Pharmacological properties
Pharmacodynamics. The analgesic ketorolac tromethamine is a non-narcotic analgesic. It is an NSAID that exhibits anti-inflammatory and weak antipyretic activity. Ketorolac tromethamine inhibits prostaglandin synthesis and is considered a peripherally acting analgesic. It has no known effect on opiate receptors. No phenomena indicating respiratory depression have been observed after the use of ketorolac tromethamine. Ketorolac tromethamine does not cause mydriasis.
Pharmacokinetics. Ketorolac tromethamine is rapidly and completely absorbed after oral administration with a peak plasma concentration of 0.87 mg/kg 50 min after a single 10 mg dose. In healthy volunteers, the terminal T½ from plasma averages 5.4 h. In the elderly (mean age 72 years) it is 6.2 h. More than 99% of ketorolac in plasma is protein bound. In humans, the pharmacokinetics of ketorolac are linear after single or multiple doses. Steady-state plasma levels are achieved within 1 day when administered 4 times daily. No changes were observed with prolonged use. After a single IV dose, the volume of distribution is 0.25 l/kg, T½ is 5 h, and clearance is 0.55 ml/min/kg. The main route of excretion of ketorolac and its metabolites (conjugates and p-hydroxymetabolites) is urine (91.4%), with the remainder excreted in feces. A high-fat diet reduces the rate of absorption but does not reduce the extent, while antacids do not affect the absorption of ketorolac.
Indication
Short-term treatment of moderate pain, including postoperative pain.
Application
It is advisable to take the tablets during or after meals. The drug is recommended for short-term use only (up to 5 days). In order to minimize side effects, the drug should be used in the lowest effective dose for the shortest period necessary to control symptoms. Before starting treatment, normovolemia should be achieved. Adults should be prescribed 10 mg every 4-6 hours if necessary. It is not recommended to use the drug in doses exceeding 40 mg/day. Opioid analgesics (e.g. morphine, pethidine) can be used in parallel, ketorolac does not affect the binding of opioid drugs and does not enhance the respiratory depression or sedative effect caused by opioids. It has been demonstrated that in cases of postoperative pain, the simultaneous use of ketorolac with opioid analgesics reduced the need for the latter. For patients receiving parenteral ketorolac and assigned to oral ketorolac tablets, the total combined daily dose should not exceed 90 mg (60 mg for the elderly, patients with renal impairment, and patients weighing 50 kg), and the oral dose should not exceed 40 mg/day if the dosage form is changed. Patients should be switched to oral administration as soon as possible.
Elderly patients. Elderly patients are at increased risk of developing serious complications, particularly gastrointestinal complications. Patients should be monitored regularly during treatment with NSAIDs; longer dosing intervals, such as 6-8 hours, are generally recommended.
Contraindication
Hypersensitivity to ketorolac or to any of the excipients; active peptic ulcer disease, recent gastrointestinal bleeding or perforation, gastrointestinal ulceration or history of gastrointestinal bleeding; urticaria, rhinitis, angioedema or urticaria caused by the use of acetylsalicylic acid or other non-steroidal anti-inflammatory drugs (due to the possibility of severe anaphylactic reactions); history of urticaria; do not use as an analgesic before and during major surgery and after coronary artery manipulation; severe heart failure; complete or partial nasal polyposis syndrome, angioedema or bronchospasm; do not use in patients who have had surgery with a high risk of hemorrhage or incomplete hemostasis, and patients receiving anticoagulants, including low-dose heparin (2500-5000 units every 12 hours); hepatic or severe renal failure (plasma creatinine level 160 μmol/l); suspected or confirmed cerebrovascular bleeding, hemorrhagic diathesis, including blood clotting disorders and high risk of bleeding; concomitant treatment with other nonsteroidal anti-inflammatory drugs (including selective cyclooxygenase inhibitors), acetylsalicylic acid, warfarin, pentoxifylline, probenecid or lithium salts; hypovolemia, dehydration; risk of renal failure due to volume depletion.
Side effects
From the side of the central nervous system: anxiety, drowsiness, dizziness, headache, nervousness, paresthesia, functional disorders, depression, euphoria, convulsions, inability to concentrate, insomnia, malaise, increased fatigue, agitation, vertigo, unusual dreams, confusion, hallucinations, hyperkinesia, aseptic meningitis with corresponding symptoms, psychotic reactions, thinking disorders.
On the part of the organ of vision: visual impairment, blurred vision, optic neuritis.
On the part of the organ of hearing: hearing loss, ringing in the ears.
From the urinary system: increased urinary frequency, oliguria, acute renal failure, hyponatremia, hyperkalemia, hemolytic uremic syndrome, flank pain (with / without hematuria), increased serum urea and creatinine, interstitial nephritis, urinary retention, nephrotic syndrome, renal failure.
From the reproductive system: female infertility.
Hepatobiliary system: liver dysfunction, hepatitis, jaundice and liver failure, hepatomegaly.
From the side of the cardiovascular system: hot flashes, bradycardia, pallor, arterial hypertension, palpitations, chest pain, edema, heart failure.
It is known that the use of some NSAIDs, especially in high doses and for a long time, may be associated with an increased risk of developing arterial thromboembolic complications (myocardial infarction or stroke).
Respiratory system: shortness of breath, asthma, pulmonary edema.
From the blood system: purpura, thrombocytopenia, neutropenia, agranulocytosis, aplastic and hemolytic anemia, eosinophilia.
Skin: itching, urticaria, skin photosensitivity, Lyell's syndrome, bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (very rare), exfoliative dermatitis, maculopapular rash.
Hypersensitivity: Hypersensitivity reactions have been reported, including non-specific allergic reactions and anaphylaxis, respiratory tract reactivity including asthma, exacerbation of asthma, bronchospasm, laryngeal edema or dyspnea, and various skin disorders including rash of various types, pruritus, urticaria, purpura, angioedema and, in rare cases, exfoliative and bullous dermatitis (including epidermal necrolysis and erythema multiforme).
Such reactions may occur in patients with or without known hypersensitivity to ketorolac or other NSAIDs. They may also occur in individuals with a history of angioedema, bronchospastic reactivity (e.g. asthma and nasal polyps). Anaphylactoid reactions, such as anaphylaxis, may be fatal.
Others: postoperative bleeding from the wound, hematoma, nosebleed, increased bleeding time, asthenia, edema, weight gain, increased body temperature, increased sweating, dry mouth, increased thirst, taste disturbance, muscle pain.
Special instructions
The maximum duration of treatment should not exceed 5 days.
Effects on Fertility: Ketorolac, as with any drug that inhibits cyclooxygenase/prostaglandin synthesis, may impair fertility and is not recommended for use in women attempting to conceive. For women who are unable to conceive or are undergoing investigation of fertility, discontinuation of ketorolac should be considered.
Gastrointestinal bleeding, ulceration and perforation. Gastrointestinal bleeding, ulceration or perforation, which can be fatal, have been reported with NSAIDs at any time during treatment, with or without warning symptoms or a history of serious gastrointestinal disorders. The risk of serious gastrointestinal bleeding is dose-dependent. This is particularly true in elderly patients receiving ketorolac at an average daily dose of more than 60 mg. For these patients, as well as for patients taking low doses of acetylsalicylic acid or other drugs that may increase the risk for the gastrointestinal tract, combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered. Ketorolac should be used with caution in patients receiving concomitant medication that may increase the risk of ulceration or bleeding, such as oral corticosteroids, selective serotonin reuptake inhibitors, or antiplatelet agents (acetylsalicylic acid). If gastrointestinal bleeding or ulceration occurs in patients receiving ketorolac, treatment should be discontinued.
Renal Effects: Prostaglandin biosynthesis inhibitors (including NSAIDs) have been reported to be nephrotoxic. Caution should be exercised in patients with renal, cardiac, or hepatic impairment, as NSAIDs may precipitate renal impairment. Patients with mild renal impairment should be given lower doses of ketorolac, and renal function should be closely monitored. As with other drugs that inhibit prostaglandin synthesis, increases in serum urea, creatinine, and potassium have been reported with ketorolac tromethamine, which may occur after a single dose.
Cardiovascular, renal and hepatic impairment. Use with caution in patients with conditions that result in decreased blood volume and/or renal blood flow, where renal prostaglandins play a supporting role in maintaining renal perfusion. Renal function should be monitored in such patients. Volume depletion should be managed and serum urea and creatinine and urine output closely monitored until the patient is normovolemic. In patients on renal dialysis, creatinine clearance was reduced by approximately half of normal and terminal half-life was increased by approximately threefold. Patients with hepatic impairment due to cirrhosis did not have any clinically significant changes in ketorolac clearance or terminal T½. Borderline elevations in one or more liver function tests may occur. These abnormalities may be transient, may remain unchanged, or may progress with continued treatment. If clinical signs and symptoms suggest the development of liver disease or if systemic manifestations are observed, the drug should be discontinued.
Ketorolac should be administered with caution to patients with a history of cardiovascular disorders.
Fluid retention and edema: Fluid retention and edema have been reported with ketorolac, and it should be administered with caution to patients with cardiac decompensation, hypertension, or similar conditions.
Cardiovascular and cerebrovascular effects. There is currently insufficient information to assess this risk for ketorolac tromethamine. Patients with uncontrolled hypertension, congestive heart failure, diagnosed coronary artery disease, peripheral arterial disease, and/or cerebrovascular disease should be monitored by a physician.
Systemic lupus erythematosus and mixed connective tissue diseases. Patients with systemic lupus erythematosus and various mixed connective tissue diseases are at increased risk of developing aseptic meningitis.
Dermatological manifestations: Ketorolac should be discontinued at the first sign of skin rash, mucosal lesions, or any other signs of hypersensitivity.
Hematological effects. Ketorolac should not be administered to patients with bleeding disorders. Patients receiving anticoagulant therapy may be at increased risk of bleeding when ketorolac is administered concomitantly. Patients receiving other medicinal products that may affect the rate of bleeding should be carefully monitored when ketorolac is administered. The incidence of major postoperative bleeding is known to be 1%. Ketorolac inhibits platelet aggregation and prolongs bleeding time. In patients with normal bleeding times, bleeding time was increased but did not exceed the normal range of 2-11 minutes. In contrast to the prolonged effect of acetylsalicylic acid, platelet function returns to normal within 24-48 hours after ketorolac discontinuation. Ketorolac should not be administered to patients undergoing surgery with a high risk of bleeding or incomplete bleeding. Caution should be exercised if mandatory bleeding control is critical. Hypovolemia should be corrected before initiating ketorolac.
Increasing the dose of ketorolac tablets above the daily dose of 40 mg does not increase its effectiveness, but increases the risk of adverse reactions.
Ketorolac is not addictive; no withdrawal syndrome has been reported when the drug is discontinued.
Use during pregnancy and lactation. The safety of ketorolac during human pregnancy has not been established. Given the known effects of NSAIDs on the fetal cardiovascular system (risk of premature closure of the ductus arteriosus), ketorolac is contraindicated during pregnancy, labor and delivery. The onset of labor may be delayed and the duration prolonged with an increased tendency for bleeding in both mother and child.
Ketorolac penetrates into breast milk in small amounts, so the drug is contraindicated during breastfeeding.
Ability to influence the reaction speed when driving or operating other mechanisms. Some patients may experience drowsiness, dizziness, vertigo, insomnia, increased fatigue, visual disturbances or depression when using ketorolac. If patients experience the above or other similar effects, they should not drive or operate other mechanisms.
Interactions
Ketorolac binds readily to plasma proteins (mean 99.2%), and the extent of binding is concentration dependent.
Drugs that should not be used with ketorolac. Due to the possibility of side effects, ketorolac should not be administered with other NSAIDs, including selective COX-2 inhibitors, or to patients receiving acetylsalicylic acid, warfarin, lithium, probenecid, cyclosporine. NSAIDs should not be administered within 8-12 days after mifepristone administration, as NSAIDs may weaken the effect of mifepristone.
Drugs that should be prescribed with caution in combination with ketorolac. In healthy, normovolemic individuals, ketorolac reduces the diuretic effect of furosemide by approximately 20%. The drug should be prescribed with particular caution to patients with cardiac decompensation. NSAIDs may aggravate heart failure, reduce glomerular filtration rate, and increase plasma levels of cardiac glycosides when administered concomitantly with cardiac glycosides. Ketorolac and other NSAIDs may weaken the effect of antihypertensive drugs. There is an increased risk of renal dysfunction when ketorolac is administered concomitantly with ACE inhibitors, especially in patients with reduced blood volume in the body. There is a possible risk of nephrotoxicity if NSAIDs are administered concomitantly with tacrolimus. Concomitant administration with diuretics may lead to a weakening of the diuretic effect and an increased risk of nephrotoxicity of NSAIDs. As with all NSAIDs, caution should be exercised when corticosteroids are administered concomitantly because of the increased risk of gastrointestinal ulceration or bleeding. There is an increased risk of gastrointestinal bleeding when NSAIDs are administered in combination with antiplatelet agents and selective serotonin reuptake inhibitors. Caution is advised when methotrexate is administered concomitantly, as some prostaglandin synthesis inhibitors have been reported to reduce the clearance of methotrexate and therefore may increase its toxicity.
Patients taking NSAIDs and quinolones may be at increased risk of developing seizures.
Concomitant use of NSAIDs with zidovudine increases the risk of hematological toxicity. There is an increased risk of hemarthrosis and hematoma in HIV-infected patients with hemophilia receiving concomitant treatment with zidovudine and ibuprofen.
It is unlikely that these drugs will interact with ketorolac. Ketorolac did not affect the binding of digoxin to plasma proteins. It is known that at therapeutic concentrations of salicylate 300 μg/mL and above, the binding of ketorolac decreased from approximately 99.2 to 97.5%. Therapeutic concentrations of digoxin, warfarin, paracetamol, phenytoin, and tolbutamide did not affect the binding of ketorolac to plasma proteins. Since ketorolac is a highly active drug and its available plasma concentrations are low, it is not expected to significantly displace other drugs that are bound to blood proteins. There is no evidence that ketorolac tromethamine induces or inhibits liver enzymes that are capable of metabolizing it or other drugs. Therefore, ketorolac is not expected to alter the pharmacokinetics of other drugs through enzyme induction or inhibition.
Antiepileptics: Isolated cases of epileptic seizures have been reported during concomitant use of ketorolac and antiepileptics (phenytoin, carbamazepine).
Psychotropic drugs: With the simultaneous use of ketorolac and psychotropic drugs (fluoxetine, thiothixene, alprazolam), hallucinations have been reported.
Laboratory Test Effects: Ketorolac inhibits platelet aggregation and may prolong bleeding time.
Overdose
Symptoms: headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding; rarely - diarrhea, disorientation, agitation, coma, drowsiness, dizziness, tinnitus, loss of consciousness, convulsions. In cases of severe poisoning, acute respiratory distress syndrome and liver damage are possible.
Treatment: gastric lavage, use of activated charcoal. Sufficient diuresis should be ensured. Kidney and liver function should be carefully monitored. Patients should be observed for at least 4 hours after the use of a potentially toxic amount. Frequent or prolonged seizures should be treated with intravenous diazepam. Other measures may be prescribed depending on the clinical condition of the patient. Treatment is symptomatic. Ketorolac is not removed by dialysis.
Storage conditions
In the original packaging at a temperature not exceeding 25 °C.
