Pharmacotherapeutic group: NSAIDs
ATC code: M01AB15
Ketorolac has pronounced analgesic effect, also has anti-inflammatory and moderate antipyretic effect.
The mechanism of action is related to non-selective inhibition of activity of cyclooxygenase enzyme (COX-1 and COX-2), mainly in peripheral tissues, which results in inhibition of prostaglandin biosynthesis – modulators of pain sensitivity, thermoregulation and inflammation. Ketorolac is a racemic mixture of [-]S and [+]R enantiomers, and the analgesic effect is due to the [-]S form.
Ketorolac does not affect opioid receptors, does not depress breathing, is not addictive and has no sedative or anxiolytic action.
In terms of analgesic effect it is comparable with morphine and is significantly superior to NSAIDs.
After oral administration, the onset of analgesic effect is noted after 1 hour respectively, the maximum effect is achieved after 1-2 hours.
When taken orally, ketorolac is well absorbed from the gastrointestinal tract (GIT). Bioavailability is 80-100%. Maximal concentration (Cmaõ) in blood plasma (0.7-1.1 mcg/ml) is reached 40 min after an empty stomach dose of 10 mg of ketorolac. Fat-rich food decreases the Cmax of the drug in plasma and delays its achievement by 1 hour.
The binding to plasma proteins is 99%. In hypoalbuminemia the amount of free ketorolac in blood plasma increases.
The time to reach equilibrium concentration (Css) when administered orally is 24 hours when used 4 times a day (above the subtherapeutic dose). Equilibrium concentration in blood plasma after oral administration of 10 mg of ketorolac is 0.39-0.79 mcg/ml. The volume of distribution is 0.15-0.33 l/kg.
More than 50% of the administered dose is metabolized in the liver to form pharmacologically inactive metabolites. The main metabolites are glucuronides, which are excreted by the kidneys, and p-hydroxyketorolac.
Evacuated by the kidneys at 91% (40% as metabolites), 6% – through the intestine.
After oral administration of 10 mg ketorolac, the half-life (T1/2) in patients with normal renal function averages 5.3 hours (2.4-9 hours). Total clearance is 0.025 l/kg/h. It is not excreted during hemodialysis.
Pharmacokinetics in special patient groups
Patients with impaired renal function
In patients with renal impairment, the distribution volume of ketorolac may increase by 2-fold and the distribution volume of its R-enantiomer by 20%.
In patients with renal insufficiency with a plasma creatinine concentration of 19-50 mg/L (168-442 μmol/L), the T1/2 is 10.3-10.8 hours; in more severe renal insufficiency, it is more than 13.6 hours.
The total clearance in renal failure with a plasma creatinine concentration of 19-50 mg/mL when administered orally with 10 mg of ketorolac is 0.016 l/kg/h.
Patients with impaired hepatic function
Hepatic function has no effect on T1/2.
Elderly and younger patients
The T1/2 is longer in older patients and shorter in younger patients.
Ketorolac penetrates into breast milk: after mother’s administration of 10 mg of ketorolac the Cmax in milk is reached after 2 hours and is 7.3 ng/ml, respectively; 2 hours after the second dose of ketorolac (when used 4 times daily) – 7.9 ng/ml.
Pain syndrome of severe and moderate intensity:
- dental pain;
- pain in the postpartum and postoperative period;
- oncological diseases;
- rheumatic diseases.
Ketorolac (Ketorolaca tromethamine) – 10.00 mg
microcrystalline cellulose – 122.41 mg
corn starch – 44.76 mg
Colloidal silica (aerosil) – 1.83 mg
Magnesium stearate – 1.00 mg
Contents of the shell:
hypromellose – 2.91 mg
titanium dioxide – 1.25 mg
macrogol 400 (polyethylene glycol 400) – 0.68 mg
talc – 0.16 mg.
How to take, the dosage
One time or repeatedly, depending on the severity of the pain syndrome.
A single dose of 10 mg (1 tablet), with repeated dosing it is recommended to take 10 mg up to 4 times a day depending on the severity of the pain.
The maximum daily dose should not exceed 40 mg.
The duration of the course should not exceed 5 days.
In order to reduce the risk of adverse events, the lowest effective dose of ketorolac should be used for the shortest possible course.
Concomitant use of ketorolac with acetylsalicylic acid or other NSAIDs, calcium preparations, glucocorticosteroids, ethanol, corticotropin may lead to a significantly increased risk of adverse reactions, including formation of gastrointestinal ulcers and development of gastrointestinal bleeding.
Concomitant use of ketorolac with anticoagulants (including warfarin, heparin), other NSAIDs, pentoxifylline and probenecid is contraindicated.
Concomitant use of ketorolac with other NSAIDs (including cyclooxygenase-2 inhibitors) may result in fluid retention, decompensation of cardiac function, and increased blood pressure.
The concomitant use of ketorolac with indirect anticoagulants, thrombolytics, antiaggregants, cefoperazone, cefotetan and pentoxifylline increases the risk of bleeding.
Probenecid decreases plasma clearance and volume of distribution of ketorolac, increases its plasma concentration and prolongs its half-life.
The co-administration of ketorolac with sodium valproate causes impairment of platelet aggregation.
The use of ketorolac with other nephrotoxic drugs (including gold drugs) increases the risk of nephrotoxicity. Concomitant use with paracetamol increases the nephrotoxicity of ketorolac. Drugs that block tubular secretion reduce the clearance of ketorolac and increase its plasma concentrations.
The co-administration of ketorolac with methotrexate increases hepato- and nephrotoxicity of methotrexate. Co-administration of ketorolac and methotrexate is possible only when using low doses of the latter. Methotrexate clearance may decrease (plasma concentration of methotrexate should be monitored).
Ketorolac may decrease lithium clearance and increase its plasma concentration, and increase the toxic effects of lithium. Simultaneous use with lithium salts is contraindicated.
Ketorolac reduces the effect of hypotensive and diuretic drugs (reduces the synthesis of prostaglandins in the kidneys).
Ketorolac increases the effect of narcotic analgesics. When combined with opioid analgesics, doses of the latter may be significantly reduced.
Ketorolac increases hypoglycemic effect of insulin and oral hypoglycemic agents; therefore the doses of these drugs should be recalculated.
Ketorolac increases plasma concentrations of verapamil and nifedipine.
The concomitant use of NSAIDs and mifepristone may decrease the effectiveness of mifepristone. NSAIDs should not be used for 8-12 days after mifepristone.
The concomitant use of NSAIDs and cyclosporine increases the risk of nephrotoxicity.
The concomitant use of NSAIDs and quinolone antibiotics increases the risk of seizures.
The concomitant use of NSAIDs and tacrolimus increases the risk of nephrotoxicity.
The concomitant use of NSAIDs and zidovudine increases the risk of hematological toxicity.
In concomitant use with digoxin, ketorolac does not impair the binding of digoxin to plasma proteins. Therapeutic concentrations of digoxin do not affect the binding of ketorolac to plasma proteins.
Antacids do not affect absorption of ketorolac.
Myelotoxic drugs increase ketorolac hematotoxicity.
Before using the drug, it is necessary to find out about previous allergies to the drug or other NSAIDs. Because of the risk of allergic reactions, the first dose should be taken under close medical supervision.
Ketorolac inhibits platelet aggregation and increases blood clotting time. The effect on platelet aggregation stops 24-48 hours after taking the drug.
Patients with clotting disorders are prescribed the drug only with continuous monitoring of platelet count, which is especially important in the postoperative period when close monitoring of hemostasis is required.
Hypovolemia increases the risk of nephrotoxic adverse reactions.
If necessary, it can be used in combination with narcotic analgesics.
Do not use with paracetamol for more than 2 days.
The risk of adverse reactions increases with prolonging the course of treatment and increasing the oral dose of ketorolac over 40 mg/day.
Continuous use of ketorolac with probenecid, pentoxifylline, acetylsalicylic acid and other NSAIDs (including cyclooxygenase-2 inhibitors), lithium salts, anticoagulants (including warfarin and heparin) is contraindicated.
Ketorolac is contraindicated for prophylactic analgesia before and during extensive surgical procedures because of the high risk of bleeding. Ketorolac is not recommended for use as a means for premedication and maintenance anesthesia.
Fluid retention, increased blood pressure, and edema have been reported with ketorolac.
Caution should be exercised when prescribing to patients with heart failure, arterial hypertension.
The concomitant use of ketorolac with other NSAIDs may result in abnormalities such as decompensation of heart failure and increased blood pressure.
According to clinical studies, use of some NSAIDs at high doses may increase the risk of arterial thrombotic complications (e.g., myocardial infarction, stroke). Although no such complications have been reported with ketorolac, there is insufficient data to rule out a risk of these complications.
The use of antacids, misoprostol, and agents that decrease gastric secretion (histamine H2-receptor blockers, proton pump inhibitors) is recommended to reduce the risk of NSAID-induced gastropathy.
In order to reduce the risk of adverse events, the lowest effective dose of ketorolac should be used for the shortest possible course.
During the treatment period, side effects of the central nervous system (drowsiness, dizziness, headache) may develop, which decreases the speed of mental and motor reactions and for this reason it is necessary to refrain from driving vehicles and other potentially dangerous activities requiring high concentration and quick psychomotor reactions.
- Hypersensitivity (including to other non-steroidal anti-inflammatory drugs);
- Complete or incomplete combination of bronchial asthma, recurrent nasal and paranasal sinus polyposis, and intolerance to acetylsalicylic acid or other non-steroidal anti-inflammatory drugs (including history);
- erosive ulcerative lesions of the gastrointestinal tract (GIT), active gastrointestinal bleeding;
- inflammatory bowel disease (including ulcerative colitis, Crohn’s disease);
- bone marrow and blood disorders (leukopenia, including history, thrombocytopenia, hypocoagulation (including hemophilia)), myelosuppression, bleeding or high risk of developing;
- severe renal failure (creatinine clearance (CK) less than 30 mL/min), confirmed hyperkalemia;
- severe hepatic failure or active liver disease;
- condition after coronary artery bypass surgery;
- prophylactic analgesia before and during major surgical procedures because of the high risk of bleeding;
- partum period;
- breastfeeding period; children under 16 years of age (safety and effectiveness of use not established);
- concomitant use with probenecid;
- concomitant use with pentoxifylline; concomitant use with acetylsalicylic acid and other nonsteroidal anti-inflammatory drugs (including cyclooxygenase-2 inhibitors);
- Simultaneous use with lithium salts;
- Simultaneous use with anticoagulants (including warfarin and heparin).
Bronchial asthma; presence of factors that increase gastrointestinal toxicity: alcoholism, tobacco smoking and cholecystitis; postoperative period; chronic heart failure; edema syndrome; arterial hypertension; moderate renal failure (CK 30-60 ml/min); cholestasis; active hepatitis; sepsis; systemic lupus erythematosus; ischemic heart disease; cerebrovascular disease; dislipidemia/hyperlipidemia; diabetes mellitus; peripheral artery disease; history of gastrointestinal ulcers, Helicobacter pylori infection; long-term use of NSAIDs; severe somatic diseases; thyroid disease; tuberculosis; concomitant use of oral glucocorticosteroids (including prednisolone), antiplatelet agents (including clopidogrel), selective serotonin reuptake inhibitors (including citalopram, fluoxetine, paroxetine, sertraline); older age (over 65 years).
The incidence of adverse events (AEs) is classified according to the World Health Organization guidelines as: very common – at least 10%; common – at least 1%, but less than 10%; infrequent – at least 0.1%, but less than 1%; rare – less than 0.01%, but less than 0.1%; very rare, including single cases – less than 0.01%; frequency is unknown (frequency cannot be determined based on available data).
Digestive system disorders
Often (especially in elderly patients over 65 years of age with a history of gastrointestinal erosive ulcers) – gastralgia, diarrhea;
infrequently – stomatitis, flatulence, constipation, vomiting, feeling of fullness of stomach;
rare – nausea, gastrointestinal erosive-ulcerative lesions (including those with perforation and/or bleeding – abdominal pain, epigastric spasm or burning, melena, “coffee grounds” type vomiting, nausea, heartburn), cholestatic jaundice, hepatitis, hepatomegaly, acute pancreatitis.
Urinary system disorders
. Rarely – acute renal failure, low back pain, hematuria, azotemia, hemolytic-uremic syndrome (hemolytic anemia, renal failure, thrombocytopenia, purpura), frequent urination, oliguria, polyuria, interstitial nephritis, edema of renal genesis;
frequency unknown – urinary retention.
Rarely – decreased hearing, tinnitus, visual impairment (including blurred vision);
frequency unknown – impaired taste.
Respiratory system disorders
Rarely – bronchospasm or dyspnea, rhinitis, laryngeal edema (shortness of breath, difficulty in breathing).
Central nervous system disorders
Often – headache, dizziness, somnolence;
Rarely – aseptic meningitis (fever, severe headache, cramps, neck and/or back muscle stiffness), hyperactivity (mood changes, anxiety), hallucinations, depression, psychosis.
Cardiovascular system disorders
Infrequent – increased blood pressure;
rarely – pulmonary edema, syncope.
Seldom – anemia, eosinophilia, leukopenia.
Hemostatic system disorders
Seldom – bleeding from the postoperative wound, nasal bleeding, rectal bleeding.
Infrequent – skin rash (including maculopapular rash), purpura;
rare – exfoliative dermatitis (fever with or without chills, redness, thickening or peeling of the skin, swelling and/or pain of the palatine tonsils), urticaria, Stevens-Johnson syndrome, Lyell syndrome.
. Rarely, anaphylaxis or anaphylactoid reactions (changes in complexion, skin rash, urticaria, pruritus, tachypnea or dyspnea, edema of the eyelids, swelling of the tongue, periorbital edema, shortness of breath, difficulty in breathing, heaviness in the chest, wheezing).
Often – edema (of face, shins, ankles, fingers, feet, weight gain);
infrequent – increased sweating;
rarely – fever;
frequency unknown – hyperkalemia, hyponatremia.
Symptoms: abdominal pain, nausea, vomiting, occurrence of peptic ulcers of the stomach or erosive gastritis, impaired renal function, metabolic acidosis.
Treatment: gastric lavage, administration of adsorbents (activated charcoal) and symptomatic therapy (maintenance of vital functions in the body). Ketorolac is not eliminated sufficiently by hemodialysis.
Dolac, Ketorol, Ketonov, Ketorolac, Ketorolac Rompharm
3 years. Do not use after the expiration date.
|Conditions of storage|
In the dark place at a temperature not exceeding 25 °С. Store out of the reach of children.
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