Ketorolac-zdorovia

INSTRUCTIONS FOR MEDICAL USE | consumption | of the medicinal product KETOROLAC-ZDOROVYE (KETOROLAC-ZDOROVYE)

Composition:

Active substance: 1 ml of solution contains ketorolac tromethamine 30 mg;

Excipients: sodium chloride, sodium metabisulfite (E 223), disodium edetate, benzyl alcohol, sodium hydroxide, water for injections.

Medicinal form. Injection solution.

Main physicochemical properties: clear colorless or slightly greenish-yellow solution.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents.

ATC code M01AB15.

Pharmacological properties.

Pharmacodynamics.

Ketorolac tromethamine is a non-steroidal anti-inflammatory drug (NSAID) that demonstrates 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-enantiomer. Ketorolac tromethamine does not possess sedative or anxiolytic properties.

The main difference between high and low doses of ketorolac lies in the duration of analgesia. The analgesic dose of ketorolac also exerts anti-inflammatory effects.

Pharmacokinetics.

Ketorolac tromethamine is a racemic mixture of [-]S- and [+]R-enantiomeric forms, with analgesic activity attributed to the S-form. 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, racemate clearance remains unchanged. This indicates that the pharmacokinetics of ketorolac tromethamine in adults after single or multiple intramuscular doses is linear. With higher recommended doses, a proportional increase in free and bound racemate concentrations is observed.

The drug poorly penetrates the blood-brain barrier. Ketorolac crosses the placenta and passes into breast milk in small amounts. More than 99% of ketorolac in plasma is protein-bound across a wide range of concentrations.

Table of approximate mean pharmacokinetic parameters (mean ± SD)

Metabolism. Ketorolac tromethamine is extensively metabolized in the liver. The metabolites are hydroxylated and conjugated forms of the parent drug. Metabolites and some unchanged drug are excreted in urine.

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 single-dose study of ketorolac 10 mg (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 indicates 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 T½ of the S-enantiomer of ketorolac tromethamine is approximately 2.5 hours (SD ± 0.4), and that of 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 tromethamine administered intravenously as a bolus every 6 hours for 5 days to healthy volunteers (n = 13) showed no significant difference between day 1 and day 5. Mean trough levels were 0.29 mcg/mL (SD ± 0.13) on day 1 and 0.55 mcg/mL (SD ± 0.23) on day 6. Steady state was achieved after the fourth dose. Accumulation of ketorolac tromethamine in specific patient populations (elderly patients, children, patients with renal or hepatic impairment) has not been studied.

Pharmacokinetics in specific patient populations.

Elderly patients. Based solely on data obtained after single-dose administration, the T½ of the ketorolac tromethamine racemate 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 lacking.

Renal impairment. Based solely on data obtained after single-dose administration, the mean T½ of ketorolac tromethamine in patients with impaired renal function ranges from 6 to 19 hours, depending on the severity of impairment. There is almost no 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, AUC8 values for each enantiomer increase by nearly 100% 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. T½, AUC8, and Cmax values in 7 patients with hepatic disease did not differ significantly from those in healthy volunteers.

Clinical characteristics.

Indications.

Management of moderate to severe postoperative pain for short-term use.

Contraindications.

• Hypersensitivity to any component of the drug.
• Patients with active peptic ulcer, recent gastrointestinal bleeding or perforation, or history of peptic ulcer or gastrointestinal bleeding.
• Existing or suspected gastrointestinal bleeding.
• Bronchial asthma, rhinitis, angioedema, or urticaria induced by acetylsalicylic acid or other NSAIDs (due to the possibility of severe anaphylactic reactions).
• History of bronchial asthma.
• Severe heart failure.
• Complete or partial nasal polyp syndrome, Quincke's edema, or bronchospasm.
• Should not be used in patients who have undergone surgery with high risk of bleeding or incomplete hemostasis, and in patients receiving anticoagulants, including low-dose heparin (2500–5000 IU every 12 hours).
• Hepatic or moderate to severe renal insufficiency (serum creatinine level > 160 μmol/L).
• Suspected or confirmed cerebrovascular hemorrhage, hemorrhagic diathesis, including coagulation disorders and high risk of bleeding.
• Concomitant therapy with other NSAIDs (including selective cyclooxygenase inhibitors), acetylsalicylic acid, warfarin, pentoxifylline, probenecid, or lithium salts.
• Hypovolemia, dehydration with risk of renal failure due to reduced fluid volume.
• The drug is contraindicated in colic.
• Epidural or intrathecal administration of the drug is contraindicated.
• Ketorolac is contraindicated for prophylactic use before surgical procedures, as it delays platelet aggregation and is also contraindicated during surgery due to increased risk of bleeding.

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 drugs via enzyme induction or inhibition.

Warfarin, digoxin, salicylates, and heparin. In vitro, ketorolac tromethamine slightly reduced the protein binding of warfarin and did not affect the protein binding of digoxin. In vitro studies indicate that at therapeutic salicylate concentrations (300 μg/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. Concomitant use of ketorolac and prophylactic low-dose heparin (2500–5000 IU every 12 hours) has not been widely studied but may be associated with an increased risk of bleeding. Ketorolac should not be administered to patients receiving anticoagulants or low-dose heparin.

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs). Increased risk of gastrointestinal bleeding (see section "Special precautions").

Acetylsalicylic acid. When used with acetylsalicylic acid, the protein binding of ketorolac decreases, 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 for increased incidence of adverse effects.

Diuretics. In some patients, ketorolac may reduce the natriuretic effect of furosemide and thiazides. Patients receiving concomitant therapy with NSAIDs should be closely monitored for signs of renal impairment and to ensure the efficacy of diuretic agents (see section "Special precautions"). In healthy volunteers with normal blood volume, ketorolac reduces the diuretic effect of furosemide by approximately 20%; therefore, special caution is required when prescribing ketorolac to patients with heart failure.

Probenecid. Concomitant use of ketorolac tromethamine and probenecid results in reduced clearance of ketorolac and significant increases in its plasma levels and half-life (T½). Therefore, concomitant use of ketorolac tromethamine and probenecid is contraindicated.

Pentoxifylline. Not recommended due to increased risk of hemorrhage.

Lithium. Concomitant use of NSAIDs and lithium preparations is contraindicated.

Opioid analgesics. The effect of opioid analgesics is enhanced, allowing for dose reduction when used for pain relief.

Anticoagulants. Concomitant use with anticoagulants may increase bleeding risk. Concomitant use with anticoagulants (such as warfarin) is contraindicated.

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

Methotrexate. Should be co-administered with caution; possible increased methotrexate toxicity due to impaired renal function.

ACE inhibitors. Concomitant use of ACE inhibitors increases the risk of renal dysfunction, 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 during concomitant use of ketorolac and psychotropic agents (fluoxetine, thiothixene, alprazolam).

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

Nondepolarizing muscle relaxants. No official studies on concomitant use of ketorolac tromethamine and muscle relaxants have been conducted. Animal and human studies have shown no 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 (increasing the risk of toxicity).

Cyclosporine. As with all NSAIDs, concomitant administration with cyclosporine should be done with caution due to increased risk of nephrotoxicity.

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

Corticosteroids. As with all NSAIDs, concomitant administration with corticosteroids should be done with caution due to increased risk of gastrointestinal bleeding.

Quinolones. Patients taking quinolones may 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.

Sulfonylurea derivatives. NSAIDs may enhance the effect of sulfonylurea derivatives.

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 may increase the risk of nephrotoxicity.

Garlic, onion, and Ginkgo biloba-containing products may enhance the effect of ketorolac and increase the risk of hemorrhagic complications.

When ketorolac is used to relieve postoperative pain, the need for concomitant opioid analgesics is reduced.

Effect on laboratory test results.

Ketorolac inhibits platelet aggregation and may prolong bleeding time.

Special precautions for use.

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 in some patients, analgesia may occur only 30 minutes after intramuscular administration. Concomitant use of ketorolac and other NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors, should be avoided (see section "Contraindications").

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 infertility investigations who are unable to conceive. Women with reduced fertility should avoid using this medication.

Gastrointestinal effects. Ketorolac tromethamine may cause gastrointestinal bleeding, ulceration, and perforation. The risk of these adverse reactions is higher in patients with a history of peptic ulcer, especially if complicated by bleeding or perforation (see section "Contraindications"), as well as in elderly patients. These adverse events may occur at any time during treatment, with or without preceding symptoms, and may be fatal. Epidemiological data suggest that, compared to some other NSAIDs, use of ketorolac (particularly off-label and/or prolonged use) may be associated with an increased risk of gastrointestinal complications (see sections "Indications", "Contraindications", "Dosage and administration"). The risk of clinically significant gastrointestinal bleeding is dose-dependent. However, adverse effects may occur even with short-term therapy. Treatment in such patients should begin with the lowest possible NSAID dose. In these cases, as well as when using low-dose acetylsalicylic acid or other medications that may increase gastrointestinal adverse event risk, careful consideration should be given to combining NSAIDs with gastroprotective agents such as misoprostol or a proton pump inhibitor (see section "Interaction with other medicinal products and other forms of interaction").

Additional risk factors include concomitant use of oral corticosteroids or anticoagulants, prolonged NSAID therapy (see section "Interaction with other medicinal products and other forms of interaction"), smoking, alcohol consumption, advanced age, and poor general health. Most spontaneous reports of gastrointestinal adverse events involve elderly or debilitated patients; therefore, special attention should be paid to these patients, and ketorolac should be discontinued if any suspicion arises. Alternative therapies not involving NSAIDs should be considered for high-risk patients. Patients (especially elderly) with a history of gastrointestinal disorders should report any abdominal symptoms (particularly gastrointestinal bleeding). Such symptoms require close monitoring, especially at the beginning of treatment.

Ketorolac use is contraindicated in patients receiving anticoagulants (e.g., warfarin).

If gastrointestinal bleeding or ulceration is diagnosed in a patient receiving ketorolac, the drug should be discontinued. NSAIDs should be used with caution in patients with Crohn's disease or ulcerative colitis in their medical history due to the potential for worsening of the disease.

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

Effect on hemostasis. Concomitant use of ketorolac tromethamine in patients receiving anticoagulant therapy may increase 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, this regimen may also increase bleeding risk. Patients already receiving anticoagulants or requiring low-dose heparin should not receive ketorolac tromethamine. Close monitoring is required for patients receiving other agents affecting hemostasis when ketorolac tromethamine is administered. 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, platelet function returns to normal within 24–48 hours after discontinuation of ketorolac. Postoperative wound bleeding has been reported following immediate parenteral administration of ketorolac during surgery. Caution should be exercised when stable hemostasis is critical, such as in cosmetic or ambulatory procedures, prostate resection, or tonsillectomy. Hematomas, other signs of wound bleeding, and epistaxis may occur with ketorolac use. When prescribing ketorolac, its similarity to other NSAIDs that inhibit cyclooxygenase and the potential bleeding risk, especially in elderly patients, should be considered. Ketorolac tromethamine should not be used in patients who have undergone surgery with a high risk of bleeding or incomplete hemostasis (see section "Contraindications"). Ketorolac tromethamine is not an anesthetic and lacks sedative or anxiolytic properties; therefore, it is not indicated for preoperative treatment when such effects are needed to enhance anesthesia.

Use in patients with renal impairment (see section "Contraindications"). Like other NSAIDs, ketorolac inhibits prostaglandin synthesis and may have nephrotoxic effects, causing glomerulonephritis, interstitial nephritis, renal papillary necrosis, nephrotic syndrome, and acute renal failure; therefore, it should be used with caution in patients with renal impairment or a history of kidney disease. As with other prostaglandin synthesis inhibitors, ketorolac may increase serum levels of urea, creatinine, and potassium ions; deviations from normal may occur even after a single dose. Since ketorolac and its metabolites are primarily excreted by the kidneys, it should not be administered to patients with moderate to severe renal impairment (serum creatinine > 160 µmol/L) (see section "Contraindications"). Caution is advised in patients with conditions that may reduce blood volume and/or renal blood flow, where prostaglandins play an important role in maintaining perfusion. In such patients, NSAID use may cause dose-dependent inhibition of prostaglandin synthesis and renal failure. High-risk groups include patients with renal impairment, hypovolemia, heart failure, hepatic dysfunction, those taking diuretics, and elderly patients. Renal function usually normalizes after discontinuation of NSAIDs. Inadequate fluid/blood replacement during surgery leading to subsequent hypovolemia may cause renal dysfunction exacerbated by ketorolac administration. Correction of reduced extracellular fluid volume is required, along with careful monitoring of serum urea and creatinine levels and urine output until blood volume is normalized.

Patients with mild renal impairment should receive lower doses of ketorolac (not exceeding 60 mg/day intramuscularly). Their renal status should be closely monitored. Patients should be well hydrated before starting treatment. In patients undergoing hemodialysis, ketorolac clearance was approximately halved compared to normal, and terminal half-life increased nearly threefold.

Effect on cardiovascular system and cerebral vessels. Close monitoring is required for patients with hypertension and/or mild to moderate heart failure in their medical history.

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

Clinical trials and epidemiological data suggest that use of some NSAIDs, particularly at high doses and for prolonged periods, may be associated with a small increased risk of arterial thromboembolic events such as myocardial infarction or stroke. Such risk cannot be excluded for ketorolac.

Use in patients with hepatic impairment. Ketorolac tromethamine should be used with caution in patients with hepatic impairment or a history of liver disease. Significant elevations (more than three times the upper normal limit) of serum ALT and AST were observed in less than 1% of patients. Additionally, isolated cases of severe hepatic reactions, including jaundice, fatal fulminant hepatitis, hepatic necrosis, and liver failure (sometimes fatal), have been reported. Ketorolac should be discontinued if clinical signs of liver disease or systemic manifestations (e.g., eosinophilia, rash) appear.

Respiratory system. Patient status should be monitored for the potential development of bronchospasm.

Systemic lupus erythematosus and mixed connective tissue diseases. Use of the drug in patients with systemic lupus erythematosus or connective tissue diseases may be associated with an increased risk of aseptic meningitis.

Dermatological. 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. Patients should discontinue the drug at the first sign of rash, mucosal lesions, or other signs of hypersensitivity.

Use in elderly patients. In elderly patients (aged 65 years and older), NSAID use more frequently causes adverse reactions, particularly gastrointestinal bleeding and perforation, including fatal outcomes (see section "Dosage and administration"). The age-related increase in such risk is characteristic of all NSAIDs. These patients have a prolonged plasma elimination half-life and reduced plasma clearance compared to younger patients. Therefore, daily doses exceeding 60 mg are not recommended for elderly patients (see section "Dosage and administration").

Anaphylactic (anaphylactoid) reactions. Anaphylactic (anaphylactoid) reactions (e.g., anaphylaxis, bronchospasm, flushing, rash, hypotension, laryngeal edema, and angioedema) may occur in patients with known hypersensitivity to acetylsalicylic acid, other NSAIDs, or intravenous ketorolac, as well as in those without prior hypersensitivity reactions. Such reactions may occur in individuals with angioedema, bronchospastic reactions in their history (e.g., asthma), or nasal polyps. These anaphylactic reactions can be fatal. Therefore, ketorolac is contraindicated in patients with asthma, complete or partial nasal polyp syndrome, angioedema, or bronchospasm (see section "Contraindications").

Fluid retention and edema. Fluid retention and edema have been reported during ketorolac use; therefore, the drug should be used with caution in patients with cardiac decompensation, hypertension, or similar conditions.

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

This medicinal product contains sodium metabisulfite (E 223), which may rarely cause hypersensitivity reactions and bronchospasm.

Use during pregnancy or breastfeeding.

Pregnancy.

The safety of using this drug during pregnancy has not been established. It has been demonstrated that ketorolac crosses the placental barrier and reaches the fetal circulation. Therefore, ketorolac tromethamine is contraindicated during pregnancy and labor.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or embryonic/fetal development. Epidemiological data indicate an increased risk of spontaneous abortion, cardiac malformations, and gastroschisis following use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk of cardiac malformations increased from less than 1% to approximately 1.5%. This risk is considered to increase with higher doses and longer duration of therapy.

From the 20th week of pregnancy, NSAID use may cause oligohydramnios due to fetal renal dysfunction. This disorder may occur soon after starting treatment and is usually reversible upon discontinuation. Additionally, there are reports of arterial duct constriction in the fetus following NSAID treatment in the second trimester, which in most cases resolved after stopping treatment.

Animal studies have shown that prostaglandin synthesis inhibitors lead to increased pre-implantation loss of fertilized ova and post-implantation pregnancy loss, as well as increased embryonic and fetal mortality. Furthermore, increased incidence of various malformations, including cardiovascular, has been reported in animals treated with prostaglandin synthesis inhibitors during organogenesis.

Throughout pregnancy, all prostaglandin synthesis inhibitors may cause in the fetus:

• cardiopulmonary toxicity (with premature constriction/closure of the arterial duct and pulmonary hypertension);
• renal dysfunction, which may progress to renal failure with development of oligohydramnios (reduced amniotic fluid volume).

At the end of pregnancy, this medicinal product may affect both the mother and newborn by:

• potentially prolonging bleeding time due to anti-aggregatory effects, which may occur even with very low doses;
• inhibiting uterine contractions, potentially leading to delayed or prolonged labor.

Period of breastfeeding.

Ketorolac has been detected in breast milk in low concentrations. Ketorolac should not be used during lactation.

Fertility.

Use of other cyclooxygenase/prostaglandin synthesis inhibitors suggests that ketorolac may negatively affect fertility; therefore, it is not recommended for women planning to become pregnant. Women with fertility problems or undergoing infertility evaluation should discontinue ketorolac use.

Ability to affect reaction speed when driving or operating machinery.

During treatment, patients should avoid potentially hazardous activities requiring increased attention and psychomotor speed due to possible adverse effects on the nervous system and vision (dizziness, fatigue, somnolence, vertigo, visual disturbances, insomnia, and depression).

Method of Administration and Dosage

It is recommended to use the drug under hospital conditions.

After intramuscular administration, analgesic effect occurs approximately within 30 minutes, with maximum pain relief achieved 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. Continuous 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 were either switched to oral administration of the drug or no longer required analgesic therapy after the intramuscular administration period. 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 is 10 mg (0.3 mL of the drug), followed by doses of 10–30 mg (0.3–1 mL of the drug) every 4–6 hours (as needed). In the early postoperative period, ketorolac tromethamine may be administered every 2 hours if necessary. The minimum effective dose should be prescribed. The total daily dose must not exceed 90 mg (3 mL of the drug) in younger patients, and 60 mg (2 mL of the drug) in elderly patients, patients with renal impairment, and patients with body weight less than 50 kg. The maximum duration of treatment must not exceed 2 days. The dose should be reduced in patients with body weight less than 50 kg.

Concomitant use of opioid analgesics (morphine, pethidine) is possible. Ketorolac does not negatively affect opioid receptor binding and does not potentiate respiratory depression or sedative effects of opioid drugs.

For patients receiving the drug parenterally 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 patients with body weight less than 50 kg). On the day of switching the dosage form, the dose of the oral component must not exceed 40 mg. Patients should be switched to oral formulation as soon as possible.

Elderly patients. In patients aged 65 years and older, the lowest dose within the recommended range should be prescribed. The total daily dose must not exceed 60 mg.

Patients with renal impairment. Ketorolac is contraindicated in moderate to severe renal impairment. In mild renal impairment, dosage reduction is required (not exceeding 60 mg/day intramuscularly).

Children.

Not to be used in children under 16 years of age. Ketorolac may be used in children aged 16 to 18 years at the same dosage as in adults.

Overdose.

Symptoms: depressed state, lethargy, drowsiness, nausea, vomiting, epigastric pain, gastrointestinal bleeding, arterial hypertension, acute renal failure, respiratory depression and coma, seizures. Anaphylactoid reactions have been reported.

Single overdoses of ketorolac at various times have led to abdominal pain, nausea, vomiting, hyperventilation, peptic ulcers and/or erosive gastritis, and impaired renal function, which resolved after discontinuation of the drug.

Following intramuscular administration of 360 mg of ketorolac over 5 days, abdominal pain and peptic ulcers were observed, which resolved after discontinuation of the drug. In cases of overdose, nausea, headache, dizziness, disorientation, tinnitus, and hyperventilation may also occur. Suicide attempts have been reported. In cases of intentional overdose, metabolic acidosis may develop.

Treatment: symptomatic and supportive therapy. There is no specific antidote. In patients who present symptoms of overdose or have taken a large overdose (oral dose 5–10 times higher than usual), vomiting should be induced within 4 hours of drug intake, and activated charcoal (60–100 g for adults) and/or an osmotic laxative should be administered. Forced diuresis, urine alkalinization, hemodialysis, or blood transfusion are ineffective due to the high plasma protein binding of the drug. Close monitoring of the patient is required, including liver and kidney function tests. For prolonged seizures, intravenous diazepam is recommended.

Side effects.

Adverse reactions occurring more frequently than isolated cases are classified by system organ classes and frequency using conventional terms: very common (> 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).

Gastrointestinal system: the most common adverse reactions observed are gastrointestinal disorders. Erosive and ulcerative gastrointestinal lesions, ulcer perforation, and gastrointestinal bleeding (hematemesis, melena) are possible, sometimes with fatal outcomes (especially in elderly patients) (see section "Special precautions"). Reported side effects include: nausea, vomiting, dyspepsia, abdominal discomfort, abdominal pain, spasm or burning sensation in the epigastric region, taste disturbances, diarrhea, dry mouth, thirst, flatulence, constipation, acute pancreatitis, sensation of stomach fullness, esophagitis, belching, exacerbation of colitis and Crohn’s disease, ulcerative stomatitis; uncommon: gastritis.

Hepatobiliary system: uncommon: cholestatic jaundice, hepatitis; frequency not known: liver function abnormalities, hepatomegaly, increased liver transaminase activity, liver failure.

Nervous system: uncommon: drowsiness, headache, difficulty concentrating, pathological thinking, vertigo, aseptic meningitis (particularly in patients with autoimmune diseases such as systemic lupus erythematosus or mixed connective tissue disease, presenting symptoms such as fever, severe headache, seizures, neck and/or back stiffness), hyperactivity (mood changes, restlessness), nervousness, hallucinations, depression, psychosis, syncope; frequency not known: insomnia, euphoria, dizziness, anxiety, asthenic syndrome, paresthesia, functional disturbances, malaise, increased fatigue, excitement, irritability, unusual dreams, confusion, disorientation, hyperkinesia.

Cardiovascular system: common: pallor; uncommon: tachycardia, palpitations, chest pain; frequency not known: bradycardia, flushing. There have been reports of development of edema, arterial hypertension, and heart failure associated with NSAID use (especially at high doses and prolonged use). May increase the risk of arterial thromboembolic complications, such as myocardial infarction or stroke (see section "Special precautions").

Hematopoietic system: frequency not known: aplastic anemia, hemolytic anemia, purpura, agranulocytosis, leukopenia, eosinophilia, thrombocytopenia, neutropenia.

Respiratory system: uncommon: bronchial asthma, exacerbation of bronchial asthma, pulmonary edema; frequency not known: bronchospasm, dyspnea, laryngeal edema.

Urinary system: uncommon: hemolytic-uremic syndrome (hemolytic anemia, renal failure, thrombocytopenia, purpura), acute renal failure; frequency not known: nephrotoxicity, including increased frequency of urination, oliguria, flank pain (with or without hematuria), interstitial nephritis, urinary retention, nephrotic syndrome, dysuria, hyponatremia, hyperkalemia, increased creatinine and urea levels, papillary necrosis, back pain, hematuria, azotemia. Use of ketorolac (even after a single intravenous dose), like other drugs that inhibit renal prostaglandin synthesis, may lead to signs of renal impairment, not limited to elevated blood creatinine and potassium levels.

Skin: common: pruritus, purpura; uncommon: exfoliative dermatitis (erythema, skin thickening or desquamation, enlarged and/or painful palatine tonsils); frequency not known: photosensitivity, skin rashes (including maculopapular eruptions), bullous reactions, erythema multiforme.

Hemostasis system: uncommon: postoperative wound bleeding, epistaxis, rectal bleeding, subcutaneous hemorrhage, reduced blood clotting speed; frequency not known: prolonged bleeding time, hematoma.

Reproductive system: frequency not known: female infertility.

Immune system: allergic reactions, including uncommon cases of anaphylaxis (which may be fatal) or anaphylactoid reactions (facial skin discoloration, skin rashes, urticaria, pruritus, tachypnea or dyspnea, eyelid edema, periorbital edema, suffocation, dyspnea, chest tightness, wheezing); very rare: severe exudative erythema (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome), angioneurotic edema. Such reactions are possible in individuals with a history of angioneurotic edema and bronchospastic reactions (e.g., asthma or nasal polyps).

Sensory organs: uncommon: hearing loss, deafness, tinnitus, visual disturbances, blurred vision; frequency not known: optic neuritis.

General disorders: frequency not known: myalgia, increased sweating; rare: pain, injection site reactions.

Other: common: facial edema, edema of legs, fingers, feet, tongue swelling, weight gain, anorexia, increased sweating, fever with or without chills, sepsis.

Laboratory test abnormalities: frequency not known: deviations from normal in liver function tests.

Shelf life. 3 years.

Storage conditions. Store in original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Incompatibility. The drug should not be mixed with other medicinal products in the same container.

Packaging. 1 ml in ampoules, pack of 10 in a box; pack of 5×2, pack of 10 in blister packs in a box.

Release category. Prescription only.

Manufacturer. LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVIYA".

Manufacturer's address and location of business activity.

22 Shevchenka Street, Kharkiv, Kharkiv Oblast, 61013, Ukraine.