during the course of ongoing therapy. patients should also be encouraged to read the nsaid medication guide that accompanies each prescription dispensed. advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their healthcare provider immediately (see warnings ). ketorolac tromethamine, like other nsaids, can cause gi discomfort and, rarely, serious gi side effects, such as ulcers and bleeding, which may result in hospitalization and even death. although serious gi tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. patients should be apprised of the importance of this follow-up (see warnings, gastrointestinal effects: risk of ulceration, bleeding, and perforation ). serious skin reactions, including dress advise patients to stop taking ketorolac tromethamine immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible (see warnings ). advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur (see warnings ). patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). if these occur, patients should be instructed to stop therapy and seek immediate medical therapy. patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). if these occur, patients should be instructed to seek immediate emergency help (see warnings ). fetal toxicity inform pregnant women to avoid use of ketorolac tromethamine and other nsaids starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. if treatment with ketorolac tromethamine is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours (see warnings; fetal toxicity , precautions; pregnancy ) .