Ketodexa

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

Composition:

Active substance: dexketoprofen;

1 ml of the preparation contains 25 mg of dexketoprofen;

Excipients: ethanol 96%, sodium chloride, sodium hydroxide, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group. Non-steroidal anti-inflammatory and antirheumatic agents. Propionic acid derivatives. Dexketoprofen. ATC code M01AE17.

Pharmacological Properties

Pharmacodynamics

Dexketoprofen trometamol is the tromethamine salt of (S)-(+)-2-(3-benzoylphenyl) propionic acid, exerting analgesic, anti-inflammatory, and antipyretic effects, and belongs to the class of nonsteroidal anti-inflammatory drugs (NSAIDs).

Mechanism of action

The mechanism of action of NSAIDs is based on the reduction of prostaglandin synthesis through inhibition of cyclooxygenase activity. Specifically, the conversion of arachidonic acid into cyclic endoperoxides PGG2 and PGH2 is inhibited, from which prostaglandins PGE1, PGE2, PGF2α, PGD2, as well as prostacyclin PGI2 and thromboxanes TxА2 and TxВ2 are formed. In addition, inhibition of prostaglandin synthesis may influence other mediators of inflammation such as kinins, which may also indirectly affect the primary action of the drug.

Pharmacodynamic effects

Inhibitory effects of dexketoprofen trometamol on the activity of cyclooxygenase-1 and cyclooxygenase-2 have been demonstrated in laboratory animals and in humans.

Clinical efficacy and safety

Clinical studies in various types of pain have demonstrated that dexketoprofen trometamol exerts pronounced analgesic effects. The analgesic effect of dexketoprofen trometamol following intramuscular or intravenous administration in patients with moderate to severe pain intensity has been studied in various surgical procedures (orthopedic and gynecological surgeries, abdominal surgeries), as well as in musculoskeletal pain (acute low back pain) and renal colic. In these studies, the analgesic effect of the drug began rapidly and reached its maximum within the first 45 minutes.

The duration of analgesic effect after administration of 50 mg of dexketoprofen trometamol is generally 8 hours. Clinical studies have shown that the use of the drug allows a significant reduction in opioid dosage when used concomitantly to manage postoperative pain. In patients receiving morphine via a patient-controlled analgesia device for postoperative pain relief, co-administration of dexketoprofen trometamol resulted in a significantly lower morphine requirement (by 30–45%) compared to patients receiving placebo.

Pharmacokinetics

Absorption

After intramuscular administration of dexketoprofen trometamol in humans, maximum concentration is reached approximately within 20 minutes (10–45 minutes). It has been demonstrated that after single intramuscular or intravenous administration of 25–50 mg of the drug, the area under the concentration–time curve (AUC) is dose-proportional.

Distribution

Similar to other drugs with a high degree of plasma protein binding (99%), the volume of distribution of dexketoprofen averages 0.25 L/kg. The distribution half-life is approximately 0.35 hours, and the elimination half-life ranges from 1 to 2.7 hours.

Pharmacokinetic studies with repeated administration of the drug demonstrated that Cmax and AUC after the last intramuscular or intravenous dose were not different from those after single administration, indicating absence of drug accumulation.

Biotransformation and elimination

Metabolism of dexketoprofen occurs mainly via conjugation with glucuronic acid, followed by renal excretion. After administration of dexketoprofen trometamol, only the S-(+) optical isomer is detected in urine, indicating absence of transformation of the drug into the R-(–) optical isomer in humans.

Elderly patients

Following administration of single and multiple doses, the extent of exposure in elderly healthy volunteers (aged 65 years and older) participating in the study was significantly higher (up to 55%) compared to younger volunteers; however, no statistically significant differences were observed in maximum concentration or time to reach it. The mean elimination half-life increased (by up to 48%), and the total clearance decreased.

Preclinical safety data

Standard preclinical studies—evaluating pharmacological safety, genotoxicity, and immunopharmacology—did not reveal any specific hazard for humans. Chronic toxicity studies in animals identified the no-observed-adverse-effect level (NOAEL), which was 2 times higher than the recommended human dose. When higher doses were administered to monkeys, the main adverse reactions included fecal blood, reduced body weight gain, and at the highest dose, gastrointestinal lesions such as erosions. These effects occurred at doses where drug exposure was 14–18 times higher than at the maximum recommended human dose. Carcinogenicity studies in animals have not been conducted.

Like all NSAIDs, dexketoprofen may cause embryotoxicity or fetotoxicity in animals, either directly by affecting embryonic or fetal development or indirectly via maternal gastrointestinal toxicity.

Clinical characteristics.

Indications.

Symptomatic treatment of moderate to severe acute pain when oral administration of the drug is inappropriate, e.g., in postoperative pain, renal colic, and low back pain.

Contraindications.

• Hypersensitivity to dexketoprofen, to any other nonsteroidal anti-inflammatory drug (NSAID), or to excipients of the medicinal product;
• patients in whom administration of drugs with similar activity, e.g., acetylsalicylic acid or other NSAIDs, triggers attacks of bronchial asthma, bronchospasm, acute rhinitis, nasal polyps, urticaria, or angioedema;
• if photoallergic or phototoxic reactions occurred during treatment with ketoprofen or fibrates;
• gastrointestinal bleeding or perforation in medical history associated with NSAID therapy;
• active peptic ulcer/gastrointestinal bleeding, or history of gastrointestinal bleeding, ulcers, or perforations;
• chronic dyspepsia;
• active bleeding or increased bleeding tendency;
• Crohn’s disease or ulcerative colitis;
• severe heart failure;
• moderate to severe renal impairment (creatinine clearance ≤ 59 ml/min);
• severe hepatic impairment (10–15 points on the Child-Pugh scale);
• hemorrhagic diathesis and other coagulation disorders;
• severe dehydration (due to vomiting, diarrhea, or insufficient fluid intake);
• third trimester of pregnancy and breastfeeding period.

Due to the ethanol content in the medicinal product, it is contraindicated for neuroaxial (intrathecal or epidural) administration.

Interaction with other medicinal products and other types of interactions.

Concomitant use of the following agents with NSAIDs is not recommended:

• other NSAIDs (including selective cyclooxygenase-2 inhibitors), including salicylates in high doses (≥ 3 g/day). Concomitant use of multiple NSAIDs increases the risk of gastrointestinal ulceration and gastrointestinal bleeding due to their mutually enhanced effects;
• anticoagulants: NSAIDs enhance the effects of anticoagulants, e.g., warfarin, due to the high degree of plasma protein binding of dexketoprofen and due to inhibition of platelet function and damage to the gastric and duodenal mucosa. If concomitant use is necessary, it should be performed under physician supervision with careful monitoring of relevant laboratory parameters;
• heparins: increased risk of bleeding (due to inhibition of platelet function and damage to the gastric and duodenal mucosa). If concomitant use is necessary, it should be performed under physician supervision with careful monitoring of relevant laboratory parameters;
• corticosteroids: increased risk of gastrointestinal ulceration or gastrointestinal bleeding;
• lithium (reports with several NSAIDs): NSAIDs increase blood lithium levels, potentially leading to toxicity (reduced renal excretion of lithium). Therefore, lithium levels in blood should be monitored at the start of dexketoprofen therapy, during dose adjustments, or upon discontinuation of the drug;
• high-dose methotrexate (≥ 15 mg per week): due to reduced renal clearance of methotrexate under NSAID therapy, its overall negative effect on the blood system is enhanced;
• hydantoin derivatives and sulfonamides: possible enhancement of toxicity of these agents.

Concomitant use of the following agents with NSAIDs requires caution:

• diuretics, angiotensin-converting enzyme (ACE) inhibitors, aminoglycoside antibiotics, and angiotensin II receptor antagonists. Dexketoprofen reduces the effectiveness of diuretics and other antihypertensive agents. In some patients with impaired renal function (e.g., in dehydrated patients or elderly individuals), concomitant use of cyclooxygenase inhibitors with ACE inhibitors, angiotensin II receptor antagonists, or aminoglycoside antibiotics may worsen renal function, which is usually reversible. When using dexketoprofen with any diuretic, ensure the patient is not dehydrated and monitor renal function at the beginning of treatment;
• low-dose methotrexate (less than 15 mg per week): due to reduced renal clearance of methotrexate under NSAID therapy, its overall negative effect on the blood system is enhanced. During the first weeks of concomitant use, weekly blood tests are required. Even with mild renal impairment and in elderly patients, treatment should be conducted under strict medical supervision;
• pentoxifylline: risk of bleeding. Enhanced monitoring and more frequent assessment of bleeding time are required;
• zidovudine: risk of increased toxic effect on erythrocytes due to effects on reticulocytes, leading to severe anemia after one week of NSAID use. Blood tests and reticulocyte count should be performed 1–2 weeks after initiation of NSAID therapy;
• sulfonylurea preparations: NSAIDs may enhance the hypoglycemic effect of these agents by displacing sulfonylureas from plasma protein binding sites.

Potential interactions should be considered when using the following agents:

• beta-blockers: NSAIDs may reduce their antihypertensive effect due to inhibition of prostaglandin synthesis;
• cyclosporine and tacrolimus: possible enhancement of nephrotoxicity due to NSAID effects on renal prostaglandins. Renal function should be monitored during combination therapy;
• thrombolytic agents: increased risk of bleeding;
• antiplatelet agents and selective serotonin reuptake inhibitors (SSRIs): increased risk of gastrointestinal bleeding;
• probenecid: possible increase in dexketoprofen plasma concentration, likely due to inhibition of renal tubular secretion and glucuronide conjugation of the drug, requiring dose adjustment of dexketoprofen;
• cardiac glycosides: NSAIDs may increase glycoside plasma concentrations;
• mifepristone: theoretically, there is a risk of altered mifepristone efficacy under the influence of prostaglandin synthetase inhibitors. Limited data suggest that concomitant administration of NSAIDs on the same day as prostaglandin does not adversely affect the efficacy of mifepristone or prostaglandin regarding cervical ripening or contractility, nor does it reduce the clinical efficacy of drugs for medical termination of pregnancy;
• quinolone antibiotics: animal studies have shown that high-dose quinolone derivatives in combination with NSAIDs increase the risk of seizures;
• tenofovir: when used concomitantly with NSAIDs, plasma concentrations of blood urea nitrogen and creatinine may increase; therefore, renal function should be monitored to assess the potential impact of concomitant use;
• deferasirox: risk of increased gastrointestinal toxicity when used concomitantly with NSAIDs. Close patient monitoring is required when using this medicinal product with deferasirox;
• pemetrexed: concomitant use with NSAIDs may reduce pemetrexed elimination; therefore, particular caution is required when using NSAIDs at high doses. In patients with mild to moderate renal impairment (creatinine clearance 45–79 ml/min), NSAID use should be avoided for two days before and two days after pemetrexed administration.

Special precautions for use.

Use with caution in patients with a history of allergic conditions. Avoid using the medicinal product in combination with other NSAIDs, including selective cyclooxygenase-2 inhibitors. Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to relieve symptoms.

Gastrointestinal safety

Gastrointestinal bleeding, ulceration, or perforation, in some cases fatal, have been observed during treatment with all NSAIDs at any stage of therapy, regardless of the presence of warning symptoms or a history of serious gastrointestinal disorders. If gastrointestinal bleeding or ulceration occurs, the drug should be discontinued. The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher NSAID doses, particularly in patients with a history of peptic ulcer, especially complicated by bleeding or perforation, and in elderly patients.

Elderly patients: Elderly patients have an increased frequency of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, sometimes fatal. Treatment in these patients should be initiated with the lowest possible dose. As with all NSAIDs, patients with a history of esophagitis, gastritis, and/or peptic ulcer should be ensured to have these conditions in remission. Patients with existing gastrointestinal symptoms or a history of gastrointestinal disorders should be monitored for possible gastrointestinal disturbances during treatment, particularly gastrointestinal bleeding. NSAIDs should be used with caution in patients with a history of gastrointestinal diseases (ulcerative colitis, Crohn's disease), as there is a risk of exacerbation. For such patients and those taking low-dose acetylsalicylic acid or other agents increasing the risk of gastrointestinal adverse reactions, combination therapy with protective agents (e.g., misoprostol or proton pump inhibitors) should be considered.

Patients, especially the elderly, with a history of gastrointestinal adverse reactions should inform their physician about any unusual gastrointestinal symptoms, including gastrointestinal bleeding, particularly during the initial stages of treatment.

The drug should be prescribed with caution to patients concurrently using agents that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors, or antiplatelet agents such as acetylsalicylic acid.

Renal safety

The medicinal product should be used with caution in patients with impaired renal function, as NSAIDs may worsen renal function, cause fluid retention, and edema. Due to the increased risk of nephrotoxicity, the drug should be used cautiously in patients treated with diuretics or those at risk of hypovolemia. During treatment, adequate fluid intake should be maintained to prevent dehydration, which may exacerbate renal toxicity. Like other NSAIDs, the drug may increase plasma concentrations of blood urea nitrogen and creatinine. Similar to other prostaglandin synthesis inhibitors, its use may be associated with renal adverse reactions, including glomerulonephritis, interstitial nephritis, papillary necrosis, nephrotic syndrome, and acute renal failure. Renal function disturbances occur most frequently in elderly patients.

Hepatic safety

The medicinal product should be used with caution in patients with impaired liver function. Similar to other NSAIDs, the drug may cause transient and mild elevations in certain liver parameters, as well as marked increases in AST and ALT activity. If such elevations occur, therapy should be discontinued.

Hepatic function disturbances occur most frequently in elderly patients.

Cardiovascular and cerebrovascular safety

Patients with hypertension and/or mild to moderate heart failure require monitoring and medical supervision. Particular caution is required when treating patients with a history of heart disease, especially previous episodes of heart failure (the risk of heart failure increases during treatment), as NSAIDs may cause fluid retention and edema. Clinical studies and epidemiological data suggest that some NSAIDs (particularly at high doses and prolonged use) may slightly increase the risk of arterial thrombosis (e.g., myocardial infarction or stroke). Data to exclude this risk with dexketoprofen use are insufficient. Therefore, dexketoprofen should be prescribed only after careful patient assessment in cases of uncontrolled hypertension, congestive heart failure, ischemic heart disease, peripheral artery disease, and/or cerebrovascular disease. A similarly careful assessment should be performed before initiating long-term treatment in patients with cardiovascular risk factors (such as hypertension, hyperlipidemia, diabetes, smoking).

Cases of Kounis syndrome have been reported in patients receiving dexketoprofen treatment. Kounis syndrome is defined as cardiovascular symptoms caused by an allergic or hypersensitivity reaction associated with coronary artery spasm, potentially leading to myocardial infarction.

Non-selective NSAIDs can reduce platelet aggregation and prolong bleeding time by inhibiting prostaglandin synthesis. The concomitant use of dexketoprofen trometamol and prophylactic doses of low-molecular-weight heparin in the postoperative period has been studied in clinical trials, and no effect on coagulation parameters was observed. However, patients taking dexketoprofen trometamol concurrently with agents affecting hemostasis (e.g., warfarin, other coumarins, or heparins) require close medical supervision. Cardiovascular function disturbances occur most frequently in elderly patients.

Skin reactions

Very rare cases of serious skin reactions (some fatal) have been reported with NSAID use, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The highest risk likely occurs early in treatment, with most cases appearing within the first month of therapy. If skin rashes, signs of mucosal involvement, or other hypersensitivity symptoms occur, the drug should be discontinued.

Masking symptoms of underlying infections

The medicinal product may mask symptoms of infection, potentially interfering with diagnosis and timely treatment, thereby worsening infection outcomes. Such cases have been observed in bacterial pneumonia and bacterial complications of varicella. When the drug is administered to relieve pain associated with an infectious process, monitoring of the infection is recommended. In outpatient settings, patients should consult a physician if symptoms persist or worsen.

Other information

Particular caution should be exercised when prescribing the medicinal product to patients:

• with hereditary porphyrin metabolism disorders (e.g., acute intermittent porphyria);
• with dehydration;
• immediately after major surgical procedures.

If prolonged use of dexketoprofen is deemed necessary by the physician, regular monitoring of liver and kidney function is recommended.

Very rare cases of severe acute hypersensitivity reactions (e.g., anaphylactic shock) have been observed. If early signs of severe hypersensitivity reactions occur after drug intake, treatment should be discontinued. Depending on symptoms, any necessary treatment should be administered under medical supervision.

Patients suffering from asthma combined with chronic rhinitis, chronic sinusitis, and/or nasal polyps are at higher risk of allergy to acetylsalicylic acid and/or NSAIDs compared to other patients. Prescribing this drug may trigger asthma attacks or bronchospasm, especially in patients allergic to acetylsalicylic acid or NSAIDs.

Severe skin and soft tissue infectious complications may occur during varicella. Data to exclude the role of NSAIDs in exacerbating this infection are lacking. Therefore, the drug is not recommended during varicella.

The drug should be administered with caution in patients with coagulation disorders, systemic lupus erythematosus, and mixed connective tissue diseases.

Like other NSAIDs, dexketoprofen trometamol may mask symptoms of infectious diseases during its use. In isolated cases, activation of soft tissue infections has been reported during NSAID use. Therefore, if symptoms of bacterial infection appear or worsen during treatment, patients are advised to seek immediate medical attention.

This medicinal product contains 12.35% v/v ethanol (alcohol), i.e., 200 mg/dose, equivalent to 5 mL of beer or 2.08 mL of wine per dose. It is harmful for patients with alcoholism. Caution is advised when used in pregnant and breastfeeding women, children, and patients with liver disease or epilepsy.

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

Use during pregnancy or breastfeeding.

The use of the medicinal product is contraindicated in the third trimester of pregnancy and during breastfeeding.

Pregnancy

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or fetal development. According to epidemiological studies, the use of drugs that inhibit prostaglandin synthesis in early pregnancy increases the risk of miscarriage and fetal congenital heart defects and abdominal wall defects. The absolute risk of cardiovascular abnormalities increases from <1% to approximately 1.5%. The risk is considered to increase with higher drug doses and longer treatment duration. Animal studies with prostaglandin synthesis inhibitors have shown increased pre- and post-implantation losses and increased embryofetal mortality. Furthermore, in animals treated with prostaglandin synthesis inhibitors during organogenesis, an increased incidence of fetal malformations, including cardiovascular abnormalities, was observed. However, animal studies with dexketoprofen trometamol did not reveal reproductive toxicity. Dexketoprofen use from the 20th week of pregnancy may cause oligohydramnios due to fetal renal dysfunction. This may occur soon after starting treatment and is usually reversible upon discontinuation. Additionally, cases of fetal arterial duct constriction have been reported after maternal use of the drug in the second trimester, most of which resolved after treatment cessation. Therefore, dexketoprofen trometamol may be prescribed during the first and second trimesters only if absolutely necessary. When prescribing dexketoprofen trometamol to women planning pregnancy or during the first and second trimesters, the lowest possible effective dose should be used for the shortest possible duration. Prenatal monitoring for oligohydramnios and fetal arterial duct constriction should be considered if dexketoprofen is used for several days starting from the 20th gestational week. Pregnant women should discontinue dexketoprofen if oligohydramnios or fetal arterial duct constriction is detected.

During the third trimester, all prostaglandin synthesis inhibitors cause:

Risks to the fetus:

• cardiopulmonary toxic syndrome (narrowing/occlusion of the arterial duct and pulmonary hypertension);
• impaired renal function (see above).

Risks to mother and child at the end of pregnancy:

• prolonged bleeding time (due to platelet aggregation inhibition), which may occur even with low doses;
• delayed uterine contractions, leading to delayed and prolonged labor.

Breastfeeding

There are no data on the passage of dexketoprofen into breast milk. The drug is contraindicated during breastfeeding.

Fertility

Like all other NSAIDs, dexketoprofen trometamol may reduce female fertility and is therefore not recommended for women planning pregnancy. Women experiencing fertility problems or undergoing infertility evaluation should consider discontinuing the drug.

Ability to affect reaction speed when driving or operating machinery.

Dizziness, visual disturbances, or somnolence may occur during treatment with the medicinal product. In such cases, the ability to react quickly, orient in traffic situations, and drive vehicles or operate machinery may be impaired.

Dosage and Administration

To minimize adverse reactions, the lowest effective dose for the shortest duration should be used (see section "Special Warnings and Precautions for Use").

Adults. The recommended dose is 50 mg every 8–12 hours. If necessary, the next dose may be administered after 6 hours. The maximum daily dose should not exceed 150 mg. The drug is intended for short-term use and should only be administered during episodes of acute pain (no longer than 2 days). Patients should be switched to oral analgesics as soon as possible. For moderate to severe postoperative pain, the drug may be used as indicated at the same recommended doses in combination with opioid analgesics.

Elderly patients. Dose adjustment is generally not required. However, due to physiological decline in renal function, a lower dose is recommended—specifically, the maximum daily dose should be limited to 50 mg in patients with mild renal impairment.

Hepatic impairment. In patients with mild to moderate liver disease (5–9 points on the Child-Pugh scale), the maximum daily dose should be reduced to 50 mg, and liver function should be closely monitored. The drug is contraindicated in patients with severe hepatic impairment (10–15 points on the Child-Pugh scale).

Renal impairment. In patients with mild renal impairment (creatinine clearance 60–89 mL/min), the maximum daily dose should be reduced to 50 mg. The drug is contraindicated in patients with moderate to severe renal impairment (creatinine clearance < 59 mL/min).

Children and adolescents. The medicinal product should not be used in children and adolescents due to lack of data on efficacy and safety.

Administration

Intramuscular injection.

The contents of one ampoule (2 mL) should be administered slowly by deep intramuscular injection.

Intravenous infusion.

For intravenous infusion, the contents of one 2 mL ampoule should be diluted in 30–100 mL of 0.9% sodium chloride solution, glucose solution, or Ringer’s lactate solution. The infusion solution should be prepared under aseptic conditions, avoiding exposure to natural daylight. The prepared solution must be clear. The infusion should be administered intravenously slowly over 10–30 minutes.

The drug diluted in 100 mL of 0.9% sodium chloride solution or glucose solution may be mixed with dopamine, heparin, hydroxyzine, lidocaine, morphine, pethidine, and theophylline.

Intravenous injection (bolus administration).

If necessary, the contents of one ampoule (2 mL of injection solution) may be administered intravenously slowly over at least 15 seconds. The drug may be mixed in small volumes (e.g., in a syringe) with injection solutions of heparin, lidocaine, morphine, and theophylline.

The drug must not be mixed in small volumes (e.g., in a syringe) with solutions of dopamine, promethazine, pentazocine, pethidine, or hydroxyzine, as precipitation may occur.

Diluted infusion solutions must not be mixed with promethazine or pentazocine.

The drug may only be mixed with medicinal products listed above.

When administered intramuscularly or as an intravenous bolus, the drug should be administered immediately after being drawn from the ampoule.

No changes in active substance content due to adsorption were observed during storage of diluted solutions in polyethylene bags or in administration devices made of ethyl vinyl acetate, cellulose propionate, low-density polyethylene, or polyvinyl chloride.

The drug is intended for single use only; any unused portion of the prepared solution should be discarded. The solution should be visually inspected before administration to ensure it is clear and colorless. Solutions containing particulate matter must not be used.

Children.

The medicinal product should not be used in children and adolescents due to lack of data on efficacy and safety.

Overdose.

Symptoms of overdose are unknown. Similar medicinal products may cause gastrointestinal disturbances (vomiting, anorexia, abdominal pain) and nervous system effects (drowsiness, dizziness, disorientation, headache). In case of accidental overdose, symptomatic treatment appropriate to the patient’s condition should be initiated immediately. Dexketoprofen trometamol is eliminated from the body by dialysis.

Adverse reactions.

The table below lists adverse reactions by organ systems and frequency of occurrence, which, based on clinical trial data, are considered at least possible to be related to dexketoprofen trometamol, as well as adverse reactions reported after marketing of the drug.

Gastrointestinal disorders were observed most frequently.

The development of peptic ulcer, perforation, or gastrointestinal bleeding, sometimes fatal, is possible, particularly in elderly patients. According to available data, nausea, vomiting, diarrhea, flatulence, constipation, dyspeptic symptoms, abdominal pain, melena, hematemesis, ulcerative stomatitis, exacerbation of colitis, and Crohn's disease may occur during treatment with the drug. Gastritis is observed less frequently. Edema, arterial hypertension, and heart failure, which may be caused by the use of NSAIDs, have also been reported. As with other NSAIDs, the following adverse reactions are possible: aseptic meningitis, which generally occurs in patients with systemic lupus erythematosus or mixed connective tissue diseases, and blood disorders (purpura, aplastic and hemolytic anemia, rarely agranulocytosis and bone marrow hypoplasia). Bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (very rare), may also occur.

According to results of clinical studies and epidemiological data, the use of certain NSAIDs, especially at high doses and for prolonged periods, may be associated with a small increased risk of arterial thrombotic events, such as myocardial infarction and stroke.

Reporting of suspected adverse reactions

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

Shelf life. 2 years.

Storage conditions.

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

After dilution, the solution should be stored for up to 24 hours at a temperature of 2 to 8 °C in a refrigerator.

Keep out of reach of children.

Incompatibilities.

The medicinal product must not be mixed in small volumes (e.g., in a syringe) with solutions of dopamine, promethazine, pentazocine, meperidine, or hydroxyzine, as precipitation may occur.

Diluted infusion solutions prepared as described in the section "Administration and dosage" must not be mixed with promethazine or pentazocine.

Packaging.

2 ml in an ampoule; 5 ampoules in a blister pack, 2 blisters per cardboard box.

2 ml in an ampoule; 10 ampoules in a blister pack, 1 blister per cardboard box.

Prescription status.

By prescription only.

Manufacturer.

LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVIYA".

Manufacturer's address and site of operations.

22 Shevchenko Street, Kharkiv, Kharkiv Oblast, 61013, Ukraine