Ketorolac Tromethamine Injection

Ketorolac is a nonsteroidal anti-inflammatory drug (NSAID) of the acetic acid chemical class. Ketorolac possesses antipyretic and analgesic properties. As a pyrrolo-pyrrole, ketorolac is chemically related to indomethacin and tolmetin. The onset and efficacy of analgesia after systemic administration are claimed to be comparable to that of morphine, but ketorolac causes less drowsiness, nausea, and vomiting. Post-marketing studies have not found IM ketorolac to be superior to oral ibuprofen for the treatment of acute musculoskeletal pain.^[1] Unlike other NSAIDs, ketorolac should only be used for up to 5 consecutive days. Also, oral use is only for therapy continuation after parenteral administration. Ketorolac was approved by the FDA for parenteral use in November 1989, oral use in December 1991, ophthalmic use in November 1992, and intranasal use in May 2010. A preservative-free and a lower strength ophthalmic solution were FDA-approved in November 1997 and May 2003, respectively.

Ketorolac competitively inhibits both cyclooxygenase (COX) isoenzymes, COX-1 and COX-2, by blocking arachidonate binding resulting in analgesic, antipyretic, and anti-inflammatory pharmacologic effects. The enzymes COX-1 and COX-2 catalyze the conversion of arachidonic acid to prostaglandin G2 (PGG2), the first step of the synthesis prostaglandins and thromboxanes that are involved in rapid physiological responses. COX isoenzymes are also responsible for a peroxidase reaction, which is not affected by NSAIDs. In addition, NSAIDs do not suppress leukotriene synthesis by lipoxygenase pathways. COX-1 is constitutively expressed in almost all tissues, while COX-2 appears to only be constitutively expressed in the brain, kidney, bones, reproductive organs, and some neoplasms (e.g., colon and prostate cancers). COX-1 is responsible for prostaglandin synthesis in response to stimulation by circulating hormones, as well as maintenance of normal renal function, gastric mucosal integrity, and hemostasis. However, COX-2 is inducible in many cells in response to certain mediators of inflammation (e.g., interleukin-1, tumor necrosis factor, lipopolysaccharide, mitogens, and reactive oxygen intermediates).

Anti-Inflammatory Activity

The anti-inflammatory mechanism of ketorolac is due to decreased prostaglandin synthesis via inhibition of COX-1 and COX-2. It appears that the anti-inflammatory effects may be primarily due to inhibition of the COX-2 isoenzyme. However, COX-1 is expressed at some sites of inflammation. COX-1 is expressed in the joints of rheumatoid arthritis or osteoarthritis patients, especially the synovial lining, and it is the primary enzyme of prostaglandin synthesis in human bursitis.

Analgesic Activity

Ketorolac is effective in cases where inflammation has caused sensitivity of pain receptors (hyperalgesia). It appears prostaglandins, specifically prostaglandins E and F, are responsible for sensitizing the pain receptors; therefore, ketorolac has an indirect analgesic effect by inhibiting the production of further prostaglandins and does not directly affect hyperalgesia or the pain threshold.

Antipyretic Activity

Ketorolac promotes a return to a normal body temperature set point in the hypothalamus by suppressing the synthesis of prostaglandins, specifically PGE2, in circumventricular organs in and near the hypothalamus. Ketorolac may mask fever in some patients, especially with high or chronic dosing.

Ophthalmic Activity

Following topical application to the eye, ketorolac inhibits miosis by inhibiting the biosynthesis of ocular prostaglandins. Prostaglandins play a role in the miotic response produced during ocular surgery by constricting the iris sphincter independently of cholinergic mechanisms. In the eye, prostaglandins also have been shown to disrupt the blood-aqueous humor barrier, cause vasodilation, increase vascular permeability, promote leukocytosis, and increase intraocular pressure (IOP). The degree of ocular inflammatory response is correlated with prostaglandin-induced increases in ciliary epithelium permeability. When applied topically to the eye, NSAIDs inhibit the synthesis of prostaglandins in the iris, ciliary body, and conjunctiva. Thus, NSAIDs may prevent many of the manifestations of ocular inflammation. Ketorolac does not affect intraocular pressure or tonographic aqueous outflow resistance and does not interfere with the action of acetylcholine administered during ocular surgery. Ketorolac also does not prevent increases in intraocular pressure or decreases in aqueous outflow induced by topical corticosteroids.

GI Effects

Gastrointestinal side effects of ketorolac are primarily contributed to COX-1 inhibition; however, potential role of COX-2 inhibition in the GI tract has not been fully elucidated. In comparison to other NSAIDs, ketorolac has been associated an increased incidence of GI effects and has dosing restrictions to limit these effects.

Platelet Effects

The inhibition of platelet aggregation seen with ketorolac is due to dose-dependent inhibition of COX-1 in platelets leading to decreased levels of platelet thromboxane A2and an increase in bleeding time. The inhibition of platelet aggregation is reversible within 24—48 hours of ketorolac discontinuation. This differs from aspirin, which irreversibly binds to COX-1 in platelets inhibiting this enzyme for the life of the cell.

Renal Effects

In the kidney, prostaglandins, produced by both COX-1 and COX-2, are important regulators of sodium and water reabsorption through PGE2 and of renal function and hemodynamics via PGI2 in response to vasoconstrictive factors (e.g., endothelin-1, a factor that increases peripheral vascular resistance) and through effects on the renin-angiotensin system. In the setting of decreased volume, PGI2, helps maintain renal blood flow by counteracting other vasoconstrictive autocoids. In conditions where renal blood flow is dependent upon prostaglandin synthesis, administration of NSAIDs can result in significant decreases in renal blood flow leading to acute renal failure. In addition, alterations in sodium and water reabsorption may worsen increased blood pressure, which can be significant in selected individuals.

Systemic use of ketorolac is only indicated for the short-term management of moderately severe acute pain that requires analgesia at the opioid level. The oral tablets are only indicated as continuation treatment after IV or IM administration, if necessary. Limit duration of use so the total combined duration of oral and parenteral ketorolac does not exceed 5 days because of the increased risk of serious adverse events. Also, doses higher than recommended will not increase efficacy but will increase the risk of developing serious adverse events; the maximum recommended daily oral dose is significantly lower than the maximum daily parenteral dose.^[2][3] Ketorolac ophthalmic drops may be administered for up to 4 days after corneal refractive surgery.^[4]

Ketorolac is contraindicated for use by patients with ketorolac or other NSAID hypersensitivity, and the systemic formulations are contraindicated for use by patients with salicylate hypersensitivity or who have experienced asthma, urticaria, or other allergic reactions after taking aspirin or other NSAIDs; cautious use of the ophthalmic solution is advised in salicylate-sensitive patients. Severe, rarely fatal, serious hypersensitivity reactions or anaphylaxis have been reported after systemic ketorolac use in salicylate-sensitive patients. After ketorolac tromethamine ophthalmic solution use, reports of bronchospasm or exacerbation of asthma exist among patients who have either a known hypersensitivity to aspirin/nonsteroidal anti-inflammatory drugs or a past medical history of asthma. Appropriate counteractive measures must be available when administering the first dose of ketorolac. Do not use ketorolac in patients with aspirin-sensitive asthma or the aspirin triad because of the approximate 5% cross-sensitivity that occurs between aspirin and NSAIDs. The triad typically occurs in patients with asthma who experience rhinitis with or without nasal polyps or who experience severe, potentially fatal, acute bronchospasm after taking aspirin or other NSAIDs.^[3][5][6]

Like all NSAIDs, ketorolac may increase the potential for hematological complications. Systemic formulations are contraindicated for use as a prophylactic analgesic before major surgery and contraindicated for use during surgery when hemostasis is critical; cautious use of the ophthalmic solution is advised with ocular surgery.^[3][5] Perioperative use has been associated with postoperative hematomas and other events. Postoperative use when hemostasis is critical is not recommended. Bleeding after a single IV or IM dose in pediatric patients was greater after tonsillectomy vs. other procedures.^[3][5] Ketorolac, in all forms, should be used with caution in patients with known bleeding tendencies and in patients who are receiving other medications that may prolong bleeding time (e.g., anticoagulant therapy) as such patients have an increased risk of bleeding complications.^[3][5] There have been reports that ocular-applied NSAIDs may cause increased bleeding of ocular tissues (including hyphemas) in conjunction with ocular procedures.^[6]

Using systemic ketorolac can result in gastritis, ulceration with or without perforation, and/or bleeding, which can occur at any time, often without preceding symptoms. It is, therefore, contraindicated in patients with a history of or active peptic ulcer disease, GI bleeding, or GI perforation. Cautious use is warranted for patients with other types of GI disease such as inflammatory bowel disease (ulcerative colitis, Crohn’s disease), as these conditions may be exacerbated. Ulcerative stomatitis and exacerbations of inflammatory bowel disease have been noted during post-marketing surveillance with ketorolac or other NSAIDs. Older patients seem to tolerate GI ulceration or bleeding less well than younger patients. Most fatal GI events occur in older or debilitated patients. Patients should be monitored closely for bleeding while receiving systemic ketorolac, receiving concurrent myelosuppressive chemotherapy, corticosteroid therapy, or anticoagulant therapy, tobacco smoking patients, or in patients with alcoholism. Ketorolac is contraindicated for use by patients who take aspirin or another NSAID because of the cumulative risk of inducing serious NSAID-related side effects.^[3][5]

Use systemic ketorolac products cautiously in patients with hepatic disease. Severe hepatic reactions can occur during treatment, and patients with hepatic impairment are at an increased risk for these complications. Elevations in liver-function tests can also occur. Discontinue treatment if elevated liver-function tests persist or worsen, or if signs or symptoms of hepatic disease, such as jaundice, develop. Patients with hepatic disease are also at increased risk for ketorolac-related toxicity, as hypoalbuminemia increases the amount of active drug available in the serum. Additionally, there is a dose-dependent decrease in prostaglandin synthesis, which can cause renal blood flow reduction in patients that utilize prostaglandins to support renal blood flow. Due to the role of prostaglandins in renal function and hemodynamics, patients with hypoalbuminemia should be closely observed during therapy due to an increased risk for reduced renal blood flow or volume.^[3][5] Such precautions are not expected in conjunction with ophthalmic use.^[6]

Systemic ketorolac is contraindicated for use by patients with advanced renal impairment such as renal failure and in patients at risk for renal failure due to hypovolemia (dehydration); cautious use is recommended in patients with milder forms of renal disease or renal impairment.^[3][5] These precautions are not expected to apply with ophthalmic use.^[6] Ketorolac and its metabolites are renally excreted. Accumulation of parent drug and metabolites can occur with impaired renal function; dosage adjustment is needed.^[3][5] There is a dose-dependent decrease in prostaglandin synthesis, which can cause renal blood flow reduction in patients who utilize prostaglandins to support renal blood flow. Due to the role of prostaglandins in renal function and hemodynamics, certain patients should be closely observed during therapy due to an increased risk for reduced renal blood flow or volume. Conditions such as congestive heart failure, edema, or hypertension can be exacerbated by the fluid retention cause by suboptimal renal perfusion. Use ketorolac cautiously in patients with any of these conditions or other diseases that predispose to fluid retention.^[3][5] Meta-analyses have demonstrated that the effect of NSAIDs on blood pressure is the greatest in hypertensive individuals receiving antihypertensive medication. In addition, normotensive patients receiving antihypertensive therapy had higher increases in blood pressure than subjects with uncontrolled hypertension or normotensive subjects receiving no hypertensive therapy.^[7] Patients with renal impairment, renal failure, hepatic disease, diabetes mellitus, systemic lupus erythematosus (SLE), congestive heart failure, rheumatoid arthritis, edema, extracellular volume depletion (i.e., hypovolemia or dehydration), sepsis; those taking diuretics or nephrotoxic drugs; and elderly patients are at the highest risk for complications related to suboptimal renal perfusion. The oral tablets are only indicated for the short-term management of moderately severe acute pain that requires analgesia at the opioid level and only as continuation treatment following IV or IM administration, if necessary. The total combined duration of use of oral and parenteral ketorolac should not exceed 5 days because of the increased risk of serious adverse events. Also, doses higher than recommended will not increase efficacy but will increase the risk of developing serious adverse events; the maximum recommended daily oral dose is significantly lower than the maximum daily parenteral dose. Also, ketorolac is contraindicated for use by patients who take aspirin or another NSAID because of the cumulative risk of inducing serious NSAID-related side effects.

Ketorolac is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft surgery (CABG). An increased incidence of myocardial infarction and stroke was found through analysis of data regarding the use of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days after CABG surgery. Ketorolac, like all nonsteroidal anti-inflammatory drugs (NSAIDs), may cause an increased risk of serious cardiovascular thromboembolism, myocardial infarction, and stroke, which can be fatal. The FDA has warned that the risk of myocardial infarction or stroke can occur as early as the first weeks of using a NSAID, and risk may increase with higher doses and longer duration of use. NSAIDs may increase the risk of a cardiovascular thrombotic event in patients with or without underlying heart disease or risk factors for heart disease. Patients with known heart disease or risk factors appear to have a greater likelihood of an event following NSAID use, likely due to a higher baseline risk. Current evidence is insufficient to determine if the risk of an event is higher or lower for any particular NSAID compared to other NSAIDs. There is no consistent evidence that concomitant use of aspirin mitigates the increased risk for cardiovascular thrombotic events.^[5] Clinical practice guidelines state NSAIDs should not be administered to patients presenting with and hospitalized for ST-elevation myocardial infarction (STEMI) due to increased risk of mortality, reinfarction, hypertension, heart failure, and myocardial rupture associated with their use.^[8] Observational data from a national registry demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, cardiovascular-related death, and all-cause mortality beginning the first week of treatment. An increased relative risk of death in NSAID users continued during the follow-up period of 4 years. Data demonstrate that patients treated with NSAIDs were more likely to die in the first year following a myocardial infarction compared to those not treated with NSAIDs. Avoid ketorolac use in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. Congestive heart failure and hypertension can be exacerbated by ketorolac. A meta-analysis of randomized, controlled trials demonstrated an approximately 2-fold increase in hospitalizations for heart failure among non-selective and COX-2 selective-treated patients compared to placebo.^[5] In patients with hypertension, monitor blood pressure during the initiation of NSAID treatment and throughout therapy. A meta-analysis demonstrated that the effect of NSAIDs on blood pressure is the greatest in hypertensive individuals receiving antihypertensive medication. Normotensive patients receiving antihypertensive therapy had higher increases in blood pressure than subjects with uncontrolled hypertension or normotensive subjects receiving no hypertensive therapy.^[7] Caution is recommended when administering ketorolac to patients with cardiac disease, cardiomyopathy, cardiac arrhythmias (e.g., tachycardia), significant coronary artery disease (including acute myocardial infarction, angina, or history of myocardial infarction), peripheral vascular disease, cerebrovascular disease (e.g., stroke, transient ischemic attack), hypertension, pre-existing renal disease, or fluid retention. Closely monitor blood pressure during ketorolac receipt. Use the lowest effective dose for the shortest duration possible to minimize the potential risk for an adverse cardiovascular event. Inform patients to seek immediate medical attention if they experience any signs or symptoms of a cardiovascular thrombotic event.^[5]

Ketorolac should be used extremely cautiously, if at all, in patients with preexisting coagulation disorders (e.g., coagulopathy, hemophilia) or thrombocytopenia due to the effect of the drug on platelet function and vascular response to bleeding. Systemic ketorolac is contraindicated in patients with hematological disease (hemorrhagic diathesis), with incomplete hemostasis, with a high bleeding risk, or with known or suspected intracranial bleeding; cautious use of ophthalmic solution is advised in patients with known bleeding tendencies.^[3][5][6] Anemia may be exacerbated with the use of systemic NSAIDs. This may be due to fluid retention, GI blood loss, or an incompletely described effect upon erythrogenesis. Patients who have initial hemoglobin values of 10 g/dL or less and who are to receive long-term NSAID therapy should have hemoglobin values determined periodically. NSAIDs should be used with caution in patients with immunosuppression or neutropenia. NSAIDs may mask the signs of infection such as fever or pain in patients with bone marrow suppression. Systemic use is only indicated for the short-term management of moderately severe acute pain that requires analgesia at the opioid level. The total combined duration of use should not exceed 5 consecutive days because of the increased risk of serious adverse events. Also, doses higher than recommended will not increase efficacy but will increase the risk of developing serious adverse events; the maximum recommended daily oral dose is a lot lower than the maximum daily parenteral dose. Additionally, it is contraindicated for use by patients who take aspirin or another NSAID because of the cumulative risk of inducing serious NSAID-related side effects.^[3][5]

Post-marketing experience with ophthalmic NSAIDs, including ketorolac, suggests that patients with complicated ocular surgery, corneal denervation, corneal epithelial defects, diabetes mellitus, ocular disease affecting the ocular surface (e.g., xerophthalmia, dry eye syndrome), rheumatoid arthritis, or repeat ocular surgeries within a short period of time may be at increased risk for corneal adverse events (corneal thinning, corneal erosion, corneal ulceration, corneal perforation) that may become sight-threatening. Ocular NSAIDs should be used with caution in these patients. Use of ocular NSAIDs may also result in keratitis. Post-marketing experience also suggests that use more than 24 hours prior to ocular surgery or use beyond 14 days post-surgery may increase patient risk for the occurrence and severity of corneal adverse events.

Patients need to remove contact lenses before administering ketorolac ophthalmic solution. Unless the preservative-free formulation is used, ketorolac ophthalmic solution contains the preservative benzalkonium chloride, which may be absorbed by soft contact lenses. Also, contact lens removal is needed for drug penetration into the eye.

Ketorolac injection is contraindicated for epidural administration or intrathecal administration because of the alcohol content (10% weight per volume) of the parenteral preparation.

Although it is used clinically, systemic ketorolac is not indicated for use in pediatric patients (neonates, infants, children, or adolescents). Ketorolac is also not indicated for and should not be used for minor or chronic painful conditions. Increasing the dose of ketorolac beyond the labeled recommendations will not provide better efficacy and will increase the risk of developing serious adverse reactions. Do not exceed 5 days of systemic therapy. Adjust dosages for patients weighing less than 50 kg.^[2][3][5]

Systemic and intranasal ketorolac is contraindicated in labor and obstetric delivery because it may adversely affect fetal circulation and uterine contractions.^[2][3][5] Avoid ketorolac use during the third trimester of pregnancy (starting at 30 weeks of gestation) due to the risk of premature closure of the fetal ductus arteriosus and persistent pulmonary hypertension in the neonate.^[2][3][5][6] If NSAID treatment is deemed necessary between 20 to 30 weeks of pregnancy, limit use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if NSAID treatment extends beyond 48 hours. Discontinue the NSAID if oligohydramnios occurs and follow up according to clinical practice. Use of NSAIDs around 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 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.^[9] Observational data regarding embryofetal risks of NSAID use during the first trimester is inconclusive. There are no adequate and well-controlled studies of ketorolac in pregnant women.^[2][3][5][6]

Due to the potential adverse effects of prostaglandin-inhibiting drugs on nursing infants, caution is advised when administering ketorolac to lactating mothers. If used during breastfeeding, instruct the patient to closely monitor the breastfed infant and report any adverse events that may develop.^[3][5][6] Ketorolac is excreted into breast milk. Of 10 lactating mothers, ketorolac was undetectable in the milk of 4 of the women, and the maximum milk concentration observed was 7.9 ng/mL in the other 6 women after 1 day of dosing with 10 mg every 6 hours. Based on a daily infant intake of 400—1000 mL/day of breast milk and a maternal body weight of 60 kg, the calculated maximum infant dose would be equivalent to 0.4% of the weight-adjusted maternal dose.^[5] The American Academy of Pediatrics (AAP) considers ketorolac to be a drug which is usually compatible with breastfeeding; however, their assessment was published prior to recent recommendations to ensure safe use of the drug; other analgesics and anti-inflammatory agents considered to be usually compatible with breastfeeding by the AAP include acetaminophen, ibuprofen, indomethacin, naproxen, and piroxicam and would be preferred to limit infant risk.^[10] Consider the benefits of breastfeeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breastfeeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Avoid ocular exposure of ketorolac nasal spray; advise patients to avoid spraying in the eyes. If eye contact occurs, the patient should wash the affected eye(s) with water or saline, and seek medical attention if irritation persists for more than one hour.^[5]

Dosage adjustments of systemic ketorolac are needed for geriatric patients 65 years of age and older and use in the geriatric patient should be approached with extreme caution. Systemic ketorolac is only indicated for short-term pain management due to the increased risk for side effects relative to other NSAIDs. The total combined duration of use of oral ketorolac and parenteral ketorolac tromethamine should not exceed 5 days. The elderly and debilitated are typically at the highest risk for developing complications related to NSAID therapy, such as GI bleeding and ulceration, fluid retention, and reduced renal perfusion.^[3] According to the Beers Criteria, systemic ketorolac is a potentially inappropriate medication (PIM) in geriatric patients and avoidance is recommended in those with or without a history of gastrointestinal (GI) ulcers due to an increased risk of gastrointestinal bleeding, peptic ulcer disease, and acute kidney injury in older adults. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs); the total combined duration of use of oral ketorolac and parenteral ketorolac tromethamine should not exceed 5 days. Avoid ketorolac use if possible in the skilled care resident due to the increased risks of ketorolac vs. other NSAIDs. NSAIDs should be reserved for symptoms and inflammatory conditions for which lower risk analgesics (e.g., acetaminophen) have either failed or are not clinically indicated. NSAIDs may cause GI bleeding in patients with a prior history of, or with increased risk for, GI bleeding. Also, NSAIDs may cause or worsen renal failure, increase blood pressure, or exacerbate heart failure.^[11]

The most frequently reported adverse effects of orally and parenterally administered ketorolac are gastrointestinal; these events with respective oral and parenteral incidences include abdominal pain (more than 10% vs. 13%), dyspepsia (more than 10% vs. 12%), nausea (more than 10% vs. 12%), vomiting (1% to 10% vs. 1% to 3%), and diarrhea (1% to 10% vs. 7%). Constipation, stomatitis, and flatulence each occurred in 1% to 10% of those receiving oral products as compared to 1% to 3% of patients receiving parenteral products.^[2][3] Gastrointestinal adverse events were not reported among patients in clinical trials of intranasal ketorolac; however, ketorolac nasal spray has systemic effect and such events may occur.^[5] Gastritis, rectal bleeding, glossitis, xerostomia, eructation, anorexia, and polyphagia occurred in 1% or less of patients on systemic ketorolac. Severe GI reactions (peptic ulcer, GI bleeding, and GI perforation) occurred in 0.4% to 4.6% of patients without a history of a peptic ulcer or bleed and in 2.1% to 15.4% of patients with a history of a peptic ulcer or bleed. Most fatal GI events as a result of GI ulceration or bleeding occurred in older or debilitated patients. Melena and/or hematemesis may be present. The risk of severe GI events is increased by the presence of the following factors: history of peptic ulcer disease or GI bleed, smoking, alcohol usage, concomitant usage of anticoagulants, or oral corticosteroids, older age, and poor general health status. Also, the incidence and severity of GI problems increases with higher doses and longer treatment duration; total systemic therapy with ketorolac should not exceed 5 days. Use the lowest effective dose for the shortest possible duration to minimize the potential for an adverse GI event. Gastrointestinal bleeding or erosive gastritis can be minor or life-threatening and may result from a combination of direct irritant action on the stomach mucosa and a prolonged bleeding time due to changes in platelet aggregation. Occult GI bleeding occurs in many patients and is not necessarily correlated with GI distress. While the amount of blood lost is usually not significant, blood loss can result in iron deficiency anemia. Patients on prolonged therapy should undergo regular blood monitoring. If a serious GI event is suspected, discontinue ketorolac until the adverse event is ruled out. Consider other therapies besides a nonsteroidal anti-inflammatory drug for high risk patients.^[2][3]

Rare cases of esophagitis have been reported in patients receiving systemic NSAIDs, including ketorolac.^[2] NSAID-induced esophagitis is characterized by sudden onset odynophagia, pyrosis (heartburn), retrosternal pain, and dysphagia. Severe complications such as esophageal ulceration, esophageal stricture, bleeding, and perforation have been reported rarely. Risk factors for NSAID-induced esophageal effects include taking the medication without water and at night. Symptoms usually resolve within days to weeks after stopping the medication. Such effects are not reported with ophthalmic use ketorolac.^[6]

Ketorolac-induced platelet dysfunction may lead to prolonged bleeding time, purpura, and anemia, all of which have been reported in 1% to 10% of patients taking ketorolac or another NSAID during clinical trials. Anemia may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect on erythropoiesis. Check hemoglobin and hematocrit if signs and symptoms of anemia present.^[2][3][5] There have been reports that ocularly applied NSAIDs may cause increased bleeding of ocular tissues (including hyphema) when used in conjunction with ocular surgery.^[4] Other hematologic effects, including ecchymosis, eosinophilia, epistaxis, leukopenia, and thrombocytopenia, have been reported in less than 1% of patients during clinical trials. Agranulocytosis, aplastic anemia, hemolytic anemia, lymphadenopathy, pancytopenia, and postoperative wound hemorrhage (rarely requiring blood transfusion) have been rarely observed with postmarketing use.^[2][3][5]

Headache (more than 10%) is the most common nervous system reaction associated with systemic ketorolac, followed by drowsiness and dizziness (both 1% to 10%). Abnormal dreams, abnormal thinking, anxiety, asthenia, confusion, depression, euphoria, extrapyramidal symptoms, hallucinations, hyperkinesis, inability to concentrate, insomnia, nervousness, paresthesias, somnolence, stupor, tremor, vertigo, and malaise have been reported in less than 1% of patients during clinical trials for ketorolac or other NSAIDs. Seizures, psychosis, and coma have been rarely reported; however, a causal relationship has not been established.^[2][3][5] Headache has also been reported in approximately 1% to 5% of patients receiving ophthalmic ketorolac during clinical trials.^[4]

Aseptic meningitis has been reported rarely with NSAID therapy. Meningitis has occurred with ketorolac therapy but a causal relationship has not been established. Ibuprofen has been the most common NSAID implicated in this adverse reaction; however, cases have been reported with sulindac, naproxen, tolmetin, diclofenac, ketoprofen, rofecoxib, and piroxicam. Aseptic meningitis from one NSAID does not preclude use of another NSAID; most patients can be treated with another drug without incident. However, one patient with Sjogren’s syndrome experienced aseptic meningitis after receipt of naproxen, ibuprofen, and rofecoxib at different times; aseptic meningitis developed about a week after each drug exposure, and the symptoms abated roughly 2 days following each drug cessation. The occurrence of aseptic meningitis is not related to NSAID chemical class or prostaglandin inhibition. A Type III or IV immunological hypersensitivity reaction is the proposed mechanism of action. Drug-induced aseptic meningitis usually occurs shortly after drug initiation but can occur after years of drug usage. Although NSAID-induced aseptic meningitis is primarily reported in patients with systemic lupus erythematosus (SLE), healthy patients and patients with other disease states such as ankylosing spondylitis, connective tissue disease, osteoarthritis, and rheumatoid arthritis have developed NSAID-induced aseptic meningitis. Symptoms of aseptic meningitis include confusion, drowsiness, general feeling of illness, severe headache, nausea, nuchal rigidity, and photophobia. As aseptic meningitis is a diagnosis of exclusion, the suspected drug should be discontinued and not restarted unless a rechallenge is desired.

Elevated hepatic enzymes occur in up to 15% of patients receiving systemic NSAIDs; these abnormalities may progress, remain unchanged, or be transient with continued therapy. Significant elevations of AST or ALT (3 to 4-times the ULN) have been reported in approximately 1% of the patients during clinical trials.^[2][3][5] Rare cases of acute pancreatitis, jaundice, fulminant hepatitis, hepatic necrosis, and hepatic failure have been reported, sometimes with fatal outcomes. Evaluate patients with abnormal liver function tests or signs and symptoms suggesting liver dysfunction for more severe hepatic reactions. Discontinue ketorolac if clinical signs and symptoms consistent with liver disease develop or systemic manifestations (e.g., eosinophilia, rash) occur.^[2][3]

Fever, infection, sepsis, asthma, dyspnea, cough, and pulmonary edema occurred in less than 1% of patients who received ketorolac. Respiratory depression and pneumonia have been reported with postmarketing use; however, causality has not been established.^[2][3][5]

Ophthalmic administration of ketorolac may result in impaired wound healing of the eye and keratitis. Continued use may result in epithelial breakdown, corneal degeneration (corneal thinning, corneal erosion), corneal ulceration, or corneal perforation in susceptible patients; these events may be site-threatening. Discontinue ketorolac ophthalmic solution immediately in patients with evidence of corneal epithelial breakdown. Transient stinging and burning on instillation are the most commonly reported adverse reactions associated with the use of ketorolac ophthalmic solution, reported by up to 40% of patients during clinical trials. Allergic reactions (e.g., ocular swelling, eyelid edema, and conjunctival hyperemia), corneal edema, iritis, ocular inflammation, ocular irritation, superficial keratitis, and superficial ocular infection have been reported in 1% to 10% of patients. Conjunctival hyperemia, corneal infiltrates, headache, ocular edema, and ocular pain have occurred in approximately 1% to 5% of patients. Other reactions reported rarely include corneal ulcer, headaches, xerophthalmia, and visual impairment. Bronchial spasm or exacerbation of asthma have been reported with postmarketing use of the ophthalmic solution; however, causality and frequency have not been established.^[4][6]

Sweating (diaphoresis), rash, and pruritus have been reported in 1% to 10% of patients receiving systemic ketorolac. Urticaria, alopecia, and photosensitivity occurred in less than 1% of patients in clinical trials. Bullous rash reactions including Stevens-Johnson syndrome and Lyell’s syndrome (toxic epidermal necrolysis), exfoliative dermatitis, erythema multiforme, and anaphylactoid reactions including anaphylactic shock, angioedema, and tongue or laryngeal edema have been reported through the postmarketing surveillance program. Anaphylactoid reactions may occur in patients without a known previous exposure or hypersensitivity to ketorolac. Severe, rarely fatal, serious hypersensitivity reactions or anaphylaxis have been reported after systemic ketorolac use in salicylate-sensitive patients. Allergic reactions to ketorolac are more likely in patients with asthma; ketorolac is contraindicated for use in patients with aspirin-sensitive asthma or the aspirin triad because of the approximate 5% cross-sensitivity that occurs between aspirin and NSAIDs. The triad typically occurs in patients with asthma who experience rhinitis with or without nasal polyps or who experience severe, potentially fatal, acute bronchospasm after taking aspirin or other NSAIDs. Bronchospasm or exacerbation of asthma has been reported with the use of ketorolac ophthalmic solution. Discontinue ketorolac at the first appearance of a skin rash or any other sign of hypersensitivity.^[2][3][4][5]

An injection site reaction consisting of pain occurred in 1% to 10% of patients that received multiple doses of ketorolac injection.^[2]

Tinnitus has been reported in 1% to 10% of patients receiving systemic ketorolac or another NSAID during clinical trials. Other abnormalities of the senses, such as abnormal taste (dysgeusia), abnormal vision, blurred vision, and hearing loss have been reported in less than 1% of patients. Conjunctivitis has been reported during postmarketing use.^[2][3][5] A 20-year-old female with polyarteritis nodosa developed sudden bilateral sensorineural hearing loss throughout the entire frequency range, tinnitus, and vertigo with nausea and vomiting 25 minutes after receiving 30 mg of intravenous ketorolac. Some subjective resolution of the generalized hearing loss occurred by 48 hours, but she had persistent high-frequency loss from 3 to 8 kHz in her right ear 9 days after the dose. The hearing loss may have been potentiated by her underlying illness and oral methotrexate and prednisone usage. Sensorineural hearing loss also developed in another patient who initially received 60 mg of ketorolac intramuscularly and then 8 doses of 10 mg orally every 6 hours. Similar to the other case, the hearing loss was sudden and associated with tinnitus. Four days after discontinuation of ketorolac, the hearing loss and tinnitus resolved. An audiogram was not performed to determine if any permanent high-frequency loss occurred. Tinnitus and hearing loss have also occurred with the NSAIDs naproxen and piroxicam. The hearing loss from NSAID usage is believed to be due to altered cochlear sensory cell function from tissue ischemia as a result of an imbalance between vasodilatory prostaglandins and vasoconstricting leukotrienes. Ketorolac may also have a direct ototoxic mechanism. Ketorolac is thought to be concentrated in the basilar inner hair cell of the organ of Corti, accounting for the high-frequency losses. Although no known morphologic changes are known to occur, hearing loss may be permanent. Coadministration of other ototoxic drugs, such as gentamicin or furosemide, may increase the risk of ototoxicity. Most ototoxic drugs have at least additive ototoxic interactions. Further, NSAIDs can be nephrotoxic, and impaired renal function can increase the ototoxic potential of NSAIDs. Patients taking long-term NSAIDs should be directly questioned about tinnitus and hearing loss.

NSAIDs may increase the risk of serious cardiovascular thromboembolism, myocardial infarction, and stroke, which can be fatal. Estimates of increased relative risk range from 10% to 50% or more, based on the drug and dose studied. The risk may increase with increased exposure, as measured in dose or duration. Significant cardiovascular risk has been observed within days to weeks of NSAID initiation. The relative increase in cardiovascular thrombotic events over baseline appears to be similar in patients with or without cardiovascular disease or risk factors for cardiovascular disease; however, patients with known cardiovascular disease or risk factors may be at greater risk because of a higher baseline risk of events. In observational studies, data demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality; the incidence of death in the first year post-MI in NSAID-treated patients was 20 per 100 person years compared to 12 per 100 person years in non-NSAID exposed patients. An increased relative risk of death in NSAID users was observed across 4 years of follow-up. A meta-analysis of randomized, controlled trials demonstrated an approximate 2-fold increase in hospitalizations for heart failure among nonselective- and COX-2 selective NSAID-treated patients compared to placebo.^[5] Ketorolac-induced increases in water retention and decreases in renal perfusion may exacerbate pre-existing cardiovascular complications, including hypertension and congestive heart failure. Hypertension occurred in 1% to 10% of patients taking ketorolac or other NSAIDs during clinical trials; in postoperative pain studies with ketorolac nasal spray specifically, hypertension occurred in 2% of ketorolac-treated patients. In clinical trials of ketorolac or another NSAID, heart failure, palpitations, pallor, sinus tachycardia, and syncope were reported in less than 1% of patients. Bradycardia was reported in 2% of patients during intranasal ketorolac trials. Arrhythmia exacerbation, chest pain (unspecified), flushing, hypotension, myocardial infarction, and vasculitis have been observed during postmarketing experience. Inform patients of the signs and symptoms of CV events, and advise them to seek medical help immediately if such signs or symptoms occur.^[2][3][5]

Systemic ketorolac may cause renal insufficiency and nephrotic syndrome. Impairment of renal function may result from inhibition of renal prostaglandin synthesis. It is well known that vasodilatory renal prostaglandins and the potent vasoconstrictor angiotensin II work in concert to maintain renal blood flow. Inhibition of prostaglandin synthesis by NSAIDs potentiates water reabsorption. Edema has occurred in 1% to 10% of those receiving systemic ketorolac.^[2][3] Hyponatremia due to water intoxication has been reported with NSAID use. Patients may experience proteinuria (less than1%), hematuria (less than1%), or polyuria (less than 1%), due to inadequate renal function or renal damage. The incidence of oliguria is reported as less than 1% with systemic ketorolac or other NSAID use; however, intranasal use of ketorolac in postoperative patients resulted in oliguria (3%) and decreased urine output (2%) in clinical trials. Cystitis, dysuria, increased urinary frequency, and urinary retention have been reported in less than 1% of patients. Acute renal failure (unspecified), hyponatremia, hyperkalemia, flank pain with or without hematuria and/or azotemia, hemolytic-uremic syndrome, and interstitial nephritis have been reported to occur with systemic ketorolac, but a causal relationship has not been established. With other NSAIDS, renal papillary necrosis has been reported. Exacerbations of congestive heart failure and peripheral vascular disease may occur. Monitoring of the patient’s fluid status, serum creatinine, and blood urea nitrogen concentrations is recommended.^[2][3][5]

In clinical trials, intranasal administration of ketorolac most commonly resulted in local adverse events including nasal irritation or discomfort (15%), rhinalgia (13%), increased lacrimation (5%), rhinitis (2%), and throat irritation (4%).^[5] Rhinitis (<= 1%) has also been reported with IV and oral therapy.^[2][3] Myalgia, hyperglycemia, and weight change have been rarely observed during postmarketing experience in patients taking ketorolac or other NSAIDs.^[2][3][5] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), a multi-organ hypersensitivity reaction, has occurred with NSAIDs. Some of these events have been life-threatening or fatal. DRESS typically presents as fever, rash, and/or lymphadenopathy in conjunction with other organ system involvement including hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Early manifestations such as fever and lymphadenopathy may be present without evidence of a rash. Discontinue the NSAID in patients presenting with such signs and symptoms in whom an alternative etiology cannot be identified.^[3]

Systemic and intranasal ketorolac is contraindicated in labor and obstetric delivery because it may adversely affect fetal circulation and uterine contractions.^[3][5] Avoid ketorolac use during the third trimester of pregnancy (starting at 30 weeks of gestation) due to the risk of premature closure of the fetal ductus arteriosus and persistent pulmonary hypertension in the neonate.^[3][5][6] If NSAID treatment is deemed necessary between 20 to 30 weeks of pregnancy, limit use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if NSAID treatment extends beyond 48 hours. Discontinue the NSAID if oligohydramnios occurs and follow up according to clinical practice. Use of NSAIDs around 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 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.^[9] Observational data regarding embryofetal risks of NSAID use during the first trimester is inconclusive. There are no adequate and well-controlled studies of ketorolac in pregnant women.^[2][3][5][6]

Due to the potential adverse effects of prostaglandin-inhibiting drugs on nursing infants, caution is advised when administering ketorolac to lactating mothers. If used during breastfeeding, instruct the patient to closely monitor the breastfed infant and report any adverse events that may develop.^[3][5][6] Ketorolac is excreted into breast milk. Of 10 lactating mothers, ketorolac was undetectable in the milk of 4 of the women, and the maximum milk concentration observed was 7.9 ng/mL in the other 6 women after 1 day of dosing with 10 mg every 6 hours. Based on a daily infant intake of 400—1000 mL/day of breast milk and a maternal body weight of 60 kg, the calculated maximum infant dose would be equivalent to 0.4% of the weight-adjusted maternal dose.^[5] The American Academy of Pediatrics (AAP) considers ketorolac to be a drug which is usually compatible with breastfeeding; however, their assessment was published prior to recent recommendations to ensure safe use of the drug; other analgesics and anti-inflammatory agents considered to be usually compatible with breastfeeding by the AAP include acetaminophen, ibuprofen, indomethacin, naproxen, and piroxicam and would be preferred to limit infant risk.^[10] Consider the benefits of breastfeeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breastfeeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Store this medication in its original container at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond-use date. Do not flush unused medications or pour down a sink or drain.

1. Turturro MA, et al. Intramuscular ketorolac versus oral ibuprofen in acute musculoskeletal pain. Ann Emerg Med 1995;26:117-20.
2. Ketorolac tromethamine injection package insert. Eatontown, NJ: West-Ward Pharmaceuticals; 2017 Sept.
3. Ketorolac tromethamine tablets package insert. Morgantown, WV: Mylan Pharmaceuticals, Inc.; 2021 Apr.
4. Acular LS (ketorolac tromethamine) 0.4% ophthalmic solution package insert. Madison, NJ: Allergan USA, Inc.; 2021 Mar.
5. Sprix (ketorolac tromethamine) Nasal Spray package insert. Wayne, PA: Zyla Life Sciences US, Inc.; 2021 Apr.
6. Acular (ketorolac tromethamine) 0.5% ophthalmic solution package insert. Irvine, CA: Allergan, Inc.; 2012 May.
7. Frishman WH. Effects of nonsteroidal anti-inflammatory drug therapy on blood pressure and peripheral edema. Am J Cardiol 2002;89(suppl):18D-25D.
8. O’Gara P, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
9. Food and Drug Administration MedWatch. Nonsteroidal anti-inflammatory drugs (NSAIDs): Drug safety communication – avoid use of NSAIDs in pregnancy at 20 weeks or later.
10. American Academy of Pediatrics (AAP) Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001;108(3):776-789.
11. Health Care Financing Administration. Interpretive Guidelines for Long-term Care Facilities. Title 42 CFR 483.25(l) F329: Unnecessary Drugs. Revised 2015.