Instructions Ketorol solution for injection 30 mg ampoule 1 ml No. 10
Composition
active ingredient: ketorolac;
1 ml of solution contains ketorolac tromethamine 30 mg;
Excipients: anhydrous ethanol, sodium chloride, disodium edetate, octoxynol 9, sodium hydroxide, propylene glycol, water for injections.
Dosage form
Solution for injection.
Main physicochemical properties: transparent liquid from colorless to light yellow, practically free from visible particles and foreign inclusions.
Pharmacotherapeutic group
Nonsteroidal anti-inflammatory and antirheumatic drugs.
ATX code M01A B15.
Pharmacological properties
Pharmacodynamics.
Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug that exhibits analgesic activity. The mechanism of action of ketorolac (as with other NSAIDs) is not fully understood, but may involve inhibition of prostaglandin synthesis. The biological activity of ketorolac tromethamine is associated with the S-form. Ketorolac tromethamine does not have sedative or anxiolytic properties.
The maximum analgesic effect of ketorolac is achieved within 2-3 hours. This effect is not statistically significantly different 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 tromethamine is a racemic mixture of [˗]S- and [+]R-enantiomeric forms, with the analgesic activity being due to the S-form. Ketorolac is rapidly and completely absorbed after intramuscular administration. The mean maximum plasma concentration of 2.2 μg/mL is reached on average 50 minutes after administration of a single 30 mg dose.
Linear pharmacokinetics.
In adults, clearance of the racemate is not altered after intramuscular administration of ketorolac tromethamine in the recommended dosage range. This indicates that the pharmacokinetics of ketorolac tromethamine in adults following single or multiple intramuscular administrations of ketorolac tromethamine are linear. At higher recommended doses, there is a proportional increase in concentrations of the free and bound racemate.
The drug penetrates poorly through the blood-brain barrier. Ketorolac penetrates the placenta and in small quantities into breast milk. More than 99% of ketorolac in blood plasma is bound to proteins within a wide range of concentrations.
Metabolism.
Ketorolac tromethamine 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 eliminated twice as rapidly as the R-enantiomer, and clearance is independent of route of administration. This means that the ratio of S-enantiomer/R-enantiomer plasma concentrations after each dose decreases over time. There is little or no difference between the S- and R-forms in humans.
The half-life of the S-enantiomer of ketorolac tromethamine is approximately 2.5 hours (SD ± 0.4) and the R-enantiomer is 5 hours (SD ± 1.7). In other studies, the half-life of the racemate has been reported to be 5-6 hours.
Accumulation.
Ketorolac tromethamine administered intravenously as a bolus every 6 hours for 5 days to healthy volunteers (n = 13) showed no significant difference 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 fourth dose. Accumulation of ketorolac tromethamine in specific patient groups (elderly, pediatric, renally impaired, or hepatically impaired) has not been studied.
Pharmacokinetics in certain patient groups.
Elderly patients.
Based on data obtained after a single administration, the elimination half-life of the racemate ketorolac tromethamine increased from 5 to 7 hours in elderly patients (65-78 years) compared to young healthy volunteers (24-35 years).
Children: Pharmacokinetic data on intramuscular administration of ketorolac tromethamine in children are not available.
Kidney failure.
Based on data obtained after a single dose, the mean elimination half-life of ketorolac tromethamine in patients with renal impairment ranges from 6 to 19 hours and is dependent on the severity of the impairment. There is little correlation between creatinine clearance and total clearance of ketorolac tromethamine in elderly patients and patients with renal impairment (r = 0.5). In patients with renal disease, the AUC8 of each enantiomer is increased by almost 100% compared to healthy volunteers. The volume of distribution is doubled for the S-enantiomer and increased by 1/5 for the R-enantiomer. The increase in the volume of distribution of ketorolac tromethamine indicates an increase in the unbound fraction.
The values of half-life, AUC8 and Cmax in 7 patients with liver disease did not differ significantly from those in healthy volunteers.
Indication
Short-term relief of moderate to severe postoperative pain.
Contraindication
Hypersensitivity to ketorolac or to any other component of the drug;
– patients with active peptic ulcer, recent gastrointestinal bleeding or perforation, or a history of peptic ulcer disease or gastrointestinal bleeding;
– bronchial asthma, 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 bronchial asthma;
– do not use as an analgesic before and during surgery;
– severe heart failure;
– complete or partial syndrome of nasal polyps, angioedema or bronchospasm;
– do not use in patients who have had surgery with a high risk of hemorrhage or incomplete bleeding and in patients receiving anticoagulants, including low doses of heparin (2500-5000 units every 12 hours);
– hepatic or moderate or severe renal failure (serum creatinine clearance more than 160 μmol/l);
– suspected or confirmed cerebrovascular bleeding, hemorrhagic diathesis, including blood clotting disorders and high risk of bleeding;
– concomitant treatment with other non-steroidal anti-inflammatory drugs (NSAIDs) (including selective cyclooxygenase inhibitors), acetylsalicylic acid, warfarin, pentoxifylline, probenecid or lithium salts;
– hypovolemia, dehydration;
– the drug is contraindicated during labor and delivery;
– patients at risk of renal failure due to fluid depletion;
– epidural or intrathecal administration of the drug is contraindicated.
Interaction with other medicinal products and other types of interactions
Ketorolac is extensively bound to plasma proteins (average 99.2%). Ketorolac tromethamine does not alter the pharmacokinetics of other agents through enzyme induction or inhibition.
Warfarin, digoxin, salicylates and heparin.
Ketorolac tromethamine slightly reduced the plasma protein binding of warfarin in vitro and did not alter the plasma protein binding of digoxin. In vitro studies indicate that at therapeutic concentrations of salicylates (300 mcg/mL), ketorolac binding was reduced from approximately 99.2% to 97.5%, indicating a potential 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 tromethamine.
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 NSAIDs, it is not recommended to prescribe ketorolac tromethamine and acetylsalicylic acid simultaneously due to the potential increase in the frequency of adverse events.
Diuretics.
In some patients, ketorolac may reduce the natriuretic effect of furosemide and thiazides. During concomitant therapy with NSAIDs, the patient should be closely monitored for signs of renal failure and to ensure the effectiveness of the diuretic.
Probenecid.
Concomitant use of ketorolac tromethamine and probenecid resulted in a decrease in ketorolac clearance and a significant increase in its plasma levels and half-life. Therefore, concomitant use of ketorolac tromethamine and probenecid is contraindicated.
Lithium.
Patients should be closely monitored for signs of lithium toxicity when NSAIDs are used concomitantly with lithium. Increased plasma lithium concentrations have been reported with concomitant use of ketorolac.
Anticoagulants.
Ketorolac tromethamine should be administered with caution with anticoagulants, as concomitant administration may enhance the anticoagulant effect.
Cardiac glycosides.
NSAIDs may exacerbate heart failure, reduce glomerular filtration rate, and increase plasma levels of cardiac glycosides when used concomitantly with the latter.
Methotrexate.
Simultaneous 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 together with ACE inhibitors.
Anticonvulsants.
Isolated cases of seizures have been reported during concomitant use of ketorolac tromethamine and anticonvulsants (phenytoin, carbamazepine).
Psychotropic drugs.
With the simultaneous use of ketorolac and psychotropic drugs (fluoxetine, thiotexene, alprazolam), hallucinations have been reported.
Concomitant use of ketorolac tromethamine and pentoxifylline increases the risk of bleeding.
Non-depolarizing muscle relaxants.
No formal studies have been conducted on the concomitant use of ketorolac tromethamine and muscle relaxants. Cases of a possible interaction between ketorolac and non-depolarizing muscle relaxants resulting in apnea have been reported.
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 are at increased risk of seizures.
β-blockers.
Ketorolac and other NSAIDs weaken the hypotensive effect of β-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 concomitantly with zidovudine and ibuprofen.
Impact on laboratory test results.
Ketorolac inhibits platelet aggregation and may prolong bleeding time.
Application features
The likelihood of side effects can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms. Physicians should be aware that some patients may not experience pain relief until 30 minutes after intramuscular injection.
Combined use of ketorolac tromethamine intramuscularly and orally in adult patients should not exceed 5 days.
Impact on fertility.
Women who are unable to become pregnant and are undergoing evaluation for this should discontinue use of ketorolac tromethamine. Women of reduced fertility should avoid use of the drug.
Effect on the digestive tract.
Ketorolac tromethamine can cause serious gastrointestinal adverse reactions. These adverse reactions can occur at any time in patients taking ketorolac tromethamine, with or without warning symptoms, and can be fatal. The risk of clinically significant gastrointestinal bleeding is dose-related. However, adverse reactions can occur even with short-term therapy. In addition to a history of peptic ulcer disease, predisposing factors include concomitant use of oral corticosteroids, anticoagulants, long-term use of nonsteroidal anti-inflammatory drugs, smoking, alcohol consumption, advanced age, and poor general health. Most spontaneous reports of gastrointestinal events have occurred in elderly or debilitated patients, and caution should be exercised in these patients, and ketorolac should be discontinued if suspected. Patients at risk should be prescribed an alternative type of therapy that does not include nonsteroidal anti-inflammatory drugs (NSAIDs).
Effect on the circulatory system.
Concomitant use of ketorolac tromethamine in patients receiving anticoagulant therapy increases the risk of bleeding. Detailed studies of the simultaneous use of ketorolac and prophylactic low-dose heparin (2500-5000 IU every 12 hours) have not been conducted, therefore, with this regimen, the risk of bleeding should also be considered. Patients already taking anticoagulants or who require low-dose heparin should not receive ketorolac tromethamine. Patients taking other drugs that negatively affect hemostasis should be closely monitored when ketorolac tromethamine is administered. Ketorolac inhibits platelet aggregation and prolongs bleeding time. In patients with normal function, bleeding time was increased, but did not exceed the normal range of 2-11 minutes. Unlike the prolonged action after taking acetylsalicylic acid, platelet function returns to normal within 24-48 hours after discontinuation of ketorolac. Ketorolac tromethamine should not be used in patients undergoing surgery with a high risk of bleeding or incomplete hemostasis. Ketorolac tromethamine is not an anesthetic and does not have sedative or anxiolytic properties.
Use in patients with renal impairment (see Contraindications). Patients with less severe renal impairment should receive lower doses of ketorolac (not to exceed 60 mg/day, intramuscularly). The renal status of such patients should be closely 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 half-life was increased by almost threefold.
Effects on the cardiovascular system and cerebral vessels.
To minimize the risk of cardiovascular adverse events in patients receiving NSAIDs, the lowest effective dose should be used for the shortest duration possible. Ketorolac tromethamine 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 for 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 impaired liver function.
Ketorolac tromethamine should be administered with caution to patients with impaired hepatic function or a history of liver disease. Significant elevations (greater than three times the upper limit of normal) in serum ALT and AST have been observed in less than 1% of patients. In addition, there have been isolated reports of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, hepatic necrosis, and hepatic failure, some of which were fatal. Ketorolac should be discontinued if clinical signs of liver disease or systemic manifestations (e.g., eosinophilia, rash) develop.
Nonsteroidal anti-inflammatory drugs 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 elderly patients. Hypovolemia should be corrected before starting ketorolac. Use in patients with systemic lupus erythematosus or connective tissue disease may be associated with an increased risk of aseptic meningitis. Serious skin reactions such as exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. The risk of these reactions is highest at the beginning of treatment, with the first symptoms occurring in most cases within the first month of treatment. Patients should discontinue treatment at the first appearance of rash, mucosal lesions or other signs of hypersensitivity. Diuresis and renal function should be closely monitored in patients with cardiac, renal or hepatic insufficiency receiving diuretics or in patients with hypovolemia after surgery. The total dose for patients over 65 years of age should not exceed 60 mg. Cases of fluid retention, edema, NaCl retention, oliguria, increased serum urea nitrogen and creatinine levels have been reported with ketorolac, so ketorolac should be used with caution in patients with cardiac decompensation, arterial hypertension and similar conditions.
This medicine contains a small amount of ethanol (alcohol), less than 100 mg/dose.
This medicinal product contains less than 1 mmol (23 mg) sodium/dose, i.e. essentially 'sodium-free'.
Use during pregnancy or breastfeeding
Due to the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system, ketorolac should not be used during pregnancy (especially in the third trimester). The use of ketorolac tromethamine is contraindicated during pregnancy, labor and delivery.
Do not use during breastfeeding due to the possible negative effects of prostaglandin synthesis inhibitors on infants.
Ability to influence reaction speed when driving vehicles or other mechanisms
During the treatment period, it is necessary to refrain from potentially dangerous activities that require increased attention and speed of psychomotor reactions due to the possible development of adverse reactions from the nervous system.
Method of administration and doses
After intramuscular 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 intramuscular administration of multiple daily doses of ketorolac 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 intramuscular administration, patients no longer needed analgesic therapy. The likelihood of side effects can be minimized by using the lowest effective dose for the shortest period of time necessary to control symptoms. The drug should not be administered epidurally or intraspinally.
Adults.
The recommended initial dose of ketorolac tromethamine, solution for intramuscular injection, is 10 mg, followed by 10-30 mg every 4-6 hours (if necessary). In the initial postoperative period, ketorolac tromethamine 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 body weight less than 50 kg. The maximum duration of treatment should not exceed 2 days. The dose should be reduced in patients weighing less than 50 kg. Concomitant use of opioid analgesics (morphine, pethidine) is possible. Ketorolac does not negatively affect the binding of opioid receptors and does not increase the respiratory depression or sedative effect of opioid drugs. For parenterally treated patients who are switched to oral ketorolac tromethamine tablets, the total combined daily dose should not exceed 90 mg (60 mg for elderly patients, patients with renal impairment, and patients weighing less than 50 kg), and on the day of the change, the dose of the oral component should not exceed 40 mg. Patients should be switched to the oral formulation as soon as possible.
Elderly patients.
It is recommended that patients aged 65 years and over should be prescribed the lower end of the dosage range. The total daily dose should not exceed 60 mg.
Patients with renal impairment.
Ketorolac is contraindicated in moderate to severe renal impairment. In less severe impairment, the dose should be reduced (not higher than 60 mg/day intramuscularly).
Children
Do not use in children under 16 years of age.
Overdose
Symptoms: lethargy, drowsiness, nausea, vomiting, epigastric pain, gastrointestinal bleeding, hypertension, acute renal failure, respiratory depression and coma. Anaphylactoid reactions have been reported. Metabolic acidosis has been observed after intentional overdose.
Treatment. Symptomatic and supportive therapy. There is no specific antidote. If symptoms of overdose occur after taking the drug or after a large overdose (when taking an oral dose that is 5-10 times higher than usual) within 4 hours, the patient should be induced to vomit, activated charcoal (60-100 g for adults) and/or an osmotic laxative should be administered. Forced diuresis, urine alkalization, hemodialysis or blood transfusion are ineffective due to the high binding of the drug to blood plasma proteins. Single overdoses of ketorolac at different times have led to abdominal pain, nausea, vomiting, hyperventilation, peptic ulcers and/or erosive gastritis, and impaired renal function, which resolved after drug withdrawal.
Adverse reactions
On the part of the digestive system: nausea, vomiting, dyspepsia, 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, unconscious states, pathological thinking.
Cardiovascular: bradycardia, hot flushes, purpura, pallor, palpitations, chest pain. There have been reports of edema, hypertension, and heart failure associated with the use of nonsteroidal anti-inflammatory drugs. Increased risk of arterial thromboembolic complications, such as myocardial infarction or stroke.
Respiratory tract: bronchospasm, dyspnea, pulmonary edema, laryngeal edema, bronchial asthma, exacerbation of bronchial 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 maculopapular rashes), purpura, exfoliative dermatitis (hyperemia, thickening or peeling of the skin, enlargement and/or tenderness of the palatine 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, skin itching, tachypnea or dyspnea, eyelid edema, periorbital edema, shortness of breath, difficulty breathing, chest tightness, wheezing, 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: sweating, edema, myalgia, tenderness, changes at the injection site.
Changes in laboratory parameters: eosinophilia, increased activity of hepatic transaminases.
Others: swelling of the face, lower legs, fingers, feet, swelling of the tongue, weight gain, increased sweating, fever with or without chills, anorexia.
Expiration date
3 years.
Storage conditions
Store out of the reach of children in the original packaging at a temperature not exceeding 25 ºС.
Incompatibility
Do not mix in the same container with other medicines.
Packaging
1 ml in dark glass ampoules. 10 ampoules together with instructions for medical use in a blister. Blisters in group packaging.
Vacation category
According to the recipe.
Producer
Dr. Reddy's Laboratories Ltd., India.
Location of the manufacturer and its business address
Plot No. 137, 138 and 146, S. V. Cooperative Industrial Estate, Bolaram, Jinaram Mandal, Medak District, Andhra Pradesh, India.
