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. 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. 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.
Rare cases of esophagitis have been reported in patients receiving systemic NSAIDs, including ketorolac. 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.
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. There have been reports that ocularly applied NSAIDs may cause increased bleeding of ocular tissues (including hyphema) when used in conjunction with ocular surgery. 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.
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. Headache has also been reported in approximately 1% to 5% of patients receiving ophthalmic ketorolac during clinical trials.
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. Increased ALT and/or AST were reported in 2% of adult patients receiving intranasal ketorolac during clinical trials. 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.
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.
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.
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.
An injection site reaction consisting of pain occurred in 1% to 10% of patients that received multiple doses of ketorolac injection.
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. 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. 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.
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. 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.
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%). Rhinitis (<= 1%) has also been reported with IV and oral therapy.
Myalgia, hyperglycemia, and weight change have been rarely observed during postmarketing experience in patients taking ketorolac or other NSAIDs.
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.