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Ketorolac: Epidemiological evidence suggests that ketorolac may be associated with a high risk of serious gastrointestinal toxicity, relative to some other NSAIDs, especially when used outside the licensed indications and/or for prolonged periods.
Physicians should be aware that in some patients pain relief may not occur until upwards of 30 minutes after IV or IM administration.
The use of ketorolac with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided.
Undesirable effects may be minimised by using the minimum effective dose for the shortest duration necessary to control symptoms.
Gastrointestinal ulceration, bleeding and perforation: GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs including ketorolac therapy, at anytime during treatment, with or without warning symptoms or a previous history of serious GI events.
Increased rates of clinically serious GI bleeding were seen in patients < 65 years of age who received an average daily dose of > 90 mg ketorolac IM as compared to those patients receiving parenteral opioids.
The elderly have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation which may be fatal.
The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, including ketorolac IV, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation, and in the elderly. The risk of clinically serious gastrointestinal bleeding is dose dependent. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose aspirin, or other drugs likely to increase gastrointestinal risk. This age-related risk of gastrointestinal bleeding and perforation is common to all NSAIDs. Compared to young adults, the elderly have an increased plasma half-life and reduced plasma clearance of ketorolac. A longer dosing interval is advisable.
NSAIDs should be given with care to patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn's disease) as these conditions may be exacerbated. Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment. When GI bleeding or ulceration occurs in patients receiving ketorolac IV, treatment should be withdrawn.
Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, selective serotonin-reuptake inhibitors or anti-platelet agents such as aspirin.
Use in patients taking anti-coagulants such as warfarin is contraindicated.
As with other NSAIDs the incidence and severity of gastrointestinal complications may increase with increasing dose and duration of treatment with ketorolac IV. The risk of clinically serious gastrointestinal bleeding is dose-dependent. This is particularly true in elderly patients who receive an average daily dose greater than 60 mg/day of ketorolac IV. A history of peptic ulcer disease increases the possibility of developing serious gastrointestinal complications during ketorolac therapy.
Haematological effects: Patients with coagulation disorders should not receive Ketorolac. Patients on anti-coagulation therapy may be at increased risk of bleeding if given Ketorolac concurrently. The concomitant use of ketorolac and prophylactic low dose heparin (2500 - 5000 units 12-hourly) and dextrans has not been studied extensively and may also be associated with an increased risk of bleeding. Patients already on anti-coagulants or who require low-dose heparin should not receive ketorolac. Patients who are receiving other drug therapy that interferes with haemostasis should be carefully observed if Ketorolac is administered. In controlled clinical studies, the incidence of clinically significant postoperative bleeding was less than 1%.
Ketorolac inhibits platelet aggregation and prolongs bleeding time. In patients with normal bleeding function, bleeding times were raised, but not outside the normal range of two to eleven minutes. Unlike the prolonged effects from aspirin, platelet function returns to normal within 24 to 48 hours after ketorolac is discontinued.
Postoperative wound haemorrhage has been reported in association with the peri-operative use of Ketorolac IM/IV. Therefore, ketorolac should not be used in patients who have had operations with a high risk of haemorrhage or incomplete haemostasis. Caution should be used where strict haemostasis is critical, e.g. in cosmetic or day-case surgery, resection of the prostate or tonsillectomy. Haematomas and other signs of wound haemorrhage and epistaxis have been reported with the use of Ketorolac. Physicians should be aware of the pharmacological similarity of ketorolac to other non-steroidal anti-inflammatory drugs that inhibit cyclooxygenase and the risk of bleeding, particularly in the elderly.
Skin reactions: Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs. Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reactions occurring in the majority of cases within the first month of treatment. Ketorolac should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.
SLE and mixed connective tissue disease: In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis.
Sodium/fluid retention in cardiovascular conditions and peripheral oedema: Caution is required in patients with a history of hypertension and /or heart failure as fluid retention and oedema have been reported in association with NSAID therapy.
Fluid retention, hypertension and peripheral oedema has been observed in some patients taking NSAIDs including ketorolac and it should therefore be used with caution in patients with cardiac decompensation, hypertension or similar conditions.
Cardiovascular and cerebrovascular effects: Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy.
Clinical trial and epidemiological data suggest that use of coxibs and some NSAIDs (particularly at high doses) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Although ketorolac has not been shown to increase thrombotic events such as myocardial infarction, there are insufficient data to exclude such a risk for ketorolac.
Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease should only be treated with ketorolac after careful consideration. Similar consideration should be made before initiating treatment of patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus and smoking).
Cardiovascular, Renal and Hepatic Impairment: Caution should be observed in patients with conditions leading to a reduction in blood volume and/or renal blood flow, where renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in renal prostaglandin formation and may precipitate overt renal failure. Patients at greatest risk of this reaction are those who are volume depleted because of blood loss or severe dehydration, patients with impaired renal function, heart failure, liver dysfunction, the elderly and those taking diuretics. Renal function should be monitored in these patients. Discontinuation of NSAID therapy is typically followed by recovery to the pre-treatment state. Inadequate fluid/blood replacement during surgery, leading to hypovolaemia, may lead to renal dysfunction which could be exacerbated when Ketorolac is administered. Therefore, volume depletion should be corrected and close monitoring of serum urea and creatinine and urine output is recommended until the patient is normovolaemic. In patients on renal dialysis, ketorolac clearance was reduced to approximately half the normal rate and terminal half-life increased approximately three-fold.
Renal effects: As with other NSAIDs ketorolac 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. Caution should be observed as renal toxicity has been seen with ketorolac and other NSAIDs in patients with conditions leading to a reduction in bloodvolume and/or renal blood flow where renal prostaglandins have a supportive role in the maintenance of renal perfusion.
In these patients administration of ketorolac or other NSAIDs may cause a dose-dependent reduction in renal prostaglandin formation and may precipitate overt renal decompensation or failure. Patients at greatest risk of this reaction are those with impaired renal function, hypovolaemia, heart failure, liver dysfunction, those taking diuretics and the elderly. Discontinuation of ketorolac or other non-steroidal anti-inflammatory therapy is usually followed by recovery to the pre-treatment state.
As with other drugs that inhibit prostaglandin synthesis, elevations of serum urea, creatinine and potassium have been reported with ketorolac trometamol and may occur after one dose.
Patients with impaired renal function: Since ketorolac trometamol and its metabolites are excreted primarily by the kidney, patients with moderate to severe impairment of renal function (serum creatinine greater than 160 micromol/l) should not receive Ketorolac. Patients with lesser renal impairment should receive a reduced dose of ketorolac (not exceeding 60 mg/day IM or IV) and their renal status should be closely monitored.
Use in patients with impaired liver function: Patients with impaired hepatic function from cirrhosis do not have any clinically important changes in ketorolac clearance or terminal half-life.
Borderline elevations of one or more liver function tests may occur. These abnormalities may be transient, may remain unchanged, or may progress with continued therapy. Meaningful elevations (greater than 3 times normal) of serum glutamate pyruvate transaminase (SGPT/ALT) or serum glutamate oxaloacetate transaminase (SGOT/AST) occurred in controlled clinical trials in less than 1% of patients. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur, Ketorolac should be discontinued.
Anaphylactic (anaphylactoid) reactions: Anaphylactic (anaphylactoid) reactions (including, but not limited to, anaphylaxis, bronchospasm, flushing, rash, hypotension, laryngeal oedema and angioedema) may occur in patients with or without a history of hypersensitivity to aspirin, other NSAIDs or ketorolac IV. These may also occur in individuals with a history of angioedema, bronchospastic reactivity (e.g. asthma) and nasal polyps. Anaphylactoid reactions, like anaphylaxis, may have a fatal outcome. Therefore, ketorolac should not be used in patients with a history of asthma and in patients with the complete or partial syndrome of nasal polyps, angioedema and bronchospasm.
Fluid retention and oedema: Fluid retention, hypertension and oedema have been reported with the use of ketorolac and it should therefore be used with caution in patients with cardiac decompensation, hypertension or similar conditions.
Caution is advised when methotrexate is administered concurrently since some prostaglandin synthesis-inhibiting drugs have been reported to reduce the clearance of methotrexate, and thus possibly enhance its toxicity.
Drug Abuse and Dependence: Ketorolac is devoid of addictive potential. No withdrawal symptoms have been observed following abrupt discontinuation of ketorolac IV.
Effects on ability to drive and use machines: Some patients may experience dizziness, drowsiness, fatigue, visual disturbances, headaches, vertigo, insomnia or depression with the use of ketorolac. If patients experience these, or other similar undesirable effects, patients should not drive or operate machinery.
Precautions related to fertility: The use of ketorolac 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 fertility, withdrawal of ketorolac should be considered.
