Ketolong-darnitsa®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Ketolong – Darnitsa® (ketolong – Darnitsa)

Composition:

Active substance: ketorolac tromethamine;

1 tablet contains ketorolac tromethamine 10 mg;

Excipients: lactose monohydrate, microcrystalline cellulose, crospovidone, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white round tablets with a slight yellowish tint, flat cylindrical in shape, with beveled edges.

Pharmacotherapeutic group. Nonsteroidal anti-inflammatory and antirheumatic agents. Ketorolac. ATC code M01AB15.

Pharmacological Properties

Pharmacodynamics

Ketorolac tromethamine is a non-narcotic analgesic. It is a non-steroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory and weak antipyretic activity. Ketorolac tromethamine inhibits prostaglandin synthesis and is considered a peripherally-acting analgesic. It has no known effect on opioid receptors. In controlled clinical studies, administration of ketorolac tromethamine did not result in respiratory depression. Ketorolac tromethamine does not cause miosis.

Pharmacokinetics

Ketorolac tromethamine is rapidly and completely absorbed after oral administration, reaching peak plasma concentration of 0.87 mg/kg within 45 minutes following a single 10 mg dose. Ketorolac penetrates poorly into brain tissue. Only a small amount can be detected in breast milk. In healthy individuals, less than 50% of the administered dose is metabolized. The major metabolites are glucuronide conjugate and 4-hydroxy-ketorolac, both of which are pharmacologically inactive. In humans, following single or multiple dosing, the pharmacokinetics of ketorolac are linear. Steady-state plasma concentrations are achieved within 1 day with administration four times daily. No changes were observed with prolonged dosing. In healthy volunteers, the terminal elimination half-life from plasma is 4–6 hours (mean 5.4 hours). The plasma elimination half-life increases in patients with renal impairment and in elderly patients. In elderly individuals (mean age 72 years), it is 6.2 hours. After administration of a single intravenous dose, the volume of distribution is 0.25 L/kg, elimination half-life is 5 hours, and clearance is 0.55 mL/min/kg. The primary route of excretion of ketorolac and its metabolites (conjugates and p-hydroxymetabolites) is via urine (90%), with the remainder excreted in feces. A high-fat, difficult-to-digest meal reduces the rate of absorption but not the extent, whereas antacids do not affect ketorolac absorption.

Clinical characteristics.

Indications.

Short-term treatment of moderate-intensity pain, including postoperative pain.

Contraindications.

• Hypersensitivity to ketorolac or to other NSAIDs or to any component of the medicinal product;
• patients with active and/or recurrent peptic ulcer, recent gastrointestinal bleeding or perforation in history associated with NSAID use, peptic ulcer or gastrointestinal bleeding (two or more episodes) in exacerbation stage or in history;
• hypersensitivity reactions such as bronchial asthma, rhinitis, angioneurotic edema or urticaria caused by acetylsalicylic acid or other NSAIDs (due to possible occurrence of severe anaphylactic reactions);
• history of bronchial asthma;
• not to be used as an analgesic before and during surgery and after procedures on coronary vessels due to inhibition of platelet aggregation which may cause bleeding;
• severe heart failure;
• complete or partial syndrome of nasal polyps, Quincke's edema or bronchospasm;
• not to be used in patients who have undergone surgical intervention with high risk of bleeding or incomplete cessation of bleeding and in patients receiving anticoagulants, including low-dose heparin (2500–5000 units every 12 hours);
• hepatic or moderate/severe renal insufficiency (serum creatinine clearance over 160 µmol/L);
• suspected or confirmed cerebrovascular hemorrhage, hemorrhagic diathesis, including blood coagulation disorders and high risk of bleeding;
• concomitant treatment with other NSAIDs (including selective cyclooxygenase inhibitors), acetylsalicylic acid, warfarin, pentoxifylline, probenecid or lithium salts;
• hematopoiesis disorders of unknown etiology;
• hypovolemia, dehydration;
• risk of developing renal failure due to reduced fluid volume;
• the medicinal product is contraindicated during pregnancy, labor and lactation;
• children and adolescents under 16 years of age.

Interaction with other medicinal products and other forms of interaction.

Ketorolac is highly bound to plasma proteins (mean value 99.2%), and the degree of binding depends on concentration.

Must not be used simultaneously with ketorolac.

Due to the possibility of adverse effects, ketorolac must not be prescribed together with other NSAIDs, including selective cyclooxygenase-2 inhibitors, or to patients receiving acetylsalicylic acid, due to the risk of severe adverse reactions.

Thromboxane. Ketorolac inhibits platelet aggregation, reduces thromboxane concentration and prolongs bleeding time. Unlike the long-lasting effects of acetylsalicylic acid, platelet function recovers within 24–48 hours after discontinuation of ketorolac.

Anticoagulants. Although studies have not revealed significant interaction between ketorolac and warfarin or heparin, concomitant use of ketorolac and therapies affecting hemostasis, including therapeutic doses of anticoagulants (warfarin), low-dose prophylactic heparin (2500–5000 units every 12 hours) and dextrans, may increase the risk of bleeding. Concomitant use with anticoagulants (such as warfarin) is contraindicated.

Lithium salts. Inhibition of renal lithium clearance by some drugs that inhibit prostaglandin synthesis may lead to increased plasma lithium concentration. Cases of elevated plasma lithium concentration during ketorolac therapy have been reported.

Probenecid. Probenecid should not be administered simultaneously with ketorolac due to reduced plasma clearance and volume of distribution of ketorolac, increased plasma concentration of ketorolac and prolonged elimination half-life.

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

Pentoxifylline (oxpentifylline). Not recommended due to increased risk of hemorrhage.

Medicinal products to be used with caution in combination with ketorolac.

Glucocorticosteroids. As with all NSAIDs, corticosteroid medicinal products should be used concomitantly with caution due to increased risk of gastrointestinal ulcers or bleeding.

Antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs). There is an increased risk of gastrointestinal bleeding when NSAIDs are prescribed in combination with antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs).

Methotrexate. Caution is recommended when prescribing methotrexate concomitantly, as some prostaglandin synthesis inhibitors have been reported to reduce methotrexate clearance and thus possibly increase its toxicity.

Diuretics. In healthy individuals with normovolemia, ketorolac reduces the diuretic effect of furosemide by approximately 20%; therefore, special caution is required when administering the drug to patients with cardiac decompensation.

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

Concomitant administration with diuretics may lead to reduced diuretic effect and increased risk of NSAID nephrotoxicity.

Cyclosporine antibiotics. Ketorolac should be prescribed with caution concomitantly with cyclosporine due to increased risk of nephrotoxicity.

Tacrolimus. There is a possible risk of nephrotoxicity when NSAIDs are administered together with tacrolimus.

ACE inhibitors, angiotensin receptor blockers (ARBs). Ketorolac and other NSAIDs may reduce the effect of antihypertensive agents. When ketorolac is used concomitantly with ACE inhibitors or ARB antagonists, there is an increased risk of impaired kidney function, especially in patients with reduced blood volume or elderly patients. When such combination is used, careful monitoring of renal function is required at the beginning of treatment and periodically during therapy.

Opioid analgesics. Opioid analgesics (e.g., morphine, pethidine) may be used in parallel; ketorolac does not affect binding of opioid drugs and does not enhance respiratory depression or sedative effects caused by opioids. It has been demonstrated that in cases of postoperative pain, concomitant use of ketorolac with opioid analgesics reduced the need for the latter.

Administration of ketorolac tablets after a high-fat meal resulted in reduced peak plasma concentration of ketorolac and increased time to peak concentration by approximately 1 hour. Antacids do not affect the extent of absorption.

Quinolones. Patients taking NSAIDs and quinolones may have an increased risk of seizures.

Concomitant use of NSAIDs with zidovudine leads to increased 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.

Medicinal products containing garlic, onion, ginkgo biloba, may enhance the effect of ketorolac and increase the risk of hemorrhagic complications.

Effect on laboratory test results. Ketorolac inhibits platelet aggregation and may prolong bleeding time.

It is unlikely that the following medicinal products interact with ketorolac.

Ketorolac does not affect protein binding of digoxin in plasma. In vitro studies indicate that at therapeutic salicylate concentrations (300 µg/mL) and higher, ketorolac binding decreased from approximately 99.2% to 97.5%. Therapeutic concentrations of digoxin, warfarin, ibuprofen, naproxen, piroxicam, paracetamol, acetaminophen, phenytoin and tolbutamide did not affect ketorolac binding to plasma proteins. Since ketorolac is a highly potent drug and its plasma concentration is low, significant displacement of other plasma protein-bound drugs is not expected.

In animal and human studies, there was no evidence that ketorolac induces or inhibits liver enzymes capable of metabolizing it or other medicinal products. Therefore, ketorolac is not expected to alter the pharmacokinetics of other drugs via enzyme induction or inhibition mechanisms.

Antiepileptic agents. Isolated cases of epileptic seizures have been reported during concomitant use of ketorolac and antiepileptic agents (phenytoin, carbamazepine).

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

Special precautions for use.

To reduce the risk of adverse effects, ketorolac therapy should be conducted for the shortest possible duration and at the lowest doses necessary to control pain. The maximum duration of treatment should not exceed 5 days.

Gastrointestinal bleeding, ulceration, and perforation.

Gastrointestinal bleeding, ulceration, or perforation, which may be fatal, have been reported with the use of NSAIDs (including ketorolac) at any time during treatment, with or without symptoms or prior history of severe gastrointestinal disorders. The risk of serious gastrointestinal bleeding, ulceration, or perforation depends on dosage and increases with higher doses in patients with a history of peptic ulcer, especially if complicated by bleeding or perforation, and in elderly patients. Therefore, such patients should be started on the lowest available dose, particularly elderly and debilitated patients receiving ketorolac at average daily doses exceeding 60 mg. The greatest number of fatal cases associated with gastrointestinal adverse reactions due to NSAIDs have been observed in elderly or debilitated patients. These patients should be warned to report any unusual gastrointestinal symptoms (especially gastrointestinal bleeding), particularly in the early stages of treatment. For these patients, as well as for those concurrently receiving low-dose acetylsalicylic acid or other drugs that may increase gastrointestinal risk, consideration should be given to concomitant use of protective agents (e.g., misoprostol or proton pump inhibitors). Ketolong-Darnytsia® should be used with caution in patients receiving concomitant medications that may increase the risk of ulceration or bleeding, such as oral corticosteroids, SSRIs, or antiplatelet agents such as acetylsalicylic acid. If gastrointestinal bleeding or ulceration occurs in patients receiving Ketolong-Darnytsia®, treatment should be discontinued.

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

NSAIDs should be used with caution in patients with inflammatory bowel disease (Crohn’s disease, ulcerative colitis).

Hematological effects.

Ketolong-Darnytsia® should not be prescribed to patients with coagulation disorders. Patients receiving anticoagulant therapy may have an increased risk of bleeding when taking ketorolac concomitantly. Patients receiving other drugs that may affect blood clotting speed should be closely monitored when ketorolac is prescribed. In controlled clinical trials, the incidence of significant postoperative bleeding was less than 1%. Ketorolac inhibits platelet aggregation and prolongs bleeding time. In patients with normal bleeding time, bleeding duration increased but remained within the normal range of 2–11 minutes. Unlike the prolonged effect of acetylsalicylic acid, platelet function returns to normal within 24–48 hours after discontinuation of ketorolac. Ketorolac should not be prescribed to patients who have undergone surgery with a high risk of bleeding or incomplete hemostasis. Caution should be exercised when definitive hemostasis is critical.

Respiratory function disorders.

Caution is required when administering the drug to patients with bronchial asthma (or history of asthma), as NSAIDs have been reported to trigger bronchospasm in such patients.

Renal effects.

Inhibitors of prostaglandin synthesis (including NSAIDs) have been reported to exert nephrotoxic effects. The drug should be prescribed with caution in patients with impaired renal, cardiac, or hepatic function and in those with a history of kidney disease, as NSAID use may worsen renal function due to inhibition of prostaglandin synthesis (see above). Since ketorolac tromethamine and its metabolites are primarily excreted via the kidneys, patients with moderate to severe renal impairment (serum creatinine > 160 µmol/L) should not take Ketolong-Darnytsia®. Patients with mild renal impairment should receive lower doses of ketorolac (not exceeding 60 mg daily intramuscularly or intravenously), and renal function should be closely monitored in such patients. As with other drugs that inhibit prostaglandin synthesis, cases of increased serum urea, creatinine, and potassium have been reported during ketorolac use, which may occur after a single dose. Discontinuation of the drug usually leads to recovery of renal function.

Cardiovascular, renal, and hepatic disorders.

The drug should be prescribed with caution in patients with conditions leading to reduced blood volume and/or renal blood flow, where renal prostaglandins play a supportive role in maintaining renal perfusion. Renal function should be monitored in these patients. Reduced blood volume should be corrected, and serum urea and creatinine levels and urine output should be carefully monitored until normovolemia is achieved, as there is a risk of developing renal failure if these recommendations are not followed.

In patients undergoing dialysis, creatinine clearance was approximately halved compared to normal rates, and elimination half-life was prolonged about threefold.

Ketorolac should be prescribed with caution in patients with impaired liver function or a history of liver disease. Marked elevations (more than three times the upper normal limit) of ALT and AST in serum were observed in less than 1% of patients in controlled clinical trials. Additionally, isolated cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, hepatic necrosis, and liver failure, some fatal, have been reported.

Patients with liver dysfunction due to cirrhosis showed no clinically significant changes in ketorolac clearance or terminal half-life. Marginal elevations in one or more liver function tests (ALT/AST) may occur. These deviations from normal may be transient, remain unchanged, or progress with continued treatment. Ketolong-Darnytsia® should be discontinued if clinical signs and symptoms suggest liver disease or if systemic manifestations are observed.

Ketolong-Darnytsia® should be prescribed with caution in patients with a history of cardiovascular disorders.

Fluid retention and edema.

Fluid retention, hypertension, and edema have been reported during ketorolac use; therefore, the drug should be prescribed with caution in patients with mild to moderate heart failure, arterial hypertension, or similar conditions.

Cardiovascular and cerebrovascular effects.

There is currently insufficient information to assess this risk for ketorolac tromethamine. Patients with uncontrolled arterial hypertension, congestive heart failure, diagnosed ischemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should be under medical supervision, as drug use may be associated with a slightly increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke). Clinical trials and epidemiological data suggest that the use of coxibs and certain NSAIDs (mainly at high doses) may be associated with a slightly increased risk of arterial thrombotic events (e.g., myocardial infarction or stroke). Although ketorolac treatment has not demonstrated an increased frequency of thrombotic events such as myocardial infarction, data are insufficient to exclude such a risk for ketorolac.

Systemic lupus erythematosus and mixed connective tissue diseases.

Patients with systemic lupus erythematosus and various mixed connective tissue diseases have an increased risk of developing aseptic meningitis.

Anaphylactic reactions.

Anaphylactic/anaphylactoid reactions (including, but not limited to, anaphylaxis, bronchospasm, flushing, rash, hypotension, laryngeal edema, and angioedema) have occurred in patients with hypersensitivity to acetylsalicylic acid or any other NSAID or with a history of intravenous ketorolac administration. These reactions may also occur in individuals with angioedema, bronchospasm (e.g., asthma), and adenoids. Anaphylactoid reactions, such as anaphylaxis, may develop slowly. Therefore, ketorolac is contraindicated in patients with a history of asthma and in those with complete or partial nasal polyp syndrome, angioedema, and bronchospasm.

Dermatological effects.

Severe skin reactions, sometimes fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been very rarely reported in association with NSAID use (see Adverse Reactions). The risk of such reactions is higher at the beginning of treatment.

Ketolong-Darnytsia® should be discontinued at the first signs of skin rash, mucosal lesions, or any other signs of hypersensitivity.

Other important information.

Ketolong-Darnytsia® is not an anesthetic agent and has no sedative or anxiolytic properties; therefore, it is not recommended as a premedication prior to surgery for anesthesia support.

Hypovolemia should be corrected before initiating ketorolac therapy.

Increasing the dose of ketorolac tablets above the daily dose of 40 mg does not enhance efficacy but increases the risk of adverse reactions.

Ketolong-Darnytsia® does not cause dependence, and no withdrawal syndrome has been observed upon discontinuation of the drug.

Important information about excipients.

This medicinal product contains lactose monohydrate. If you have been diagnosed with an intolerance to certain sugars, consult your doctor before taking this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy.

The safety of ketorolac during pregnancy has not been established. Approximately 10% of ketorolac crosses the placenta.

Due to the known effects of NSAIDs on the fetal cardiovascular system (risk of premature closure of the ductus arteriosus), the drug is contraindicated during pregnancy, labor, and delivery. Onset of labor may be delayed, and duration prolonged due to inhibition of uterine contractility. The risk of bleeding increases in both mother and child.

Suppression of prostaglandin synthesis by NSAIDs in early pregnancy may lead to embryonic/fetal developmental abnormalities, including cardiac malformations and gastroschisis, and urinary tract disorders leading to oligohydramnios. Starting from the 20th week of pregnancy, use of the drug Ketolong-Darnytsia® may cause oligohydramnios due to fetal renal dysfunction. This disorder may occur soon after initiation of treatment and is usually reversible upon discontinuation of therapy. Additionally, there are reports of ductus arteriosus constriction after treatment in the second trimester, which in most cases resolves after discontinuation of therapy. Prenatal monitoring for oligohydramnios and ductus arteriosus constriction may be advisable after exposure to ketorolac for several days starting from the 20th gestational week.

The absolute risk of cardiovascular malformation with NSAID use increases from less than 1% to approximately 1.5%. The risk is considered to increase with dose and duration of therapy. Epidemiological data indicate an increased risk of spontaneous abortion (miscarriage).

In the third trimester of pregnancy, all prostaglandin synthesis inhibitors may affect the fetus as follows:

• Cardio-pulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension);
• Impaired renal function with possible subsequent development of renal failure with oligohydramnios (see above).

At the end of pregnancy, prostaglandin synthesis inhibitors may affect the mother and fetus as follows:

• Prolonged bleeding time, anti-aggregatory effect, even after very low doses, increased bleeding in both mother and child;
• Inhibition of uterine contractions, which may lead to delayed or prolonged labor.

Approximately 10% of ketorolac crosses the placenta.

Breastfeeding.

Ketorolac passes into breast milk in low amounts; therefore, the drug is contraindicated during breastfeeding.

Effect on fertility.

The use of ketorolac, like any other drug that inhibits cyclooxygenase/prostaglandin synthesis, may impair fertility and is not recommended for use in women attempting to conceive. For women who are infertile or undergoing fertility investigations, discontinuation of ketorolac should be considered.

Ability to influence reaction speed when driving or operating machinery.

In some patients, use of ketorolac may cause drowsiness, dizziness, vertigo, insomnia, increased fatigue, visual disturbances, headache, or depression. If patients experience these or similar effects, they should not drive or operate machinery.

Method of Administration and Dosage

Tablets should be taken during or after meals. The medicinal product is recommended for short-term use only. The total duration of treatment (parenteral administration followed by oral intake) should not exceed 5 days.

To minimize adverse effects, the medicinal product should be used at the lowest effective dose for the shortest duration necessary to control symptoms. Normovolemia should be achieved prior to initiating treatment.

Ketolong-Darnytsia®: administer 10 mg every 4–6 hours as needed. Doses exceeding 40 mg per day are not recommended.

If treatment continues after parenteral therapy:

• For patients aged 16 to 64 years, with body weight ≥50 kg and normal renal function: initially administer a single dose of 20 mg, followed by 10 mg up to 4 times daily at intervals of 4 to 6 hours as needed, but not exceeding 40 mg per day;
• For elderly patients, patients with impaired renal function, or patients with body weight <50 kg: administer 10 mg up to 4 times daily at intervals of 4 to 6 hours as needed, but not exceeding 40 mg per day.

For patients receiving parenteral ketorolac and transitioning to oral ketorolac tablets, the total combined daily dose should not exceed 90 mg in adults and 60 mg in elderly patients, patients with impaired renal function, and patients with body weight <50 kg. The dosage of the oral formulation should not exceed 40 mg per day, regardless of changes in the route of administration. Patients should be switched to oral administration of the medicinal product as early as possible.

Elderly Patients

Elderly patients have a higher risk of developing severe complications, particularly gastrointestinal adverse events. During treatment with NSAIDs, patients should be monitored regularly. A longer dosing interval, for example, 6–8 hours, is generally recommended.

Children

The efficacy and safety of the medicinal product in children under 16 years of age have not been established; therefore, it should not be prescribed to this patient group.

Overdose

Symptoms: headache, nausea, vomiting, epigastric pain, peptic ulcers, erosive gastritis, gastrointestinal bleeding, hyperventilation, hypertension; rarely – diarrhea, disorientation, excitement, respiratory depression, coma, drowsiness, lethargy, dizziness, tinnitus, loss of consciousness, seizures. In cases of severe poisoning, acute renal failure and hepatic injury may occur. Anaphylactoid reactions have been reported and may also occur in overdose.

Treatment: gastric lavage and administration of activated charcoal. Adequate diuresis should be maintained. Renal and hepatic functions should be closely monitored. Patients should be observed for at least 4 hours after ingestion of a potentially toxic dose. Frequent or prolonged seizures should be treated by intravenous administration of diazepam. Other interventions may be implemented depending on the patient's clinical condition. Treatment is symptomatic. There is no specific antidote. Dialysis does not remove ketorolac from the circulation.

Adverse Reactions

Eye disorders: optic neuritis, visual disturbances, blurred vision.

Ear and labyrinth disorders: hearing loss, tinnitus, possible deafness.

Respiratory, thoracic and mediastinal disorders: dyspnea, bronchial asthma, pulmonary edema.

Gastrointestinal disorders: peptic ulcer, perforation or gastrointestinal hemorrhage, sometimes fatal (especially in elderly patients), nausea, dyspepsia, abdominal pain, abdominal discomfort, dry mouth, vomiting, vomiting with blood, gastritis, esophagitis, diarrhea, constipation, eructation, flatulence, bloating, melena, rectal bleeding, stomatitis, ulcerative stomatitis, hemorrhages, perforation, pancreatitis, exacerbation of colitis and Crohn's disease, epigastric pain, spasm or burning in epigastric region.

Hepatobiliary disorders: liver function abnormalities, hepatitis, jaundice and hepatic failure, hepatomegaly, disturbances in liver function laboratory tests.

Renal and urinary disorders: increased frequency of urination, oliguria, renal failure (including acute), hyponatremia, hyperkalemia, hemolytic uremic syndrome, flank pain (with or without hematuria), elevated serum urea and creatinine levels, interstitial nephritis, urinary retention, nephrotic syndrome.

Metabolism and nutrition disorders: anorexia.

Nervous system disorders: drowsiness, dizziness, stupor, headache, dry mouth, increased thirst, nervousness, paresthesia, functional disturbances, depression, euphoria, convulsions, inability to concentrate, sleep disturbances, insomnia, unusual dreams, malaise, increased fatigue, weakness, excitement, vertigo, confusion, hallucinations, hyperkinesia, aseptic meningitis with corresponding symptoms (neck stiffness, headache, nausea, vomiting, fever or disorientation).

Psychiatric disorders: hyperactivity (mood changes, restlessness), anxiety, psychotic reactions, thought disturbances.

Cardiovascular disorders: palpitations, hot flushes, bradycardia, pallor, arterial hypertension, arterial hypotension, palpitation, chest pain, development of edema, cardiac failure.

Clinical and epidemiological data indicate that use of certain NSAIDs, especially at high doses and for prolonged periods, may be associated with increased risk of arterial thromboembolic complications (myocardial infarction or stroke). Although such reactions have not been observed with ketorolac, the possibility of their occurrence cannot be excluded.

Blood and lymphatic system disorders: purpura, thrombocytopenia, leukopenia, neutropenia, eosinophilia, agranulocytosis, aplastic and hemolytic anemia, postoperative wound hemorrhage, hematoma, epistaxis, prolonged bleeding time.

Immune system disorders: hypersensitivity reactions have been reported, including non-specific allergic reactions and anaphylaxis, respiratory tract reactivity including bronchial asthma, worsening of bronchial asthma, bronchospasm, laryngeal edema or dyspnea, as well as various skin disorders including rashes of different types, pruritus, urticaria, purpura, angioedema, and in isolated cases – exfoliative and bullous dermatitis (including epidermal necrolysis and erythema multiforme).

Such reactions may occur in patients with or without known hypersensitivity to ketorolac or other NSAIDs. They may also occur in individuals with a history of angioedema or bronchospastic reactivity (e.g., bronchial asthma and nasal polyps). Anaphylactoid reactions such as anaphylaxis may be fatal.

Skin and subcutaneous tissue disorders: erythema, pruritus, urticaria, photosensitivity, Lyell's syndrome, bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis (very rare), exfoliative dermatitis, rash (including maculopapular and exudative), facial skin discoloration.

Musculoskeletal and connective tissue disorders: myalgia, functional disorders.

Reproductive system and breast disorders: female infertility.

General disorders: asthenia, malaise, facial, ankle, finger, foot and tongue edema, taste disturbances, weight gain, increased sweating, elevated body temperature.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicine authorization is an important procedure. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals are required to report any suspected adverse reactions via the national reporting system.

Shelf life. 2 years.

Storage conditions.

Store in original packaging at temperature not exceeding 25 °C. Keep out of reach and sight of children.

Packaging.

10 tablets in a blister pack; 1 blister pack in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnitsya".

Manufacturer's address.

13, Boryspilska Street, Kyiv, 02093, Ukraine.