INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KETOROL (KETOROL)

Composition:

Active ingredient: ketorolac;

1 ml of solution contains 30 mg of ketorolac tromethamine;

Excipients: anhydrous ethanol, sodium chloride, disodium edetate, octoxynol 9, sodium hydroxide, propylene glycol, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless to pale yellow liquid, in 1 ml vials of USP Type I.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents. ATC code M01AB15.

Pharmacological properties.

Pharmacodynamics.

Ketorolac tromethamine is a non-opioid nonsteroidal anti-inflammatory drug that demonstrates analgesic activity. Its mechanism of action is mediated by non-selective inhibition of cyclooxygenase 1 and 2, predominantly in peripheral tissues, thereby suppressing the biosynthesis of prostaglandins—mediators of pain sensitivity, thermoregulation, and inflammation. Ketorolac is a racemic mixture of [–] S and [+] R enantiomers; its analgesic effect is mediated by the [–] S form. The analgesic effect is comparable to that of morphine and significantly exceeds the effect of other nonsteroidal anti-inflammatory drugs. The drug does not affect opioid receptors, does not suppress respiration, does not cause narcotic dependence, and does not exhibit sedative or anxiolytic effects. After oral administration, onset of analgesic effect occurs within 0.5 hours, with maximum effect achieved within 1–2 hours. The analgesic dose of ketorolac also exerts anti-inflammatory action.

Pharmacokinetics.

Absorption. Bioavailability ranges from 50% to 100%. After intramuscular administration, ketorolac is rapidly and completely absorbed. The mean peak plasma concentration of 2.2 µg/mL is reached on average within 50 minutes after a single 30 mg dose.

Linear pharmacokinetics.

In adults, following intramuscular administration of ketorolac tromethamine within the recommended dosage range, the clearance of the racemate remains unchanged. This indicates that the pharmacokinetics of ketorolac tromethamine in adults after single or multiple intramuscular doses is linear. At higher recommended doses, a proportional increase in concentrations of both free and bound racemate is observed.

Distribution. 99% of the drug is bound to plasma proteins; in hypoalbuminemia, the amount of free drug in the blood tends to increase.

The volume of distribution ranges from 0.15 to 0.33 L/kg. In subjects with renal impairment, the volume of distribution may be doubled; the volume of distribution of its R-enantiomer may increase by 20%. The drug poorly penetrates the blood-brain barrier. Ketorolac crosses the placenta and is excreted in small amounts into breast milk. More than 99% of ketorolac in plasma is protein-bound across a wide concentration range.

Metabolism. Ketorolac tromethamine is extensively metabolized in the liver (more than 50% of the dose), forming pharmacologically inactive metabolites. The main metabolites are glucuronides, excreted in urine, and p-hydroxyketorolac.

Excretion. The primary route of elimination of ketorolac and its metabolites is renal. Approximately 92% of the administered dose is recovered in urine: 40% as metabolites and 60% as unchanged ketorolac. Approximately 6% of the dose is excreted in feces. In a study of a single 10 mg dose of ketorolac (n = 9), it was demonstrated that the S-enantiomer is eliminated twice as fast as the R-enantiomer, and clearance is independent of the route of administration. This implies that the plasma concentration ratio of S-enantiomer to R-enantiomer decreases over time after each dose. Differences between S- and R-forms in the human body are negligible or absent.

The elimination half-life (T_1/2) of the drug in patients with normal renal function averages 5.3 hours (3.5–9.2 hours after intramuscular administration of 30 mg; 4–7.9 hours after intravenous administration of a 30 mg dose). T_1/2 is longer in elderly individuals and shorter in younger subjects. Hepatic function does not affect T_1/2. In individuals with impaired renal function and plasma creatinine levels of 19–50 mg/L (168–442 µmol/L), T_1/2 ranges from 10.3 to 10.8 hours; in cases of more severe renal insufficiency, it exceeds 13.6 hours.

Total clearance after intramuscular administration of 30 mg is 0.023 L/kg/h (0.019 L/kg/h in elderly patients); in subjects with renal impairment and plasma creatinine clearance of 19–50 mg/L, clearance after intramuscular administration of 30 mg is 0.015 L/kg/h. The drug is not removed by hemodialysis.

Accumulation. Ketorolac tromethamine administered intravenously as a bolus every 6 hours for 5 days to healthy volunteers (n = 13) did not show significant differences between day 1 and day 5. Trough levels averaged 0.29 µg/mL (standard deviation (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 patients, children, patients with renal or hepatic impairment) has not been studied.

Pharmacokinetics in specific patient populations.

Elderly patients. Data obtained after single-dose administration show that the elimination half-life of ketorolac tromethamine racemate increases from 5 to 7 hours in elderly patients (65–78 years) compared to younger healthy volunteers (24–35 years).

Children. Pharmacokinetic data on intramuscular administration of ketorolac tromethamine in children are lacking.

Renal impairment. Data from single-dose administration studies indicate that the mean elimination half-life of ketorolac tromethamine in patients with impaired renal function ranges from 6 to 19 hours, depending on the severity of impairment. The correlation between creatinine clearance and total clearance of ketorolac tromethamine in elderly patients and those with renal impairment is weak (r = 0.5). In patients with renal disease, AUC₈ values for each enantiomer are nearly doubled compared to healthy volunteers. The volume of distribution doubles for the S-enantiomer and increases by 1/5 for the R-enantiomer. The increased volume of distribution of ketorolac tromethamine indicates an increased unbound fraction.

Hepatic impairment. Values of elimination half-life, AUC₈, and C_max in 7 patients with liver disease did not differ significantly from those in healthy volunteers.

Clinical characteristics.

Indications.

For the short-term management of moderate to severe postoperative pain.

Contraindications.

Hypersensitivity to ketorolac or to any other component of the medicinal product;
intolerance to acetylsalicylic acid or other nonsteroidal anti-inflammatory drugs (NSAIDs), particularly in the patient's history;
recurrent nasal and paranasal polyposis;
erosive and ulcerative gastrointestinal and duodenal lesions; active peptic ulcer, active gastrointestinal bleeding; recent gastrointestinal bleeding or perforation, history of peptic ulcer or gastrointestinal bleeding;
bronchial asthma, rhinitis, angioneurotic edema, or urticaria induced by acetylsalicylic acid or other NSAIDs (due to the possibility of severe anaphylactic reactions);
history of bronchial asthma;
should not be used as an analgesic before and during surgery due to increased risk of bleeding;
severe heart failure; period following coronary artery bypass grafting;
complete or partial syndrome of nasal polyps, Quincke's edema, or bronchospasm;
should not be administered to patients who have undergone surgical procedures with a high risk of bleeding or incomplete hemostasis, and to patients receiving anticoagulants, including low-dose heparin (2500–5000 units every 12 hours);
severe hepatic insufficiency or active liver disease;
progressive renal disease; moderate or severe renal insufficiency (creatinine clearance < 30 mL/min);
suspected or confirmed cerebrovascular hemorrhage or other bleeding, confirmed or suspected intracranial hemorrhage; hemorrhagic diathesis, including coagulation disorders and high risk of bleeding, hemophilia, and other coagulation disorders;
inflammatory bowel diseases (ulcerative colitis, Crohn's disease) in the acute phase;
concomitant therapy with other NSAIDs (including selective cyclooxygenase inhibitors), acetylsalicylic acid, anticoagulants, including warfarin and heparin, pentoxifylline, probenecid, or lithium salts;
concomitant use with oxpentifylline;
hypovolemia, dehydration;
confirmed hyperkalemia;
pregnancy or breastfeeding;
contraindicated during labor and delivery;
contraindicated in patients at risk of renal failure due to reduced fluid volume;
contraindicated for epidural or intrathecal administration;
contraindicated for pediatric use (under 16 years of age).

The drug should not be used for the treatment of chronic pain.

Interaction with other medicinal products and other forms of interaction.

Ketorolac is highly bound to plasma proteins (on 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 protein binding of warfarin in vitro and did not alter the protein binding of digoxin. In vitro studies indicate that at therapeutic salicylate concentrations (300 mcg/mL), ketorolac binding decreased from approximately 99.2% to 97.5%, suggesting a potential doubling of unbound ketorolac levels in plasma. Therapeutic concentrations of digoxin, warfarin, ibuprofen, naproxen, piroxicam, acetaminophen, phenytoin, and tolbutamide do not alter the protein binding of ketorolac tromethamine.

Acetylsalicylic acid

When used with acetylsalicylic acid, the protein binding of ketorolac is reduced, although the clearance of free ketorolac remains unchanged. The clinical significance of this interaction is unknown; however, as with other NSAIDs, concomitant administration of ketorolac tromethamine and acetylsalicylic acid is not recommended due to the potential increased frequency of adverse effects, particularly gastrointestinal ulcers and gastrointestinal bleeding.

Diuretics

In some patients, ketorolac may reduce the natriuretic effect of furosemide and thiazides (due to decreased renal prostaglandin synthesis). During concomitant therapy with NSAIDs, patients should be closely monitored for signs of renal impairment and to ensure the effectiveness of diuretic agents.

Probenecid

Concomitant use of ketorolac tromethamine and probenecid results in decreased ketorolac clearance and significant elevation of its plasma levels and half-life. Therefore, concomitant use of ketorolac tromethamine and probenecid is contraindicated.

Lithium

Patients receiving NSAIDs and lithium preparations should be closely monitored for signs of lithium toxicity, as ketorolac may reduce lithium clearance. Increased plasma lithium concentrations have been reported with concomitant use of ketorolac.

Anticoagulants, antiplatelet agents, thrombolytics

Ketorolac tromethamine should be used cautiously with anticoagulants, antiplatelet agents, and thrombolytics, as concomitant use may enhance anticoagulant effects and increase the risk of bleeding.

The risk of gastrointestinal bleeding increases when antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs) are combined with NSAIDs.

Cardiac glycosides

NSAIDs may exacerbate heart failure, reduce glomerular filtration rate, and increase plasma levels of cardiac glycosides when used concomitantly.

Methotrexate

Concomitant use with methotrexate increases hepatotoxicity and nephrotoxicity. Concomitant use of ketorolac and methotrexate is possible only if methotrexate is administered in low doses (plasma methotrexate levels should be monitored).

ACE inhibitors

Concomitant use of angiotensin-converting enzyme (ACE) inhibitors increases the risk of renal function impairment, particularly in patients with reduced extracellular fluid volume.

NSAIDs may reduce the antihypertensive effect of ACE inhibitors. This interaction should be considered 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 agents

Hallucinations have been reported with concomitant use of ketorolac and psychotropic agents (fluoxetine, thiothixene, alprazolam).

Pentoxifylline, oxpentifylline

Concomitant use of ketorolac tromethamine and pentoxifylline or oxpentifylline increases the risk of bleeding.

Non-depolarizing muscle relaxants

No formal studies on the concomitant use of ketorolac tromethamine and muscle relaxants have been conducted. Studies have not shown evidence that ketorolac tromethamine induces or inhibits liver enzymes capable of metabolizing it or other drugs. Therefore, ketorolac is not expected to alter the pharmacokinetics of other drugs via enzyme induction or inhibition. NSAIDs may reduce the elimination of baclofen (increased risk of toxicity).

Cyclosporine

As with all NSAIDs, concomitant use of cyclosporine should be done with caution due to an increased risk of nephrotoxic effects.

Mifepristone

NSAIDs should not be used within 8–12 days after mifepristone administration, as they may reduce the efficacy of mifepristone.

Corticosteroids

As with all NSAIDs, concomitant use of corticosteroids should be done with caution due to an increased risk of gastrointestinal ulcers and gastrointestinal bleeding.

Quinolones

Patients taking quinolones have an increased risk of seizures.

β-blockers

Ketorolac and other NSAIDs reduce the antihypertensive effect of β-blockers.

Angiotensin-II receptor antagonists

Ketorolac and other NSAIDs reduce the antihypertensive effect of angiotensin-II receptor antagonists.

Verapamil, nifedipine

Ketorolac may increase plasma levels of verapamil and nifedipine.

Antiviral agents

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 who are treated concomitantly with zidovudine and ibuprofen. Ritonavir may increase NSAID plasma concentrations.

Tacrolimus

NSAIDs increase the risk of nephrotoxicity.

Valproic acid

Concomitant use with valproic acid impairs platelet aggregation.

Opioid analgesics

When combined with opioid analgesics, doses of the latter may be significantly reduced.

Paracetamol

Concomitant use of ketorolac with paracetamol increases nephrotoxicity.

Calcium preparations

There is an increased risk of gastrointestinal ulcers and gastrointestinal bleeding.

Hypoglycemic (antidiabetic) medicinal products

Ketorolac enhances the hypoglycemic effect of insulin and oral hypoglycemic agents (dose adjustment required).

Antacids

Concomitant use of antacids does not affect the extent of drug absorption.

Alcohol

Concomitant use of ketorolac with ethanol may cause gastrointestinal ulcers and gastrointestinal bleeding.

Effect on laboratory test results

Ketorolac inhibits platelet aggregation and may prolong bleeding time.

Animal study data indicate that NSAIDs increase the risk of seizures associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing seizures.

Special precautions for use.

Use with caution in the following cases:

presence of factors increasing gastrointestinal (GI) tract toxicity, such as history of GI ulceration, Helicobacter pylori infection, prolonged use of NSAIDs;
alcoholism, smoking, cholecystitis; cholestasis; active hepatitis, sepsis;
postoperative period;
advanced age (>65 years);
dyslipidemia/hyperlipidemia; diabetes mellitus;
hypertension, ischemic heart disease, cerebrovascular diseases, chronic heart failure, edema syndrome;
peripheral arterial diseases, severe somatic diseases, thyroid disorders;
moderate renal impairment (creatinine clearance 30–60 mL/min);
systemic lupus erythematosus;
tuberculosis.

Warnings and precautions for use

Hypovolemia increases the risk of renal adverse reactions.
Combination with opioid analgesics may be considered if necessary.
The drug is not recommended for premedication or for anesthesia maintenance.
Patients with coagulation disorders should receive the drug under constant monitoring of platelet count, especially in the postoperative period, which requires careful hemostasis control.
The risk of drug-related complications increases with prolonged therapy (in patients with chronic pain) and with doses exceeding 40 mg per day. To minimize the risk of NSAID-induced gastropathy, use of antacids, misoprostol, or omeprazole is recommended.

Concomitant use of oral glucocorticosteroids (including prednisolone), antiplatelet agents (including clopidogrel), and selective serotonin reuptake inhibitors (including citalopram, fluoxetine, paroxetine, sertraline) increases the risk of gastrointestinal ulcers and GI bleeding.

The likelihood of adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms. Physicians should be aware that analgesia may occur only 30 minutes after intramuscular administration in some patients.

Combined intramuscular and oral administration of ketorolac tromethamine in adult patients should not exceed 5 days.

Effect on fertility.

Ketorolac tromethamine should be discontinued in women undergoing fertility investigations due to inability to conceive. Women with reduced fertility should avoid using the drug.

Effect on the gastrointestinal tract.

Ketorolac tromethamine may cause severe adverse reactions in the gastrointestinal tract. These adverse events may occur at any time during treatment, with or without preceding symptoms, and may be fatal. The risk of clinically significant GI bleeding is dose-dependent. However, adverse effects may occur even during short-term therapy. In addition to a history of peptic ulcer disease, predisposing factors include concomitant use of oral corticosteroids, anticoagulants, prolonged NSAID therapy, smoking, alcohol consumption, advanced age, and poor general health. Most spontaneous reports of GI events involved elderly or debilitated patients; therefore, special attention should be paid when treating such patients, and ketorolac should be discontinued if any suspicion arises. Alternative therapy not involving NSAIDs should be considered for high-risk patients.

NSAIDs, including ketorolac, may be associated with an increased risk of gastrointestinal anastomotic dehiscence. Careful medical supervision and caution are recommended when using ketorolac after gastrointestinal surgery.

Effect on the blood system.

Concomitant use of ketorolac tromethamine in patients receiving anticoagulant therapy increases the risk of bleeding. Detailed studies on the simultaneous use of ketorolac and prophylactic low-dose heparin (2500–5000 IU every 12 hours) have not been conducted; therefore, the risk of bleeding should also be considered with this regimen. Patients already taking anticoagulants or requiring low-dose heparin should not receive ketorolac tromethamine. Close monitoring is required in patients receiving other agents affecting hemostasis during ketorolac tromethamine administration. Ketorolac inhibits platelet aggregation and prolongs bleeding time. In patients with normal bleeding function, bleeding time increased but did not exceed the normal range of 2–11 minutes. Unlike the prolonged effect after acetylsalicylic acid intake, platelet function returns to normal within 24–48 hours after discontinuation of ketorolac. Ketorolac tromethamine should not be used in patients who have undergone surgery with high risk of bleeding or incomplete hemostasis. Ketorolac is not an anesthetic and has no sedative or anxiolytic properties.

Use in patients with impaired renal function (see "Contraindications"). Patients with mild to moderate renal impairment should receive lower doses of ketorolac (no more than 60 mg/day intramuscularly). Close monitoring of renal function in such patients is required. Patients should be well hydrated before starting treatment. In patients undergoing hemodialysis, ketorolac clearance was reduced by approximately half compared to normal rates, and terminal half-life was nearly tripled.

Effect on the cardiovascular system and cerebral vessels.

Close monitoring is required in patients with arterial hypertension and/or a history of mild to moderate heart failure.

To minimize the risk of cardiovascular complications in patients using NSAIDs, the lowest effective dose for the shortest possible duration should be used. 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 benefits and risks. Similarly, the appropriateness of prescribing ketorolac should be evaluated before initiating long-term treatment in patients at risk of cardiovascular disease (e.g., those with hypertension, hyperlipidemia, diabetes mellitus, or smokers).

Respiratory system.

Monitor patients for possible development of bronchospasm.

Use in patients with impaired liver function.

Ketorolac tromethamine should be used cautiously in patients with impaired liver function or a history of liver disease. Marked elevations (more than three times above normal) of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been observed in less than 1% of patients. Additionally, isolated cases of severe hepatic reactions, including jaundice, fatal fulminant hepatitis, liver necrosis, and liver failure (some fatal), have been reported. Ketorolac should be discontinued if clinical signs of liver disease or systemic manifestations (e.g., eosinophilia, rash) appear.

NSAIDs should be used cautiously in patients with Crohn's disease or a history of ulcerative colitis due to the potential for worsening of the disease. Clinical and epidemiological data suggest that use of certain NSAIDs, especially at high doses and over prolonged periods, may be associated with a small increased risk of arterial thromboembolic complications such as myocardial infarction or stroke. Such a risk cannot be excluded for ketorolac. Like other NSAIDs, ketorolac inhibits prostaglandin synthesis and may have nephrotoxic effects; therefore, it should be used cautiously in patients with impaired renal function or a history of kidney disease. Risk groups include patients with impaired renal function, hypovolemia, heart failure, impaired liver function, those taking diuretics, and elderly patients. Hypovolemia should be corrected before initiating ketorolac therapy. Use of the drug in patients with systemic lupus erythematosus or connective tissue diseases 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 highest risk of these reactions occurs early in treatment, with most cases appearing within the first month of therapy. Patients should discontinue the drug at the first sign of rash, mucosal lesions, or other signs of hypersensitivity. Careful monitoring of diuresis and renal function is required when treating patients with cardiac, renal, or hepatic insufficiency who are taking diuretics, or post-surgical patients with hypovolemia. The total dose in patients over 65 years of age should not exceed 60 mg. Cases of fluid retention, edema, sodium chloride retention, oliguria, elevated blood urea nitrogen, and creatinine levels have been reported with ketorolac use; therefore, ketorolac should be used cautiously in patients with decompensated heart failure, arterial hypertension, and similar conditions.

This medicinal product contains a small amount of ethanol (alcohol), less than 100 mg per dose.

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy

The drug is contraindicated during pregnancy.

From the 20th week of pregnancy, use of ketorolac may cause oligohydramnios due to renal dysfunction and adversely affect the fetal cardiovascular system. This condition may occur shortly after starting treatment and is usually reversible upon discontinuation.

The drug should not be prescribed during the first and second trimesters of pregnancy unless clearly necessary. If the drug is used by a woman attempting to conceive or during the first and second trimesters of pregnancy, the dose should be as low as possible and the duration of treatment as short as possible.

Fetal monitoring for oligohydramnios should be considered after drug exposure over several days starting from the 20th gestational week. The drug should be discontinued if oligohydramnios is detected.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may cause:

Risks to the fetus:

cardiopulmonary toxicity (premature closure of the ductus arteriosus and pulmonary hypertension);
renal dysfunction (which may progress to renal failure with oligohydramnios (see above));

Risks to the mother at the end of pregnancy and to the newborn:

possible prolongation of bleeding time, anti-aggregatory effect, which may occur even at very low doses;
inhibition of uterine contractions, leading to delayed or prolonged labor.

Breastfeeding

Ketorolac is contraindicated during breastfeeding. The drug is excreted in breast milk.

Do not use during breastfeeding due to the potential negative effects of prostaglandin synthesis inhibitors on infants.

Ability to affect reaction speed when driving or operating machinery.

During treatment, patients should refrain from potentially hazardous activities requiring high attention and rapid psychomotor reactions (such as driving vehicles or operating machinery) due to possible adverse reactions affecting the nervous system (such as drowsiness, dizziness, fatigue, visual disturbances, headache, vertigo, insomnia, or depression).

Method of Administration and Dosage.

It is recommended to use the drug in a hospital setting. For intramuscular or intravenous use only. Ketorolac tromethamine must not be administered epidurally or intraspinally.

Analgesic effect is observed approximately 30 minutes after intramuscular or intravenous administration, with maximum pain relief occurring within 1–2 hours. Overall, the average duration of analgesia is 4–6 hours. The dose should be adjusted according to the severity of pain and the patient's response to treatment. Repeated intramuscular administration of multiple daily doses of ketorolac should not exceed 2 days, as prolonged use increases the risk of adverse reactions. Experience with long-term use is limited, since most patients are either switched to oral medication or no longer require analgesic therapy after the intramuscular phase. The likelihood of adverse effects can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms. The drug must not be administered epidurally or intraspinally.

Adults.

The recommended initial dose of ketorolac tromethamine injection solution is 10 mg, followed by doses of 10–30 mg every 4–6 hours (as needed). In the immediate postoperative period, ketorolac tromethamine may be administered every 2 hours if necessary. The lowest effective dose should be prescribed.

Intramuscular administration.

Administer via deep intramuscular injection. For adult patients under 65 years of age without renal impairment – 10–30 mg, followed by 10–30 mg every 4–6 hours. For patients aged 65 years and older and those with renal impairment (creatinine clearance above 30 mL/min – see section "Contraindications") – 10–15 mg every 4–6 hours.

Intravenous administration.

For adult patients under 65 years of age without renal impairment – 10–30 mg as a slow (over at least 15 seconds) intravenous injection, followed by 10–30 mg every 6 hours. When using an infusion pump for continuous intravenous infusion, the initial dose is 30 mg, followed by an infusion rate of 5 mg/hour.

For patients aged 65 years and older and those with renal impairment (creatinine clearance above 30 mL/min – see section "Contraindications") – 10–15 mg as a slow intravenous injection every 6 hours.

Intravenous administration must not exceed 24 hours.

The total daily dose must not exceed 90 mg for younger patients, and 60 mg for elderly patients, patients with renal insufficiency, and those weighing less than 50 kg. The maximum duration of treatment must not exceed 2 days. The dose should be reduced for patients weighing less than 50 kg. Concomitant use of opioid analgesics (morphine, pethidine) is possible. Ketorolac has no negative effect on opioid receptor binding and does not potentiate respiratory depression or sedative effects of opioid drugs. For patients receiving parenteral administration and being switched to oral ketorolac tromethamine tablets, the total combined daily dose must not exceed 90 mg (60 mg for elderly patients, patients with renal impairment, and those weighing less than 50 kg). On the day of switching formulations, the oral component dose must not exceed 40 mg. Patients should be switched to oral therapy as soon as possible.

Ketorolac injection solution must not be mixed in the same syringe with morphine sulfate, promethazine, or hydroxyzine due to precipitate formation.

The product is pharmaceutically incompatible with tramadol solution and lithium-containing products.

Ketorolac injection solution is compatible with normal saline, 5% dextrose solution, Ringer's solution, lactated Ringer's solution, aqueous solution "Plasma-Lyte 148", and infusion solutions containing aminophylline, lidocaine hydrochloride, dopamine hydrochloride, short-acting insulin, and sodium heparin.

Elderly patients.

For patients aged 65 years and older, the lowest possible dose is recommended. The total daily dose must not exceed 60 mg.

Patients with renal impairment.

Ketorolac is contraindicated in moderate to severe renal impairment. In milder forms of renal dysfunction, the dose should be reduced (not exceeding 60 mg/day intramuscularly).

Children. Not to be used in children under 16 years of age.

Overdose.

Symptoms: depressed consciousness, lethargy, agitation, confusion, tinnitus, unconsciousness, seizures, somnolence, nausea, vomiting, headache, epigastric pain, abdominal pain, tachypnea, peptic ulcers and/or erosive gastritis, diarrhea, gastrointestinal bleeding, arterial hypertension, renal dysfunction, acute renal failure, respiratory depression, and coma. Anaphylactoid reactions have been reported. Metabolic acidosis has been observed following intentional overdose.

Treatment. Symptomatic and supportive therapy. There is no specific antidote. The patient should be monitored in a medical facility. Dialysis removes ketorolac from the bloodstream only to a minor extent. Adequate diuresis should be maintained. Renal and hepatic function should be monitored. Intravenous diazepam may be used in cases of frequent or prolonged seizures.

In the presence of overdose symptoms after drug administration or following a significant overdose (oral dose 5–10 times higher than usual), within 4 hours, induce vomiting, administer activated charcoal (60–100 g for adults) and/or an osmotic laxative. Forced diuresis, urine alkalinization, hemodialysis, or blood transfusion are ineffective due to the high plasma protein binding of the drug. Single episodes of ketorolac overdose have caused abdominal pain, nausea, vomiting, hyperventilation, peptic ulcers and/or erosive gastritis, and renal dysfunction, which resolved after discontinuation of the drug.

Adverse Reactions.

Gastrointestinal system: erosive-ulcerative lesions of the gastrointestinal tract, ulcer perforation, bleeding (hematemesis, melena), sometimes with fatal outcome (especially in elderly patients) (see section "Special precautions"). The following adverse effects have been reported: nausea, vomiting, dyspepsia, discomfort in the abdomen, abdominal pain, spasm or burning sensation in the epigastric region, taste disturbances, diarrhea, dry mouth, thirst sensation, flatulence, constipation, acute pancreatitis, feeling of stomach fullness, esophagitis, belching, exacerbation of ulcerative colitis and Crohn's disease, ulcerative stomatitis, gastritis, cholestatic jaundice, hepatitis, hepatomegaly.

Central nervous system: drowsiness, difficulty concentrating, euphoria, headache, dizziness, anxiety, asthenic syndrome, paresthesia, insomnia, malaise, increased fatigue, excitement, unusual dreams, confusion, vertigo, hyperkinesia, seizures; aseptic meningitis (fever, severe headache, seizures, neck and/or back muscle rigidity), hyperactivity (mood changes, restlessness), hallucinations, depression, psychosis, loss of consciousness, pathological thinking.

Cardiovascular system: bradycardia, flushing, purpura, pallor, tachycardia, chest pain. Cases of edema, hypertension, heart failure, and pulmonary edema associated with the use of nonsteroidal anti-inflammatory drugs have been reported. Increased risk of arterial thromboembolic complications, such as myocardial infarction or stroke.

Hematopoietic system: anemia, aplastic anemia, hemolytic anemia, agranulocytosis, leukopenia, eosinophilia, thrombocytopenia, neutropenia.

Respiratory system: bronchospasm, rhinitis, dyspnea, pulmonary edema, laryngeal edema, bronchial asthma, exacerbation of bronchial asthma.

Urinary system: nephrotic syndrome, oliguria, dysuria, increased or decreased frequency of urination, hyponatremia, hyperkalemia, elevated creatinine and urea levels, interstitial nephritis, urinary retention, flank or back pain with or without hematuria or azotemia, acute renal failure, hematuria, azotemia, hemolytic-uremic syndrome (hemolytic anemia, renal failure, thrombocytopenia, purpura), renal-origin edema.

Skin: skin rashes (including maculopapular rashes), purpura, exfoliative dermatitis (with or without fever and chills, hyperemia, induration or desquamation of the skin, enlarged and/or painful palatine tonsils), urticaria, photosensitization, Stevens-Johnson syndrome (erythema multiforme major), Lyell's syndrome (toxic epidermal necrolysis), bullous reactions.

Musculoskeletal system: myalgia, functional disorders.

Hemostasis system: bleeding from postoperative wounds, epistaxis, rectal bleeding, prolonged bleeding time.

Reproductive system: female infertility.

Allergic reactions: anaphylaxis (may be fatal) or anaphylactoid reactions (facial skin discoloration, skin rashes, urticaria, itching, skin redness, tachypnea or dyspnea, eyelid swelling, periorbital edema, hypotension, laryngeal edema, shortness of breath, difficulty breathing, chest tightness, wheezing). These reactions may occur in patients with angioneurotic edema or bronchospastic reactivity (e.g., asthma, nasal polyps).

Sensory organs: hearing loss, tinnitus, vertigo, visual disturbances, blurred vision, optic neuritis, taste disturbances.

General disorders: sweating, edema, myalgia, pain, injection site reactions.

Injection site reactions: burning sensation, pain at the injection site.

Laboratory test abnormalities: prolonged bleeding time, increased serum urea levels, elevated creatinine levels, eosinophilia, increased liver transaminase activity.

Other disorders: facial, leg, finger, foot edema, tongue swelling, weight gain, increased sweating, fever with or without chills, anorexia, bruising, hyperkalemia, hyponatremia.

Reporting adverse reactions after drug registration is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua/.

Shelf life. 3 years.

Storage conditions. Store in a tightly closed original packaging, protected from light and out of reach of children, at a temperature not exceeding 25 ºC.

Incompatibility. Do not mix with other medicinal products in the same container. The product is pharmaceutically incompatible with tramadol solution and lithium-containing products.

Packaging. 1 ml in amber glass ampoules. 10 ampoules per blister pack with instructions for medical use. Blister packs in a carton box.

Prescription status. Prescription only.

Manufacturer.

Dr. Reddy’s Laboratories Limited.

Manufacturer’s address and site of manufacturing.

Manufacturing site – VI Village Khol, Nalagarh Road, Baddi, District Solan, Himachal Pradesh, 173205, India.