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4.3 Contraindications
Ketorolac is contraindicated in patients with previously demonstrated hypersensitivity to Ketorolac, any of its excipients, or other NSAIDs and patients in whom aspirin or other prostaglandin synthesis inhibitors induce allergic reactions (severe anaphylactic-like reactions have been observed in such patients). Such reactions have included asthma, rhinitis, angioedema, or urticaria.
Ketorolac is also contraindicated in
- those with a history of asthma
- children under 16 years of age.
Ketorolac is contraindicated in patients with active or a history of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy. Active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding).
As with other NSAIDs, Ketorolac is contraindicated in patients with severe heart failure, hepatic failure and renal failure (see section 4.4).
Ketorolac is contraindicated in patients with moderate or severe renal impairment (serum creatinine >160 µmol/l) or in patients at risk for renal failure due to volume depletion or dehydration.
− active peptic ulcer, or any history of gastrointestinal bleeding, ulceration or perforation
− severe heart failure, hepatic failure and renal failure (see section 4.4)
− suspected or confirmed cerebrovascular bleeding
− haemorrhagic diatheses, including coagulation disorders
− hypersensitivity to ketorolac trometamol or any of the excipients or other NSAIDs
− patients in whom ibuprofen, aspirin or other prostaglandin synthesis inhibitors
induce allergic reactions e.g. asthma, rhinitis, angioedema, or urticaria (severe
anaphylactic-like reactions have been observed in such patients)
− the complete or partial syndrome of nasal polyps, angioedema or bronchospasm
− concurrent treatment with other NSAIDs, (including cyclooxygenase-2 selective inhibitors), oxpentifylline, probenecid or lithium salts
Ketorolac is contraindicated in patients with − hypovolaemia from any cause or dehydration.
− moderate or severe renal impairment (serum creatinine > 160 micromol/l)
− a history of asthma
− patients who have had operations with a high risk of haemorrhage or incomplete
haemostasis
− patients on anticoagulants including low dose heparin (2500 - 5000 units 12
hourly)
Ketorolac is contraindicated in − during pregnancy, labour, delivery orand lactation (see section 4.6).
− children under 16 years of age
Ketorolac− Toradol is contra-indicated as prophylatic analgesia before surgery due to inhibition of platelet aggregation and is contra-indicated intraoperatively because of the increased risk of bleeding.
− Toradol is contra-indicated in patients currently receiving aspirin.
Ketorolac inhibits platelet function and is, therefore, contraindicated in patients with suspected or confirmed cerebrovascular bleeding, patients who have had operations with a high risk of haemorrhage or incomplete haemostasis and those at high risk of bleeding such as those with with haemorrhagic diatheses, including coagulation disorders.
It is also contraindicated in patients on anticoagulants, including warfarin and low dose heparin (2500 - 5000 units 12 hourly).
Ketorolac is contraindicated in patients currently receiving ASA or other NSAIDs (including cyclooxygenase-2 selective inhibitors).
The combination of Ketorolac with oxpentifylline is contraindicated.
Concurrent treatment with ketorolac and probenecid or lithium salts is contraindicated.
Ketorolac is contra-indicated in patients with the complete or partial syndrome of nasal polyps, angioedema or bronchospasm.
4.4 Special warnings and precautions for use
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 (see also section 4.1, 4.2 and 4.3).
The use of Ketorolac with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided.
Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2 and GI and cardiovascular risks below).
Use in the elderly: The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal. This age-related risk 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 (see section 4.2).
Effects on fertility: The use of Toradol, 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 Toradol should be considered.
Gastrointestinal ulceration, bleeding, ulceration 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.
The risk of clinically serious gastro-intestinal bleeding is dose-dependent. This is particularly true in elderly patients who receive an average daily dose greater than 60mg/day of Toradol.
In a non-randomised, in-hospital post-marketing surveillance study, increased rates of clinically serious GI bleeding were seen in patients ≤ 65 years of age who received an average daily dose of > 90mg ketorolac IM as compared to those patients receiving parenteral opioids.
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 (see also section 4.1, 4.2 and 4.3).
The elderly have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation which may be fatal. Debilitated patients seem to tolerate ulceration or bleeding less well than others. Most of the fatal gastrointestinal events associated with non-steroidal anti-inflammatory drugs occurred in the elderly and/or debilitated patients. The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, including ketoroloac IV, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), 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 (see below and section 4.5). 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 (see section 4.2).
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.
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 (see section 4.5).
Use in patients taking anticoagulants such as warfarin is contraindicated (see section 4.3).
When GI bleeding or ulceration occurs in patients receiving Ketorolac Trometamol, the treatment should be withdrawn.
NSAIDs should be given with care to patients with a history of inflammatory bowel disease gastrointestinal disease (ulcerative colitis, Crohn’s disease) as these conditions may be exacerbated (see section 4.8). 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 (see section 4.5).
Use in patients taking anticoagulants such as warfarin is contraindicated (see section 4.3).
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 Toradol. Patients on anticoagulation therapy may be at increased risk of bleeding if given Toradol 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 anticoagulants 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 Toradol 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 2 - 11 minutes. Unlike the prolonged effects from aspirin, platelet function returns to normal within 24 to 48 hours after ketorolac is discontinued.
In post-marketing experience, postoperative wound haemorrhage has been reported in association with the peri-operative use of Toradol 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 Toradol. Physicians should be aware of the pharmacological similarity of ketorolac to other non-steroidal anti-inflammatory drugs that inhibit cyclo-oxygenase 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 (see section 4.8). 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. Toradol 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 (see section 4.8).
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.
Respiratory disorders: Caution is required if administered to patients suffering from, or with a previous history of, bronchial asthma since NSAIDs have been reported to precipitate bronchospasm in such patients.
Renal effects: Drugs that inhibit prostaglandin biosynthesis (including non-steroidal anti-inflammatory drugs) have been reported to cause nephrotoxicity, including but not limited to glomerular nephritis, interstitial nephritis, renal papillary necrosis, nephrotic syndrome and acute renal failure. In patients with renal, cardiac or hepatic impairment, caution is required since the use of NSAIDs may result in deterioration of renal function.
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 Toradol. Patients with lesser renal impairment should receive a reduced dose of ketorolac (not exceeding 60mg/day IM or IV) and their renal status should be closely monitored.
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 Toradol 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 (see section 4.3).
Fluid retention and oedema: Fluid retention and oedema have been reported with the use of Toradol 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 and in long term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). ). Although ketorolac has not shown to increase thrombotic events such as myocardial infarction,T there are insufficient data to exclude such a risk for Ketorolac. Trometamol.
Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with Ketorolac Trometamol after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, and smoking).
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 (see section 4.8).
Dermatological:
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 (see section 4.8). 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. Toradol should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.
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 Toradol 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 (see section 4.3).
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, Toradol should be discontinued.
Haematological effects: Patients with coagulation disorders should not receive Toradol. Patients on anticoagulation therapy may be at increased risk of bleeding if given Toradol concurrently. The concomitant use of ketorolac and prophylactic low dose heparin (2500 - 5000 units 12-hourly) has not been studied extensively and may also be associated with an increased risk of bleeding. Patients already on anticoagulants 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 Toradol is administered. In controlled clinical studies, the incidence of clinically significant postoperative bleeding was less than 1%.
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 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 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.
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 2 - 11 minutes. Unlike the prolonged effects from aspirin, platelet function returns to normal within 24 to 48 hours after ketorolac is discontinued.
In post-marketing experience, postoperative wound haemorrhage has been reported in association with the immediate peri-operative use of Toradol 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. Haematomata and other signs of wound haemorrhage and epistaxis have been reported with the use of Toradol. Physicians should be aware of the pharmacological similarity of ketorolac to other non-steroidal anti-inflammatory drugs that inhibit cyclo-oxygenase and the risk of bleeding, particularly in the elderly.
Toradol is not an anaesthetic agent and possesses no sedative or anxiolytic properties; therefore it is not recommended as a pre-operative medication for the support of anaesthesia when these effects are required.
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 Toradol. Patients with lesser renal impairment should receive a reduced dose of ketorolac (not exceeding 60mg/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, Toradol 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 be used with caution in patients with a history of asthma and in patients with the complete or partial syndrome of nasal polyps, angioedema and bronchospasm.
Precautions related to fertility
The use of Toradol, 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 Toradol should be considered.
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.
Pediatric Use:
Ketorolac tablets are not recommended for use in children.Ketorolac given parenterally is not recommended in children younger than 2 years of age.
Drug Abuse and Dependence
Ketorolac is devoid of addictive potential. No withdrawal symptoms have been observed following abrupt discontinuation of Ketorolac IV.
4.5 Interaction with other medicinal products and other forms of interaction
Ketorolac is highly bound to human plasma protein (mean 99.2%) and binding is concentration-independent.
The following medicinal products are NOT to be co-administered with Toradol:
Toradol should not be used with ASA or other NSAIDs including cyclooxygenase-2 selective inhibitors or in patients receiving aspirin because of the potentialas the risk of inducing serious for adverse effects NSAID-related adverse events may be increased (see section 4.3).
Ketorolac inhibits platelet aggregation, reduces thromboxane concentrations and prolongs bleeding time. Unlike the prolonged effects from aspirin, platelet function returns to normal within 24-48 hours after Ketorolac is discontinued.
Toradol is contraindicated in combination with anti-coagulants, such as warfarin since co-administration of NSAIDs and anticoagulants may cause an enhanced anti-coagulant effect (see section 4.3).
Although studies do not indicate a significant interaction between Ketorolac and warfarin or heparin the concurrent use of Ketorolac and therapy that affects haemostasis, including therapeutic doses of anticoagulation therapy (warfarin) prophylactic low-dose heparin (2500-5000 units 12-hourly) and dextrans may be associated with an increased risk of bleeding.
In patients receiving lithium, there is a possible iInhibition of renal lithium clearance, leading to an increased in plasma lithium concentration, and potential lithium toxicity. (see section 4.3) has been reported with some prostaglandin synthesis-inhibiting drugs. Cases of increased lithium plasma concentrations during Ketorolac therapy have been reported.
Probenecid should not be administered concurrently with ketorolac because of increases in ketorolac plasma levelconcentrations and half-life.
NSAIDs should not be used for 8 to 12 days after mifepristone administration as NSAIDs can reduce the effects of mifepristone.
The following medicinal products, in combination with Toradol, are to be co-administered with caution:
In normovolaemic healthy subjects, ketorolac reduces the diuretic response to furosemide by approximately 20%, so particular care should be taken in patients with cardiac decompensation.
NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma cardiac glycoside levels when co-administered with cardiac glycosides.
Toradol and other non-steroidal anti-inflammatory drugs can reduce the antihypertensive effect of anti-hypertensives.
There is an increased risk of renal impairment when ketorolac is administered concurrently with ACE inhibitors, particularly in volume depleted patients.
As with all NSAIDs caution is advised when ciclosporin is co-administered because of the increased risk of nephrotoxicity.
There is a possible risk of nephrotoxicity when NSAIDs are given with tacrolimus.
Co-administration with diuretics can lead to a reduced diuretic effect, and increase the risk of nephrotoxicity of NSAIDs.
As with all NSAIDs, caution should be taken when co-administering with corticosteroids because of the increased risk of gastro-intestinal ulceration or bleeding (see section 4.4).
There is an increased risk of gastrointestinal bleeding (see section 4.4) when antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs) are combined with NSAIDs.
Because of an increased tendency to bleeding wWhen ketorolac is administered concurrently with oxpentifylline, there is an increased tendency to bleeding.is administered concurrently, this combination should be avoided.
Caution is advised when methotrexate is administered concurrently, since sSome prostaglandin synthesis- inhibiting drugs have been reported to reduce the clearance of methotrexate, and thus possibly enhance its toxicity.
Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.
NSAIDs given with zidovudine increase the risk of haematological toxicity. There is evidence of an increased risk of haemarthroses and haematoma in HIV (+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.
The following medicinal products are unlikely to have an interaction with Toradol:
Ketorolac tromethamine doesid not alter digoxin protein binding. In vitro studies indicated that at therapeutic concentrations of salicylate (300mmcg/ml) and above, the binding of ketorolac was reduced from approximately 99.2% to 97.5% representing a potential twofold increase in unbound ketorolac plama concentrations. Therapeutic concentrations of digoxin, warfarin, paracetamolibuprofen, naproxen, piroxicam, acetaminophen, phenytoin and tolbutamide did not alter ketorolac protein binding. Because ketorolac is a highly potent drug and present in low concentrations in plasma, it would not be expected to displace other protein-bound drugs significantly.
Ketorolac Solution for injection reduced the diuretic response to furosemide in normovolemic healthy subjects by approximately 20% so particular care should be taken in patients with cardiac decompensation.
Co-administration with diuretics can lead to a reduced diuretic effect, and increase the risk of nephrotoxicity of NSAIDs.
As with all NSAIDs caution is advised when ciclosporin is co-administered because of the increased risk of nephrotoxicity.
There is a possible risk of nephrotoxicity when NSAIDs are given with tacrolimus.
NSAIDs may reduce the effect of diuretics and antihypertensive medicinal products such as beta-blockers. The risk of acute renal insufficiency, which is usually reversible, may be increased in some patients with compromised renal function (e.g. dehydrated patients or elderly patients) when ACE inhibitors and/or angiotensin II receptor antagonists are combined with NSAIDs. Therefore, the combination should be administered with caution, especially in the elderly. Patients should be adequately titrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.
NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma cardiac glycoside levels when co-administered with cardiac glycosides.
Ketorolac has been shown to reduce the need for concomitant opioid analgesia when it is given for the relief of postoperative pain.
Oral administration of Ketorolac Tablets after a high-fat meal resulted in decreased peak and delayed time-to-peak concentrations of ketorolac by about 1 hour. Antacids did not affect the extent of absorption.
Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.
NSAIDs given with zidovudine increase the risk of haematological toxicity. There is evidence of an increased risk of haemarthroses and haematoma in HIV (+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.
There is no evidence in animal or human studies that ketorolac trometamol induces or inhibits the hepatic enzymes capable of metabolising itself or other drugs. Hence Toradol would not be expected to alter the pharmacokinetics of other drugs due to enzyme induction or inhibition mechanisms.
4.6 Pregnancy and lactation
Pregnancy
The safety of Toradol during human pregnancy has not been established.
There was no evidence of teratogenicity in rats or rabbits studied at maternally-toxic doses of ketorolac. Prolongation of the gestation period and/or delayed parturition were seen in the rat. Congenital abnormalities have been reported in association with NSAID administration in man; however, these are low in frequency and do not appear to follow any discernible pattern. In view of the known effects of NSAIDs on the foetal cardiovascular system (risk of closure of the ductus arteriosus) ketorolac is contraindicated during pregnancy, labour or delivery. The onset of labour may be delayed and the duration increased with an increased bleeding tendency in both mother and child (see section 4.3).
See section 4.4 regarding female fertility.
Ketorolac crosses the placenta to the extent of approximately 10%.
Labour and Delivery:
Ketorolac is contraindicated in labour and delivery because, through its prostaglandin synthesis inhibitory effect it may adversely affect foetal circulation and inhibit uterine contractions, thus increasing the risk of uterine haemorrhage.
There may be increased bleeding tendency in both mother and child (see section 4.3)
Lactation Nursing Mothers:
Ketorolac and its metabolites have been shown to pass into the foetus and milk of animals. Ketorolac has been detected in human milk at low levelsconcentrations, therefore, ketorolac
4.8 Undesirable effects
The following side-effects have been reported with Toradol.
Post Marketing
The following undesirable effects may occur in patients receiving Ketorolac; frequencies of reported events are not known, because they were reported voluntarily from a population of uncertain size.
Gastro-intestinal disorders: The most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, ulcer, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur (see section 4.4). Nausea, vomiting diarrhoea, constipation dyspepsia, abdominal pain / discomfort, melaena, haematemesis, stomatitis, ulcerative stomatitis, eructation, flatulence, oesophagitis, gastrointestinal ulceration, rectal bleeding, pancreatitis, dry mouth, fullness exacerbation of colitis and Crohn’s disease (see section 4.4) have been reported following administration. Less frequently, gastritis has been observed. Nausea, dyspepsia, gastro-intestinal pain, abdominal discomfort, haematemesis, gastritis, oesophagitis, diarrhoea, eructation, constipation, flatulence, fullness, melaena, rectal bleeding, ulcerative stomatitis, vomiting, haemorrhage, perforation, pancreatitis, exacerbation of colitis and Crohn’s disease (see section 4.4) have been reported following administration.
Infection: meningitis aseptic (especially in patients with existing auto-immune disorders, such as systemic lupus erythematosus, mixed connective tissue disease), with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation (see section 4.4)
Blood and Lymphatic System Disorders: thrombocytopenia
Additionally purpura, neutropenia, agranulocytosis, aplastic anaemia and haemolytic anaemia have been observed.
Immune System Disorders: anaphylaxis, anaphylactoid reactions, anaphylactoid reactions like anaphylaxis, may have a fatal outcome, hypersensitivity reactions such as bronchospasm flushing, rash, hypotension, laryngeal oedema.
These may also occur in individuals with a history of angioedema, bronchospastic reactivity (e.g. asthma and nasal polyps).
Metabolic and Nutrition Disorders: anorexia, hyperkalaemia, hyponatraemia
Psychiatric Disorders: abnormal thinking, depression, insomnia, anxiety, nervousness, psychotic reactions, abnormal dreams, hallucinations, euphoria, concentration ability impaired, drowsiness.
Confusion and stimulation have been observed.
Central nervous/musculoskeletal systems: Anxiety, visual disturbances, optic neuritis, drowsiness, dizziness, headaches, sweating, dry mouth, nervousness, paraesthesia, functional disorders, abnormal thinking, depression, euphoria, convulsions, excessive thirst, inability to concentrate, insomnia, malaise, fatigue, stimulation, vertigo, abnormal taste and vision, myalgia, abnormal dreams, confusion, hallucinations, hyperkinesia, hearing loss, tinnitus, aseptic meningitis (especially in patients with existing auto-immune disorders, such as systemic lupus erythematosus, mixed connective tissue disease), with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation (see section 4.4), psychotic reactions.
Nervous system disorders: headache, dizziness, convulsions, paresthesia, hyperkinesias, taste abnormality.
Eye Disorders: abnormal vision, visual disturbances, optic neuritis.
Ear Disorders: tinnitus, hearing loss, vertigo.
Renal: increased urinary frequency, oliguria, acute renal failure, hyponatraemia, hyperkalaemia, haemolytic uraemic syndrome, flank pain (with or without haematuria), raised serum urea and creatinine, interstitial nephritis, urinary retention, nephrotic syndrome, renal failure.
Renal and Urinary Disorders: acute renal failure, increased urinary frequency, interstitial nephritis, nephrotic syndrome, urinary retention, oliguria, haemolytic uremic syndrome, flank pain(with or without haematuria +- azotemia). As with other drugs that inhibit renal prostaglandin synthesis signs of renal impairment, such as, but not limited to elevations of creatinine and potassium can occur after one dose of Ketorolac IV.
Hepatic: abnormal liver function, hepatitis, jaundice and liver failure.
Cardiovascular: Flushing, bradycardia, pallor, hypertension, palpitations, chest pain.
Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment. Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with an increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4).
Cardiac Disorders: palpitations, bradycardia, cardiac failure.
Vascular disorders: hypertension, hypotension, haematoma, flushing, pallor, postoperative wound haemorrhage.
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 shown to increase thrombotic events, such as myocardial infarction, there are insufficient data to exclude such a risk with ketorolac.
Reproductive, female: Infertility.
Reproductive System and Breast Disorders: female infertility.
Respiratory, Thoracic and Mediastinal Disorders: asthma, dyspnoea, pulmonary oedema.
Additionally epistaxis has been observed.
Respiratory: Dyspnoea, asthma, pulmonary oedema.
Haematological: Purpura, thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia and haemolytic anaemia.
Hepatobiliary Disorders: hepatitis, cholestatic jaundice, liver failure.
Dermatological: Pruritus, urticaria, skin photosensitivity, Lyell's syndrome, bullous reactions including Stevens-Johnson syndrome and Toxic Epidermal Necrolysis (very rare), exfoliative dermatitis, maculopapular rash.
Skin and Subcutaneous Tissue Disorders: exfoliative dermatitis, maculopapular rash, pruritus, urticaria, purpura, angioedema, sweating, bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis (very rare).
Additionally erythema multiforme and skin photosensitivity has been observed.
Musculoskeletal and Connective Tissue Disorders: myalgia, functional disorder.
Hypersensitivity: Hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of (a) non-specific allergic reactions and anaphylaxis (b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm, laryngeal oedema or dyspnoea, or (c) assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angio-oedema and more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme). Other reactions include hypotension and flushing. Such reactions may occur in patients with or without known sensitivity to Toradol or other non-steroidal anti-inflammatory drugs.
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 (see section 4.3).
Bleeding: Postoperative wound haemorrhage, haematomata, epistaxis, increased bleeding time.
General Disorders and Administration Site Condition: excessive thirst, asthenia, oedema, injection site reactions and pain (IV), fever, chest pain.
Additionally, malaise, fatigue and weight gain has been observed.
Investigations: bleeding time prolonged, serum urea increased, creatinine increased, abnormal liver function tests.
Other: Asthenia, oedema, weight gain, fever.
Laboratory Abnormalities
See Section Post Marketing (Undesirable Effects).
4.9 Overdose
Symptoms and signs
Single overdoses of Ketorolac 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.
Gastrointestinal bleeding may occur. Hypertension, acute renal failure, respiratory depression and coma may occur after the ingestion of NSAIDs but are rare.
a) Symptoms
Symptoms include hHeadache, nausea, vomiting, epigastric pain,
gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma,
drowsiness, dizziness, tinnitus, and fainting, occasionally have also been observed. convulsions. In cases of Rare cases of diarrhoea and occasional convulsions have been reported.
significant poisoning acute renal failure and liver damage are possible.
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 NSAIDs overdose. There are no specific antidotes. Dialysis does not significantly clear ketorolac from the blood stream.
b) Therapeutic measure
Patients should be treated symptomatically as required. Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered. Alternatively, in adults, gastric lavage should be considered with one hour of ingestion of a potentially life-threatening overdose.
Good urine output should be ensured. Renal and liver function should be closely monitored. Patients should be observed for at least four hours after ingestion of potentially toxic amounts. Frequent or prolonged convulsions should be treated with intravenous diazepam. Other measures may be indicated by the patient’s clinical condition.
Doses of 360mg given intramuscularly over an 8-hour interval for five
consecutive days have caused abdominal pain and peptic ulcers which have
healed after discontinuation of dosing. Two patients recovered from
unsuccessful suicide attempts. One patient experienced nausea after 210mg
ketorolac, and the other hyperventilation after 300mg ketorolac.
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