Ketorolac Other names: Ketorolac trometamol

All non-steroidal anti-inflammatory drugs (NSAIDs) may slow down or delay wound healing. Concomitant use of NSAIDs and topical steroids can increase the potential for healing problems.

Concomitant use of ketorolac and topical corticosteroids should be exercised with caution in patients susceptible to corneal epithelial breakdown.

As with all NSAIDs, caution should be taken when co-administering with corticosteroids because of the increased risk of gastrointestinal ulceration or bleeding.

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.

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.

There is an increased risk of gastrointestinal bleeding when anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs) are combined with NSAIDs.

The use of ketorolac tromethamine, as with any drug known to inhibit cyclooxygenase/prostaglandin synthesis, may impair fertility and is not recommended in women attempting to conceive. In women who have difficulty conceiving or are undergoing investigation of infertility, withdrawal of ketorolac tromethamine should be considered.

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.

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.

Topical NSAIDs should be used with caution in patients with complicated ocular surgeries, corneal denervation, corneal epithelial defects, diabetes mellitus, ocular surface diseases (e.g. dry eye syndrome), rheumatoid arthritis, or repeat ocular surgeries within a short period of time, as they may be at increased risk for corneal adverse events which may become sight threatening.

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).

Oral / IV / IM dministration

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 safety of ketorolac 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 follow any discernible pattern.

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1%, up to approximately 1.5%. The risk is believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period.

From the 20th week of pregnancy onward, ketorolac use may cause oligohydramnios resulting from foetal renal dysfunction. This may occur shortly after treatment initiation and is usually reversible upon discontinuation. In addition, there have been reports of ductus arteriosus constriction following treatment in the second trimester, most of which resolved after treatment cessation. Therefore, during the first and second trimester of pregnancy, ketorolac should not be given unless clearly necessary.

If ketorolac is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible.

Antenatal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after exposure to ketorolac for several days from gestational week 20 onward. Ketorolac should be discontinued if oligohydramnios or ductus arteriosus constriction are found.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:

• cardiopulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension);
• renal dysfunction (see above);

The mother and neonate, at the end of pregnancy, to:

• possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses;
• inhibition of uterine contractions resulting in delayed or prolonged labour

Consequently, ketorolac is contraindicated during the third trimester of pregnancy.

Ocular administration

There are no adequate data from the use of eye drops containing ketorolac in pregnant women. Studies in animals have shown reproductive toxicity. Inhibition of prostaglandin synthesis may negatively affect pregnancy and/or embryonal/foetal development and/or postnatal development. Although a very low systemic exposure is expected after the use of ketorolac eye drops, ketorolac is not recommended during pregnancy.

Oral / IV / IM administration

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 concentrations, therefore ketorolac is contraindicated in mothers who are breast-feeding.

Ocular administration

Ketorolac should not be used during breast-feeding. Ketorolac is excreted in human milk after systemic administration.

Fertility

The use of ketorolac tromethamine, as with any drug known to inhibit cyclooxygenase/prostaglandin synthesis, may impair fertility and is not recommended in women attempting to conceive. In women who have difficulty conceiving or are undergoing investigation of infertility, withdrawal of ketorolac tromethamine should be considered.

Oral / IV / IM administration

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.

Ocular administration

Transient blurring of vision may occur on instillation of eye drops. Do not drive or use hazardous machinery unless vision is clear.

Oral administration

Adverse reaction rates increase with higher doses of ketorolac tromethamine. Practitioners should be alert for the severe complications of treatment with ketorolac tromethamine, such as G.I. ulceration, bleeding and perforation, postoperative bleeding, acute renal failure, anaphylactic and anaphylactoid reactions and liver failure. These NSAID-related complications can be serious in certain patients for whom ketorolac tromethamine is indicated, especially when the drug is used inappropriately.

In patients taking ketorolac tromethamine or other NSAIDs in clinical trials, the most frequently reported adverse experiences in approximately 1% to 10% of patients are:

^* Incidence greater than 10%

Additional adverse experiences reported occasionally (<1% in patients taking ketorolac tromethamine or other NSAIDs in clinical trials) include:

Body as a Whole: fever, infections, sepsis

Cardiovascular: congestive heart failure, palpitation, pallor, tachycardia, syncope

Dermatologic: alopecia, photosensitivity, urticaria

Gastrointestinal: anorexia, dry mouth, eructation, esophagitis, excessive thirst, gastritis,glossitis, hematemesis, hepatitis, increased appetite, jaundice, melena, rectal bleeding

Hemic and Lymphatic: ecchymosis, eosinophilia, epistaxis, leukopenia, thrombocytopenia

Metabolic and Nutritional: weight change

Nervous System: abnormal dreams, abnormal thinking, anxiety, asthenia, confusion, depression, euphoria, extrapyramidal symptoms, hallucinations, hyperkinesis, inability to concentrate, insomnia, nervousness, paresthesia, somnolence, stupor, tremors, vertigo, malaise

Reproductive, female: infertility

Respiratory: asthma, cough, dyspnea, pulmonary edema, rhinitis

Special Senses: abnormal taste, abnormal vision, blurred vision, hearing loss

Urogenital: cystitis, dysuria, hematuria, increased urinary frequency, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure, urinary retention

Other rarely observed reactions (reported from post-marketing experience in patients taking ketorolac tromethamine or other NSAIDs) are:

Body as a Whole: angioedema, death, hypersensitivity reactions such as anaphylaxis, anaphylactoid reaction, laryngeal edema, tongue edema, myalgia

Cardiovascular: arrhythmia, bradycardia, chest pain, flushing, hypotension, myocardial infarction, vasculitis

Dermatologic: exfoliative dermatitis, erythema multiforme, Lyell's syndrome, bullous reactions including Stevens-Johnson Syndrome, toxic epidermal necrolysis, and fixed drug eruption (FDE)

Gastrointestinal: acute pancreatitis, liver failure, ulcerative stomatitis, exacerbation of inflammatory bowel disease (ulcerative colitis, Crohn's disease)

Hemic and Lymphatic: agranulocytosis, aplastic anemia, hemolytic anemia, lymphadenopathy, pancytopenia, postoperative wound hemorrhage (rarely requiring blood transfusion)

Metabolic and Nutritional: hyperglycemia, hyperkalemia, hyponatremia

Nervous System: aseptic meningitis, convulsions, coma, psychosis

Respiratory: bronchospasm, respiratory depression, pneumonia

Special Senses: conjunctivitis

Urogenital: flank pain with or without hematuria and/or azotemia, hemolytic uremic syndrome

Post-Marketing Surveillance Study: A large post-marketing observational, nonrandomized study, involving approximately 10,000 patients receiving ketorolac tromethamine IV or IM, demonstrated that the risk of clinically serious gastrointestinal (G.I.) bleeding was dose dependent (see Tables 3A and 3B). This was particularly true in elderly patients who received an average daily dose greater than 60 mg/day of ketorolac tromethamine IV or IM (see Table 3A).

Table 3. Incidence of Clinically Serious G.I. Bleeding as Related to Age, Total Daily Dose and History of G.I. Perforation, Ulcer, Bleeding (PUB) after up to 5 Days of Treatment with Ketorolac Tromethamine IV/IM:

IV administration

Post Marketing

The following undesirable effects may occur in patients receiving ketorolac IV; 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, ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur. 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 have been reported following administration. Less frequently, gastritis has been observed.

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.

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.

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 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.

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 System and Breast Disorders: female infertility.

Respiratory, Thoracic and Mediastinal Disorders: asthma, dyspnoea, pulmonary oedema. Additionally epistaxis has been observed.

Hepatobiliary Disorders: hepatitis, cholestatic jaundice, liver failure.

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.

General Disorders and Administration Site Condition: excessive thirst, asthenia, oedema, injection site reactions and pain, 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.

Laboratory Abnormalities:

Ocular administration

The most frequent adverse events reported with the use of ketorolac are transient stinging and burning on instillation.

The frequency of adverse reactions documented during clinical trials of ketorolac trometamol and through post-marketing experience is given below and is defined as follows:

Very Common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very Rare (<1/10,000); Not Known (cannot be estimated from available data).

^* Occasional post marketing reports of corneal damage including corneal thinning, corneal erosion, epithelial breakdown and corneal perforation have been received. These occurred mainly in patients using concomitant topical corticosteroids and/or with predisposing co-morbidity.
^** There have been post-marketing reports of bronchospasm or exacerbation of asthma, in patients, who have either a known hypersensitivity to aspirin/non-steroidal anti-inflammatory drugs or a past medical history of asthma, associated with the use of ketorolac which may be contributory.

None of the typical adverse reactions reported with the systemic non-steroidal anti-inflammatory agents (including ketorolac trometamol) have been observed at the doses used in topical ophthalmic therapy.