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WARNING Ketorolac tromethamine, a nonsteroidal anti-inflammatory drug (NSAID), is indicated for the short-term (up to 5 days in adults) management of moderately severe acute pain that requires analgesia at the opioid level. Oral ketorolac tromethamine is indicated only as continuation treatment following intravenous or intramuscular dosing of ketorolac tromethamine, if necessary. The total combined duration of use of oral ketorolac tromethamine and ketorolac tromethamine injection should not exceed 5 days. Ketorolac tromethamine is not indicated for use in pediatric patients and it is NOT indicated for minor or chronic painful conditions. Increasing the dose of ketorolac tromethamine beyond the label recommendations 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 THROMBOTIC EVENTS • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (see WARNINGSand PRECAUTIONS). • Ketorolac tromethamine is CONTRAINDICATED in the setting of coronary artery bypass graft (CABG) surgery (see CONTRAINDICATIONSand 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. 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 CONTRAINDICATIONSand 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. 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. 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.

bor and delivery is CONTRAINDICATED because it may adversely affect fetal circulation and inhibit uterine contractions. 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). Doses of ketorolac tromethamine injection are not to exceed 60 mg (total dose per day) in these patients. 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).

Ketorolac Tromethamine Injection, USP is a member of the pyrrolo-pyrrole group of nonsteroidal anti-inflammatory drugs (NSAIDs). The chemical name for ketorolac tromethamine is (±)-5-benzoyl-2,3-dihydro-1 H-pyrrolizine-1-carboxylic acid, compound with 2-amino-2-(hydroxymethyl)-1,3-propanediol (1:1), and the structural formula is presented in Figure 1. FIGURE 1 [ketorolac-structure] C 15H 13NO 3• C 4H 11NO 3 Ketorolac tromethamine is a racemic mixture of [-]S and [+]R ketorolac tromethamine. Ketorolac tromethamine may exist in three crystal forms. All forms are equally soluble in water. Ketorolac tromethamine has a pKa of 3.5 and an n-octanol/water partition coefficient of 0.26. The molecular weight of ketorolac tromethamine is 376.40. Ketorolac Tromethamine Injection, USP is available for intravenous (IV) or intramuscular (IM) administration as: 15 mg in 1 mL (1.5%) and 30 mg in 1 mL (3%) in sterile solution; 60 mg in 2 mL (3%) of ketorolac tromethamine in sterile solution is available for intramuscular administration only. The solutions contain 10% (w/v) alcohol, USP, and 6.68 mg, 4.35 mg, and 8.70 mg, respectively, of sodium chloride in sterile water. The pH range is 6.9 to 7.9 and is adjusted with sodium hydroxide and/or hydrochloric acid. The sterile solutions are clear to slightly yellow in color.

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 Pharmacokinetic Parameters (units) Oral † Intramuscular* Intravenous Bolus ‡ 10 mg 15 mg 30 mg 60 mg 15 mg 30 mg Bioavailability (extent) 100% T max1(min) 44±34 33±21** 44±29 33±21** 1.1±0.7** 2.9±1.8 C max2(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 min3(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 avg4(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 β5(L/kg) ——————0.175±0.039—————— 0.210±0.044 % Dose metabolized=<50 % Dose excreted in feces=6 % Dose excreted in urine=91 % Plasma protein binding=99 1Time-to-peak plasma concentration †Derived from oral pharmacokinetic studies in 77 normal fasted volunteers 2Peak plasma concentration *Derived from intramuscular pharmacokinetic studies in 54 normal volunteers 3Trough plasma concentration ‡Derived from intravenous pharmacokinetic studies in 24 normal volunteers 4Average plasma concentration ††Not applicable because 60 mg is only recommended as a single dose 5Volume of distribution **Mean value was simulated from observed plasma concentration data and standard deviation was simulated from percent coefficient of variation for observed C maxand T maxdata 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.

ravenous 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 maxon 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). Kinetics in Special Populations Geriatric Patients Based on single-dose data only, the half-life of the ketorolac tromethamine racemate increased from 5 to 7 hours in the elderly (65 to 78 years) compared with young healthy volunteers (24 to 35 years) (see Table 2). There was little difference in the C max for the two groups (elderly, 2.52 mcg/mL ± 0.77; young, 2.99 mcg/mL ± 1.03) (see PRECAUTIONS – Geriatric Use). Pediatric Patients Limited information is available regarding the pharmacokinetics of dosing of ketorolac tromethamine in the pediatric population. Following a single intravenous bolus dose of 0.5 mg/kg in 10 children 4 to 8 years old, the half-life was 5.8 ± 1.6 hours, the average clearance was 0.042 ± 0.01 L/hr/kg, the volume of distribution during the terminal phase (V β) was 0.34 ± 0.12 L/kg and the volume of distribution at steady state (V ss) was 0.26 ± 0.08 L/kg. The volume of distribution and clearance of ketorolac in pediatric patients was higher than those observed in adult subjects (see Table 1).

as 0.042 ± 0.01 L/hr/kg, the volume of distribution during the terminal phase (V β) was 0.34 ± 0.12 L/kg and the volume of distribution at steady state (V ss) was 0.26 ± 0.08 L/kg. The volume of distribution and clearance of ketorolac in pediatric patients was higher than those observed in adult subjects (see Table 1). There are no pharmacokinetic data available for administration of ketorolac tromethamine by the intramuscular route in pediatric patients. Renal Insufficiency Based on single-dose data only, the mean half-life of ketorolac tromethamine in renally impaired patients is between 6 and 19 hours and is dependent on the extent of the impairment. There is poor correlation between creatinine clearance and total ketorolac tromethamine clearance in the elderly and populations with renal impairment (r = 0.5). In patients with renal disease, the AUC ∞ of each enantiomer increased by approximately 100% compared with healthy volunteers. The volume of distribution doubles for the S-enantiomer and increases by 1/5th for the R-enantiomer. The increase in volume of distribution of ketorolac tromethamine implies an increase in unbound fraction. The AUC ∞-ratio of the ketorolac tromethamine enantiomers in healthy subjects and patients remained similar, indicating there was no selective excretion of either enantiomer in patients compared to healthy subjects (see WARNINGS – Renal Effects). Hepatic Insufficiency There was no significant difference in estimates of half-life, AUC ∞ and C maxin 7 patients with liver disease compared to healthy volunteers (see PRECAUTIONS – Hepatic Effectsand Table 2). Race Pharmacokinetic differences due to race have not been identified. Table 2: The Influence of Age, Liver and Kidney Function, on the Clearance and Terminal Half-life of Ketorolac Tromethamine (Intramuscular 1and Oral 2) in Adult Populations Total Clearance [in L/h/kg] 3 Terminal Half-life [in hours] Type of Subjects Intramuscular Mean (range) Oral Mean (range) Intramuscular Mean (range) Oral Mean (range) Normal Subjects Intramuscular (n = 54) mean age = 32, range = 18-60 Oral (n = 77) mean age = 32, range = 20-60 0.023 (0.010-0.046) 0.025 (0.013-0.050) 5.3 (3.5-9.2) 5.3 (2.4-9) Healthy Elderly Subjects Intramuscular (n = 13), Oral (n = 12) mean age = 72, range = 65-78 0.019 (0.013-0.034) 0.024 (0.018-0.034) 7 (4.7-8.6) 6.1 (4.3-7.6) Patients with Hepatic Dysfunction Intramuscular and Oral (n = 7) mean age = 51, range = 43-64 0.029 (0.013-0.066) 0.033 (0.019-0.051) 5.4 (2.2-6.9) 4.5 (1.6-7.6) Patients with Renal Impairment Intramuscular (n = 25), Oral (n = 9) serum creatinine = 1.9-5.0 mg/dL, mean age (Intramuscular) = 54, range = 35-71 mean age (Oral) = 57, range = 39-70 0.015 (0.005-0.043) 0.016 (0.007-0.052) 10.3 (5.9-19.2) 10.8 (3.4-18.9) Renal Dialysis Patients Intramuscular and Oral (n = 9) mean age = 40, range = 27-63 0.016 (0.003-0.036) - 13.6 (8.0-39.1) - 1Estimated from 30 mg single intramuscular doses of ketorolac tromethamine 2Estimated from 10 mg single oral doses of ketorolac tromethamine 3Liters/hour/kilogram Intravenous-Administration:In normal subjects (n=37), the total clearance of 30 mg intravenous-administered ketorolac tromethamine was 0.030 (0.017 to 0.051) L/h/kg. The terminal half-life was 5.6 (4.0 to 7.9) hours. (see Kinetics in Special Populationsfor use of intravenous dosing of ketorolac tromethamine in pediatric patients.) CLINICAL STUDIES Adult Patients In a postoperative study, where all patients received morphine by a PCA device, patients treated with ketorolac tromethamine intravenous as fixed intermittent boluses (e.g., 30 mg initial dose followed by 15 mg every 3 hours), required significantly less morphine (26%) than the placebo group.

CAL STUDIES Adult Patients In a postoperative study, where all patients received morphine by a PCA device, patients treated with ketorolac tromethamine intravenous as fixed intermittent boluses (e.g., 30 mg initial dose followed by 15 mg every 3 hours), required significantly less morphine (26%) than the placebo group. Analgesia was significantly superior, at various postdosing pain assessment times, in the patients receiving ketorolac tromethamine intravenous plus PCA morphine as compared to patients receiving PCA-administered morphine alone.

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.

(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. Ketorolac tromethamine is contraindicated 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 WARNINGSfor 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 WARNINGSand 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.

(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 to 5000 units every 12 hours), warfarin and dextrans have not been studied extensively, but may also be associated with an increased risk of bleeding.

mitant therapy only extremely cautiously. The concurrent use of ketorolac tromethamine and therapy that affects hemostasis, including prophylactic low-dose heparin (2500 to 5000 units every 12 hours), 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 CONTRAINDICATIONSand PRECAUTIONS–Pre-existing Asthma). 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 three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs.

X-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first few weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the 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, such as ketorolac tromethamine, increases the risk of serious gastrointestinal (GI) events (see WARNINGS). Status Post Coronary Artery Bypass Graft (CABG) Surgery 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. NSAIDs are contraindicated in the setting of CABG surgery (see CONTRAINDICATIONS). Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years follow-up. Avoid the use of ketorolac tromethamine in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If ketorolac tromethamine is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. Hypertension NSAIDs, including ketorolac tromethamine, can lead to onset of new hypertension or worsening of pre-existing 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. Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients.

Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of ketorolac tromethamine may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers (ARBs) (see PRECAUTIONS – Drug Interactions). Avoid the use of ketorolac tromethamine in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If ketorolac tromethamine is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 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 or any other sign of hypersensitivity. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as ketorolac tromethamine. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue ketorolac tromethamine and evaluate the patient immediately. Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs, including ketorolac tromethamine, in pregnant women at about 30 weeks gestation and later. NSAIDs including ketorolac tromethamine, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment: Use of NSAIDs, including ketorolac tromethamine, at about 20 weeks gestation or later in pregnancy may cause 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. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit ketorolac tromethamine use to the lowest effective dose and shortest duration possible.

ation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit ketorolac tromethamine use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if ketorolac tromethamine treatment extends beyond 48 hours. Discontinue ketorolac tromethamine if oligohydramnios occurs and follow up according to clinical practice (see PRECAUTIONS; Pregnancy).

General Ketorolac tromethamine cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. The pharmacological activity of ketorolac tromethamine in reducing inflammation may diminish the utility of this diagnostic sign in detecting complications of presumed noninfectious, painful conditions. Hepatic Effects Ketorolac tromethamine should be used 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 tromethamine. 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 and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with ketorolac tromethamine. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), ketorolac tromethamine should be discontinued. Hematologic Effects Anemia is sometimes seen in patients receiving NSAIDs, including ketorolac tromethamine. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including ketorolac tromethamine, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving ketorolac tromethamine who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored. Pre-existing 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 nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, ketorolac tromethamine should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with pre-existing asthma. Information for Patients Ketorolac tromethamine is a potent NSAID and may cause serious side effects such as gastrointestinal bleeding or kidney failure, which may result in hospitalization and even fatal outcome.

ith this form of aspirin sensitivity and should be used with caution in patients with pre-existing asthma. Information for Patients Ketorolac tromethamine is a potent NSAID and may cause serious side effects such as gastrointestinal bleeding or kidney failure, which may result in hospitalization and even fatal outcome. Physicians, when prescribing ketorolac tromethamine, should inform their patients or their guardians of the potential risks of ketorolac tromethamine treatment (see Boxed WARNING, WARNINGS, PRECAUTIONS, and ADVERSE REACTIONSsections), instruct patients to seek medical advice if they develop treatment-related adverse events, and advise patients not to give oral ketorolac tromethamine to other family members and to discard any unused drug. Remember that 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. Patients should be informed of the following information before initiating therapy with 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. 1. 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 health care provider immediately (see WARNINGS). 2. 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). 3. 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). 4. 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). 5. 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. 6. 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). 7. 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). Laboratory Tests Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding.

she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours (see WARNINGS; Fetal Toxicity,PRECAUTIONS; Pregnancy). Laboratory Tests Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs, should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash etc.) or if abnormal liver tests persist or worsen, ketorolac tromethamine should be discontinued. Drug Interactions Ketorolac is highly bound to human plasma protein (mean 99.2%). There is no evidence in animal or human studies that ketorolac tromethamine induces or inhibits hepatic enzymes capable of metabolizing itself or other drugs. Warfarin, Digoxin, Salicylate, and Heparin The in vitrobinding of warfarinto plasma proteins is only slightly reduced by ketorolac tromethamine (99.5% control vs 99.3%) when ketorolac plasma concentrations reach 5 to 10 mcg/mL. Ketorolac does not alter digoxinprotein binding. In vitrostudies indicate that, at therapeutic concentrations of salicylate(300 mcg/mL), the binding of ketorolac was reduced from approximately 99.2% to 97.5%, representing a potential two-fold increase in unbound ketorolac plasma levels. Therapeutic concentrations of digoxin, warfarin, ibuprofen, naproxen, piroxicam, acetaminophen, phenytoinand tolbutamidedid not alter ketorolac tromethamine protein binding. In a study involving 12 adult volunteers, oral ketorolac tromethamine was coadministered with a single dose of 25 mg warfarin, causing no significant changes in pharmacokinetics or pharmacodynamics of warfarin. In another study, ketorolac tromethamine dosed intravenous or intramuscular was given with two doses of 5000 U of heparinto 11 healthy volunteers, resulting in a mean template bleeding time of 6 minutes (3.2 to 11.4 min) compared to a mean of 6.0 minutes (3.4 to 7.5 min) for heparin alone and 5.1 minutes (3.5 to 8.5 min) for placebo. Although these results do not indicate a significant interaction between ketorolac tromethamine and warfarin or heparin, the administration of ketorolac tromethamine to patients taking anticoagulants should be done extremely cautiously, and patients should be closely monitored (see WARNINGSand PRECAUTIONS – Hematologic Effects). The effects of warfarin and NSAIDs, in general, on GI bleeding are synergistic, such that the users of both drugs together have a risk of serious GI bleeding higher than the users of either drug alone. Aspirin When ketorolac tromethamine is administered with aspirin, its protein binding is reduced, although the clearance of free ketorolac tromethamine is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of ketorolac tromethamine and aspirin is not generally recommended because of the potential of increased adverse effects. Diuretics Clinical studies, as well as postmarketing observations, have shown that ketorolac tromethamine can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS – Renal Effects), as well as to assure diuretic efficacy.

iuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS – Renal Effects), as well as to assure diuretic efficacy. Probenecid Concomitant administration of oral ketorolac tromethamine and probenecid resulted in decreased clearance and volume of distribution of ketorolac and significant increases in ketorolac plasma levels (total AUC increased approximately three-fold from 5.4 to 17.8 mcg/h/mL) and terminal half-life increased approximately two-fold from 6.6 to 15.1 hours. Therefore, concomitant use of ketorolac tromethamine and probenecid is contraindicated. Lithium NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. Methotrexate NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate. ACE Inhibitors/Angiotensin II Receptor Antagonists Concomitant use of ACE inhibitors and/or angiotensin II receptor antagonistsmay increase the risk of renal impairment, particularly in volume-depleted patients. Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors and/or angiotensin II receptor antagonists. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors and/or angiotensin II receptor antagonists. Antiepileptic Drugs Sporadic cases of seizures have been reported during concomitant use of ketorolac tromethamine and antiepileptic drugs (phenytoin, carbamazepine). Psychoactive Drugs Hallucinations have been reported when ketorolac tromethamine was used in patients taking psychoactive drugs (fluoxetine, thiothixene, alprazolam). Pentoxifylline When ketorolac tromethamine is administered concurrently with pentoxifylline, there is an increased tendency to bleeding. Nondepolarizing Muscle Relaxants In postmarketing experience there have been reports of a possible interaction between ketorolac tromethamine intravenous/intramuscular and nondepolarizing muscle relaxantsthat resulted in apnea. The concurrent use of ketorolac tromethamine with muscle relaxants has not been formally studied. Selective Serotonin Reuptake Inhibitors (SSRIs) There is an increased risk of gastrointestinal bleeding when selective serotonin reuptake inhibitors(SSRIs) are combined with NSAIDs. Caution should be used when NSAIDs are administered concomitantly with SSRIs. Carcinogenesis, Mutagenesis, and Impairment of Fertility An 18-month study in mice with oral doses of ketorolac tromethamine tablets at 2 mg/kg/day (0.9 times the human systemic exposure at the recommended intramuscular or intravenous dose of 30 mg qid, based on area-under-the-plasma-concentration curve [AUC]), and a 24-month study in rats at 5 mg/kg/day (0.5 times the human AUC) showed no evidence of tumorigenicity. Ketorolac tromethamine was not mutagenic in the Ames test, unscheduled DNA synthesis and repair, and in forward mutation assays. Ketorolac tromethamine did not cause chromosome breakage in the in vivomouse micronucleus assay.

h study in rats at 5 mg/kg/day (0.5 times the human AUC) showed no evidence of tumorigenicity. Ketorolac tromethamine was not mutagenic in the Ames test, unscheduled DNA synthesis and repair, and in forward mutation assays. Ketorolac tromethamine did not cause chromosome breakage in the in vivomouse micronucleus assay. At 1590 mcg/mL and at higher concentrations, ketorolac tromethamine increased the incidence of chromosomal aberrations in Chinese hamster ovarian cells. Impairment of fertility did not occur in male or female rats at oral doses of 9 mg/kg (0.9 times the human AUC) and 16 mg/kg (1.6 times the human AUC) of ketorolac tromethamine, respectively. Pregnancy Risk Summary Use of NSAIDs, including ketorolac tromethamine, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of ketorolac tromethamine use between about 20 and 30 weeks of gestation, and avoid ketorolac tromethamine use at about 30 weeks of gestation and later in pregnancy (see WARNINGS; Fetal Toxicity). Premature Closure of Fetal Ductus Arteriosus: Use of NSAIDs, including ketorolac tromethamine, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal 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 tromethamine, 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 to 4% and 15 to 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.

, 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. Labor and Delivery The use of ketorolac tromethamine is contraindicated in labor and delivery because, through its prostaglandin synthesis inhibitory effect, it may adversely affect fetal circulation and inhibit uterine contractions, thus increasing the risk of uterine hemorrhage (see CONTRAINDICATIONS). Effects on Fertility The use of ketorolac tromethamine, as with any drug known to inhibit cyclooxygenase/ prostaglandin synthesis, may impair fertility and is not recommended in women attempting to conceive. In women who have difficulty conceiving or are undergoing investigation of infertility, withdrawal of ketorolac tromethamine should be considered. Nursing Mothers Limited data from one published study that included 10 breastfeeding women 2-6 days postpartum showed low levels of ketorolac in breast milk and were undetectable (less than 5 ng/mL) in 4 of the patients. After a single administration of 10 mg of ketorolac tromethamine, the maximum milk concentration observed was 7.3 ng/mL, and the maximum milk-to-plasma ratio was 0.037. After 1 day of dosing (10 mg every 6 hours), the maximum milk concentration was 7.9 ng/mL, and the maximum milk-to-plasma ratio was 0.025.

he patients. After a single administration of 10 mg of ketorolac tromethamine, the maximum milk concentration observed was 7.3 ng/mL, and the maximum milk-to-plasma ratio was 0.037. After 1 day of dosing (10 mg every 6 hours), the maximum milk concentration was 7.9 ng/mL, and the maximum milk-to-plasma ratio was 0.025. Assuming a daily intake of 400 to 1,000 mL of human milk per day and a maternal body weight of 60 kg, the calculated maximum daily infant exposure was 0.00263 mg/kg/day, which is 0.4% of the maternal weight-adjusted dose. Exercise caution when ketorolac is administered to a nursing woman. Available information has not shown any specific adverse events in nursing infants; however, instruct patients to contact their infant's healthcare provider if they note any adverse events. Pediatric Use Ketorolac tromethamine is not indicated for use in pediatric patients. The safety and effectiveness of ketorolac tromethamine in pediatric patients below the age of 17 years have not been established. Geriatric Use (≥ 65 Years of Age) Because ketorolac tromethamine may be cleared more slowly by the elderly (see CLINICAL PHARMACOLOGY) who are also more sensitive to the dose-related adverse effects of NSAIDs (see WARNINGS - Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation), extreme caution and reduced dosages (see DOSAGE AND ADMINISTRATION) and careful clinical monitoring must be used when treating the elderly with ketorolac tromethamine .

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.

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 ketorolactromethamine 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 3Aand 3B).

otemia, 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 3Aand 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% To report SUSPECTED ADVERSE REACTIONS, contact Fosun Pharma USA Inc. at 1-866-611-3762 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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. 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.

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 formulationshould notbe given as an initial dose. Use minimum effective dosefor 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 “as needed” 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 "as needed" unless otherwise contraindicated.

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 "as needed" 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.

Ketorolac Tromethamine Injection, USP is supplied as follows: NDC Number Ketorolac Tromethamine Injection USP Package Factor 72266-234-25 15 mg/mL, 1 mL single-dose vial 25 vials per carton 72266-118-25 30 mg/mL, 1 mL single-dose vial 25 vials per carton 72189-583-01 60 mg/2 mL, 2 mL single-dose vial 25 vials per carton

*FOR IM USE ONLY Storage Conditions Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Protect from light. Retain in carton until time of use. Distributed by: Fosun Pharma USA Inc. Princeton, NJ 08540 Made in India Revised: 05/2023 1313000885-00

What is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: • Increased risk of a heart attack or stroke that can lead to death.This risk may happen early in treatment and may increase: o with increasing doses of NSAIDs o with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a"coronary artery bypass graft (CABG)." Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. • Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: • anytime during use • without warning symptoms • that may cause death The risk of getting an ulcer or bleeding increases with: • past history of stomach ulcers, or stomach or intestinal bleeding with the use of NSAIDs • taking medicines called "corticosteroids","anticoagulants", "SSRIs", or "SNRIs" • increasing doses of NSAIDs • longer use of NSAIDs • smoking • drinking alcohol • older age • poor health • advanced liver disease • bleeding problems NSAIDs should only be used: • exactly as prescribed • at the lowest dose possible for your treatment • for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. Who should not take NSAIDs? Do not take NSAIDs: • if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. • right before or after heart bypass surgery. Before taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you: • have liver or kidney problems • have high blood pressure • have asthma • are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not takeNSAIDs after about 30 weeks of pregnancy. • are breastfeeding or plan to breast feed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbalsupplements.NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See "What is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) ?" • new or worse high blood pressure • heart failure • liver problems including liver failure • kidney problems including kidney failure • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • Other side effects of NSAIDs include:stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness.

failure • liver problems including liver failure • kidney problems including kidney failure • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • Other side effects of NSAIDs include:stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms: • shortness of breath or trouble breathing • chest pain • weakness in one part or side of your body • slurred speech • swelling of the face or throat Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: • nausea • more tired or weaker than usual • diarrhea • itching • your skin or eyes look yellow • indigestion or stomach pain • flu-like symptoms • vomit blood • there is blood in your bowel movement or it is black and sticky like tar • unusual weight gain • skin rash or blisters with fever • swelling of the arms and legs, hands and feet If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs • Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. This Medication Guide has been approved by the U.S. Food and Drug Administration. Distributed by: Fosun Pharma USA Inc. Princeton, NJ 08540 Made in India Revised: 05/2023 1313000885-00

WARNING Ketorolac tromethamine, a nonsteroidal anti-inflammatory drug (NSAID), is indicated for the short-term (up to 5 days in adults) management of moderately severe acute pain that requires analgesia at the opioid level. Oral ketorolac tromethamine is indicated only as continuation treatment following intravenous or intramuscular dosing of ketorolac tromethamine, if necessary. The total combined duration of use of oral ketorolac tromethamine and ketorolac tromethamine injection should not exceed 5 days. Ketorolac tromethamine is not indicated for use in pediatric patients and it is NOT indicated for minor or chronic painful conditions. Increasing the dose of ketorolac tromethamine beyond the label recommendations 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 THROMBOTIC EVENTS Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (see WARNINGS and PRECAUTIONS ). Ketorolac tromethamine is CONTRAINDICATED in the setting of coronary artery bypass graft (CABG) surgery (see CONTRAINDICATIONS and 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. 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. 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. 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.

labor and delivery is CONTRAINDICATED because it may adversely affect fetal circulation and inhibit uterine contractions. 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 ). Doses of ketorolac tromethamine injection are not to exceed 60 mg (total dose per day) in these patients. 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 ).

DESCRIPTION Ketorolac Tromethamine Injection, USP is a member of the pyrrolo-pyrrole group of nonsteroidal anti-inflammatory drugs (NSAIDs). The chemical name for ketorolac tromethamine is (±)-5-benzoyl- 2,3- dihydro-1 H -pyrrolizine-1-carboxylic acid, compound with 2-amino-2-(hydroxymethyl)-1,3- propanediol (1:1), and the structural formula is presented in Figure 1. Ketorolac tromethamine is a racemic mixture of [-]S and [+]R ketorolac tromethamine. Ketorolac tromethamine may exist in three crystal forms. All forms are equally soluble in water. Ketorolac tromethamine has a pKa of 3.5 and an n-octanol/water partition coefficient of 0.26. The molecular weight of ketorolac tromethamine is 376.40. Ketorolac Tromethamine Injection, USP is available for intravenous (IV) or intramuscular (IM) administration as: 30 mg in 1 mL (3%) in sterile solution. The solutions contain 10% (w/v) alcohol, USP, and 4.35 mg of sodium chloride in sterile water. The pH range is 6.9 to 7.9 and is adjusted with sodium hydroxide and/or hydrochloric acid. The sterile solutions are clear, colorless to slight yellow in color. ketorolac-structure

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 feces = 6 1 Time-to-peak plasma concentration % Dose excreted in urine = 91 % Plasma protein binding = 99 † Derived from oral pharmacokinetic studies in 77 normal fasted volunteers 2 Peak plasma concentration *Derived from intramuscular pharmacokinetic studies in 54 normal volunteers 3 Trough plasma concentration ‡ Derived from intravenous pharmacokinetic studies in 24 normal volunteers 4 Average plasma concentration †† Not applicable because 60 mg is only recommended as a single dose 5 Volume of distribution ** 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 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.

hange. 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). Kinetics in Special Populations Geriatric Patients Based on single-dose data only, the half-life of the ketorolac tromethamine racemate increased from 5 to 7 hours in the elderly (65 to 78 years) compared with young healthy volunteers (24 to 35 years) (see Table 2). There was little difference in the C max for the two groups (elderly, 2.52 mcg/mL ± 0.77; young, 2.99 mcg/mL ± 1.03) (see PRECAUTIONS – Geriatric Use ). Pediatric Patients Limited information is available regarding the pharmacokinetics of dosing of ketorolac tromethamine in the pediatric population. Following a single intravenous bolus dose of 0.5 mg/kg in 10 children 4 to 8 years old, the half-life was 5.8 ± 1.6 hours, the average clearance was 0.042 ± 0.01 L/hr/kg, the volume of distribution during the terminal phase (Vβ) was 0.34 ± 0.12 L/kg and the volume of distribution at steady state (Vss) was 0.26 ± 0.08 L/kg.

owing a single intravenous bolus dose of 0.5 mg/kg in 10 children 4 to 8 years old, the half-life was 5.8 ± 1.6 hours, the average clearance was 0.042 ± 0.01 L/hr/kg, the volume of distribution during the terminal phase (Vβ) was 0.34 ± 0.12 L/kg and the volume of distribution at steady state (Vss) was 0.26 ± 0.08 L/kg. The volume of distribution and clearance of ketorolac in pediatric patients was higher than those observed in adult subjects (see Table 1). There are no pharmacokinetic data available for administration of ketorolac tromethamine by the intramuscular route in pediatric patients. Renal Insufficiency Based on single-dose data only, the mean half-life of ketorolac tromethamine in renally impaired patients is between 6 and 19 hours and is dependent on the extent of the impairment. There is poor correlation between creatinine clearance and total ketorolac tromethamine clearance in the elderly and populations with renal impairment (r = 0.5). In patients with renal disease, the AUC∞ of each enantiomer increased by approximately 100% compared with healthy volunteers. The volume of distribution doubles for the S-enantiomer and increases by 1/5th for the R-enantiomer. The increase in volume of distribution of ketorolac tromethamine implies an increase in unbound fraction. The AUC∞-ratio of the ketorolac tromethamine enantiomers in healthy subjects and patients remained similar, indicating there was no selective excretion of either enantiomer in patients compared to healthy subjects (see WARNINGS – Renal Effects ). Hepatic Insufficiency There was no significant difference in estimates of half-life, AUC∞ and C max , in 7 patients with liver disease compared to healthy volunteers (see PRECAUTIONS – Hepatic Effects and Table 2). Race Pharmacokinetic differences due to race have not been identified. Table 2: The Influence of Age, Liver and Kidney Function, on the Clearance and Terminal Half-life of Ketorolac Tromethamine (Intramuscular 1 and Oral 2 ) in Adult Populations Total Clearance [in L/h/kg] 3 Terminal Half-life [in hours] Type of Subjects Intramuscular Mean (range) Oral Mean (range) Intramuscular Mean (range) Oral Mean (range) Normal Subjects Intramuscular (n = 54) mean age = 32, range = 18-60 Oral (n = 77) mean age = 32, range = 20-60 0.023 (0.010- 0.046) 0.025 (0.013- 0.050) 5.3 (3.5-9.2) 5.3 (2.4-9) Healthy Elderly Subjects Intramuscular (n = 13), Oral (n = 12) mean age = 72, range = 65-78 0.019 (0.013- 0.034) 0.024 (0.018- 0.034) 7 (4.7-8.6) 6.1 (4.3-7.6) Patients with Hepatic Dysfunction Intramuscular and Oral (n = 7) mean age = 51, range = 43-64 0.029 (0.013- 0.066) 0.033 (0.019- 0.051) 5.4 (2.2-6.9) 4.5 (1.6-7.6) Patients with Renal Impairment Intramuscular (n = 25), Oral (n = 9) serum creatinine = 1.9-5.0 mg/dL, mean age (Intramuscular) = 54, range = 35-71 mean age (Oral) = 57, range = 39-70 0.015 (0.005- 0.043) 0.016 (0.007- 0.052) 10.3 (5.9-19.2) 10.8 (3.4-18.9) Renal Dialysis Patients Intramuscular and Oral (n = 9) mean age = 40, range = 27-63 0.016 (0.003- 0.036) – 13.6 (8.0-39.1) – 1 Estimated from 30 mg single intramuscular doses of ketorolac tromethamine 2 Estimated from 10 mg single oral doses of ketorolac tromethamine 3 Liters/hour/kilogram Intravenous-Administration: In normal subjects (n=37), the total clearance of 30 mg intravenous-administered ketorolac tromethamine was 0.030 (0.017-0.051) L/h/kg. The terminal half-life was 5.6 (4.0-7.9) hours. (see Kinetics in Special Populations for use of intravenous dosing of ketorolac tromethamine in pediatric patients.)

CLINICAL STUDIES Adult Patients In a postoperative study, where all patients received morphine by a PCA device, patients treated with ketorolac tromethamine intravenous as fixed intermittent boluses (e.g., 30 mg initial dose followed by 15 mg every 3 hours), required significantly less morphine (26%) than the placebo group. Analgesia was significantly superior, at various postdosing pain assessment times, in the patients receiving ketorolac tromethamine intravenous plus PCA morphine as compared to patients receiving PCA-administered morphine alone.

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.

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. Ketorolac tromethamine is contraindicated 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.

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 to 5000 units every 12 hours), warfarin and dextrans have not been studied extensively, but may also be associated with an increased risk of bleeding.

mitant therapy only extremely cautiously. The concurrent use of ketorolac tromethamine and therapy that affects hemostasis, including prophylactic low-dose heparin (2500 to 5000 units every 12 hours), 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. Cardiovascular Effects Cardiovascular 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 cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs.

X-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first few weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the 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, such as ketorolac tromethamine, increases the risk of serious gastrointestinal (GI) events (see WARNINGS ). Status Post Coronary Artery Bypass Graft (CABG) Surgery 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. NSAIDs are contraindicated in the setting of CABG surgery (see CONTRAINDICATIONS ). Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years follow-up. Avoid the use of ketorolac tromethamine in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If ketorolac tromethamine is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. Hypertension NSAIDs, including ketorolac tromethamine, can lead to onset of new hypertension or worsening of pre-existing 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. Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo -treated patients.

ailure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo -treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of ketorolac tromethamine may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers (ARBs) (see PRECAUTIONS – Drug Interactions ). Avoid the use of ketorolac tromethamine in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If ketorolac tromethamine is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. Serious Skin Reactions NSAIDs, including ketorolac tromethamine, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of ketorolac tromethamine injection at the first appearance of skin rash or any other sign of hypersensitivity. Ketorolac tromethamine injection is contraindicated in patients with previous serious skin reactions to NSAIDs (see CONTRAINDICATIONS ) . Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as ketorolac tromethamine. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue ketorolac tromethamine and evaluate the patient immediately. Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs, including ketorolac tromethamine, in pregnant women at about 30 weeks gestation and later. NSAIDs including ketorolac tromethamine, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment: Use of NSAIDs, including ketorolac tromethamine, at about 20 weeks gestation or later in pregnancy may cause 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. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation.

weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit ketorolac tromethamine use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if ketorolac tromethamine treatment extends beyond 48 hours. Discontinue ketorolac tromethamine if oligohydramnios occurs and follow up according to clinical practice (see PRECAUTIONS; Pregnancy ).

PRECAUTIONS General Ketorolac tromethamine cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. The pharmacological activity of ketorolac tromethamine in reducing inflammation may diminish the utility of this diagnostic sign in detecting complications of presumed noninfectious, painful conditions. Hepatic Effects Ketorolac tromethamine should be used 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 tromethamine. 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 and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with ketorolac tromethamine. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), ketorolac tromethamine should be discontinued. Hematologic Effects Anemia is sometimes seen in patients receiving NSAIDs, including ketorolac tromethamine. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including ketorolac tromethamine, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving ketorolac tromethamine who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored. Pre-existing 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 nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, ketorolac tromethamine should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with pre-existing asthma. Information for Patients Ketorolac tromethamine is a potent NSAID and may cause serious side effects such as gastrointestinal bleeding or kidney failure, which may result in hospitalization and even fatal outcome.

ith this form of aspirin sensitivity and should be used with caution in patients with pre-existing asthma. Information for Patients Ketorolac tromethamine is a potent NSAID and may cause serious side effects such as gastrointestinal bleeding or kidney failure, which may result in hospitalization and even fatal outcome. Physicians, when prescribing ketorolac tromethamine, should inform their patients or their guardians of the potential risks of ketorolac tromethamine treatment (see Boxed WARNING , WARNINGS , PRECAUTIONS , and ADVERSE REACTIONS sections), instruct patients to seek medical advice if they develop treatment-related adverse events, and advise patients not to give oral ketorolac tromethamine to other family members and to discard any unused drug. Remember that 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. Patients should be informed of the following information before initiating therapy with 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 ). Laboratory Tests Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding.

e may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours (see WARNINGS; Fetal Toxicity , PRECAUTIONS; Pregnancy ). Laboratory Tests Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs, should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash etc.) or if abnormal liver tests persist or worsen, ketorolac tromethamine should be discontinued. Drug Interactions Ketorolac is highly bound to human plasma protein (mean 99.2%). There is no evidence in animal or human studies that ketorolac tromethamine induces or inhibits hepatic enzymes capable of metabolizing itself or other drugs. Warfarin, Digoxin, Salicylate, and Heparin The in vitro binding of warfarin to plasma proteins is only slightly reduced by ketorolac tromethamine (99.5% control vs 99.3%) when ketorolac plasma concentrations reach 5 to 10 mcg/mL. Ketorolac does not alter digoxin protein binding. In vitro studies indicate that, at therapeutic concentrations of salicylate (300 mcg/mL), the binding of ketorolac was reduced from approximately 99.2% to 97.5%, representing a potential two-fold increase in unbound ketorolac plasma levels. Therapeutic concentrations of digoxin, warfarin, ibuprofen, naproxen , piroxicam, acetaminophen, phenytoin and tolbutamide did not alter ketorolac tromethamine protein binding. In a study involving 12 adult volunteers, oral ketorolac tromethamine was coadministered with a single dose of 25 mg warfarin, causing no significant changes in pharmacokinetics or pharmacodynamics of warfarin . In another study, ketorolac tromethamine dosed intravenous or intramuscular was given with two doses of 5000 U of heparin to 11 healthy volunteers, resulting in a mean template bleeding time of 6 minutes (3.2 to 11.4 min) compared to a mean of 6.0 minutes (3.4 to 7.5 min) for heparin alone and 5.1 minutes (3.5 to 8.5 min) for placebo. Although these results do not indicate a significant interaction between ketorolac tromethamine and warfarin or heparin, the administration of ketorolac tromethamine to patients taking anticoagulants should be done extremely cautiously and patients should be closely monitored (see WARNINGS and PRECAUTIONS – Hematologic Effects ). The effects of warfarin and NSAIDs, in general, on GI bleeding are synergistic, such that the users of both drugs together have a risk of serious GI bleeding higher than the users of either drug alone. Aspirin When ketorolac tromethamine is administered with aspirin, its protein binding is reduced, although the clearance of free ketorolac tromethamine is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of ketorolac tromethamine and aspirin is not generally recommended because of the potential of increased adverse effects. Diuretics Clinical studies, as well as postmarketing observations, have shown that ketorolac tromethamine can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS – Renal Effects ), as well as to assure diuretic efficacy.

uretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS – Renal Effects ), as well as to assure diuretic efficacy. Probenecid Concomitant administration of oral ketorolac tromethamine and probenecid resulted in decreased clearance and volume of distribution of ketorolac and significant increases in ketorolac plasma levels (total AUC increased approximately three-fold from 5.4 to 17.8 mcg/h/mL) and terminal half-life increased approximately two-fold from 6.6 to 15.1 hours. Therefore, concomitant use of ketorolac tromethamine and probenecid is contraindicated. Lithium NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. Methotrexate NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate. ACE Inhibitors/Angiotensin II Receptor Antagonists Concomitant use of ACE inhibitors and/or angiotensin II receptor antagonists may increase the risk of renal impairment, particularly in volume-depleted patients. Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors and/or angiotensin II receptor antagonists. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors and/or angiotensin II receptor antagonists. Antiepileptic Drugs Sporadic cases of seizures have been reported during concomitant use of ketorolac tromethamine and antiepileptic drugs (phenytoin, carbamazepine). Psychoactive Drugs Hallucinations have been reported when ketorolac tromethamine was used in patients taking psychoactive drugs (fluoxetine, thiothixene, alprazolam). Pentoxifylline When ketorolac tromethamine is administered concurrently with pentoxifylline , there is an increased tendency to bleeding. Nondepolarizing Muscle Relaxants In postmarketing experience there have been reports of a possible interaction between ketorolac tromethamine intravenous/intramuscular and nondepolarizing muscle relaxants that resulted in apnea. The concurrent use of ketorolac tromethamine with muscle relaxants has not been formally studied. Selective Serotonin Reuptake Inhibitors (SSRIs) There is an increased risk of gastrointestinal bleeding when selective serotonin reuptake inhibitors (SSRIs) are combined with NSAIDs. Caution should be used when NSAIDs are administered concomitantly with SSRIs. Carcinogenesis, Mutagenesis, and Impairment of Fertility An 18-month study in mice with oral doses of ketorolac tromethamine tablets at 2 mg/kg/day (0.9 times the human systemic exposure at the recommended intramuscular or intravenous dose of 30 mg qid, based on area-under-the-plasma-concentration curve [AUC]), and a 24-month study in rats at 5 mg/kg/day (0.5 times the human AUC) showed no evidence of tumorigenicity. Ketorolac tromethamine was not mutagenic in the Ames test, unscheduled DNA synthesis and repair, and in forward mutation assays. Ketorolac tromethamine did not cause chromosome breakage in the in vivo mouse micronucleus assay.

study in rats at 5 mg/kg/day (0.5 times the human AUC) showed no evidence of tumorigenicity. Ketorolac tromethamine was not mutagenic in the Ames test, unscheduled DNA synthesis and repair, and in forward mutation assays. Ketorolac tromethamine did not cause chromosome breakage in the in vivo mouse micronucleus assay. At 1590 mcg/mL and at higher concentrations, ketorolac tromethamine increased the incidence of chromosomal aberrations in Chinese hamster ovarian cells. Impairment of fertility did not occur in male or female rats at oral doses of 9 mg/kg (0.9 times the human AUC) and 16 mg/kg (1.6 times the human AUC) of ketorolac tromethamine, respectively. Pregnancy Risk Summary Use of NSAIDs, including ketorolac tromethamine, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of ketorolac tromethamine use between about 20 and 30 weeks of gestation, and avoid ketorolac tromethamine use at about 30 weeks of gestation and later in pregnancy (see WARNINGS; Fetal Toxicity ). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including ketorolac tromethamine, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal 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 tromethamine, 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.

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. Labor and Delivery The use of ketorolac tromethamine is contraindicated in labor and delivery because, through its prostaglandin synthesis inhibitory effect, it may adversely affect fetal circulation and inhibit uterine contractions, thus increasing the risk of uterine hemorrhage (see CONTRAINDICATIONS ). Effects on Fertility The use of ketorolac tromethamine, as with any drug known to inhibit cyclooxygenase/ prostaglandin synthesis, may impair fertility and is not recommended in women attempting to conceive. In women who have difficulty conceiving or are undergoing investigation of infertility, withdrawal of ketorolac tromethamine should be considered. Nursing Mothers Limited data from one published study that included 10 breastfeeding women 2-6 days postpartum showed low levels of ketorolac in breast milk and were undetectable (less than 5 ng/mL) in 4 of the patients. After a single administration of 10 mg of ketorolac tromethamine, the maximum milk concentration observed was 7.3 ng/mL, and the maximum milk-to-plasma ratio was 0.037. After 1 day of dosing (10 mg every 6 hours), the maximum milk concentration was 7.9 ng/mL, and the maximum milk-to-plasma ratio was 0.025.

he patients. After a single administration of 10 mg of ketorolac tromethamine, the maximum milk concentration observed was 7.3 ng/mL, and the maximum milk-to-plasma ratio was 0.037. After 1 day of dosing (10 mg every 6 hours), the maximum milk concentration was 7.9 ng/mL, and the maximum milk-to-plasma ratio was 0.025. Assuming a daily intake of 400-1,000 mL of human milk per day and a maternal body weight of 60 kg, the calculated maximum daily infant exposure was 0.00263 mg/kg/day, which is 0.4% of the maternal weight-adjusted dose. Exercise caution when ketorolac is administered to a nursing woman. Available information has not shown any specific adverse events in nursing infants; however, instruct patients to contact their infant’s healthcare provider if they note any adverse events. Pediatric Use Ketorolac tromethamine is not indicated for use in pediatric patients. The safety and effectiveness of ketorolac tromethamine in pediatric patients below the age of 17 years have not been established. Geriatric Use (≥65 Years of Age) Because ketorolac tromethamine may be cleared more slowly by the elderly (see CLINICAL PHARMACOLOGY ) who are also more sensitive to the dose-related adverse effects of NSAIDs (see WARNINGS – Gastrointestinal Effects – Risk of Ulceration, Bleeding , and Perforation ), extreme caution and reduced dosages (see DOSAGE AND ADMINISTRATION ) and careful clinical monitoring must be used when treating the elderly with ketorolac tromethamine.

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.

te 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, and fixed drug eruption (FDE) 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).

temia, 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% To report SUSPECTED ADVERSE REACTIONS, contact Alembic Pharmaceuticals, Inc. at 1-866-210-9797 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

<table cellspacing="0" cellpadding="0" border="0" width="612"><col width="34.8039215686275%"/><col width="32.843137254902%"/><col width="32.3529411764706%"/><tbody><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule" valign="top">Gastrointestinal (GI) experiences including: </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">abdominal pain </td><td styleCode="Rrule" valign="top">constipation/diarrhea </td><td styleCode="Rrule" valign="top">dyspepsia </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">flatulence </td><td styleCode="Rrule" valign="top">GI fullness </td><td styleCode="Rrule" valign="top">GI ulcers (gastric/duodenal) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">gross bleeding/perforation </td><td styleCode="Rrule" valign="top">heartburn </td><td styleCode="Rrule" valign="top">nausea* </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">stomatitis </td><td styleCode="Rrule" valign="top">vomiting </td><td styleCode="Rrule" valign="top"> </td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule" valign="top">Other experiences: </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">abnormal renal function </td><td styleCode="Rrule" valign="top">anemia </td><td styleCode="Rrule" valign="top">dizziness </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">drowsiness </td><td styleCode="Rrule" valign="top">edema </td><td styleCode="Rrule" valign="top">elevated liver enzymes </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">headaches* </td><td styleCode="Rrule" valign="top">hypertension </td><td styleCode="Rrule" valign="top">increased bleeding time </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">injection site pain </td><td styleCode="Rrule" valign="top">pruritus </td><td styleCode="Rrule" valign="top">purpura </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">rashes </td><td styleCode="Rrule" valign="top">tinnitus </td><td styleCode="Rrule" valign="top">sweating </td></tr><tr><td colspan="3" align="justify" styleCode="Lrule Rrule" valign="top">*Incidence greater than 10% </td></tr></tbody></table>

ra </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">rashes </td><td styleCode="Rrule" valign="top">tinnitus </td><td styleCode="Rrule" valign="top">sweating </td></tr><tr><td colspan="3" align="justify" styleCode="Lrule Rrule" valign="top">*Incidence greater than 10% </td></tr></tbody></table> <table cellspacing="0" cellpadding="0" border="0" width="97%"><col width="20.44%"/><col width="20.42%"/><col width="20.42%"/><col width="20.42%"/><col width="18.3%"/><tbody><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">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</content> </td></tr><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">A. Adult Patients without History of PUB</content> </td></tr><tr styleCode="Botrule"><td rowspan="2" styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Age of Patients</content> </td><td colspan="4" styleCode="Rrule" valign="middle"><content styleCode="bold">Total Daily Dose of Ketorolac Tromethamine Injection</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">&#x2264;60 mg</content> </td><td styleCode="Rrule" valign="middle"><content styleCode="bold">&gt;60 to 90 mg</content> </td><td styleCode="Rrule" valign="middle"><content styleCode="bold">&gt;90 to 120 mg</content> </td><td styleCode="Rrule" valign="middle"><content styleCode="bold">&gt;120 mg</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">&lt;65 years of age </td><td styleCode="Rrule" valign="middle">0.4% </td><td styleCode="Rrule" valign="middle">0.4% </td><td styleCode="Rrule" valign="middle">0.9% </td><td styleCode="Rrule" valign="middle">4.6% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">&#x2265;65 years of age </td><td styleCode="Rrule" valign="middle">1.2% </td><td styleCode="Rrule" valign="middle">2.8% </td><td styleCode="Rrule" valign="middle">2.2% </td><td styleCode="Rrule" valign="middle">7.7% </td></tr><tr styleCode="Botrule"><td colspan="5" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">B. Adult Patients with History of PUB</content> </td></tr><tr styleCode="Botrule"><td rowspan="2" styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Age of Patients</content> </td><td colspan="4" styleCode="Rrule" valign="middle"><content styleCode="bold">Total Daily Dose of Ketorolac Tromethamine Injection</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">&#x2264;60 mg</content> </td><td styleCode="Rrule" valign="middle"><content styleCode="bold">&gt;60 to 90 mg</content> </td><td styleCode="Rrule" valign="middle"><content styleCode="bold">&gt;90 to 120 mg</content> </td><td styleCode="Rrule" valign="middle"><content styleCode="bold">&gt;120 mg</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">&lt;65 years of age </td><td styleCode="Rrule" valign="top">2.1% </td><td styleCode="Rrule" valign="top">4.6% </td><td styleCode="Rrule" valign="top">7.8% </td><td styleCode="Rrule" valign="top">15.4% </td></tr><tr><td styleCode="Lrule Rrule" valign="top">&#x2265;65 years of age </td><td styleCode="Rrule" valign="top">4.7% </td><td styleCode="Rrule" valign="top">3.7% </td><td styleCode="Rrule" valign="top">2.8% </td><td styleCode="Rrule" valign="top">25.0% </td></tr></tbody></table>

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. 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.

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 “as needed” 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 “as needed” unless otherwise contraindicated.

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 “as needed” 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.

HOW SUPPLIED Ketorolac Tromethamine Injection, USP is a clear, colorless to slight yellow solution and supplied as follows: Unit of Sale Each Concentration (mg/mL) Fill Volume/ Container Size Total Ketorolac Tromethamine (Per Container) NDC 85766-064-25 (relabeled from NDC 62332-600-25) Carton of 25 NDC 85766-064-01 (relabeled from NDC 62332-600-25) 2 mL Single-Dose Glass Fliptop Vial 30 mg/mL 1 mL/2 mL 30 mg Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature]. Discard unused portion. Protect from light. Retain in carton until time of use. Medication Guide is available at http://www.alembicusa.com/medicationguide.aspx Distributed by: Sportpharm LLC 379 Van Ness Ave 1401, Torrance, CA 90501 Relabeled by: Enovachem PHARMACEUTICALS Torrance, CA 90501 Medication Guide for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: • Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: • with increasing doses of NSAIDs • with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG)." Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. •Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: anytime during use without warning symptoms that may cause death The risk of getting an ulcer or bleeding increases with: • past history of stomach ulcers, or stomach or intestinal bleeding with the use of NSAIDs • taking medicines called "corticosteroids", "anticoagulants", "SSRIs", or "SNRIs" • increasing doses of NSAIDs • longer use of NSAIDs • smoking • drinking alcohol • older age • poor health • advanced liver disease • bleeding problems NSAIDs should only be used: • exactly as prescribed • at the lowest dose possible for your treatment • for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. Who should not take NSAIDs? Do not take NSAIDs: • if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. • right before or after heart bypass surgery. Before taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you: • have liver or kidney problems • have high blood pressure • have asthma • are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy. • are breastfeeding or plan to breast feed Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects .

r about 30 weeks of pregnancy. • are breastfeeding or plan to breast feed Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects . Do not start taking any new medicine without talking to your healthcare provider first. What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See "What is the most important information I should know about medicines called NonSteroidal Anti-inflammatory Drugs (NSAIDs)?" • new or worse high blood pressure • heart failure • liver problems including liver failure • kidney problems including kidney failure • low red blood cells (anemia) • life-threatening skin reactions • life-threatening allergic reactions • Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms: • shortness of breath or trouble breathing • chest pain • weakness in one part or side of your body • slurred speech • swelling of the face or throat Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: • nausea • more tired or weaker than usual • diarrhea • itching • your skin or eyes look yellow • indigestion or stomach pain • flu-like symptoms • vomit blood • there is blood in your bowel movement or it is black and sticky like tar • unusual weight gain • skin rash or blisters with fever • swelling of the arms and legs, hands and feet If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs • Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. • Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. Medication Guide is available at http://www.alembicusa.com/medicationguide.aspx or call 1-866-210-9797. This Medication Guide has been approved by the U.S. Food and Drug Administration. Rx Only Distributed by: Sportpharm LLC 379 Van Ness Ave 1401, Torrance, CA 90501 Relabeled by: Enovachem PHARMACEUTICALS Torrance, CA 90501

<table cellpadding="0" cellspacing="0"><colgroup><col width="20.2211690363349%"/><col width="20.2211690363349%"/><col width="20.2211690363349%"/><col width="19.1153238546604%"/><col width="20.2211690363349%"/></colgroup><tbody><tr styleCode="Botrule First"><td align="center" styleCode="Lrule Rrule" valign="middle"> <content styleCode="bold">Unit of Sale</content></td><td align="center" styleCode="Rrule" valign="middle"> <content styleCode="bold">Each</content></td><td align="center" styleCode="Rrule" valign="middle"> <content styleCode="bold">Concentration</content> <content styleCode="bold">(mg/mL)</content></td><td align="center" styleCode="Rrule" valign="top"> <content styleCode="bold">Fill Volume/</content> <content styleCode="bold">Container</content> <content styleCode="bold">Size</content></td><td align="center" styleCode="Rrule" valign="top"> <content styleCode="bold">Total Ketorolac</content> <content styleCode="bold">Tromethamine</content> <content styleCode="bold">(Per Container)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><paragraph>NDC 85766-064-25</paragraph><paragraph>(relabeled from NDC 62332-600-25) Carton of 25 </paragraph></td><td styleCode="Rrule" valign="top"><paragraph>NDC 85766-064-01</paragraph><paragraph>(relabeled from NDC 62332-600-25) 2 mL Single-Dose Glass Fliptop Vial </paragraph></td><td styleCode="Rrule" valign="middle">30 mg/mL</td><td styleCode="Rrule" valign="middle">1 mL/2 mL</td><td styleCode="Rrule" valign="middle">30 mg</td></tr></tbody></table>

WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [ see Warnings and Precautions ( 5.1 ) ]. SPRIX ® is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [ see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 ) ]. Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [ see Warnings and Precautions ( 5.2 ) ]. WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. Nonsteroidal anti-inflammatory drugs (NSAIDS) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use ( 5.1 ) SPRIX ® is contraindicated in the setting of coronary artery bypass graft (CABG) surgery ( 4 , 5.1 ) NSAIDS cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events ( 5.2 )

<table width="100%"><tbody><tr><td align="left"/><td align="right"/></tr><tr><td align="left">Warnings and Precautions (<linkHtml href="#s_0509">5.9</linkHtml>)</td><td align="right">11/2024</td></tr></tbody></table>

1 INDICATIONS AND USAGE SPRIX is indicated in adult patients for the short term (up to 5 days) management of moderate to moderately severe pain that requires analgesia at the opioid level. Limitations of Use Sprix is not for use in pediatric patients less than 2 years of age. SPRIX is a nonsteroidal anti-inflammatory drug indicated in adult patients for the short term (up to 5 days) management of moderate to moderately severe pain that requires analgesia at the opioid level. ( 1 )

2 DOSAGE AND ADMINISTRATION Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. ( 2.1 ) SPRIX is not an inhaled product. For adult patients < 65 years of age: 31.5 mg (one 15.75 mg spray in each nostril) every 6 to 8 hours. The maximum daily dose is 126 mg. ( 2.2 , 2.3 ) For patients ≥ 65 years of age, renally impaired patients, and patients less than 50 kg (110 lbs): 15.75 mg (one 15.75 mg spray in only one nostril) every 6 to 8 hours. The maximum daily dose is 63 mg. ( 2.4 ) SPRIX nasal spray should be discarded within 24 hours of taking the first dose, even if the bottle still contains some medication. ( 2.5 ) 2.1 General Dosing Instructions Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [ see Warnings and Precautions ( 5 ) ]. The total duration of use of SPRIX alone or sequentially with other formulations of ketorolac (IM/IV or oral) must not exceed 5 days because of the potential for increasing the frequency and severity of adverse reactions associated with the recommended doses [ see Warnings and Precautions ( 5.15 ) ]. Do not use SPRIX concomitantly with other formulations of ketorolac or other NSAIDs [ see Warnings and Precautions ( 5.15 ) ]. 2.2 Administration SPRIX is not an inhaled product. Do not inhale when administering this product. Instruct patients to administer as follows: 1. First hold the finger flange with fingers, and remove the clear plastic cover with opposite hand; then remove the blue plastic safety clip. Keep the clear plastic cover; and throw away the blue plastic safety clip. 2. Before using the bottle for the FIRST time, activate the pump. To activate the pump, hold the bottle at arm’s length away from the body with index finger and middle finger resting on the top of the finger flange and thumb supporting the base. Press down evenly and release the pump 5 times. Patient may not see a spray the first few times he/she presses down. The bottle is now ready to use. There is no need to activate the pump again if more doses are used from the bottle. 3. It’s important to get the medication to the correct place in the nose so it will be most effective. - Blow nose gently to clear nostrils. - Sit up straight or stand. Tilt head slightly forward. - Insert the tip of the container into your right nostril. - Point the container away from the center of your nose. - Hold your breath and spray once into your right nostril, pressing down evenly on both sides. - Immediately after administration, resume breathing through mouth to reduce expelling the product. Also pinch the nose to help retain the spray if it starts to drip. If only one spray per dose is prescribed, administration is complete; skip to Step 5 below. 4. If a dose of 2 sprays is prescribed, repeat the process in Step 3 for the left nostril. Again, be sure to point the spray away from the center of nose. Spray once into the left nostril. 5. Replace the clear plastic cover and place the bottle in a cool, dry location out of direct sunlight, such as inside a medication cabinet. Keep out of reach of children. 2.3 Adult Patients < 65 Years of Age The recommended dose is 31.5 mg SPRIX (one 15.75 mg spray in each nostril) every 6 to 8 hours. The maximum daily dose is 126 mg (four doses).

over and place the bottle in a cool, dry location out of direct sunlight, such as inside a medication cabinet. Keep out of reach of children. 2.3 Adult Patients < 65 Years of Age The recommended dose is 31.5 mg SPRIX (one 15.75 mg spray in each nostril) every 6 to 8 hours. The maximum daily dose is 126 mg (four doses). 2.4 Reduced Doses for Special Populations For patients ≥ 65 years of age, renally impaired patients, and adult patients less than 50 kg (110 lbs), the recommended dose is 15.75 mg SPRIX ( one 15.75 mg spray in only one nostril) every 6 to 8 hours. The maximum daily dose is 63 mg (four doses) [ see Warnings and Precautions ( 5.2 , 5.6 ) ]. 2.5 Discard Used SPRIX Bottle after 24 Hours Do not use any single SPRIX bottle for more than one day as it will not deliver the intended dose after 24 hours. Therefore, the bottle must be discarded no more than 24 hours after taking the first dose, even if the bottle still contains some liquid.

3 DOSAGE FORMS AND STRENGTHS SPRIX (ketorolac tromethamine) Nasal spray: 15.75 mg of ketorolac tromethamine in each 100 μL spray. Each 1.7 g bottle contains 8 sprays. SPRIX (ketorolac tromethamine) Nasal Spray: 15.75 mg of ketorolac tromethamine in each 100 μL spray. Each 1.7 g bottle contains 8 sprays. ( 3 )

4 CONTRAINDICATIONS SPRIX is contraindicated in the following patients: Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to ketorolac or any components of the drug product [ see Warnings and Precautions ( 5.7 , 5.9 ) ] History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [ see Warnings and Precautions ( 5.7 , 5.8 ) ] In the setting of coronary artery bypass graft (CABG) surgery [ see Warnings and Precautions ( 5.1 ) ] Use in patients with active peptic ulcer disease and in patients with recent gastrointestinal bleeding or perforation [ see Warnings and Precautions ( 5.2 ) ] Use as a prophylactic analgesic before any major surgery [ see Warnings and Precautions ( 5.11 ) ] Use in patients with advanced renal disease or patients at risk for renal failure due to volume depletion [ see Warnings and Precautions ( 5.6 ) ] Use in labor and delivery. Through its prostaglandin synthesis inhibitory effect, ketorolac may adversely affect fetal circulation and inhibit uterine contractions, thus increasing the risk of uterine hemorrhage [ see Use in Specific Populations ( 8.1 ) ] Use in patients with suspected or confirmed cerebrovascular bleeding, hemorrhagic diathesis, incomplete hemostasis, or those for whom hemostasis is critical [ see Warnings and Precautions ( 5.11 ), Drug Interactions ( 7 ) ] Concomitant use with probenecid [ see Drug Interactions ( 7 ) ] Concomitant use with pentoxifylline [ see Drug Interactions ( 7 ) ] Known hypersensitivity to ketorolac or any components of the drug product ( 4 ) History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs ( 4 ) In the setting of CABG surgery ( 4 ) Use in patients with active peptic ulcer disease or with recent GI bleeding or perforation ( 4 ) Use as a prophylactic analgesic before any major surgery ( 4 ) Use in patients with advanced renal disease or patients at risk for renal failure due to volume depletion ( 4 ) Use in patients with suspected or confirmed cerebrovascular bleeding, patients with hemorrhagic diathesis, incomplete hemostasis, and those at high risk of bleeding ( 4 ) Use in labor and delivery ( 4 )

5 WARNINGS AND PRECAUTIONS Hepatotoxicity : Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop. ( 5.3 ) Hypertension : Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure. ( 5.4 , 7 ) Heart Failure and Edema : Avoid use of SPRIX in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure. ( 5.5 ) Renal Toxicity : Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of SPRIX in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function. ( 5.6 ) Anaphylactic Reactions : Seek emergency help if an anaphylactic reaction occurs. ( 5.7 ) Exacerbation of Asthma Related to Aspirin Sensitivity : SPRIX is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity). ( 5.8 ) Serious Skin Reactions : Discontinue SPRIX at first appearance of skin rash or other signs of hypersensitivity. ( 5.9 ) Fetal Toxicity : Limit use of NSAIDs, including SPRIX, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal dysfunction and premature closure of the fetal ductus arteriosus ( 5.10 , 8.1 ) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) : Discontinue and evaluate clinically ( 5.11 ) Hematologic Toxicity : Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia. Do not use SPRIX in patients for whom hemostasis is critical. ( 5.12 , 7 ) Limitations of Use : SPRIX should not be used concomitantly with IM/IV or oral ketorolac, aspirin, or other NSAIDs. ( 5.16 ) 5.1 Cardiovascular 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 cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.

effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the 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, such as ketorolac, increases the risk of serious gastrointestinal (GI) events [ see Warnings and Precautions ( 5.2 ) ]. Status Post Coronary Artery Bypass Graft (CABG) Surgery 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. NSAIDs are contraindicated in the setting of CABG [ see Contraindications ( 4 ) ]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of SPRIX in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If SPRIX is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation SPRIX is contraindicated in patients with active peptic ulcers and/or GI bleeding and in patients with recent gastrointestinal bleeding or perforation [ see Contraindications ( 4 ) ]. NSAIDs, including ketorolac, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, 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 NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients: Use the lowest effective dosage for the shortest possible duration. Avoid administration of more than one NSAID at a time.

or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients: Use the lowest effective dosage for the shortest possible duration. Avoid administration of more than one NSAID at a time. Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, consider alternate therapies other than NSAIDs. Do not use Sprix in those with active GI bleeding. Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue SPRIX until a serious GI adverse event is ruled out. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [ see Drug Interactions ( 7 ) ]. 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 Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including ketorolac. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue SPRIX immediately, and perform a clinical evaluation of the patient. 5.4 Hypertension NSAIDs, including SPRIX, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [ see Drug Interactions ( 7 ) ]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of ketorolac may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [ see Drug Interactions ( 7 ) ]. Avoid the use of SPRIX in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If SPRIX is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia 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 ( 12.3 ) ].

ients with severe heart failure, monitor patients for signs of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia 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 ( 12.3 ) ]. SPRIX is contraindicated in patients with advanced renal impairment [ see Contraindications ( 4 ) ]. Renal Toxicity 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 an 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, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of SPRIX in patients with advanced renal disease. The renal effects of SPRIX may hasten the progression of renal dysfunction in patients with preexisting renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating SPRIX. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of SPRIX [ see Drug Interactions ( 7 ) ]. Avoid the use of SPRIX in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If SPRIX is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. 5.7 Anaphylactic Reactions Ketorolac has been associated with anaphylactic reactions in patients with and without known hypersensitivity to ketorolac and in patients with aspirin-sensitive asthma [ see Contraindications ( 4 ) and Warnings and Precautions ( 5.8 ) ]. Seek emergency help if an anaphylactic reaction occurs. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, SPRIX is contraindicated in patients with this form of aspirin sensitivity [ see Contraindications ( 4 ) ]. When SPRIX is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.9 Serious Skin Reactions NSAIDs, including ketorolac, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning.

is, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of SPRIX at the first appearance of skin rash or any other sign of hypersensitivity. SPRIX is contraindicated in patients with previous serious skin reactions to NSAIDs [ see Contraindications ( 4 ) ]. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as SPRIX. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue SPRIX and evaluate the patient immediately. 5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including SPRIX, in pregnant women at about 30 weeks gestation and later. NSAIDs, including SPRIX, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including SPRIX, at about 20 weeks gestation or later in pregnancy may cause 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. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit SPRIX use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if SPRIX treatment extends beyond 48 hours. Discontinue SPRIX if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Population ( 8.1 )] 5.12 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect upon erythropoiesis. If a patient treated with SPRIX has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. Do not use SPRIX in patients for whom hemostasis is critical [ see Contraindications ( 4 ), Drug Interactions ( 7 ) ]. NSAIDs, including SPRIX, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [ see Drug Interactions ( 7 ) ].

ns such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [ see Drug Interactions ( 7 ) ]. The concurrent use of ketorolac 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. 5.13 Masking of Inflammation and Fever The pharmacological activity of SPRIX in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.14 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [ see Warnings and Precautions ( 5.2 , 5.3 , 5.6 ) ]. 5.15 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. 5.16 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 ) ].

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Cardiovascular Thrombotic Events [ see Warnings and Precautions ( 5.1 ) ] GI Bleeding, Ulceration and Perforation [ see Warnings and Precautions ( 5.2 ) ] Hepatotoxicity [ see Warnings and Precautions ( 5.3 ) ] Hypertension [ see Warnings and Precautions ( 5.4 ) ] Heart Failure and Edema [ see Warnings and Precautions ( 5.5 ) ] Renal Toxicity and Hyperkalemia [ see Warnings and Precautions ( 5.6 ) ] Anaphylactic Reactions [ see Warnings and Precautions ( 5.7 ) ] Serious Skin Reactions [ see Warnings and Precautions ( 5.9 ) ] Hematologic Toxicity [ see Warnings and Precautions ( 5.12 ) ] Most common adverse reactions (incidence ≥2%) in patients treated with SPRIX and occurring at a rate at least twice that of placebo are nasal discomfort, rhinalgia, increased lacrimation, throat irritation, oliguria, rash, bradycardia, decreased urine output, increased ALT and/or AST, hypertension, and rhinitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Zyla Life Sciences US Inc. at 1-800-518-1084 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to SPRIX in patients enrolled in placebo-controlled efficacy studies of acute pain following major surgery. The studies enrolled 828 patients (183 men, 645 women) ranging from 18 years to over 75 years of age. The patients in the postoperative pain studies had undergone major abdominal, orthopedic, gynecologic, or other surgery; 455 patients received SPRIX (31.5 mg) three or four times a day for up to 5 days, and 245 patients received placebo. Most patients were receiving concomitant opioids, primarily PCA morphine. The most frequently reported adverse reactions were related to local symptoms, i.e., nasal discomfort or irritation. These reactions were generally mild and transient in nature. The most common drug-related adverse events leading to premature discontinuation were nasal discomfort or nasal pain (rhinalgia). Table 1: Post-Operative Patients with Adverse Reactions Observed at a Rate of 2% or More and at Least Twice the Incidence of the Placebo Group. SPRIX (N = 455) Placebo (N = 245) Nasal discomfort 15% 2% Rhinalgia 13% <1% Lacrimation increased 5% 0% Throat irritation 4% <1% Oliguria 3% 1% Rash 3% <1% Bradycardia 2% <1% Urine output decreased 2% <1% ALT and/or AST increased 2% 1% Hypertension 2% 1% Rhinitis 2% <1% In controlled clinical trials in major surgery, primarily knee and hip replacements and abdominal hysterectomies, seven patients (N=455, 1.5%) treated with SPRIX experienced serious adverse events of bleeding (4 patients) or hematoma (3 patients) at the operative site versus one patient (N=245, 0.4%) treated with placebo (hematoma). Six of the seven patients treated with SPRIX underwent a surgical procedure and/or blood transfusion and the placebo patient subsequently required a blood transfusion. Adverse Reactions Reported in Clinical Trials with Other Dosage Forms of Ketorolac or Other NSAIDs Adverse reaction rates increase with higher doses of ketorolac.

seven patients treated with SPRIX underwent a surgical procedure and/or blood transfusion and the placebo patient subsequently required a blood transfusion. Adverse Reactions Reported in Clinical Trials with Other Dosage Forms of Ketorolac or Other NSAIDs Adverse reaction rates increase with higher doses of ketorolac. It is necessary to remain alert for the severe complications of treatment with ketorolac, such as GI ulceration, bleeding, and perforation, postoperative bleeding, acute renal failure, anaphylactic and anaphylactoid reactions, and liver failure. These complications can be serious in certain patients for whom ketorolac is indicated, especially when the drug is used inappropriately. In patients taking ketorolac or other NSAIDs in clinical trials, the most frequently reported adverse experiences in approximately 1% to 10% of patients are: * Incidence greater than 10% Gastrointestinal (GI) experiences including: abdominal pain flatulence gross bleeding/perforation stomatitis constipation/diarrhea GI fullness heartburn vomiting dyspepsia GI ulcers (gastric/duodenal) nausea* Other experiences: abnormal renal function drowsiness headache* injection site pain rash anemia edema hypertension pruritus tinnitus dizziness elevated liver enzymes increased bleeding time purpura sweating Additional adverse experiences reported occasionally (<1% in patients taking ketorolac or other NSAIDs in clinical trials) include: Body as a Whole: fever, infection, sepsis Cardiovascular System: congestive heart failure, palpitation, pallor, tachycardia, syncope Digestive System: 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 Respiratory: asthma, 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 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of ketorolac or other NSAIDs. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Experience The following adverse reactions have been identified during post approval use of ketorolac or other NSAIDs. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Other observed reactions (reported from postmarketing experience in patients taking ketorolac or other NSAIDs) are: Body as a Whole: angioedema, death, hypersensitivity reactions such as anaphylaxis, anaphylactoid reaction, laryngeal edema, tongue edema, 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, fixed drug eruption (FDE), 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) 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

<table ID="table1" width="550"><caption>Table 1: Post-Operative Patients with Adverse Reactions Observed at a Rate of 2% or More and at Least Twice the Incidence of the Placebo Group. </caption><colgroup><col width="40%"/><col width="30%"/><col width="30%"/></colgroup><tbody><tr><td styleCode="Botrule Lrule Rrule Toprule"/><td styleCode="Botrule Lrule Rrule Toprule" align="center"><content styleCode="bold">SPRIX (N = 455)</content></td><td styleCode="Botrule Lrule Rrule Toprule" align="center"><content styleCode="bold">Placebo (N = 245)</content></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Nasal discomfort</content></td><td styleCode="Botrule Lrule Rrule Toprule" align="center">15%</td><td styleCode="Botrule Lrule Rrule Toprule" align="center">2%</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Rhinalgia</content></td><td styleCode="Botrule Lrule Rrule Toprule" align="center">13%</td><td styleCode="Botrule Lrule Rrule Toprule" align="center">&lt;1%</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Lacrimation increased</content></td><td styleCode="Botrule Lrule Rrule Toprule" align="center">5%</td><td styleCode="Botrule Lrule Rrule Toprule" align="center">0%</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Throat irritation</content></td><td styleCode="Botrule Lrule Rrule Toprule" align="center">4%</td><td styleCode="Botrule Lrule Rrule Toprule" align="center">&lt;1%</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Oliguria</content></td><td styleCode="Botrule Lrule Rrule Toprule" align="center">3%</td><td styleCode="Botrule Lrule Rrule Toprule" align="center">1%</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Rash</content></td><td styleCode="Botrule Lrule Rrule Toprule" align="center">3%</td><td styleCode="Botrule Lrule Rrule Toprule" align="center">&lt;1%</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Bradycardia</content></td><td styleCode="Botrule Lrule Rrule Toprule" align="center">2%</td><td styleCode="Botrule Lrule Rrule Toprule" align="center">&lt;1%</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Urine output decreased</content></td><td styleCode="Botrule Lrule Rrule Toprule" align="center">2%</td><td styleCode="Botrule Lrule Rrule Toprule" align="center">&lt;1%</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">ALT and/or AST increased</content></td><td styleCode="Botrule Lrule Rrule Toprule" align="center">2%</td><td styleCode="Botrule Lrule Rrule Toprule" align="center">1%</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Hypertension</content></td><td styleCode="Botrule Lrule Rrule Toprule" align="center">2%</td><td styleCode="Botrule Lrule Rrule Toprule" align="center">1%</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Rhinitis</content></td><td styleCode="Botrule Lrule Rrule Toprule" align="center">2%</td><td styleCode="Botrule Lrule Rrule Toprule" align="center">&lt;1%</td></tr></tbody></table>

tyleCode="Botrule Lrule Rrule Toprule" align="center">1%</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Rhinitis</content></td><td styleCode="Botrule Lrule Rrule Toprule" align="center">2%</td><td styleCode="Botrule Lrule Rrule Toprule" align="center">&lt;1%</td></tr></tbody></table> <table width="600"><colgroup><col width="33%"/><col width="33%"/><col width="34%"/></colgroup><tfoot><tr><td colspan="2">*<content styleCode="italics">Incidence greater than 10%</content></td></tr></tfoot><tbody><tr><td colspan="3">Gastrointestinal (GI) experiences including:</td></tr><tr><td styleCode="Toprule">abdominal pain flatulence gross bleeding/perforation stomatitis</td><td styleCode="Toprule">constipation/diarrhea GI fullness heartburn vomiting</td><td styleCode="Toprule" valign="top">dyspepsia GI ulcers (gastric/duodenal) nausea*</td></tr><tr><td/><td/><td/></tr><tr><td>Other experiences:</td><td/><td/></tr><tr><td styleCode="Botrule">abnormal renal function drowsiness headache* injection site pain rash</td><td styleCode="Botrule">anemia edema hypertension pruritus tinnitus</td><td styleCode="Botrule">dizziness elevated liver enzymes increased bleeding time purpura sweating</td></tr></tbody></table>

7 DRUG INTERACTIONS See Table 2 for clinically significant drug interactions with ketorolac. Table 2: Clinically Significant Drug Interactions with Ketorolac Drugs that Interfere with Hemostasis Clinical Impact: Ketorolac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of ketorolac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone [ see Clinical Pharmacology ( 12.3 ) ]. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. When ketorolac is administered concurrently with pentoxifylline, there is an increased risk of bleeding. Intervention: Monitor patients with concomitant use of SPRIX with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions ( 5.12 ) ]. Concomitant use of SPRIX and pentoxifylline is contraindicated [ see Contraindications ( 4 ) and Warnings and Precautions ( 5.12 ) ]. Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions ( 5.2 ) ]. Intervention: Concomitant use of SPRIX and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5.12 ) ]. SPRIX is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-blockers Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: During concomitant use of SPRIX and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of SPRIX and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions ( 5.6 ) ]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients.

hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis Intervention: During concomitant use of SPRIX with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions ( 5.6 ) ]. Digoxin Clinical Impact: The concomitant use of ketorolac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of SPRIX and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of SPRIX and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of SPRIX and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of SPRIX and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of SPRIX and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of ketorolac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions ( 5.2 ) and Clinical Pharmacology ( 12.3 ) ]. Intervention: The concomitant use of ketorolac with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of SPRIX and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of SPRIX and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Probenecid Clinical Impact: Concomitant administration of oral ketorolac and probenecid results in increased half-life and systemic exposure. [ see Clinical Pharmacology ( 12.3 ) ]. Intervention: Concomitant use of SPRIX and probenecid is contraindicated. Antiepileptic Drugs Clinical Impact: Sporadic cases of seizures have been reported during concomitant use of ketorolac and antiepileptic drugs (phenytoin, carbamazepine). Intervention: During concomitant use of SPRIX and antiepileptic drugs, monitor patients for seizures. Psychoactive Drugs Clinical Impact: Hallucinations have been reported when ketorolac was used in patients taking psychoactive drugs (fluoxetine, thiothixene, alprazolam).

antiepileptic drugs (phenytoin, carbamazepine). Intervention: During concomitant use of SPRIX and antiepileptic drugs, monitor patients for seizures. Psychoactive Drugs Clinical Impact: Hallucinations have been reported when ketorolac was used in patients taking psychoactive drugs (fluoxetine, thiothixene, alprazolam). Intervention: During concomitant use of SPRIX and psychoactive drugs, monitor patients for hallucinations. Nondepolarizing Muscle Relaxants Clinical Impact: In postmarketing experience there have been reports of a possible interaction between ketorolac and nondepolarizing muscle relaxants that resulted in apnea. The concurrent use of ketorolac with muscle relaxants has not been formally studied. Intervention: During concomitant use of SPRIX and nondepolarizing muscle relaxants, monitor patients for apnea. Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs) : Monitor patients for bleeding who are concomitantly taking SPRIX with drugs that interfere with hemostasis. Concomitant use of SPRIX and analgesic doses of aspirin is not generally recommended. ( 7 ) ACE inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers : Concomitant use with SPRIX may diminish the antihypertensive effect of these drugs. Monitor blood pressure. ( 7 ) ACE Inhibitors and ARBs : Concomitant use with SPRIX in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function. ( 7 ) Diuretics : NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects. ( 7 ) Digoxin : Concomitant use with SPRIX can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels. ( 7 )

<table ID="table2" width="750px"><caption>Table 2: Clinically Significant Drug Interactions with Ketorolac</caption><colgroup><col width="20%"/><col width="80%"/></colgroup><tbody><tr><td styleCode="Botrule Lrule Rrule Toprule" colspan="2" align="left"><content styleCode="bold">Drugs that Interfere with Hemostasis</content></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Botrule Lrule Rrule Toprule"><list listType="unordered" styleCode="Disc"><item>Ketorolac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of ketorolac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone [<content styleCode="italics">see Clinical Pharmacology (<linkHtml href="#s_1203">12.3</linkHtml>)</content>].</item><item>Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.</item><item>When ketorolac is administered concurrently with pentoxifylline, there is an increased risk of bleeding.</item></list></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><content styleCode="italics">Intervention:</content></td><td styleCode="Botrule Lrule Rrule Toprule">Monitor patients with concomitant use of SPRIX with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [<content styleCode="italics">see Warnings and Precautions (<linkHtml href="#Lfec287c8-222b-4f9f-a1b3-387985f4554b">5.12</linkHtml>)</content>]. Concomitant use of SPRIX and pentoxifylline is contraindicated [<content styleCode="italics">see Contraindications (<linkHtml href="#s_0400">4</linkHtml>) and Warnings and Precautions (<linkHtml href="#Lfec287c8-222b-4f9f-a1b3-387985f4554b">5.12</linkHtml>)</content>].</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" colspan="2" align="left"><content styleCode="bold">Aspirin</content></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Botrule Lrule Rrule Toprule">Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone.

Toprule" align="center" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Botrule Lrule Rrule Toprule">Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [<content styleCode="italics">see Warnings and Precautions (<linkHtml href="#s_0502">5.2</linkHtml>)</content>].</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" rowspan="2" align="center" valign="top"><content styleCode="italics">Intervention:</content></td><td styleCode="Lrule Rrule">Concomitant use of SPRIX and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [<content styleCode="italics">see Warnings and Precautions (<linkHtml href="#Lfec287c8-222b-4f9f-a1b3-387985f4554b">5.12</linkHtml>)</content>].</td></tr><tr><td styleCode="Botrule Lrule Rrule">SPRIX is not a substitute for low dose aspirin for cardiovascular protection.</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" colspan="2" align="left"><content styleCode="bold">ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-blockers</content></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Botrule Lrule Rrule Toprule"><list listType="unordered" styleCode="Disc"><item>NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).</item><item>In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.</item></list></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><content styleCode="italics">Intervention:</content></td><td styleCode="Botrule Lrule Rrule Toprule"><list listType="unordered" styleCode="Disc"><item>During concomitant use of SPRIX and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.</item><item>During concomitant use of SPRIX and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [<content styleCode="italics">see Warnings and Precautions (<linkHtml href="#s_0506">5.6</linkHtml>)</content>].</item><item>When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.</item></list></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" colspan="2" align="left"><content styleCode="bold">Diuretics</content></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Botrule Lrule Rrule Toprule">Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients.

e" align="center" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Botrule Lrule Rrule Toprule">Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><content styleCode="italics">Intervention:</content></td><td styleCode="Botrule Lrule Rrule Toprule">During concomitant use of SPRIX with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [<content styleCode="italics">see Warnings and Precautions (<linkHtml href="#s_0506">5.6</linkHtml>)</content>].</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" colspan="2" align="left"><content styleCode="bold">Digoxin</content></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Botrule Lrule Rrule Toprule">The concomitant use of ketorolac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><content styleCode="italics">Intervention:</content></td><td styleCode="Botrule Lrule Rrule Toprule">During concomitant use of SPRIX and digoxin, monitor serum digoxin levels.</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" colspan="2" align="left"><content styleCode="bold">Lithium</content></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Botrule Lrule Rrule Toprule">NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%.

="top"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Botrule Lrule Rrule Toprule">NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><content styleCode="italics">Intervention:</content></td><td styleCode="Botrule Lrule Rrule Toprule">During concomitant use of SPRIX and lithium, monitor patients for signs of lithium toxicity.</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" colspan="2" align="left"><content styleCode="bold">Methotrexate</content></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Botrule Lrule Rrule Toprule">Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><content styleCode="italics">Intervention:</content></td><td styleCode="Botrule Lrule Rrule Toprule">During concomitant use of SPRIX and methotrexate, monitor patients for methotrexate toxicity.</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" colspan="2" align="left"><content styleCode="bold">Cyclosporine</content></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Botrule Lrule Rrule Toprule">Concomitant use of SPRIX and cyclosporine may increase cyclosporine&#x2019;s nephrotoxicity.</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><content styleCode="italics">Intervention:</content></td><td styleCode="Botrule Lrule Rrule Toprule">During concomitant use of SPRIX and cyclosporine, monitor patients for signs of worsening renal function.</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" colspan="2" align="left"><content styleCode="bold">NSAIDs and Salicylates</content></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Botrule Lrule Rrule Toprule">Concomitant use of ketorolac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [<content styleCode="italics">see Warnings and Precautions (<linkHtml href="#s_0502">5.2</linkHtml>) and Clinical Pharmacology (<linkHtml href="#s_1203">12.3</linkHtml>)</content>].</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><content styleCode="italics">Intervention:</content></td><td styleCode="Botrule Lrule Rrule Toprule">The concomitant use of ketorolac with other NSAIDs or salicylates is not recommended.</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" colspan="2" align="left"><content styleCode="bold">Pemetrexed</content></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Botrule Lrule Rrule Toprule">Concomitant use of SPRIX and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><content styleCode="italics">Intervention:</content></td><td styleCode="Botrule Lrule Rrule Toprule"><paragraph>During concomitant use of SPRIX and pemetr

uppression, renal, and GI toxicity (see the pemetrexed prescribing information).</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><content styleCode="italics">Intervention:</content></td><td styleCode="Botrule Lrule Rrule Toprule"><paragraph>During concomitant use of SPRIX and pemetr exed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.</paragraph><paragraph>NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.</paragraph><paragraph>In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" colspan="2" align="left"><content styleCode="bold">Probenecid</content></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Botrule Lrule Rrule Toprule">Concomitant administration of oral ketorolac and probenecid results in increased half-life and systemic exposure.

benecid</content></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Botrule Lrule Rrule Toprule">Concomitant administration of oral ketorolac and probenecid results in increased half-life and systemic exposure. [<content styleCode="italics">see Clinical Pharmacology (<linkHtml href="#s_1203">12.3</linkHtml>)</content>].</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><content styleCode="italics">Intervention:</content></td><td styleCode="Botrule Lrule Rrule Toprule">Concomitant use of SPRIX and probenecid is contraindicated.</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" colspan="2" align="left"><content styleCode="bold">Antiepileptic Drugs</content></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Botrule Lrule Rrule Toprule">Sporadic cases of seizures have been reported during concomitant use of ketorolac and antiepileptic drugs (phenytoin, carbamazepine).</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><content styleCode="italics">Intervention:</content></td><td styleCode="Botrule Lrule Rrule Toprule">During concomitant use of SPRIX and antiepileptic drugs, monitor patients for seizures.</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" colspan="2" align="left"><content styleCode="bold">Psychoactive Drugs</content></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Botrule Lrule Rrule Toprule">Hallucinations have been reported when ketorolac was used in patients taking psychoactive drugs (fluoxetine, thiothixene, alprazolam).</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><content styleCode="italics">Intervention:</content></td><td styleCode="Botrule Lrule Rrule Toprule">During concomitant use of SPRIX and psychoactive drugs, monitor patients for hallucinations.</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" colspan="2" align="left"><content styleCode="bold">Nondepolarizing Muscle Relaxants</content></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Botrule Lrule Rrule Toprule">In postmarketing experience there have been reports of a possible interaction between ketorolac and nondepolarizing muscle relaxants that resulted in apnea. The concurrent use of ketorolac with muscle relaxants has not been formally studied.</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" align="center" valign="top"><content styleCode="italics">Intervention:</content></td><td styleCode="Botrule Lrule Rrule Toprule">During concomitant use of SPRIX and nondepolarizing muscle relaxants, monitor patients for apnea.</td></tr></tbody></table>

8 USE IN SPECIFIC POPULATIONS Infertility : NSAIDs are associated with reversible infertility. Consider withdrawal of SPRIX in women who have difficulties conceiving. ( 8.3 ) 8.1 Pregnancy Risk Summary Use of NSAIDs, including SPRIX, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of SPRIX use between about 20 and 30 weeks of gestation, and avoid SPRIX use at about 30 weeks of gestation and later in pregnancy ( see Clinical Considerations, Data ). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including SPRIX, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies in rabbits and rats tested at 0.6 and 1.5 times the human systemic exposure, respectively, at the recommended maximum IN dose of 31.5 mg four times a day, there was no evidence of teratogenicity or other adverse developmental outcomes ( see Data ). 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% to 4% and 15% to 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 SPRIX, can cause premature closure of the fetal ductus arteriosus ( see Data ). 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 SPRIX treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue SPRIX and follow up according to clinical practice ( see Data ). Data Human Data 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.

ramnios occurs, discontinue SPRIX and follow up according to clinical practice ( see Data ). Data Human Data 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. Animal Data Reproduction studies have been performed during organogenesis using daily oral doses of ketorolac tromethamine at 3.6 mg/kg (0.6 times the human systemic exposure at the recommended maximum IN dose of 31.5 mg qid, based on area-under-the-plasma-concentration curve [AUC]) in rabbits and at 10 mg/kg (1.5 times the human AUC) in rats. These studies did not reveal evidence of teratogenicity or other adverse developmental outcomes. However, because animal dosing was limited by maternal toxicity, these studies do not adequately assess ketorolac’s potential to cause adverse developmental outcomes in humans. 8.2 Lactation Risk Summary Ketorolac is excreted in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SPRIX and any potential adverse effects on the breastfed infant from the SPRIX or from the underlying maternal condition. Clinical Considerations Exercise caution when administering SPRIX to a nursing woman. Available information has not shown any specific adverse events in nursing infants; however, instruct patients to contact their infant’s health care provider if they note any adverse events. Data Limited data from one published study involving ten nursing mothers 2-6 days postpartum showed low levels of ketorolac in breast milk. Levels were undetectable (less than 5 ng/mL) in 4 of the patients. After a single administration of 10 mg ketorolac, the maximum milk concentration observed was 7.3 ng/mL, and the maximum milk to plasma ratio was 0.037. After 1 day of dosing (10 mg every 6 hours), the maximum milk concentration was 7.9 ng/mL, and the maximum milk-to-plasma ratio was 0.025. Assuming a daily intake of 400-1000 mL of human milk per day and a maternal body weight of 60 kg, the calculated maximum daily infant exposure was 0.00263 mg/kg/day, which is 0.4% of the maternal weight adjusted dose.

hours), the maximum milk concentration was 7.9 ng/mL, and the maximum milk-to-plasma ratio was 0.025. Assuming a daily intake of 400-1000 mL of human milk per day and a maternal body weight of 60 kg, the calculated maximum daily infant exposure was 0.00263 mg/kg/day, which is 0.4% of the maternal weight adjusted dose. 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including SPRIX, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including SPRIX, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use Sprix is not for use in pediatric patients less than 2 years of age. The safety and effectiveness of ketorolac in pediatric patients 17 years of age and younger have not been established. 8.5 Geriatric Use Exercise caution when treating the elderly (65 years and older) with SPRIX. Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [ see Dosage and Administration ( 2.4 ), Warnings and Precautions ( 5.1 , 5.2 , 5.3 , 5.6, 5.14 ), Clinical Pharmacology ( 12.3 ) ]. After observing the response to initial therapy with SPRIX, adjust the dose and frequency to suit an individual patient’s needs. Ketorolac and its metabolites are known to be substantially excreted by the kidneys, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, use caution in this patient population, and it may be useful to monitor renal function [ see Clinical Pharmacology ( 12.3 ) ].

8.1 Pregnancy Risk Summary Use of NSAIDs, including SPRIX, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of SPRIX use between about 20 and 30 weeks of gestation, and avoid SPRIX use at about 30 weeks of gestation and later in pregnancy ( see Clinical Considerations, Data ). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including SPRIX, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies in rabbits and rats tested at 0.6 and 1.5 times the human systemic exposure, respectively, at the recommended maximum IN dose of 31.5 mg four times a day, there was no evidence of teratogenicity or other adverse developmental outcomes ( see Data ). 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% to 4% and 15% to 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 SPRIX, can cause premature closure of the fetal ductus arteriosus ( see Data ). 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 SPRIX treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue SPRIX and follow up according to clinical practice ( see Data ). Data Human Data 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.

e 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. Animal Data Reproduction studies have been performed during organogenesis using daily oral doses of ketorolac tromethamine at 3.6 mg/kg (0.6 times the human systemic exposure at the recommended maximum IN dose of 31.5 mg qid, based on area-under-the-plasma-concentration curve [AUC]) in rabbits and at 10 mg/kg (1.5 times the human AUC) in rats. These studies did not reveal evidence of teratogenicity or other adverse developmental outcomes. However, because animal dosing was limited by maternal toxicity, these studies do not adequately assess ketorolac’s potential to cause adverse developmental outcomes in humans.

8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including SPRIX, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including SPRIX, in women who have difficulties conceiving or who are undergoing investigation of infertility.

8.4 Pediatric Use Sprix is not for use in pediatric patients less than 2 years of age. The safety and effectiveness of ketorolac in pediatric patients 17 years of age and younger have not been established.

8.5 Geriatric Use Exercise caution when treating the elderly (65 years and older) with SPRIX. Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [ see Dosage and Administration ( 2.4 ), Warnings and Precautions ( 5.1 , 5.2 , 5.3 , 5.6, 5.14 ), Clinical Pharmacology ( 12.3 ) ]. After observing the response to initial therapy with SPRIX, adjust the dose and frequency to suit an individual patient’s needs. Ketorolac and its metabolites are known to be substantially excreted by the kidneys, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, use caution in this patient population, and it may be useful to monitor renal function [ see Clinical Pharmacology ( 12.3 ) ].

10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [ see Warnings and Precautions ( 5.1 , 5.2 , 5.4 , 5.6 ) ]. There has been no experience with overdosage of SPRIX. In controlled overdosage studies with IM ketorolac injection, daily doses of 360 mg given for five days (approximately 3 times the maximum daily dose of SPRIX) caused abdominal pain and peptic ulcers, which healed after discontinuation of dosing. Single overdoses of ketorolac tromethamine have been variously associated with abdominal pain, nausea, vomiting, hyperventilation, peptic ulcers and/or erosive gastritis, and renal dysfunction. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center (1-800-222-1222).

11 DESCRIPTION SPRIX (ketorolac tromethamine) Nasal Spray is a member of the pyrrolo-pyrrole group of nonsteroidal anti-inflammatory drugs, available as a clear, colorless to yellow solution packaged in a glass vial with a snap on spray pump that delivers 15.75 mg ketorolac tromethamine per spray and is intended for intranasal administration. The chemical name is (±)-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid, compound with 2-amino-2-(hydroxymethyl)-1,3-propanediol (1:1). The molecular weight is 376.41. Its molecular formula is C 19 H 24 N 2 O 6 (C 15 H 13 NO 3 •C 4 H 11 NO 3 ), and it has the following chemical structure. Ketorolac tromethamine is highly water-soluble, allowing its formulation in an aqueous nasal spray product at pH 7.2. The inactive ingredients in SPRIX include: edetate disodium (EDTA), monobasic potassium phosphate, sodium hydroxide, and water for injection. Chemical Structure

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Ketorolac has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of SPRIX, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2), an early component of the arachidonic acid cascade, resulting in the reduced synthesis of prostaglandins, thromboxanes, and prostacyclin. Ketorolac is a potent inhibitor of prostaglandin synthesis in vitro . Ketorolac concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because ketorolac is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. 12.3 Pharmacokinetics The half-lives of ketorolac by the IN and IM routes were similar. The bioavailability of ketorolac by the IN route of administration of a 31.5 mg dose was approximately 60% compared to IM administration. (See Table 3 ). Table 3: Pharmacokinetic Parameters of Ketorolac Tromethamine after Intramuscular (IM) and Intranasal (IN) Administration C max = maximum plasma concentration; t max = time of C max ; AUC 0-∞ = complete area under the concentration-time curve; T ½ = half-life; SD = standard deviation. All values are means, except t max , for which medians are reported. Ketorolac Tromethamine C max (SD) ng/mL t max (range) hours AUC 0-∞ (SD) ng•h/mL T ½ (SD) hours 30 mg IM (1.0 mL of a 30 mg/mL solution) 2382.2 (432.7) 0.75 (0.25-1.03) 11152.8 (4260.1) 4.80 (1.18) 31.5 mg IN (SPRIX) (2 x 100 μL of a 15% w/w solution) 1805.8 (882.8) 0.75 (0.50-2.00) 7477.3 (3654.4) 5.24 (1.33) 15 mg IM (0.5 mL of a 30 mg/mL solution) 1163.4 (279.9) 0.75 (0.25-1.50) 5196.3 (2076.7) 5.00 (1.72) Absorption In a study in which SPRIX (31.5 mg) was administered to healthy volunteers four times daily for 5 days, the C max , t max , and AUC values following the final dose were comparable to those obtained in the single-dose study. Accumulation of ketorolac has not been studied in special populations, geriatric, pediatric, renal failure or hepatic disease patients. Distribution Scintigraphic assessment of drug disposition of ketorolac following SPRIX intranasal dosing demonstrated that most of the ketorolac was deposited in the nasal cavity and pharynx, with less than 20% deposited in the esophagus and stomach, and zero or negligible deposition in the lungs (<0.5%). The mean apparent volume (Vβ) 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 (99.2%). 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. Therapeutic concentrations of digoxin, warfarin, ibuprofen, naproxen, piroxicam, acetaminophen, phenytoin, and tolbutamide did not alter ketorolac protein binding.

on for each enantiomer will be constant over the therapeutic range. A decrease in serum albumin, however, will result in increased free drug concentrations. Therapeutic concentrations of digoxin, warfarin, ibuprofen, naproxen, piroxicam, acetaminophen, phenytoin, and tolbutamide did not alter ketorolac protein binding. In vitro studies indicate that, at therapeutic concentrations of salicylate (300 mcg/mL), the binding of ketorolac was reduced from approximately 99.2% to 97.5%, representing a potential twofold increase in unbound ketorolac plasma levels. The in vitro binding of warfarin to plasma proteins is only slightly reduced by ketorolac (99.5% control vs. 99.3%) when ketorolac plasma concentrations reach 5 to 10 mcg/mL. Ketorolac tromethamine is excreted in human milk. Elimination 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. There is no evidence in animal or human studies that ketorolac induces or inhibits hepatic enzymes capable of metabolizing itself or other drugs. 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 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. Specific Populations Geriatric: A single-dose study was conducted to compare the pharmacokinetics of SPRIX (31.5 mg) in subjects ≥ age 65 to the pharmacokinetics in subjects < age 65. Exposure to ketorolac was increased by 23% for the ≥ 65 population as compared to subjects < 65. Peak concentrations of 2028 and 1840 ng/mL were observed for the elderly and nonelderly adult populations, respectively, at 0.75 h after dosing. In the elderly population a longer terminal half-life was observed as compared to the nonelderly adults (4.5 h vs. 3.3 h, respectively). Race: Pharmacokinetic differences due to race have not been identified. Hepatic Impairment: There was no significant difference in estimates of half-life, AUC ∞ and C max in 7 patients with liver disease compared to healthy volunteers. Renal Impairment: Based on single-dose data only, the mean half-life of ketorolac tromethamine in renally impaired patients is between 6 and 19 hours, and is dependent on the extent of the impairment. There is poor correlation between creatinine clearance and total ketorolac tromethamine clearance in the elderly and populations with renal impairment (r = 0.5). In patients with renal disease, the AUC ∞ of each enantiomer increased by approximately 100% compared with healthy volunteers. The volume of distribution doubles for the S-enantiomer and increases by 1/5th for the R-enantiomer. The increase in volume of distribution of ketorolac tromethamine implies an increase in unbound fraction. The AUC ∞ -ratio of the ketorolac tromethamine enantiomers in healthy subjects and patients remained similar, indicating there was no selective excretion of either enantiomer in patients compared to healthy subjects.

e increase in volume of distribution of ketorolac tromethamine implies an increase in unbound fraction. The AUC ∞ -ratio of the ketorolac tromethamine enantiomers in healthy subjects and patients remained similar, indicating there was no selective excretion of either enantiomer in patients compared to healthy subjects. Allergic Rhinitis: Comparison of the pharmacokinetics of SPRIX in subjects with allergic rhinitis to data from a previous study in healthy subjects showed no differences that would be of clinical consequence for the efficacy or safety of SPRIX. Drug Interaction Studies Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 2 for clinically significant drug interactions of NSAIDs with aspirin [ see Drug Interactions ( 7 ) ]. Other Nasal Spray Products: A study was conducted in subjects with symptomatic allergic rhinitis to assess the effects of the commonly used nasal spray products oxymetazoline hydrochloride and fluticasone propionate on the pharmacokinetics of SPRIX. Subjects received a single dose of oxymetazoline nasal spray followed by a single dose (31.5 mg) of SPRIX 30 min later. Subjects also received fluticasone nasal spray (200 mcg as 2 x 50 mcg in each nostril) for seven days, with a single dose (31.5 mg) of SPRIX on the 7 th day. Administration of these common intranasal products had no effect of clinical significance on the rate or extent of ketorolac absorption. Probenecid: Concomitant administration of oral ketorolac and probenecid resulted in decreased clearance and volume of distribution of ketorolac and significant increases in ketorolac plasma levels (total AUC increased approximately threefold from 5.4 to 17.8 mcg/h/mL), and terminal half-life increased approximately twofold from 6.6 to 15.1 hours [ see Drug Interactions ( 7 ) ].

12.1 Mechanism of Action Ketorolac has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of SPRIX, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2), an early component of the arachidonic acid cascade, resulting in the reduced synthesis of prostaglandins, thromboxanes, and prostacyclin. Ketorolac is a potent inhibitor of prostaglandin synthesis in vitro . Ketorolac concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because ketorolac is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

12.3 Pharmacokinetics The half-lives of ketorolac by the IN and IM routes were similar. The bioavailability of ketorolac by the IN route of administration of a 31.5 mg dose was approximately 60% compared to IM administration. (See Table 3 ). Table 3: Pharmacokinetic Parameters of Ketorolac Tromethamine after Intramuscular (IM) and Intranasal (IN) Administration C max = maximum plasma concentration; t max = time of C max ; AUC 0-∞ = complete area under the concentration-time curve; T ½ = half-life; SD = standard deviation. All values are means, except t max , for which medians are reported. Ketorolac Tromethamine C max (SD) ng/mL t max (range) hours AUC 0-∞ (SD) ng•h/mL T ½ (SD) hours 30 mg IM (1.0 mL of a 30 mg/mL solution) 2382.2 (432.7) 0.75 (0.25-1.03) 11152.8 (4260.1) 4.80 (1.18) 31.5 mg IN (SPRIX) (2 x 100 μL of a 15% w/w solution) 1805.8 (882.8) 0.75 (0.50-2.00) 7477.3 (3654.4) 5.24 (1.33) 15 mg IM (0.5 mL of a 30 mg/mL solution) 1163.4 (279.9) 0.75 (0.25-1.50) 5196.3 (2076.7) 5.00 (1.72) Absorption In a study in which SPRIX (31.5 mg) was administered to healthy volunteers four times daily for 5 days, the C max , t max , and AUC values following the final dose were comparable to those obtained in the single-dose study. Accumulation of ketorolac has not been studied in special populations, geriatric, pediatric, renal failure or hepatic disease patients. Distribution Scintigraphic assessment of drug disposition of ketorolac following SPRIX intranasal dosing demonstrated that most of the ketorolac was deposited in the nasal cavity and pharynx, with less than 20% deposited in the esophagus and stomach, and zero or negligible deposition in the lungs (<0.5%). The mean apparent volume (Vβ) 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 (99.2%). 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. Therapeutic concentrations of digoxin, warfarin, ibuprofen, naproxen, piroxicam, acetaminophen, phenytoin, and tolbutamide did not alter ketorolac protein binding. In vitro studies indicate that, at therapeutic concentrations of salicylate (300 mcg/mL), the binding of ketorolac was reduced from approximately 99.2% to 97.5%, representing a potential twofold increase in unbound ketorolac plasma levels. The in vitro binding of warfarin to plasma proteins is only slightly reduced by ketorolac (99.5% control vs. 99.3%) when ketorolac plasma concentrations reach 5 to 10 mcg/mL. Ketorolac tromethamine is excreted in human milk. Elimination 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. There is no evidence in animal or human studies that ketorolac induces or inhibits hepatic enzymes capable of metabolizing itself or other drugs. 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.

mal or human studies that ketorolac induces or inhibits hepatic enzymes capable of metabolizing itself or other drugs. 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 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. Specific Populations Geriatric: A single-dose study was conducted to compare the pharmacokinetics of SPRIX (31.5 mg) in subjects ≥ age 65 to the pharmacokinetics in subjects < age 65. Exposure to ketorolac was increased by 23% for the ≥ 65 population as compared to subjects < 65. Peak concentrations of 2028 and 1840 ng/mL were observed for the elderly and nonelderly adult populations, respectively, at 0.75 h after dosing. In the elderly population a longer terminal half-life was observed as compared to the nonelderly adults (4.5 h vs. 3.3 h, respectively). Race: Pharmacokinetic differences due to race have not been identified. Hepatic Impairment: There was no significant difference in estimates of half-life, AUC ∞ and C max in 7 patients with liver disease compared to healthy volunteers. Renal Impairment: Based on single-dose data only, the mean half-life of ketorolac tromethamine in renally impaired patients is between 6 and 19 hours, and is dependent on the extent of the impairment. There is poor correlation between creatinine clearance and total ketorolac tromethamine clearance in the elderly and populations with renal impairment (r = 0.5). In patients with renal disease, the AUC ∞ of each enantiomer increased by approximately 100% compared with healthy volunteers. The volume of distribution doubles for the S-enantiomer and increases by 1/5th for the R-enantiomer. The increase in volume of distribution of ketorolac tromethamine implies an increase in unbound fraction. The AUC ∞ -ratio of the ketorolac tromethamine enantiomers in healthy subjects and patients remained similar, indicating there was no selective excretion of either enantiomer in patients compared to healthy subjects. Allergic Rhinitis: Comparison of the pharmacokinetics of SPRIX in subjects with allergic rhinitis to data from a previous study in healthy subjects showed no differences that would be of clinical consequence for the efficacy or safety of SPRIX. Drug Interaction Studies Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 2 for clinically significant drug interactions of NSAIDs with aspirin [ see Drug Interactions ( 7 ) ]. Other Nasal Spray Products: A study was conducted in subjects with symptomatic allergic rhinitis to assess the effects of the commonly used nasal spray products oxymetazoline hydrochloride and fluticasone propionate on the pharmacokinetics of SPRIX. Subjects received a single dose of oxymetazoline nasal spray followed by a single dose (31.5 mg) of SPRIX 30 min later.

in subjects with symptomatic allergic rhinitis to assess the effects of the commonly used nasal spray products oxymetazoline hydrochloride and fluticasone propionate on the pharmacokinetics of SPRIX. Subjects received a single dose of oxymetazoline nasal spray followed by a single dose (31.5 mg) of SPRIX 30 min later. Subjects also received fluticasone nasal spray (200 mcg as 2 x 50 mcg in each nostril) for seven days, with a single dose (31.5 mg) of SPRIX on the 7 th day. Administration of these common intranasal products had no effect of clinical significance on the rate or extent of ketorolac absorption. Probenecid: Concomitant administration of oral ketorolac and probenecid resulted in decreased clearance and volume of distribution of ketorolac and significant increases in ketorolac plasma levels (total AUC increased approximately threefold from 5.4 to 17.8 mcg/h/mL), and terminal half-life increased approximately twofold from 6.6 to 15.1 hours [ see Drug Interactions ( 7 ) ].

<table width="750" styleCode="Noautorules" ID="table3"><caption>Table 3: Pharmacokinetic Parameters of Ketorolac Tromethamine after Intramuscular (IM) and Intranasal (IN) Administration</caption><col width="40%"/><col width="15%"/><col width="15%"/><col width="15%"/><col width="15%"/><tfoot><tr><td colspan="5">C_max = maximum plasma concentration; t_max = time of C_max; AUC_0-&#x221E; = complete area under the concentration-time curve; T_&#xBD; = half-life; SD = standard deviation. All values are means, except t_max, for which medians are reported. </td></tr></tfoot><tbody><tr><td align="center" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Ketorolac Tromethamine</content></td><td align="center" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">C_max</content> (SD) ng/mL </td><td align="center" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">t_max</content> (range) hours </td><td align="center" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">AUC_0-&#x221E;</content> (SD) ng&#x2022;h/mL </td><td align="center" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">T_&#xBD;</content> (SD) hours </td></tr><tr><td align="center" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">30 mg IM</content> (1.0 mL of a 30 mg/mL solution) </td><td align="center" styleCode="Toprule Botrule Lrule Rrule">2382.2 (432.7) </td><td align="center" styleCode="Toprule Botrule Lrule Rrule">0.75 (0.25-1.03) </td><td align="center" styleCode="Toprule Botrule Lrule Rrule">11152.8 (4260.1) </td><td align="center" styleCode="Toprule Botrule Lrule Rrule">4.80 (1.18) </td></tr><tr><td align="center" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">31.5 mg IN (SPRIX)</content> (2 x 100 &#x3BC;L of a 15% w/w solution) </td><td align="center" styleCode="Toprule Botrule Lrule Rrule">1805.8 (882.8) </td><td align="center" styleCode="Toprule Botrule Lrule Rrule">0.75 (0.50-2.00) </td><td align="center" styleCode="Toprule Botrule Lrule Rrule">7477.3 (3654.4) </td><td align="center" styleCode="Toprule Botrule Lrule Rrule">5.24 (1.33) </td></tr><tr><td align="center" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">15 mg IM</content> (0.5 mL of a 30 mg/mL solution) </td><td align="center" styleCode="Toprule Botrule Lrule Rrule">1163.4 (279.9) </td><td align="center" styleCode="Toprule Botrule Lrule Rrule">0.75 (0.25-1.50) </td><td align="center" styleCode="Toprule Botrule Lrule Rrule">5196.3 (2076.7) </td><td align="center" styleCode="Toprule Botrule Lrule Rrule">5.00 (1.72) </td></tr></tbody></table>

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis An 18-month study in mice with oral doses of ketorolac at 2 mg/kg/day (approximately 1.3 times the human systemic exposure at the recommended maximum IN dose of 31.5 mg four times a day, based on area-under-the-plasma-concentration curve [AUC]), and a 24-month study in rats at 5 mg/kg/day (approximately 0.8 times the human AUC) showed no evidence of tumorigenicity. Mutagenesis Ketorolac was not mutagenic in the Ames test, unscheduled DNA synthesis and repair, or in forward mutation assays. Ketorolac did not cause chromosome breakage in the in vivo mouse micronucleus assay. At 1590 μg/mL and at higher concentrations, ketorolac increased the incidence of chromosomal aberrations in Chinese hamster ovarian cells. Impairment of fertility Impairment of fertility did not occur in male or female rats at oral doses of 9 mg/kg (approximately 1.3 times the human AUC) and 16 mg/kg (approximately 2.4 times the human AUC) of ketorolac, respectively.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis An 18-month study in mice with oral doses of ketorolac at 2 mg/kg/day (approximately 1.3 times the human systemic exposure at the recommended maximum IN dose of 31.5 mg four times a day, based on area-under-the-plasma-concentration curve [AUC]), and a 24-month study in rats at 5 mg/kg/day (approximately 0.8 times the human AUC) showed no evidence of tumorigenicity. Mutagenesis Ketorolac was not mutagenic in the Ames test, unscheduled DNA synthesis and repair, or in forward mutation assays. Ketorolac did not cause chromosome breakage in the in vivo mouse micronucleus assay. At 1590 μg/mL and at higher concentrations, ketorolac increased the incidence of chromosomal aberrations in Chinese hamster ovarian cells. Impairment of fertility Impairment of fertility did not occur in male or female rats at oral doses of 9 mg/kg (approximately 1.3 times the human AUC) and 16 mg/kg (approximately 2.4 times the human AUC) of ketorolac, respectively.

14 CLINICAL STUDIES 14.1 Postoperative Pain The effect of SPRIX on acute pain was evaluated in two multi-center, randomized, double-blind, placebo-controlled studies. In a study of adults who had undergone elective abdominal or orthopedic surgery, 300 patients were randomized and treated with SPRIX or placebo administered every 8 hours and morphine administered via patient controlled analgesia on an as needed basis. Efficacy was demonstrated as a statistically significant greater reduction in the summed pain intensity difference over 48 hours in patients who received SPRIX as compared to those receiving placebo. The clinical relevance of this is reflected in the finding that patients treated with SPRIX required 36% less morphine over 48 hours than patients treated with placebo. In a study of adults who had undergone elective abdominal surgery, 321 patients were randomized and treated with SPRIX or placebo administered every 6 hours and morphine administered via patient controlled analgesia on an as needed basis. Efficacy was demonstrated as a statistically significant greater reduction in the summed pain intensity difference over 48 hours in patients who received SPRIX as compared to those receiving placebo. The clinical relevance of this is reflected in the finding that patients treated with SPRIX required 26% less morphine over 48 hours than patients treated with placebo.

16 HOW SUPPLIED/STORAGE AND HANDLING SPRIX (ketorolac tromethamine) Nasal Spray, 15.75 mg/spray, are single-day preservative-free spray bottles, supplied as: NDC 69344-144-43 Carton containing 5 single-day nasal spray bottles NDC 69344-144-53 Carton containing 1 single-day nasal spray bottle Each single-day nasal spray bottle contains a sufficient quantity of solution to deliver 8 sprays for a total of 126 mg of ketorolac tromethamine. Each spray delivers 15.75 mg of ketorolac tromethamine. The delivery system is designed to administer precisely metered doses of 100 µL per spray. Storage Protect from light and freezing. Store unopened SPRIX between 2°C to 8°C (36°F to 46°F). During use, keep containers of SPRIX Nasal Spray at controlled room temperature, between 15°C to 30°C (59°F to 86°F), out of direct sunlight. Bottles of SPRIX should be discarded within 24 hours of priming.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Medication Guide and Instructions for Use ) that accompanies each prescription dispensed. Instruct all patients to read and closely follow the FDA-approved SPRIX Patient Instructions to ensure proper administration of SPRIX. When prescribing SPRIX, inform patients or their caregivers of the potential risks of ketorolac treatment, instruct patients to seek medical advice if they develop treatment-related adverse events, advise patients not to give SPRIX to other family members, and advise patients to discard any unused drug. Inform patients, families, or their caregivers of the following information before initiating therapy with SPRIX and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events 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 health care provider immediately [ see Warnings and Precautions ( 5.1 ) ]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [ see Contraindications ( 4 ), Warnings and Precautions ( 5.2 ) ]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop SPRIX and seek immediate medical therapy [ see Warnings and Precautions ( 5.3 ) ]. Heart Failure and Edema 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 and Precautions ( 5.5 ) ]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [ see Contraindications ( 4 ) and Warnings and Precautions ( 5.7 ) ]. Serious Skin Reactions, including DRESS Advise patients to stop taking SPRIX immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [ see Warnings and Precautions ( 5.9 , 5.10 ) ]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including SPRIX, may be associated with a reversible delay in ovulation [ see Use in Specific Populations ( 8.3 ) ]. Fetal Toxicity Inform pregnant women to avoid use of SPRIX and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with SPRIX 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 and Precautions ( 5.10 ) and Use in Specific Populations ( 8.1 ) ].

the fetal ductus arteriosus. If treatment with SPRIX 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 and Precautions ( 5.10 ) and Use in Specific Populations ( 8.1 ) ]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of SPRIX with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [ see Warnings and Precautions ( 5.2 ) and Drug Interactions ( 7 ) ]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDS and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with SPRIX until they talk to their healthcare provider [ see Drug Interactions ( 7 ) ]. Renal Effects SPRIX is eliminated by the kidneys. Advise patients to maintain adequate fluid intake and request medical advice if urine output decreases significantly [ see Contraindications ( 4 ), Warnings and Precautions ( 5.6 ) ]. Limitations of Use Instruct patients not to use SPRIX for more than 5 days. Use of SPRIX alone or in combination with any other ketorolac product for more than 5 days increases the risk for serious complications including GI bleeding and renal injury [ see Dosage and Administration ( 2 ) ]. Single-Day Container Instruct patients not to use any single bottle of SPRIX for more than one day [ see Dosage and Administration ( 2.5 ) ]. Nasal Discomfort Advise patients that they may experience transient, mild to moderate nasal irritation or discomfort upon dosing. Manufactured for and Distributed by: Zyla Life Sciences US Inc. Wayne, PA 19087 LBL # 101.05

Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: with increasing doses of NSAIDs with longer use of NSAIDs Do not take NSAIDs right before or after a heart surgery called a “coronary artery bypass graft (CABG)." Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: anytime during use without warning symptoms that may cause death The risk of getting an ulcer or bleeding increases with: past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” increasing doses of NSAIDs longer use of NSAIDs smoking drinking alcohol older age poor health advanced liver disease bleeding problems NSAIDs should only be used: exactly as prescribed at the lowest dose possible for your treatment for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. Who should not take NSAIDs? Do not take NSAIDs: if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. right before or after heart bypass surgery. Before taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you: have liver or kidney problems have high blood pressure have asthma are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy. are breastfeeding or plan to breast feed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See “ What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? ” new or worse high blood pressure heart failure liver problems including liver failure kidney problems including kidney failure low red blood cells (anemia) life-threatening skin reactions life-threatening allergic reactions Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness.

sure heart failure liver problems including liver failure kidney problems including kidney failure low red blood cells (anemia) life-threatening skin reactions life-threatening allergic reactions Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms: shortness of breath or trouble breathing chest pain weakness in one part or side of your body slurred speech swelling of the face or throat Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: nausea more tired or weaker than usual diarrhea itching your skin or eyes look yellow indigestion or stomach pain flu-like symptoms vomit blood there is blood in your bowel movement or it is black and sticky like tar unusual weight gain skin rash or blisters with fever swelling of the arms, legs, hands and feet If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. Manufactured for: Zyla Life Sciences US Inc., Wayne, PA 19087 Distributed by: Zyla Life Sciences US Inc., Wayne, PA 19087 For more information, go to www.sprix.com or call 1-800-518-1084. This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued or Revised: 04/2021

<table width="100%"><colgroup><col width="40%" align="left"/><col width="35%" align="left"/><col width="25%" align="right"/></colgroup><tbody><tr valign="top"><td styleCode="Botrule Lrule Rrule Toprule" colspan="3" align="center"><content styleCode="bold">Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs)</content></td></tr><tr valign="top"><td styleCode="Lrule Rrule Toprule" colspan="3" align="left"><content styleCode="bold" ID="s_medguide_a">What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including:</content><list listType="unordered" styleCode="Disc"><item><content styleCode="bold">Increased risk of a heart attack or stroke that can lead to death.</content>This risk may happen early in treatment and may increase:<list listType="unordered" styleCode="Circle"><item>with increasing doses of NSAIDs</item><item>with longer use of NSAIDs</item></list></item></list><content styleCode="bold">Do not take NSAIDs right before or after a heart surgery called a &#x201C;coronary artery bypass graft (CABG).&quot; Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. </content><list listType="unordered" styleCode="Disc"><item><content styleCode="bold">Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines:</content><list listType="unordered" styleCode="Circle"><item>anytime during use</item><item>without warning symptoms</item><item>that may cause death</item></list></item></list><content styleCode="bold">The risk of getting an ulcer or bleeding increases with:</content><list listType="unordered" styleCode="Circle"><item>past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs</item><item>taking medicines called &#x201C;corticosteroids&#x201D;, &#x201C;anticoagulants&#x201D;, &#x201C;SSRIs&#x201D;, or &#x201C;SNRIs&#x201D;</item></list></td></tr><tr valign="top"><td styleCode="Lrule" align="left"><list listType="unordered" styleCode="Circle"><item>increasing doses of NSAIDs</item><item>longer use of NSAIDs</item><item>smoking</item><item>drinking alcohol</item></list></td><td styleCode="Rrule" colspan="2" align="left"><list listType="unordered" styleCode="Circle"><item>older age</item><item>poor health</item><item>advanced liver disease</item><item>bleeding problems</item></list></td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule" colspan="3" align="left"><content styleCode="bold">NSAIDs should only be used:</content><list listType="unordered" styleCode="Circle"><item>exactly as prescribed</item><item>at the lowest dose possible for your treatment</item><item>for the shortest time needed</item></list></td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule Toprule" colspan="3" align="left"><content styleCode="bold">What are NSAIDs?</content> NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain.</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule Toprule" colspan="3" align="left"><content styleCode="bold">Who should not take NSAIDs?

eat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain.</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule Toprule" colspan="3" align="left"><content styleCode="bold">Who should not take NSAIDs? Do not take NSAIDs: </content><list listType="unordered" styleCode="Disc"><item>if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs.</item><item>right before or after heart bypass surgery.</item></list></td></tr><tr valign="top"><td styleCode="Lrule Rrule Toprule" colspan="3" align="left"><content styleCode="bold">Before taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you:</content><list listType="unordered" styleCode="Disc"><item>have liver or kidney problems</item><item>have high blood pressure</item><item>have asthma</item><item>are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy.</item><item>are breastfeeding or plan to breast feed.</item></list><content styleCode="bold">Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first.</content></td></tr><tr valign="top"><td styleCode="Lrule Rrule Toprule" colspan="3" align="left"><content styleCode="bold">What are the possible side effects of NSAIDs?

es can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first.</content></td></tr><tr valign="top"><td styleCode="Lrule Rrule Toprule" colspan="3" align="left"><content styleCode="bold">What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See &#x201C;<linkHtml href="#s_medguide_a">What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?</linkHtml>&#x201D; </content><list listType="unordered" styleCode="Disc"><item>new or worse high blood pressure</item><item>heart failure</item><item>liver problems including liver failure</item><item>kidney problems including kidney failure</item><item>low red blood cells (anemia)</item><item>life-threatening skin reactions</item><item>life-threatening allergic reactions</item><item><content styleCode="bold">Other side effects of NSAIDs include:</content> stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness.</item></list><content styleCode="bold">Get emergency help right away if you get any of the following symptoms:</content></td></tr><tr valign="top"><td styleCode="Lrule" align="left"><list listType="unordered" styleCode="Disc"><item>shortness of breath or trouble breathing</item><item>chest pain</item><item>weakness in one part or side of your body</item></list></td><td styleCode="Rrule" colspan="2" align="left"><list listType="unordered" styleCode="Disc"><item>slurred speech</item><item>swelling of the face or throat</item></list></td></tr><tr valign="top"><td styleCode="Lrule Rrule" colspan="3" align="left"><content styleCode="bold">Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms:</content></td></tr><tr valign="top"><td styleCode="Lrule" align="left"><list listType="unordered" styleCode="Disc"><item>nausea</item><item>more tired or weaker than usual</item><item>diarrhea</item><item>itching</item><item>your skin or eyes look yellow</item><item>indigestion or stomach pain</item><item>flu-like symptoms</item></list></td><td styleCode="Rrule" colspan="2" align="left"><list listType="unordered" styleCode="Disc"><item>vomit blood</item><item>there is blood in your bowel movement or it is black and sticky like tar</item><item>unusual weight gain</item><item>skin rash or blisters with fever</item><item>swelling of the arms, legs, hands and feet</item></list></td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule" colspan="3" align="left"><content styleCode="bold">If you take too much of your NSAID, call your healthcare provider or get medical help right away.</content> These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule Toprule" colspan="3" align="left"><content styleCode="bold">Other information about NSAIDs</content><list listType="unordered" styleCode="Disc"><item>Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.</item><item>Some NSAIDs are sold in lower doses without a prescription (over-the-counter).

red" styleCode="Disc"><item>Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.</item><item>Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days.</item></list></td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule Toprule" colspan="3" align="left"><content styleCode="bold">General information about the safe and effective use of NSAIDs</content> Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals.</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule Toprule" colspan="3" align="left"><content styleCode="bold">Manufactured for:</content> Zyla Life Sciences US Inc., Wayne, PA 19087 <content styleCode="bold">Distributed by:</content> Zyla Life Sciences US Inc., Wayne, PA 19087 For more information, go to <linkHtml href="http://www.sprix.com">www.sprix.com</linkHtml> or call 1-800-518-1084.</td></tr><tr valign="top"><td colspan="2" align="left">This Medication Guide has been approved by the U.S. Food and Drug Administration.</td><td align="right">Issued or Revised: 04/2021</td></tr></tbody></table>

Instructions for Use SPRIX ® (spriks) (ketorolac tromethamine) Nasal Spray Read this Instructions for Use before you start using SPRIX and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. Important information: SPRIX is for use in your nose only. Do not breathe in (inhale) SPRIX. Each SPRIX bottle has enough pain medicine for 1 day. Throw away each SPRIX bottle within 24 hours of taking your first dose, even if the bottle still contains unused medicine. Your healthcare provider has prescribed SPRIX to treat moderate to severe pain. Use SPRIX exactly as your healthcare provider tells you to use it. Your healthcare provider will tell you how many sprays you should use each time you use SPRIX. Do not use SPRIX for more than 5 days. If you still have pain after 5 days, contact your healthcare provider. Do not use SPRIX more than every 6 hours. It is important that you drink plenty of fluids while you are using SPRIX. Tell your healthcare provider if you urinate less while using SPRIX. You may have discomfort or irritation in your nose when using SPRIX. This usually lasts for a short time. Do not breathe in (inhale) SPRIX while spraying. Using SPRIX Nasal Spray Parts of your SPRIX bottle Follow the instructions below to use SPRIX. Before you use SPRIX for the first time, you will need to prime the bottle. Priming SPRIX: Step 1. Hold the finger flange with your fingers (see Figure A ) , and remove the clear plastic cover with your opposite hand. Keep the clear plastic cover for later. Remove and throw away the blue plastic safety clip. If the clear plastic cover is improperly removed, the tip of the bottle may be pulled off of the glass vial. If this happens, place the tip back onto the glass vial by lining it up carefully and gently pushing it back on until it is back in the correct position (see Figure B ) . The SPRIX bottle should work properly again. Step 2. Hold the SPRIX bottle upright at arm’s length away from you with your index finger and middle finger resting on the top of the finger flange and your thumb supporting the base (see Figure C ) . Press down on the finger flange and release the pump 5 times. You may not see a spray the first few times you press down. Now the pump is primed and ready to use. You do not need to prime the pump again if you use more doses from this bottle. Step 3. Blow your nose to clear your nostrils. Step 4. Sit up straight or stand. Step 5. Keep your head tilted downward toward your toes. Step 6. Place the tip of the SPRIX bottle into your right nostril. Step 7. Hold the SPRIX bottle upright and aim the tip toward the back of your nose (see Figure D ) . Step 8. Hold your breath and spray 1 time into your right nostril, pressing down on both sides of the finger flange (see Figure D ) . Step 9. Breathe in gently through your mouth after you use SPRIX. You may also pinch your nose to help keep the medicine in your nose. Step 10. If your healthcare provider has prescribed only 1 spray per dose for you, you have now finished your dose, skip to Step 12 below. Step 11. If your healthcare provider has prescribed 2 sprays for you, repeat steps 3 - 9 above for your left nostril. Be sure to point the spray away from the center of your nose. Spray 1 time into your left nostril. Step 12. When you are finished using SPRIX, put the clear plastic cover back on the SPRIX bottle.

elow. Step 11. If your healthcare provider has prescribed 2 sprays for you, repeat steps 3 - 9 above for your left nostril. Be sure to point the spray away from the center of your nose. Spray 1 time into your left nostril. Step 12. When you are finished using SPRIX, put the clear plastic cover back on the SPRIX bottle. How should I store SPRIX? Store unopened SPRIX bottles between 36°F to 46°F (2°C to 8°C). Keep opened bottles of SPRIX at room temperature. Keep SPRIX out of direct sunlight. Do not freeze SPRIX. SPRIX does not contain a preservative. Throw away each SPRIX bottle within 24 hours of taking your first dose, even if the bottle still contains unused medicine. Keep SPRIX and all medicines out of the reach of children. General information about the safe and effective use of SPRIX. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not give SPRIX to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about SPRIX that is written for health professionals. What are the ingredients in SPRIX? Active ingredient: ketorolac tromethamine Inactive ingredient: edetate disodium (EDTA), monobasic potassium phosphate, sodium hydroxide, and water for injection This Instructions for Use has been approved by the U.S. Food and Drug Administration. Distributed by: Zyla Life Sciences US Inc. Wayne, PA 19087 LBL # 102.04 Revised: 04/2021 Parts of Bottle Figure A Figure B Figure C Figure D