Pharmacological properties
Pharmacodynamics. The active substance of the drug Medrolgin - ketorolac trometamol - is an NSAID that demonstrates analgesic activity. The mechanism of action of ketorolac (as well as other nonsteroidal anti-inflammatory drugs) is not fully understood, but may consist in the suppression of prostaglandin synthesis. The biological activity of ketorolac trometamol is associated with the s-form. Ketorolac trometamol does not have sedative or anxiolytic properties.
The maximum analgesic effect of ketorolac is achieved within 2-3 hours. This effect does not have statistically significant differences within the recommended dosage range. The greatest difference between high and low doses of ketorolac is the duration of analgesia. The analgesic dose of ketorolac also has an anti-inflammatory effect.
Pharmacokinetics. Ketorolac trometamol is a racemic mixture of [-] S- and [+] R-enantiometric forms, with the analgesic activity due to the S-form. After i / m administration, ketorolac is rapidly and completely absorbed. The average plasma C max of 2.2 μg / ml is achieved on average 50 minutes after administration of a single dose of 30 mg.
Linear pharmacokinetics. In adults, after intramuscular administration of ketorolac trometamol in the recommended dosage ranges, the clearance of the racemate is not changed. This indicates that the pharmacokinetics of ketorolac trometamol in adults after single or multiple intramuscular administration of the drug is linear. At higher recommended doses, there is a proportional increase in the concentrations of free and bound racemate.
Ketorolac does not penetrate the blood-brain barrier well. Ketorolac crosses the placenta and in small amounts into breast milk. More than 99% of ketorolac in plasma is protein bound over a wide range of concentrations.
Metabolism. Ketorolac trometamol is extensively metabolized in the liver. The products of metabolism are hydroxylated and conjugated forms of the parent drug. The products of metabolism and some of the unchanged drug are excreted in the urine.
Excretion. The primary route of elimination of ketorolac and its metabolites is renal. Approximately 92% of the administered dose is recovered in the urine: 40% as metabolites and 60% as unchanged ketorolac. Approximately 6% of the dose is excreted in the feces. A single-dose study of ketorolac 10 mg (n = 9) demonstrated that the S-enantiomer is excreted twice as rapidly as the R-enantiomer, and clearance is independent of route of administration. This means that the ratio of plasma concentrations of the S- and R-enantiomers after each dose decreases over time. There is little or no difference between the S- and R-forms in humans.
The T½ of the S-enantiomer of ketorolac trometamol is approximately 2.5 hours (standard deviation (SD) ± 0.4) and the R-enantiomer is 5 hours (SD ± 1.7). In other studies, the T½ of the racemate has been reported to be 5-6 hours.
Accumulation. Ketorolac trometamol administered as an IV bolus every 6 hours for 5 days to healthy volunteers (n = 13) showed no significant differences on days 1 and 5. Trough levels averaged 0.29 μg/mL (SD ± 0.13) on day 1 and 0.55 μg/mL (SD ± 0.23) on day 6. Steady state was achieved after the 4th dose. Accumulation of ketorolac trometamol in specific patient groups (elderly, pediatric, renal or hepatic impairment) has not been studied.
Pharmacokinetics in specific patient groups
Elderly patients. Based on single-dose data only, the T½ of ketorolac trometamol racemate was increased from 5 to 7 hours in elderly patients (65-78 years) compared to young healthy volunteers (24-35 years).
Children: Pharmacokinetic data on the intramuscular administration of ketorolac trometamol in children are not available.
Renal impairment. Based only on data obtained after a single dose of the drug, T ½ of ketorolac trometamol in patients with impaired renal function is 6-19 hours and depends on the severity of the impairment. There is almost no correlation between creatinine clearance and total clearance of ketorolac trometamol in elderly patients and patients with impaired renal function (r = 0.5). In patients with renal disease, the AUC value of each enantiomer increases by almost 100% compared with that in healthy volunteers. The volume of distribution doubles for the S-enantiomer and increases by 1/5 for the R-enantiomer. The increase in the volume of distribution of ketorolac trometamol indicates an increase in the unbound fraction.
Hepatic impairment: T½, AUC, and Cmax values in 7 patients with liver disease were not significantly different from those in healthy volunteers.
Indication
Relief of moderate to severe postoperative pain for a short period of time.
Application
After IM or IV administration, the analgesic effect is observed after approximately 30 minutes, and maximum analgesia occurs after 1-2 hours. In general, the average duration of analgesia is 4-6 hours. The dose should be adjusted depending on the severity of the pain and the patient's response to treatment. Continuous IM or IV administration of ketorolac in multiple daily doses should not last more than 2 days, since with prolonged use the risk of adverse reactions increases. Experience with long-term use is limited, since the vast majority of patients were transferred to oral administration of the drug or after a period of IM administration, patients no longer required analgesic therapy. The likelihood of side effects can be minimized by using the lowest effective dose for the minimum period of time necessary to control symptoms. The drug should not be administered epidurally or intraspinally.
Adults. The recommended initial dose of ketorolac trometamol is 10 mg, followed by 10-30 mg every 4-6 hours (if necessary). In the initial postoperative period, ketorolac trometamol can be administered every 2 hours if necessary. The minimum effective dose should be prescribed. The total daily dose should not exceed 90 mg for young patients, 60 mg for elderly patients, patients with renal insufficiency and a body weight of 50 kg. The maximum duration of treatment should not exceed 2 days. For patients weighing 50 kg, the dose should be reduced. Simultaneous use of opioid analgesics (morphine, pethidine) is possible. Ketorolac does not have a negative effect on the binding of opioid receptors and does not increase the respiratory depression or sedative effect of opioid drugs. For patients receiving parenteral therapy who are switched to oral ketorolac trometamol tablets, the total combined daily dose should not exceed 90 mg (60 mg for elderly patients, patients with renal impairment, and those weighing 50 kg), and on the day of switching to another dosage form, the dose of the component should not exceed 40 mg. Patients should be switched to the oral form as soon as possible.
Elderly patients: It is recommended that patients aged 65 years and over should be given the lowest possible dosage. The total daily dose should not exceed 60 mg.
Patients with renal impairment. Ketorolac is contraindicated in moderate to severe renal impairment. For less severe impairment, the dosage should be reduced (not higher than 60 mg/day IM or IV).
Children: Do not use in children under 16 years of age.
Contraindication
Hypersensitivity to ketorolac or any component of the drug. Active peptic ulcer, recent gastrointestinal bleeding or perforation, history of peptic ulcer or gastrointestinal bleeding. Allergic 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 allergic rhinitis. Severe heart failure. Complete or partial nasal polyposis syndrome, angioedema or bronchospasm. Hepatic or moderate or severe renal failure (plasma creatinine clearance 160 μmol/l). Suspected or confirmed cerebrovascular bleeding, hemorrhagic diathesis, including coagulation disorders and high risk of bleeding. Concomitant treatment with other nonsteroidal anti-inflammatory drugs (including selective COX inhibitors), acetylsalicylic acid, warfarin, pentoxifylline, probenecid or lithium salts. Hypovolemia, dehydration.
The drug is not used as an analgesic before and during surgery, as well as in patients who have had surgery with a high risk of hemorrhage or incomplete cessation of bleeding, and patients receiving anticoagulants, including heparin in low doses (2500-5000 IU every 12 hours).
Side effects
On the part of the digestive system: nausea, vomiting, dyspepsia, anorexia, abdominal pain, taste changes, erosive-ulcerative lesions of the gastrointestinal tract, bleeding, ulcer perforation, diarrhea, dry mouth, severe thirst, flatulence, constipation, cholestatic jaundice, hepatitis, hepatomegaly, acute pancreatitis, stomatitis, feeling of fullness of the stomach, gastritis, esophagitis, belching, hematemesis, melena, exacerbation of colitis and Crohn's disease, liver failure.
From the side of the central nervous system: drowsiness, impaired concentration, euphoria, headache, dizziness, anxiety, asthenic syndrome, paresthesia, insomnia, malaise, increased fatigue, agitation, unusual dreams, confusion, vertigo, hyperkinesia; aseptic meningitis (fever, severe headache, convulsions, stiffness of the neck and/or back muscles), hyperactivity (mood swings, restlessness), hallucinations, depression, psychosis, fainting; pathological thinking.
From the side of the hematopoietic organs: aplastic anemia, hemolytic anemia, agranulocytosis, leukopenia, eosinophilia, thrombocytopenia, neutropenia.
Respiratory tract: bronchospasm, shortness of breath, pulmonary edema, laryngeal edema, asthma, exacerbation of asthma.
From the urinary system: nephrotic syndrome, oliguria, dysuria, increased urinary frequency, hyponatremia, hyperkalemia, increased creatinine and urea levels, interstitial nephritis, urinary retention, back pain, acute renal failure, hematuria, azotemia, hemolytic-uremic syndrome (hemolytic anemia, renal failure, thrombocytopenia, purpura).
Skin: skin rashes (including macular rash), purpura, exfoliative dermatitis (hyperemia, thickening or peeling of the skin, enlargement and / or tenderness of the tonsils), photosensitivity, Lyell's syndrome, bullous reactions.
From the hemostatic system: bleeding from the postoperative wound, nosebleeds, rectal bleeding, increased bleeding time.
From the reproductive system: female infertility.
Allergic reactions: anaphylaxis (may be fatal) or anaphylactoid reactions (change in facial skin color, skin rash, urticaria, itching, tachypnea or dyspnea, eyelid edema, periorbital edema, shortness of breath, difficulty breathing, chest tightness, wheezing, urticaria, malignant exudative erythema (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell syndrome), angioedema.
From the sensory organs: hearing loss, hearing loss, tinnitus, visual impairment, blurred vision, optic neuritis.
General disorders: increased sweating, edema, muscle pain, pain, changes at the injection site.
Changes in laboratory parameters: eosinophilia, increased activity of hepatic transaminases.
Others: swelling of the face, lower legs, fingers, feet, tongue, weight gain, increased sweating, fever with or without chills.
Special instructions
The likelihood of side effects can be minimized by using the lowest effective dose for the shortest time necessary to control symptoms. Physicians should be aware that some patients may not experience relief until 30 minutes after intramuscular injection.
The duration of combined use of ketorolac trometamol intramuscularly and orally in adult patients should not exceed 5 days.
Effect on fertility: Ketorolac trometamol should be discontinued in women who are unable to conceive and are undergoing investigation for this. Women with reduced fertility should avoid the drug.
Effects on the digestive tract. Ketorolac trometamol can cause severe adverse reactions from the digestive tract. These adverse reactions can occur in patients using ketorolac trometamol at any time after or without warning symptoms and can be fatal. The risk of clinically serious gastrointestinal bleeding depends on its dose. However, adverse reactions can occur even with short-term therapy. In addition to a history of peptic ulcer disease, provoking factors include concomitant use of oral corticosteroids, anticoagulants, long-term NSAID therapy, smoking, alcohol consumption, advanced age and poor general health. Most spontaneous reports of gastrointestinal events have concerned elderly or debilitated patients, therefore, special attention should be paid to them when treating this category of patients and ketorolac should be discontinued if suspected. Patients at risk should be prescribed an alternative type of therapy that does not include NSAIDs.
Use in patients with renal impairment (see Adverse Reactions). Patients with less severe renal impairment should receive ketorolac at lower doses (not more than 60 mg/day, i.m.). The renal status of such patients should be carefully monitored. Patients should be well hydrated before starting treatment. In patients undergoing hemodialysis, ketorolac clearance was reduced to approximately half the normal rate, and the terminal T½ was increased by almost threefold.
Effects on the cardiovascular system and cerebral vessels. Patients with arterial hypertension and/or a history of mild to moderate heart failure should be carefully monitored.
To minimize the potential risk of adverse cardiovascular events in patients receiving NSAIDs, the lowest effective dose should be used for the shortest duration possible. Ketorolac should be prescribed to patients with uncontrolled hypertension, congestive heart failure, established ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease only after careful consideration of the benefits and risks. Ketorolac should also be considered before initiating long-term treatment in patients at risk of cardiovascular disease (e.g., those with hypertension, hyperlipidemia, diabetes mellitus, or smokers).
Respiratory system: The patient's condition should be monitored due to the possibility of bronchospasm.
Use in patients with hepatic impairment. Ketorolac trometamol should be administered with caution to patients with hepatic impairment or a history of liver disease. Significant increases in plasma ALT and AST (more than 3 times the upper limit of normal) were observed in less than 1% of patients. In addition, isolated cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, hepatic necrosis and hepatic failure, sometimes fatal, have been reported. Ketorolac should be discontinued if clinical symptoms of liver disease or systemic manifestations (such as eosinophilia, rash) appear.
NSAIDs should be used with caution in patients with a history of Crohn's disease and ulcerative colitis because of the possibility of worsening of the disease. Clinical trials and epidemiological data suggest that the use of some NSAIDs, especially at high doses and over a long period, may be associated with a small increased risk of arterial thromboembolic events such as myocardial infarction or stroke. Such a risk cannot be excluded for ketorolac. Like other NSAIDs, ketorolac inhibits prostaglandin synthesis and may have toxic effects on the kidneys, therefore it should be used with caution in patients with impaired renal function or a history of kidney disease. Patients at risk include patients with impaired renal function, hypovolemia, heart failure, impaired liver function, patients taking diuretics, and the elderly. The use of the drug in patients with systemic lupus erythematosus or connective tissue diseases may be associated with an increased risk of developing aseptic meningitis. There have been reports of serious skin reactions such as exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis. The highest risk of these reactions occurs at the beginning of treatment, with the first manifestations being noted in most cases within the first month of treatment. Patients should discontinue treatment with the drug at the first appearance of rash, mucosal lesions or other signs of hypersensitivity. When treating patients with cardiac, renal or hepatic failure, taking diuretics, or after surgery with hypovolemia, careful monitoring of diuresis and renal function is necessary.
Use during pregnancy and breastfeeding. Due to the known effects of NSAIDs on the cardiovascular system of the fetus, ketorolac should not be used during pregnancy (especially in the third trimester). The use of ketorolac trometamol is contraindicated during pregnancy, labor and delivery.
Do not use during breastfeeding due to the possible negative effects of prostaglandin synthesis inhibitors on infants.
The ability to influence the speed of reaction when driving vehicles or working with other mechanisms. During the period of treatment, it is necessary to refrain from engaging in potentially dangerous activities that require increased attention and quick reactions, due to the possible development of adverse reactions from the nervous system.
Interactions
Warfarin, Digoxin, Salicylates, and Heparin. Ketorolac trometamol slightly reduced the plasma protein binding of warfarin in vitro and remained consistent with the plasma protein binding of digoxin. Available in vitro data indicate that at therapeutic concentrations of salicylates (300 mcg/mL), ketorolac binding was reduced from approximately 99.2 to 97.5%, suggesting a possible two-fold increase in unbound ketorolac plasma levels. Therapeutic concentrations of digoxin, warfarin, ibuprofen, naproxen, piroxicam, acetaminophen, phenytoin, and tolbutamide do not alter the plasma protein binding of ketorolac trometamol.
Acetylsalicylic acid. When used with acetylsalicylic acid, the binding of ketorolac to plasma proteins is reduced, although the clearance of free ketorolac is not changed. The clinical significance of this type of interaction is unknown, although, as with other nonsteroidal anti-inflammatory drugs, it is not recommended to prescribe ketorolac trometamol and acetylsalicylic acid simultaneously due to the potential increase in the frequency of adverse events.
Diuretics: Ketorolac may reduce the natriuretic effect of furosemide and thiazides in some patients. During concomitant therapy with NSAIDs, the patient should be closely observed for signs of renal failure and to ensure the effectiveness of diuretics.
Probenecid. Concomitant use of ketorolac trometamol and probenecid resulted in a decrease in ketorolac clearance and an increase in its plasma levels and T½. Therefore, concomitant use of ketorolac trometamol and probenecid is contraindicated.
Lithium: When NSAIDs and lithium are used concomitantly, patients should be observed closely for signs of lithium toxicity.
Anticoagulants: Ketorolac trometamol should be administered with caution with anticoagulants, as concomitant administration may potentiate the anticoagulant effect.
Cardiac glycosides: NSAIDs may worsen heart failure, reduce glomerular filtration rate, and increase plasma levels of cardiac glycosides when used concomitantly with the latter.
Methotrexate: Concomitant administration should be done with caution.
ACE inhibitors: Concomitant use of ACE inhibitors increases the risk of renal dysfunction, particularly in patients with reduced interstitial fluid volume.
NSAIDs may reduce the hypotensive effect of ACE inhibitors. This interaction should be kept in mind when prescribing NSAIDs with ACE inhibitors.
Anticonvulsants: Isolated cases of convulsions have been reported with the concomitant use of ketorolac trometamol and anticonvulsants (phenytoin, carbamazepine).
Psychotropic drugs: With the simultaneous use of ketorolac and psychotropic drugs (fluoxetine, thiothixene, alprazolam), hallucinations have been reported.
Pentoxifylline. Concomitant use of ketorolac trometamol and pentoxifylline increases the risk of bleeding.
Non-polarizing muscle relaxants. No formal studies of the concomitant use of ketorolac trometamol and muscle relaxants have been conducted.
Cyclosporine: As with all NSAIDs, caution should be exercised when co-administering cyclosporine due to the increased risk of nephrotoxicity.
Mifepristone. NSAIDs should not be used for 8-12 days after taking mifepristone, as they may weaken the effects of mifepristone.
Corticosteroids: As with all NSAIDs, caution should be exercised when corticosteroids are administered concomitantly due to the increased risk of gastrointestinal bleeding.
Quinolines: Patients taking quinolines may be at increased risk of seizures.
Beta-adrenergic blockers: Ketorolac and other NSAIDs attenuate the hypotensive effect of beta-adrenergic blockers.
Zidovudine: 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 treated with zidovudine and ibuprofen.
Incompatibility: The drug should not be mixed in the same container with morphine sulfate, promethazine, and hydroxyzine due to the formation of a precipitate.
Pharmaceutically incompatible with tramadol solution and lithium preparations.
Overdose
Symptoms: lethargy, drowsiness, nausea, vomiting, epigastric pain, gastrointestinal bleeding, angina, acute respiratory distress syndrome, respiratory depression and coma. Anaphylactoid reactions have been reported, which may also occur in case of overdose.
Treatment. Symptomatic and supportive therapy. There is no specific antidote. Patients with symptoms of overdose or after a large overdose (when taken orally in a dose that is 5-10 times higher than usual) later than 4 hours after using the drug should induce vomiting, take activated charcoal (60-100 g for adults) and / or an osmotic laxative. The use of forced diuresis, alkylation of urine, hemodialysis or blood transfusion is ineffective due to the high degree of binding of the drug to blood plasma proteins. Single overdoses of ketorolac at different times led to abdominal pain, nausea, vomiting, hyperventilation, peptic ulcer and / or erosive gastritis and impaired renal function, which resolved after drug withdrawal.
Storage conditions
At a temperature not exceeding 25 °C in the original packaging.
