Kedol

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

Composition:

Active substance: dexketoprofen;

1 ml of solution contains 25 mg of dexketoprofen (as tromethamine);

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

Pharmaceutical form. Injection solution 50 mg/2 ml.

Main physicochemical properties: colorless clear liquid.

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

Pharmacological properties.

Dexketoprofen trometamol is the tromethamine salt of (S)-(+)-2-(3-benzoylphenyl) propionic acid, exerting analgesic, anti-inflammatory, and antipyretic effects and belonging 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 affect other mediators of inflammation such as kinins, which may also indirectly influence the primary action of the drug.

Pharmacodynamics.

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 has pronounced analgesic activity. The analgesic effect of dexketoprofen trometamol following intramuscular and intravenous administration to patients with moderate to severe pain has been studied in various types of pain associated with surgical procedures (orthopedic and gynecological surgeries, abdominal surgeries), as well as 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 action after administration of 50 mg of dexketoprofen trometamol is typically 8 hours. Clinical studies have demonstrated that the use of KEDOL allows a significant reduction in opioid dosage when used concomitantly to manage postoperative pain. When patients receiving morphine via a patient-controlled analgesia device for postoperative pain relief were also administered dexketoprofen trometamol, they required significantly less morphine (by 30–45%) compared to patients receiving placebo.

Pharmacokinetics.

Absorption

Following intramuscular administration of dexketoprofen trometamol, 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 proportional to the dose.

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 is 1–2.7 hours.

Pharmacokinetic studies of repeated administration demonstrated that AUC and Cmax (mean maximum concentration) after the last intramuscular or intravenous dose did not differ 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 drug conversion into the R-(-) optical isomer in humans.

Elderly patients

After 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 in maximum concentration or time to reach it were observed. The mean elimination half-life was prolonged (by up to 48%), and the total clearance was reduced.

Preclinical safety data

Standard preclinical studies—pharmacological safety, genotoxicity, and immunopharmacology studies—did not reveal any special hazard for humans. Chronic toxicity studies in animals identified the no-observed-adverse-effect level (NOAEL), which was 2 times higher than the dose recommended for humans. When higher doses were administered to monkeys, the main adverse reactions were fecal blood, reduced body weight gain, and, at the highest dose, gastrointestinal lesions such as erosions. These reactions 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 embryotoxic or fetotoxic effects in animals, either directly by affecting embryonic or fetal development or indirectly via maternal gastrointestinal toxicity.

Clinical characteristics.

Indications.

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

Contraindications.

• Hypersensitivity to dexketoprofen, to any other non-steroidal anti-inflammatory drug (NSAID), or to excipients of the drug;
• in patients in whom administration of substances with similar action, such as acetylsalicylic acid or other NSAIDs, induces 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 (Child-Pugh score 10–15 points);
• hemorrhagic diathesis and other coagulation disorders;
• severe dehydration (due to vomiting, diarrhea, or insufficient fluid intake);
• third trimester of pregnancy or breastfeeding period;

Due to the ethanol content in the medicinal product, KEDOL is contraindicated for neuraxial (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 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 enhancing effects;
• anticoagulants: NSAIDs enhance the effects of anticoagulants, e.g., warfarin, due to high plasma protein binding of dexketoprofen, as well as inhibition of platelet function and damage to gastric and duodenal mucosa. If concomitant use is necessary, it should be performed under strict medical supervision and appropriate laboratory monitoring;
• heparin: increased risk of bleeding (due to inhibition of platelet function and damage to gastric and duodenal mucosa). If concomitant use is necessary, it should be performed under strict medical supervision and appropriate laboratory monitoring;
• corticosteroids: increased risk of gastrointestinal ulceration and gastrointestinal bleeding;
• lithium (reports exist for several NSAIDs): NSAIDs increase blood lithium levels, potentially leading to toxicity (reduced renal excretion of lithium). Therefore, monitoring of blood lithium levels is required at the start of dexketoprofen therapy, during dose adjustments, or upon discontinuation of the drug;
• high-dose methotrexate (≥ 15 mg per week): reduced renal clearance of methotrexate due to NSAID use generally enhances its adverse effects on the blood system;
• hydantoin derivatives and sulfonamides: possible increase in toxicity of these substances.

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., due to dehydration or in elderly patients), 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): reduced renal clearance of methotrexate due to NSAID use generally enhances its adverse effects on the blood system. During the first weeks of concomitant use, weekly blood tests are required. Even with mild renal impairment or in elderly patients, treatment should be conducted under strict medical supervision;
• pentoxifylline: risk of bleeding. Monitoring should be intensified, and bleeding time should be checked more frequently;
• zidovudine: risk of increased toxic effects on erythrocytes due to effects on reticulocytes, leading to severe anemia after one week of NSAID use. Blood tests and reticulocyte counts should be performed within 1–2 weeks after starting NSAID therapy;
• sulfonylurea agents: 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 increase in 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 plasma concentration of dexketoprofen, likely due to inhibition of renal tubular secretion and glucuronidation of the drug, requiring dose adjustment of dexketoprofen;
• cardiac glycosides: NSAIDs may increase plasma concentrations of glycosides;
• mifepristone: due to the theoretical possibility of reduced mifepristone efficacy under the influence of NSAID prostaglandin synthetase inhibitors, NSAIDs should be prescribed only 8–12 days after mifepristone therapy;
• quinolone antibiotics: animal studies indicate that high-dose quinolone derivatives in combination with NSAIDs increase the risk of seizures;
• tenofovir: concomitant use with NSAIDs may increase plasma concentrations of blood urea nitrogen and creatinine; therefore, renal function should be monitored to assess potential effects of combined use;
• deferasirox: concomitant use with NSAIDs may increase the risk of gastrointestinal toxicity. Close monitoring of the patient is required when using this medicinal product together with deferasirox;
• pemetrexed: concomitant use with NSAIDs may reduce pemetrexed elimination; therefore, particular caution is required when using high-dose NSAIDs. 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 KEDOL 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 improve symptoms.

Gastrointestinal safety

Gastrointestinal bleeding, ulceration, or perforation, sometimes fatal, have been reported with all NSAIDs at various stages of treatment, regardless of the presence of prior symptoms or a history of serious gastrointestinal disorders. If gastrointestinal bleeding occurs, the drug should be discontinued. The risk of gastrointestinal bleeding, ulceration, or perforation increases with higher NSAID doses, in patients with a history of peptic ulcer, particularly if complicated by bleeding or perforation, and in elderly patients.

Elderly patients: Elderly patients have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, sometimes fatal. Treatment of such patients should begin with the lowest possible dose. As with all NSAIDs, patients with a history of esophagitis, gastritis, and/or peptic ulcer should be ensured that these conditions are in remission. Patients with existing gastrointestinal symptoms or gastrointestinal disorders in their history should be monitored during treatment for possible complications, particularly gastrointestinal bleeding. NSAIDs should be used cautiously in patients with a history of gastrointestinal disorders (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, consider concomitant therapy with protective agents, such as misoprostol or proton pump inhibitors.

Patients, especially elderly ones, 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 who are concurrently using agents that may increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants (e.g., warfarin), selective serotonin reuptake inhibitors (SSRIs), or antiplatelet agents like acetylsalicylic acid.

Renal safety

The drug 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 receiving 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 blood urea nitrogen and creatinine levels in plasma. 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 drug should be used with caution in patients with impaired liver function. As with other NSAIDs, the drug may cause transient and mild elevations in certain liver function parameters, as well as marked increases in AST and ALT activity. Therapy should be discontinued if significant increases in these parameters occur. Hepatic function disturbances occur most frequently in elderly patients.

Cardiovascular and cerebrovascular safety

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

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

Skin reactions

Rare cases of serious skin reactions (some fatal) have been reported during 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, KEDOL should be discontinued.

KEDOL should be administered with caution to patients with blood disorders, systemic lupus erythematosus, and mixed connective tissue diseases.

Masking symptoms of underlying infections

KEDOL 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. If KEDOL is necessary to relieve pain associated with an infection, monitoring of the infectious process 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 drug 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 taking KEDOL, 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. Administration of this drug may trigger asthma attacks or bronchospasm, especially in patients allergic to acetylsalicylic acid or NSAIDs.

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

KEDOL should be administered with caution to patients with blood disorders, systemic lupus erythematosus, and mixed connective tissue diseases.

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

Each KEDOL ampoule contains 12.35 vol.% ethanol, i.e., up to 200 mg per dose, equivalent to 5 ml of beer or 2.08 ml of wine per dose. The drug may adversely affect individuals with alcoholism. The ethanol content should be considered when administering to pregnant women, breastfeeding women, children, and patients at risk, e.g., those with liver disease or epilepsy. The drug contains less than 1 mmol sodium (23 mg) per dose and is practically sodium-free.

Use during pregnancy or breastfeeding

KEDOL is contraindicated during 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, congenital heart defects, and abdominal wall defects. The absolute risk of cardiovascular malformations increases from <1% to approximately 1.5%. The risk of such events is believed to increase with higher drug doses and longer treatment duration. In animal studies, prostaglandin synthesis inhibitors caused increased pre- and post-implantation losses and increased embryofetal mortality. Additionally, in animals treated with prostaglandin synthesis inhibitors during organogenesis, an increased incidence of fetal developmental abnormalities, including cardiovascular anomalies, was observed. However, animal studies with dexketoprofen trometamol did not reveal reproductive toxicity. The use of dexketoprofen 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 of the drug. Furthermore, cases of fetal ductus arteriosus constriction have been reported after maternal use of the drug in the second trimester, most of which resolved after discontinuation of treatment. 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 of pregnancy, the lowest effective dose should be used for the shortest possible duration. Fetal monitoring for oligohydramnios and ductus arteriosus 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 ductus arteriosus constriction is detected.

During the third trimester, all prostaglandin synthesis inhibitors cause:

Risks to the fetus:

• cardiopulmonary toxic syndrome (constriction/occlusion of the ductus arteriosus and pulmonary hypertension);
• impaired renal function (see above);

Risks to the mother and newborn at the end of pregnancy:

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

Breastfeeding

There are no data on the passage of dexketoprofen into breast milk. KEDOL 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 investigations should consider discontinuing the drug.

Ability to affect reaction speed when driving or operating machinery

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

Method of Administration and Dosage

Adverse reactions can be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see section "Special Warnings and Precautions for Use").

Adults. The recommended dose is 50 mg administered every 8–12 hours. If necessary, the next dose may be given after 6 hours. The maximum daily dose should not exceed 150 mg. The drug is intended for short-term use only and should be administered only during episodes of acute pain (no longer than 2 days). Patients should be switched to oral analgesics as soon as possible, if feasible. 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 hepatic impairment (Child-Pugh score 5–9), 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 (Child-Pugh score 10–15).

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).

Method of Administration

Intramuscular administration. The injection solution should be administered slowly by deep intramuscular injection.

Intravenous infusion.

For intravenous infusion, the contents of a 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 must be prepared under aseptic conditions and protected from exposure to natural daylight. The prepared solution should be clear. The infusion should be administered over 10–30 minutes. The prepared solution must be protected from exposure to natural daylight.

KEDOL, when 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.

KEDOL must not be mixed in the infusion solution with promethazine or pentazocine.

Intravenous bolus injection.

If necessary, the contents of one ampoule (2 mL of injection solution) should be administered intravenously 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.

KEDOL must not be mixed in small volumes (e.g., in a syringe) with solutions of dopamine, promethazine, pentazocine, pethidine, or hydrocortisone, as a white precipitate may form.

The drug should be mixed only with medicinal products specified above.

When administered intramuscularly or intravenously by injection, the drug should be administered immediately after being drawn from the ampoule. The solution for intravenous infusion should be used immediately after preparation.

No changes in active ingredient 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.

KEDOL is intended for single use only; any unused portion of the prepared solution must be discarded. Before administration, ensure that the solution is clear and colorless. Solutions containing particulate matter must not be used.

Children.

The drug 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 disorders (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 classified by organ systems and frequency of occurrence, which are considered at least possibly related to dexketoprofen trometamol based on clinical trial data, as well as adverse reactions reported during post-marketing surveillance.

Gastrointestinal disorders were observed most frequently.

Peptic ulcer, perforation, or gastrointestinal bleeding, sometimes with fatal outcome, may possibly develop, especially in elderly patients. According to available data, nausea, vomiting, diarrhea, flatulence, constipation, dyspeptic symptoms, abdominal pain, melena, vomiting with blood admixture, 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 NSAID use, 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 disorders, 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 thrombotic events, such as myocardial infarction and stroke.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after drug registration is important. It allows continuous 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 through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

2 years.

From a microbiological standpoint, the diluted preparation should be used immediately. If not used immediately, the responsibility for the duration of its stability and the conditions prior to use lies with the person administering the drug. However, the physico-chemical stability of the diluted preparation is maintained for 24 hours at 2-8 °C.

Storage conditions.

To protect from light, store in the original packaging. This medicinal product does not require any special storage temperature conditions. Keep out of reach and sight of children.

Incompatibility.

KEDOL must not be mixed in small volumes (e.g., in a syringe) with solutions of dopamine, promethazine, pentazocine, meperidine, or hydrocortisone, as a white precipitate may form. Diluted infusion solutions prepared as described in the section "Intravenous infusions" must not be mixed with promethazine or pentazocine.

Packaging.

2 ml of the drug in an ampoule; 50 ampoules per box; 5 ampoules per blister, 1 or 2 blisters per box.

Prescription status. Prescription only.

Manufacturer.

Private Joint-Stock Company "Lekhim-Kharkiv".

Manufacturer's address and location of its operations.

36 Severina Pototskoho Street, Kharkiv, Kharkiv Oblast, 61115, Ukraine.

Marketing Authorization Holder.

Limited Liability Company "BERKANA+".

Address of the Marketing Authorization Holder. 20/1 Pushkina Street, Bohodukhiv, Bohodukhiv District, Kharkiv Oblast, 62103, Ukraine.