NEOSPASYL®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NEOSPASTIL® (NEOSPASTIL)

Composition:

Active substances: ketorolac tromethamine, pitofenone hydrochloride, fenpiverinium bromide;

One tablet contains: ketorolac tromethamine 10 mg, pitofenone hydrochloride 10 mg, fenpiverinium bromide 0.1 mg;

Excipients: microcrystalline cellulose, pregelatinized starch, crospovidone, magnesium stearate, Opadry II 85F pink.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round-shaped, biconvex tablets, film-coated, pink in colour.

Pharmacotherapeutic group. Spasmolytics in combination with analgesics.

ATC code A03D A02.

Pharmacological Properties

Pharmacodynamics

Ketorolac tromethamine is a non-narcotic analgesic. It is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits strong analgesic and anti-inflammatory activity, as well as mild 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 was not associated with respiratory depression. Ketorolac tromethamine does not cause pupillary constriction.

Phenpiverine exerts moderate ganglionic blocking and parasympatholytic effects, reducing tone and motility of the smooth musculature of the stomach, intestines, and biliary and urinary tracts.

Pitofenone exerts a papaverine-like effect on vascular and extravascular smooth muscle, with pronounced spasmolytic properties.

Clinical Studies

A pivotal, prospective, multicenter, randomized, comparative, parallel-group phase II/III clinical trial, KPF07-T, was conducted for the medicinal product Neospazil®. The objective of this study was to evaluate the efficacy and safety of Neospazil® compared to Ketanov in patients with postoperative pain following abdominal and pelvic surgery. A total of 424 patients were randomized in the study. The investigational medicinal product was administered orally when, among other criteria, pain intensity upon movement was 4–6 points on the 11-point Numerical Rating Scale [NRS], or 7 points if pain at rest did not exceed 6 points on the 11-point NRS. The medicinal product was administered at a dose of 1 tablet four times daily for 24 hours, followed by as-needed dosing from the next day onward. The total duration of investigational treatment in the KPF07-T trial did not exceed 5 days.

Superior efficacy of Neospazil®, film-coated tablets, compared to Ketanov, coated tablets, was demonstrated both for the primary efficacy endpoint and secondary efficacy endpoints, including:

• The proportion of study subjects achieving treatment response within the first 24 hours of oral administration was 76.6% in the main group (Neospazil®) versus 38.6% in the control group (Ketanov) (p < 0.001).
• The median area under the pain intensity curve on the 11-point NRS at rest over 24 hours after the first oral dose was statistically significantly lower in the main group (Neospazil®) at 46.0 compared to the control group (Ketanov) at 53.75 (p < 0.001). During movement, the corresponding values were 60.38 and 70.75, respectively (p < 0.001).
• The median sum of pain intensity differences at rest compared to baseline over the first 6 hours after oral administration was statistically significantly lower in the main group (Neospazil®) at -12.0 versus -9.5 in the control group (Ketanov) (p < 0.001). During movement, the values were -14.0 and -12.0, respectively (p < 0.001).
• The proportion of study subjects achieving treatment response based on patient's overall assessment of pain control (rated efficacy as "excellent" or "very good" and did not require additional analgesics) within the first 24 hours of oral administration was 76.6% in the main group (Neospazil®) versus 17.1% in the control group (Ketanov) (p < 0.001).
• The proportion of study subjects achieving treatment response based on patient's overall assessment of pain control (rated efficacy as "excellent" or "very good" and did not require additional analgesics) during the subsequent 3 days of oral administration was 79.3% in the main group (Neospazil®) versus 16.0% in the control group (Ketanov) (p < 0.001).

Pharmacokinetics

Neospazil®

In healthy volunteers, after single oral administration of Neospazil®, maximum concentrations of ketorolac and pitofenone were reached within 0.50 hours, and for phenpiverine within 4.00 hours (median).

Cmax and AUC0–t in healthy volunteers after single oral administration of Neospazil®, film-coated tablets, under fasting conditions (mean ± SD)

In healthy volunteers, after single oral administration of Neospazil**®**, the elimination half-life of ketorolac, pitofenone, and fenpiverine was (mean ± standard deviation) 5.98 ± 0.92 hours, 3.75 ± 1.90 hours, and 11.34 ± 4.91 hours, respectively.

Ketorolac tromethamine is rapidly and completely absorbed after oral administration, reaching a peak plasma concentration of 0.87 mg/kg within 45 minutes following a single 10 mg dose. In healthy volunteers, the terminal elimination half-life from plasma is 4–6 hours (mean 5.4 hours). In elderly individuals (mean age 72 years), it is 6.2 hours. More than 99% of ketorolac in plasma is protein-bound. Ketorolac poorly penetrates the blood-brain barrier. A small amount may be detected in breast milk. Less than 50% of the administered dose is metabolized in the body of a healthy individual. Major metabolites include 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 occur with prolonged use. The elimination half-life from plasma increases in patients with renal impairment and in elderly patients. After a single intravenous dose, the volume of distribution is 0.25 L/kg, the elimination half-life is 5 hours, and clearance is 0.55 mL/min/kg. The primary route of elimination of ketorolac and its metabolites (conjugates and p-hydroxy metabolites) is via urine (90%), with the remainder excreted in feces. A high-fat and difficult-to-digest meal reduces the rate but not the extent of absorption, whereas antacids do not affect ketorolac absorption.

Pitofenone and fenpiverine are metabolized in the liver, primarily by oxidation, with approximately 90% of the substance excreted in urine as metabolites and about 10% in feces as unchanged compound. Available data indicate that their elimination half-life from plasma is approximately 10 hours. Individual components are excreted in breast milk.

Clinical characteristics.

Indications.

For short-term symptomatic treatment of moderate pain:

• due to spasms of smooth muscle of internal organs: renal colic, bladder and ureter spasms, dysmenorrhea, hepatic colic, spasms of the stomach and intestines, spastic biliary dyskinesia;
  • after surgical procedures and diagnostic interventions on visceral organs of the abdominal cavity and pelvis.

Contraindications.

• Hypersensitivity to ketorolac, phenpiverine, pitofenone, or to any other component of the medicinal product;
• active peptic ulcer, recent gastrointestinal bleeding or perforation, history of peptic ulcer or 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;
• complete or partial nasal polyp syndrome, angioedema, or bronchospasm;
• use as an analgesic before and during surgical procedures, manipulations on coronary vessels;
• use in patients who have undergone surgery with high risk of bleeding or incomplete hemostasis;
• severe heart failure;
• severe hepatic insufficiency;
• moderate/severe renal insufficiency (serum creatinine concentration >160 μmol/L);
• suspected or confirmed cerebrovascular hemorrhage, hemorrhagic diathesis, including coagulation disorders, high risk of bleeding;
• concomitant treatment with acetylsalicylic acid or NSAIDs (including selective cyclooxygenase-2 inhibitors), pentoxifylline, probenecid, or lithium salts, anticoagulants, including warfarin or low-dose heparin (2500–5000 units every 12 hours);
• hypovolemia, dehydration with risk of renal failure due to reduced fluid volume;
• pregnancy, labor and delivery;
• breastfeeding period;
• prostatic adenoma stage II and III;
• bladder or gallbladder atony;
• tachyarrhythmia;
• collapse state;
• closed-angle glaucoma;
• gastrointestinal tract obstruction and megacolon.

Interaction with other medicinal products and other forms of interaction.

Interactions of Neospazil® are due to the presence of ketorolac tromethamine.

Ketorolac is highly bound to plasma proteins (approximately 99.2%). Ketorolac does not alter the pharmacokinetics of other drugs through enzyme induction or inhibition.

Ketorolac tromethamine does not affect the plasma protein binding of digoxin. In vitro studies show that at therapeutic concentrations of salicylates (300 μg/mL), ketorolac binding decreased from approximately 99.2% to 97.5%, indicating a potential twofold increase in unbound ketorolac levels in plasma. Digoxin, warfarin, ibuprofen, naproxen, piroxicam, acetaminophen, phenytoin, and tolbutamide at therapeutic concentrations do not alter the plasma protein binding of ketorolac tromethamine.

Since ketorolac is a potent agent with low plasma concentrations, it is unlikely that it would significantly displace other medicinal products from plasma protein binding sites.

Medicinal products that must not be used concomitantly with Neospazil®®

Acetylsalicylic acid and other NSAIDs. Ketorolac should not be used concomitantly with other NSAIDs, including selective cyclooxygenase-2 inhibitors, particularly in patients receiving acetylsalicylic acid, due to the risk of severe adverse reactions.

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

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

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

Probenecid. Concomitant administration of ketorolac tromethamine and probenecid leads to reduced ketorolac clearance, significant increase in plasma levels, and prolonged elimination half-life. Therefore, concomitant use of ketorolac tromethamine and probenecid is contraindicated.

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

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

Medicinal products that should be used with caution in combination with Neospazil®

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

Selective serotonin reuptake inhibitors (SSRIs). There is an increased risk of gastrointestinal bleeding with concomitant use of SSRIs and NSAIDs. Caution should be exercised when using them together.

Metotrexate. Since NSAIDs may reduce methotrexate clearance, increased toxicity of the latter is possible.

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

Antihypertensive agents. The effect of these medicinal products may be reduced when used concomitantly with ketorolac. Ketorolac and other NSAIDs may reduce the antihypertensive effect of beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin-II receptor antagonists, and may increase the risk of renal dysfunction; this is particularly relevant in patients with reduced blood volume or elderly patients. Therefore, this combination should be used with caution, especially in elderly patients. Patients should be under close monitoring, and renal function should be periodically assessed after initiation and discontinuation of concomitant therapy, particularly when diuretics and ACE inhibitors are used.

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

Thrombolytic agents. Concomitant use with NSAIDs increases the risk of bleeding.

Cyclosporine. As with all NSAIDs, cyclosporine should be used concomitantly with caution due to increased risk of nephrotoxic effects.

Tacrolimus. NSAIDs may increase the risk of nephrotoxicity.

Opioid analgesics. The effect of opioid analgesics is enhanced, allowing for dose reduction during analgesia.

Quinolones. In patients taking quinolones, the risk of seizures may be increased.

Zidovudine. Concomitant use of NSAIDs with zidovudine increases the risk of hematological toxicity. There is an increased risk of hemarthrosis and hematoma in HIV-infected patients with hemophilia who are treated concomitantly with zidovudine and NSAIDs.

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).

Non-depolarizing muscle relaxants. Studies on concomitant use of ketorolac tromethamine and muscle relaxants have not been conducted. Cases of possible interaction between ketorolac and non-depolarizing muscle relaxants leading to apnea have been reported.

Antidiabetic agents. NSAIDs may potentiate the effect of sulfonylurea derivatives.

Products containing garlic, onion, or Ginkgo biloba may enhance the effect of ketorolac and increase the risk of hemorrhagic complications.

Concomitant use of Neospazil® with quinine-containing preparations may enhance the anticholinergic effect.

Special precautions for use.

Epidemiological data suggest that ketorolac may be associated with a higher risk of gastrointestinal toxicity compared to other NSAIDs, especially when used outside approved indications and/or for prolonged periods.

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

Careful monitoring of diuresis and renal function is required in patients with cardiac, renal, or hepatic insufficiency, those receiving diuretics, or patients with hypovolemia following surgical procedures.

Use in elderly patients

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

The increased risk associated with age is typical for all NSAIDs. Compared to younger patients, elderly patients have a prolonged plasma elimination half-life and reduced plasma clearance. Therefore, elderly patients should not be prescribed Neospastil® at daily doses exceeding 60 mg calculated as ketorolac tromethamine (see section "Dosage and administration").

Effects on the gastrointestinal tract. Gastrointestinal bleeding, ulceration, or perforation, which may be fatal, have been reported with NSAID use at any time during treatment, with or without warning symptoms or history of severe gastrointestinal disorders. The risk of serious gastrointestinal bleeding is dose-dependent. However, adverse events may occur even during short-term therapy. Risk factors include a history of peptic ulcer disease, concomitant use of oral corticosteroids, anticoagulants, prolonged NSAID therapy, smoking, alcohol consumption, advanced age, and poor general health. Most spontaneous reports of gastrointestinal adverse events involved elderly or debilitated patients; therefore, special caution is required when treating such patients, and the drug should be discontinued if adverse reactions are suspected. Alternative therapies not involving NSAIDs should be considered for high-risk patients.

NSAIDs should be used with caution in patients with a history of Crohn’s disease or ulcerative colitis due to the potential for worsening of the disease.

The medicinal product should be used cautiously in patients with gastrointestinal obstructive disorders (achalasia, pyloroduodenal stenosis). Repeated use of Neospastil® in such cases may cause delayed gastrointestinal emptying. Use of Neospastil® in patients with gastroesophageal reflux disease, intestinal atony, inflammatory bowel diseases, including non-specific ulcerative colitis and Crohn’s disease, requires special caution and medical supervision.

Anaphylactic (anaphylactoid) reactions. Anaphylactic (anaphylactoid) reactions (such as anaphylaxis, bronchospasm, flushing, rash, hypotension, laryngeal edema, and angioedema) may occur both in patients with previously identified hypersensitivity to aspirin, other NSAIDs, or intravenous ketorolac, and in those without prior hypersensitivity reactions. Such reactions may occur in individuals with a history of angioedema, 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, complete or partial nasal polyp syndrome, angioedema, or bronchospasm (see section "Contraindications").

Hematological effects. Concomitant use of ketorolac tromethamine with anticoagulant therapy may increase the risk of bleeding. Although detailed studies on the simultaneous use of ketorolac and low-dose prophylactic heparin (2500–5000 IU every 12 hours) have not been conducted, an increased risk of bleeding under this regimen cannot be excluded. Patients already receiving anticoagulants or requiring low-dose heparin should not receive ketorolac tromethamine. Close monitoring is required in patients receiving other agents that negatively affect hemostasis. Ketorolac inhibits platelet aggregation and prolongs bleeding time. In patients with normal hemostasis, bleeding time increases but remains within normal limits (2 to 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 preparations are contraindicated in patients who have undergone surgery with a high risk of bleeding or incomplete hemostasis. Ketorolac tromethamine is not an anesthetic and does not possess sedative or anxiolytic properties.

Use in patients with renal impairment (see section "Contraindications"). Like other NSAIDs, ketorolac inhibits prostaglandin synthesis and may have a toxic effect on the kidneys; therefore, it should be used with caution in patients with impaired renal function or a history of kidney disease. High-risk patients include those with renal impairment, hypovolemia, heart failure, hepatic dysfunction, patients taking diuretics, and elderly patients.

Patients with mild renal impairment should receive lower doses of ketorolac. Their renal function should be closely monitored. Patients should be well hydrated before starting treatment. In patients undergoing hemodialysis, ketorolac clearance is reduced by approximately half compared to normal, and terminal elimination half-life is increased nearly threefold.

Due to age (>65 years) and renal impairment requiring dose reduction, and in view of the lack of clinical pharmacokinetic data in this population, the drug should be used in elderly patients with renal impairment only after careful assessment of the benefit-risk ratio associated with such therapy.

Effects on the cardiovascular system and cerebral vessels. Close monitoring is required in patients with arterial hypertension and/or a history of mild to moderate heart failure. Use of Neospastil® in patients with cardiac diseases (arrhythmias, ischemic heart disease, congestive heart failure) requires special caution and medical supervision.

To minimize the potential risk of cardiovascular adverse events in patients receiving NSAIDs, the lowest effective dose should be prescribed for the shortest possible duration. Ketorolac tromethamine preparations 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 preparations should be weighed before initiating long-term treatment in patients at risk of cardiovascular diseases (e.g., patients with arterial hypertension, hyperlipidemia, diabetes mellitus, and smokers).

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

In patients who have suffered a myocardial infarction, there is a risk of recurrent infarction during the first week of NSAID treatment. Injectable formulations containing ketorolac tromethamine should be avoided in patients who have recently experienced a myocardial infarction, except when the expected benefit outweighs the risk of recurrent cardiovascular thrombosis. If a medicinal product containing ketorolac tromethamine is used in patients with recent myocardial infarction, the patient should be under close surveillance for signs of cardiac ischemia.

Use in patients with hepatic impairment. Ketorolac tromethamine preparations should be used with caution in patients with hepatic impairment or a history of liver disease. Marked elevations (more than three times the upper limit of normal) in serum alanine aminotransferase and aspartate aminotransferase activities were observed in less than 1% of patients. Additionally, isolated cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis, and liver failure, some of which were fatal, have been reported. Ketorolac preparations should be discontinued if clinical signs of liver disease or systemic manifestations (such as eosinophilia, rash) appear.

Respiratory system. Monitor patients for the potential development of bronchospasm.

Systemic lupus erythematosus and mixed connective tissue diseases. In patients with systemic lupus erythematosus and various mixed connective tissue diseases, the risk of aseptic meningitis is increased.

Dermatological disorders. Serious skin reactions, such as exfoliative dermatitis, Stevens-Johnson syndrome, and Lyell’s syndrome, have been reported. The highest risk of these reactions occurs early in the course of treatment. 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, its preparations should be used with caution in patients with cardiac decompensation, arterial hypertension, or similar conditions.

Prostatic hyperplasia. Use with caution in prostatic hyperplasia.

Nervous system and visual organs. Use of Neospastil® in patients with glaucoma or myasthenia gravis requires special caution and medical supervision. With prolonged use, its cholinolytic effect may lead to dizziness or accommodation disorders.

Effect on fertility. In women who are unable to conceive and undergoing fertility investigations, treatment with ketorolac tromethamine preparations should be discontinued. Women with reduced fertility should avoid using the medicinal product.

Use during pregnancy or breastfeeding.

Due to the known effects of NSAIDs on the fetal cardiovascular system, medicinal products containing ketorolac are contraindicated during pregnancy (especially in the third trimester). Use of ketorolac tromethamine is contraindicated during labor and delivery, as 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.

Since ketorolac passes into breast milk in small amounts, it is not used during breastfeeding due to the potential negative effects of prostaglandin synthesis inhibitors on infants.

Ability to influence reaction speed when driving or operating machinery.

In some patients, medicinal products containing ketorolac tromethamine may cause dizziness, somnolence, visual disturbances, headache, vertigo, insomnia, or depression. If a patient experiences these or similar adverse effects, they should not drive vehicles or operate machinery.

Dosage and Administration.

It is recommended to take the tablets during or after a meal.

The lowest effective dose for the shortest duration necessary to control symptoms should be used. The total duration of treatment should not exceed 5 days (even with parenteral administration of ketorolac followed by oral administration of the medicinal product Neospastil®).

Adults.

The recommended dose of Neospastil® is 1 tablet every 6 hours. If necessary, the drug may be administered at intervals of 4 to 6 hours.

The maximum daily dose should not exceed 4 tablets (corresponding to 40 mg of ketorolac tromethamine).

On the day of switching dosage forms, for patients who have received parenteral ketorolac (including Neospastil®, injection solution) and then transitioned to oral administration of Neospastil®, the combined daily dose of ketorolac tromethamine should not exceed 90 mg (60 mg for elderly patients, patients with renal impairment, and patients with body weight below 50 kg), and the oral dose of ketorolac tromethamine as a component of Neospastil® should not exceed 40 mg. Patients should be switched to the oral form as soon as possible.

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

Elderly patients. For patients aged over 64 years, the lowest recommended dose should be used. The total daily dose should not exceed 60 mg (expressed as ketorolac tromethamine).

Children.

The safety and efficacy of the drug in children and adolescents (under 18 years of age) have not been established; therefore, Neospastil**®** is not recommended for patients in this age group.

Overdose.

Symptoms: lethargy, headache, nausea, vomiting, epigastric pain, peptic ulcers, erosive gastritis, gastrointestinal bleeding; hyperventilation, hypertension, rarely – diarrhea, disorientation, excitement, respiratory depression, coma, drowsiness, dizziness, tinnitus, loss of consciousness, seizures. In severe poisoning, acute renal failure and liver damage are possible. Cases of anaphylactoid reactions have been reported.

Treatment: gastric lavage, administration of activated charcoal. Adequate diuresis should be maintained. Renal and hepatic function 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 measures may be implemented depending on the patient's clinical condition. There is no specific antidote. Forced diuresis, urine alkalinization, hemodialysis, or blood transfusion may be ineffective due to the high plasma protein binding of ketorolac.

Side effects.

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

Ear and labyrinth disorders: hearing loss, tinnitus, vertigo.

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

Gastrointestinal disorders: dry mouth, abdominal discomfort, bloating, nausea, dyspepsia, altered taste sensation, anorexia, gastrointestinal pain, epigastric pain, diarrhea, less frequently — flatulence, belching, vomiting, constipation, erosive-ulcerative changes including gastrointestinal hemorrhage and perforation, sometimes fatal (especially in elderly patients), hematemesis, gastritis, peptic ulcer, pancreatitis, melena, rectal bleeding, ulcerative stomatitis, esophagitis, exacerbation of Crohn’s disease and colitis.

Hepatobiliary disorders: liver function abnormalities, hepatic failure, hepatomegaly, jaundice, hepatitis, increased liver transaminase activity.

Renal and urinary disorders: severe pain in the kidney area, frequent urination, oliguria, polyuria, anuria, hyponatremia, hyperkalemia, hematuria, proteinuria, increased blood urea and serum creatinine levels, urinary retention, acute renal failure, renal failure, interstitial nephritis, papillary necrosis, hemolytic uremic syndrome, nephrotic syndrome.

Metabolic and nutritional disorders: hyponatremia, hyperkalemia, anorexia.

Nervous system disorders: headache, dizziness, increased fatigue, weakness, irritability, dry mouth sensation, increased thirst, dysgeusia, nervousness, restlessness, confusion, paresthesia, functional disturbances, unusual dreams, depression, somnolence, sleep disturbances, insomnia, difficulty concentrating, euphoria, hyperactivity, hallucinations, delirium, hyperkinesia, excitability, seizures, psychotic reactions, pathological thoughts, aseptic meningitis (with corresponding symptoms: neck stiffness, headache, nausea, vomiting, fever or disorientation), anxiety, disorientation, cognitive disorders.

Cardiovascular disorders: pallor, flushing, chest pain, palpitations, bradycardia, heart failure, arterial hypertension or hypotension, edema. Clinical and epidemiological data indicate that the use of certain NSAIDs, especially at high doses and for prolonged periods, may be associated with an increased risk of arterial thromboembolic complications, including myocardial infarction or stroke (see section "Special precautions").

Blood and lymphatic system disorders: purpura, thrombocytopenia, neutropenia, agranulocytosis, granulocytopenia, anemia (aplastic, hemolytic), eosinophilia, possible development of subcutaneous hemorrhages, hematomas, epistaxis, reduced blood coagulation rate, prolonged bleeding time, increased postoperative wound bleeding, swelling of fingers, ankles and/or feet.

Immune system disorders: anaphylactic reactions, urticaria, purpura, bronchospasm, laryngeal edema, angioedema, dyspnea, arterial hypotension, flushing, exfoliative dermatitis, bullous dermatitis (including toxic epidermal necrolysis and erythema multiforme). These 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., asthma and nasal polyps). Anaphylactoid reactions such as anaphylaxis can be fatal.

Skin and subcutaneous tissue disorders: pruritus, urticaria, photosensitivity reactions, Lyell’s syndrome, bullous reactions, exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, maculopapular and exuding rashes.

Musculoskeletal and connective tissue disorders: myalgia, functional disturbances.

Reproductive system disorders: female infertility.

General disorders: asthenia, malaise, edema, increased body temperature, increased sweating, weight gain.

Reporting suspected adverse reactions.

Reporting of suspected adverse reactions after marketing authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives should report all suspected adverse reactions and/or lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua/.

Shelf life. 2 years.

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

Keep out of reach of children.

Packaging. 10 tablets per blister, 1 blister per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Pharmaceutical company "Darnytsia".

Manufacturer's address and location of business activity.

13, Boryspilska St., Kyiv, 02093, Ukraine.