Ketanov

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

Composition:

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

Excipients: sodium chloride, disodium edetate, 96% ethanol, water for injections, (sodium hydroxide or diluted hydrochloric acid are added for pH adjustment).

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless or pale yellow solution free from visible particles.

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-form. Ketorolac tromethamine has no sedative or anxiolytic properties.

The main difference between higher and lower 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. A 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 ranges, 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 concentrations of both free and bound racemate is observed.

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 range of concentrations.

Table of approximate mean pharmacokinetic parameters

[mean value ± standard deviation (SD)]

Metabolism. Ketorolac tromethamine is largely 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 10 mg ketorolac (n = 9), the S-enantiomer was eliminated twice as rapidly as the R-enantiomer, and clearance was 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 humans are negligible or absent. The half-life (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 racemate half-life 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. Minimum plasma concentrations 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 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 half-life (T½) of racemic ketorolac tromethamine increased from 5 to 7 hours in elderly patients (65–78 years) compared to younger healthy volunteers (24–35 years).

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

Renal impairment. Based solely on data obtained after single-dose administration, the mean half-life (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 are nearly doubled compared to healthy volunteers. The volume of distribution doubles for the S-enantiomer and increases by one-fifth for the R-enantiomer. The increased volume of distribution of ketorolac tromethamine suggests an increase in the unbound fraction.

Hepatic impairment. T½, AUC8, and Cmax values in 7 patients with liver 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 the active substance or to any component of the medicinal product, or to other NSAIDs (non-steroidal anti-inflammatory drugs).
• Active peptic ulcer, recent gastrointestinal bleeding or perforation, history of peptic ulcer or gastrointestinal bleeding.
• Existing or suspected gastrointestinal bleeding.
• Allergic reactions such as bronchial asthma, rhinitis, angioneurotic edema, or urticaria induced by acetylsalicylic acid or other NSAIDs in medical history (due to the possibility of severe anaphylactic reactions).
• History of bronchial asthma.
• Should not be used as an analgesic before and during coronary artery surgery or procedures, as it inhibits platelet aggregation and is also contraindicated during surgery due to increased risk of bleeding.
• Severe heart failure.
• Complete or partial syndrome of nasal polyps, Quincke's edema, or bronchospasm.
• Should not be used in patients who have undergone surgical procedures with a high risk of bleeding or incomplete hemostasis, and in patients receiving anticoagulants, including low-dose heparin (2500–5000 units every 12 hours).
• Hepatic or moderate to severe renal impairment (serum creatinine level >160 µmol/L).
• Suspected or confirmed cerebrovascular hemorrhage, hemorrhagic diathesis, including coagulation disorders and high risk of bleeding.
• Concomitant use with other NSAIDs (including selective cyclooxygenase inhibitors), acetylsalicylic acid, warfarin, pentoxifylline, probenecid, or lithium salts.
• Hypovolemia, dehydration with risk of renal impairment due to reduced fluid volume.
• Pregnancy, labor, delivery, and breastfeeding.
• Use in children under 16 years of age.
• Epidural or intrathecal administration of the drug is contraindicated.

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 induction or inhibition of enzymes.

Concomitant use with ketorolac is not permitted.

Warfarin, digoxin, salicylates, and heparin. Ketorolac tromethamine slightly reduced protein binding of warfarin in vitro and did not alter protein binding of digoxin. In vitro studies indicate that at therapeutic concentrations of salicylates (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 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.

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

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

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

Other NSAIDs and acetylsalicylic acid. When used with acetylsalicylic acid, protein binding of ketorolac decreases, although clearance of free ketorolac remains unchanged. The clinical significance of this interaction is unknown, but, as with other NSAIDs, concomitant administration of ketorolac tromethamine with acetylsalicylic acid or other NSAIDs should not be done due to potential increased frequency 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 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 cardiac decompensation.

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

Oxpentifylline. Not recommended due to increased risk of hemorrhage.

Lithium. Concomitant use of NSAIDs and lithium preparations is contraindicated, as it may inhibit renal clearance of lithium, increase plasma lithium concentration, and lead to lithium toxicity.

Opioid analgesics. The effect of opioid analgesics is enhanced, allowing for dose reduction in pain management.

Medicinal products used in combination with ketorolac should be prescribed with caution.

Antithrombotic agents and selective serotonin reuptake inhibitors (SSRIs)

Increased risk of gastrointestinal bleeding (see section "Special precautions").

Thrombolytic agents

Concomitant use with NSAIDs increases the risk of bleeding.

Methotrexate. Should be co-administered with caution. Since NSAIDs may impair renal function and thereby reduce methotrexate clearance, increased methotrexate toxicity is possible.

ACE inhibitors. Concomitant use of angiotensin-converting enzyme (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.

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.

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).

Corticosteroids. As with all NSAIDs, corticosteroids should be used concomitantly with caution due to increased risk of gastrointestinal bleeding.

Quinolones. Patients taking quinolones have an increased risk of seizures.

Antidiabetic agents. NSAIDs may potentiate 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 receiving concomitant zidovudine and ibuprofen. Ritonavir may increase NSAID concentrations.

Tacrolimus. NSAIDs increase the risk of nephrotoxicity.

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

Non-polarizing muscle relaxants. No official studies on concomitant use of ketorolac tromethamine and muscle relaxants have been conducted. NSAIDs may reduce the elimination of baclofen (increasing the risk of toxicity). 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.

Cyclosporine. As with all NSAIDs, concomitant use with cyclosporine is contraindicated due to 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.

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

Ketorolac does not affect protein binding of digoxin. In vitro studies show that at therapeutic (300 µg/mL) and higher concentrations of salicylates, the degree of ketorolac binding to plasma proteins decreases from 99.2% to 97.5%. Digoxin, warfarin, paracetamol, phenytoin, and tolbutamide at therapeutic concentrations do not alter ketorolac binding to plasma proteins. Since ketorolac is a potent agent with low plasma content, it is unlikely to significantly displace other medicinal products from plasma protein binding sites.

Effect on laboratory test results.

Ketorolac inhibits platelet aggregation and may prolong bleeding time.

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

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 parenteral administration.

Concomitant use of ketorolac and other NSAIDs, as well as selective cyclooxygenase-2 (COX-2) inhibitors, should be avoided (see section "Contraindications").

Combined intramuscular and oral administration of ketorolac tromethamine to adult patients should not exceed 2 days.

Careful monitoring of diuresis and renal function is required when treating patients with cardiac, renal, or hepatic insufficiency, patients receiving diuretics, or postoperative patients with hypovolemia.

Use in elderly patients

In elderly patients (over 65 years of age), the use of NSAIDs more frequently causes adverse reactions, especially gastrointestinal bleeding and perforation, including fatal outcomes (see section "Dosage and administration").

This age-related risk increase is characteristic of all NSAIDs. Compared to younger patients, elderly patients have an increased plasma elimination half-life and reduced plasma clearance. Therefore, a total daily dose exceeding 60 mg should not be prescribed to elderly patients (see section "Dosage and administration").

Gastrointestinal effects. Epidemiological data suggest that, compared to some other NSAIDs, the use of ketorolac (especially off-label and/or prolonged use) may be associated with an increased risk of gastrointestinal disorders. Ketorolac tromethamine can cause serious adverse gastrointestinal reactions, such as bleeding, ulceration, and gastrointestinal perforation. These adverse events may occur in patients receiving ketorolac tromethamine at any time, with or without preceding symptoms, and may be fatal. The risk of clinically significant gastrointestinal bleeding is dose-dependent. However, adverse effects may occur even during short-term therapy. In addition to a history of peptic ulcer disease, especially with bleeding or perforation, predisposing factors include concomitant use of oral corticosteroids, anticoagulants, long-term NSAID therapy, smoking, alcohol consumption, advanced age, and poor general health. In such cases, careful consideration should be given to combining NSAIDs with gastroprotective agents, such as misoprostol or a proton pump inhibitor. Most spontaneous reports of gastrointestinal events involved elderly or debilitated patients; therefore, special attention should be paid when treating these patient groups, and ketorolac should be discontinued if any suspicion arises. Alternative therapies not involving NSAIDs should be considered for patients at risk. Patients (especially elderly) with a history of gastrointestinal (GI) disorders should report any abdominal symptoms (especially gastrointestinal bleeding). These symptoms should be closely monitored at the beginning of treatment.

If gastrointestinal bleeding or ulceration is diagnosed in a patient taking ketorolac, the drug should be discontinued.

NSAIDs, including ketorolac, should be used with caution in patients with a history of Crohn's disease or ulcerative colitis due to the possibility of worsening the disease course.

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.

Anaphylactic (anaphylactoid) reactions

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

Hematological effects.

Ketorolac should not be prescribed to patients with coagulation disorders. The 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 (2,500–5,000 IU every 12 hours) have not been conducted. This regimen may also increase the risk of bleeding. Patients already receiving anticoagulants or requiring low-dose heparin should not receive ketorolac tromethamine. Close monitoring is required for patients receiving other agents that negatively affect hemostasis when ketorolac tromethamine is administered. Clinical studies have shown that the incidence of postoperative bleeding is less than 1%. 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 a high risk of bleeding or incomplete hemostasis. Caution should be exercised when stable hemostasis is critical, such as in cosmetic or outpatient procedures, prostatectomy, or tonsillectomy. Hematomas, other signs of wound bleeding, and epistaxis may occur during ketorolac use.

When prescribing ketorolac, its similarity to other NSAIDs that inhibit cyclooxygenase and the potential risk of bleeding, especially in elderly patients, should be considered. Ketorolac tromethamine is not an anesthetic and does not possess sedative or anxiolytic properties.

Use in patients with impaired renal function (see "Contraindications"). Like other NSAIDs, ketorolac inhibits prostaglandin synthesis and may have toxic effects on the kidneys (e.g., glomerular nephritis, interstitial nephritis, renal papillary necrosis, nephrotic syndrome, acute renal failure); therefore, it should be used with caution in patients with impaired renal function or a history of kidney disease. Patients at risk include those with impaired renal function, hypovolemia, heart failure, hepatic dysfunction, those taking diuretics, and elderly patients. Caution is advised in patients in whom disease-related conditions 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.

Ketorolac may increase serum levels of urea, creatinine, and potassium ions; deviations from normal may occur even after a single dose. After discontinuation of NSAID therapy, patients' condition usually normalizes.

Patients with mild to moderate renal impairment should receive lower doses of ketorolac (not exceeding 60 mg/day, intramuscularly). Close monitoring of renal function in these patients is required. Patients should be adequately hydrated before starting treatment. Inadequate fluid/blood transfusion during surgery followed by hypovolemia may lead to renal dysfunction, which may be exacerbated by ketorolac administration. Correction of reduced extracellular fluid volume is necessary; careful monitoring of serum urea and creatinine levels and observation of urine output are required until blood volume is normalized.

In patients undergoing hemodialysis, ketorolac clearance was reduced by approximately half compared to normal rates, and terminal half-life (T½) increased nearly threefold.

Effects on the cardiovascular system and cerebral vessels. Reports indicate an association between NSAID use and fluid retention and edema. Therefore, close monitoring of patients with arterial hypertension and/or a history of mild to moderate heart failure is required.

To minimize the potential risk of cardiovascular adverse events in patients using NSAIDs, the lowest effective dose should be used for the shortest possible duration. Ketorolac tromethamine may be prescribed to patients with uncontrolled arterial hypertension, congestive heart failure, established ischemic heart disease, peripheral artery disease, and/or cerebrovascular disease only after careful consideration of all benefits and risks of such treatment. 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 arterial hypertension, hyperlipidemia, diabetes mellitus, or smokers).

Clinical studies and epidemiological data suggest that the use of some NSAIDs, especially 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 a risk cannot be excluded for ketorolac.

Use in patients with impaired hepatic function. Ketorolac tromethamine should be prescribed with caution to patients with impaired liver function or a history of liver disease. In patients with hepatic impairment due to cirrhosis, ketorolac clearance and terminal elimination half-life are not clinically significantly altered.

An increase in one or more liver function test parameters may occur. Significant elevations (more than three times the upper normal limit) of serum ALT and AST were observed in less than 1% of patients. Additionally, there have been reports of isolated cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis, and hepatic failure, some of which were fatal. Ketorolac should be discontinued if clinical symptoms of liver disease or systemic manifestations (e.g., eosinophilia, rash) develop.

Respiratory system. The patient's condition should be monitored for the possible development of bronchospasm.

Systemic lupus erythematosus and mixed connective tissue diseases.

The risk of aseptic meningitis is increased in patients with systemic lupus erythematosus and various mixed connective tissue diseases.

Dermatological. Very rare serious skin reactions, such as exfoliative dermatitis, Stevens-Johnson syndrome, and Lyell's syndrome, have been reported with NSAID use. The highest risk of these reactions occurs early in the treatment course, with most cases appearing within the first month of therapy. Patients should discontinue treatment at the first sign of rash, mucosal lesions, or other signs of hypersensitivity.

Fluid retention and edema. Fluid retention and edema have been reported during ketorolac use; therefore, it should be prescribed with caution to patients with cardiac decompensation, arterial hypertension, or similar conditions.

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

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

Use during pregnancy or breastfeeding. The use of ketorolac tromethamine is contraindicated during pregnancy, labor, and delivery due to the known effects of NSAIDs on the fetal cardiovascular system.

Pregnancy.

Safety during pregnancy has not been established. It has been proven that ketorolac crosses the placental barrier and enters 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 after 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 believed to increase with higher doses and longer duration of therapy. Animal studies have shown that prostaglandin synthesis inhibitors lead to more frequent loss of fertilized ova before implantation and interruption of pregnancy after implantation, as well as increased embryonic and fetal mortality. In addition, reports indicate a higher incidence of various malformations, including cardiovascular malformations, in animals treated with a prostaglandin synthesis inhibitor during organogenesis.

From the 20th week of pregnancy, the use of ketorolac tromethamine may cause oligohydramnios due to fetal renal dysfunction. This condition may occur soon after starting treatment and is usually reversible after discontinuation of therapy. Additionally, reports of arterial duct constriction after second-trimester treatment have been documented, most of which were reversible after discontinuation of therapy.

Also, during pregnancy, all prostaglandin synthesis inhibitors may cause the following in the fetus:

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

At the end of pregnancy, these drugs may affect both the mother and the newborn by:

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

Therefore, the use of ketorolac is contraindicated throughout pregnancy.

If a pregnant woman has taken the drug, prenatal monitoring for oligohydramnios after ketorolac exposure should be considered for several days starting from the 20th week of pregnancy. Ketorolac use should be discontinued.

Breastfeeding.

Ketorolac passes into breast milk in small amounts; therefore, Ketanov is contraindicated during breastfeeding.

Fertility.

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

Ability to affect reaction speed when driving or operating machinery. During treatment, patients should refrain from potentially hazardous activities requiring increased attention and psychomotor speed due to the possible development of nervous system-related adverse reactions. Some patients may experience dizziness, fatigue, somnolence, vertigo, visual disturbances, insomnia, and depression during ketorolac therapy.

Method of Administration and Dosage

It is recommended to use the drug under hospital conditions.

After intramuscular administration, analgesic effect occurs approximately after 30 minutes; maximum pain relief is achieved within 1–2 hours. Generally, the average duration of analgesia is 4–6 hours. The dose should be adjusted depending on 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 the majority of patients are either switched to oral administration of the drug or no longer require analgesic therapy after the intramuscular administration period. The risk 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). During the initial postoperative period, ketorolac tromethamine may be administered every 2 hours if necessary. The lowest 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 weighing 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 has no negative effect on 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 weighing less than 50 kg). On the day of switching dosage forms, 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 is recommended. The total daily dose must not exceed 60 mg.

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

Children.

Do not use in children under 16 years of age.

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 resulted in 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. After intentional overdose, metabolic acidosis was observed.

Treatment: symptomatic and supportive therapy. There is no specific antidote. In patients within 4 hours after drug administration who present symptoms of overdose or after a large overdose (oral dose 5–10 times higher than usual), vomiting should be induced, 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, with regular assessment of liver and kidney function. For prolonged seizures, intravenous diazepam is recommended.

Adverse reactions:

Adverse reactions occurring more frequently than isolated cases are classified by organ systems and frequency: 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 commonly observed adverse reactions are gastrointestinal disorders. Erosive and ulcerative lesions of the gastrointestinal tract, ulcer perforation, and bleeding (hematemesis, melena) are possible, sometimes with fatal outcomes (especially in elderly patients) (see section "Special precautions"). Reported adverse effects include: nausea, vomiting, dyspepsia, discomfort in the abdomen, abdominal pain, spasms or burning sensation in the epigastric area, taste disturbances, diarrhea, dry mouth, thirst, flatulence, constipation, acute pancreatitis, feeling 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, psychotic reactions, headache, difficulty concentrating, pathological thinking, vertigo, aseptic meningitis (particularly in patients with autoimmune diseases such as systemic lupus erythematosus, mixed connective tissue disease, with symptoms such as fever, severe headache, seizures, neck and/or back stiffness), hyperactivity (mood changes, restlessness), nervousness, hallucinations, depression, psychosis, unconscious states; 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. Cases of edema, arterial hypertension or hypotension, and heart failure associated with NSAID use (especially at high doses and prolonged use) have been reported. Increased 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. The use of ketorolac (even after a single intravenous dose), as with 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, induration or desquamation of the skin, enlargement and/or tenderness of the palatine tonsils); frequency not known: photosensitivity, skin rashes (including maculopapular eruptions), bullous reactions, erythema multiforme.

Hemostatic system: uncommon: bleeding from postoperative wounds, epistaxis, rectal bleeding, subcutaneous hemorrhages, reduced blood clotting speed; frequency not known: prolonged bleeding time, hematoma.

Reproductive system: frequency not known: female infertility.

Immune system: allergic reactions, including uncommon: anaphylaxis (can be fatal) or anaphylactoid reactions (facial skin discoloration, skin rashes, urticaria, pruritus, tachypnea or dyspnea, eyelid swelling, periorbital edema, shortness of breath, difficulty breathing, chest tightness, wheezing); very rare: erythema multiforme bullosa (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome), angioneurotic edema. Such reactions may occur 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, changes at the injection site.

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

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

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging. 1 ml in a vial; 10 vials in a cardboard box.

Prescription category. Prescription only.

Manufacturer. Terapia S.A. / Terapia S.A.

Manufacturer’s address and place of business.
Str. Fabriciei, 124, 400632, Cluj-Napoca, Cluj County, Romania.